Targeting Prolyl Peptidases in Triple-Negative Breast Cancer

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2017-02-01

ABSTRACT Triple negative breast cancer (TNBC) is an aggressive sub-type with limited treatment options and poor prognosis. The most life -threatening... negative feedback loops within the pathway limit their effectiveness . For example, AKT inhibitors cause increased expression of IGF1R/ErbB3 and, as a...AWARD NUMBER: W81XWH-16-1-0025 TITLE: Targeting Prolyl Peptidases in Triple- Negative Breast Cancer PRINCIPAL INVESTIGATOR: Carl G. Maki, PhD

Molecular basis of the triple negative breast cancer

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Ayse Feyda Nursal

2015-06-01

Full Text Available Breast cancer is the most common type of cancer in women and more than 1 million breast cancer cases are diagnosed each year all over the world. Breast cancer is a complex and heterogeneous disease in terms of its molecular structure, mutation type, metastase properties, clinical course and therapeutic response. Breast cancer is divided into subtypes based on expression properties of molecular markers as estrogen receptor, progestron receptor, human epidermal growth factor receptor 2. Triple-negative breast cancer is characterized by the lack of tumors that estrogen receptor, progestron receptor, human epidermal growth factor receptor 2 gene expression. These type of tumors lead to agressive clinical course due to unresponsiveness to systemic endocrine therapy and poor prognosis. Triple negative breast cancer constitutes 10-20% of all breast cancers. It affects generally young and African-American women. Triple negative breast cancer have several subtypes based on the gene expression properties. The majority of them are basal-like breast cancers. In this review, current literature is revised and summarized with respect to the molecular basis of triple negative cancers. [Archives Medical Review Journal 2015; 24(2.000: 251-259

Adjuvant chemotherapy and radiotherapy in triple-negative breast carcinoma: A prospective randomized controlled multi-center trial

International Nuclear Information System (INIS)

Wang, Jianhua; Shi, Mei; Ling, Rui; Xia Yuesheng; Luo Shanquan; Fu Xuehai; Xiao Feng; Li Jianping; Long Xiaoli; Wang Jianguo; Hou Zengxia; Chen Yunxia; Zhou Bin; Xu, Man

2011-01-01

Background and purpose: Triple-negative breast cancer (TNBC) presents a high risk breast cancer that lacks the benefit from hormone treatment, chemotherapy is the main strategy even though it exists in poor prognosis. Use of adjuvant radiation therapy, which significantly decreases breast cancer mortality, has not been well described among poor TNBC women. The aim of this study was to evaluate whether the combination of chemotherapy and radiotherapy could significantly increase survival outcomes in TNBC women after mastectomy. Patients and methods: A prospective randomized controlled multi-center study was performed between February 2001 and February 2006 and comprised 681 women with triple-negative stage I-II breast cancer received mastectomy, of them, 315 cases received systemic chemotherapy alone, 366 patients received radiation after the course of chemotherapy. Recurrence-free survival (RFS) and overall survival (OS) were estimated. Simultaneously local and systemic toxicity were observed. Results: After a median follow-up of 86.5 months, five-year RFS rates were 88.3% and 74.6% for adjuvant chemotherapy plus radiation and adjuvant chemotherapy alone, respectively, with significant difference between the two groups (HR 0.77 [95% CI 0.72, 0.98]; P = 0.02). Five-year OS significantly improved in adjuvant chemotherapy plus radiation group compared with chemotherapy alone (90.4% and 78.7%) (HR 0.79 [95% CI 0.74, 0.97]; P = 0.03). No severe toxicity was reported. Conclusions: Patients received standard adjuvant chemotherapy plus radiation therapy was more effective than chemotherapy alone in women with triple-negative early-stage breast cancer after mastectomy.

Identifying Triple-Negative Breast Cancer Using Background Parenchymal Enhancement Heterogeneity on Dynamic Contrast-Enhanced MRI: A Pilot Radiomics Study.

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Jeff Wang

Full Text Available To determine the added discriminative value of detailed quantitative characterization of background parenchymal enhancement in addition to the tumor itself on dynamic contrast-enhanced (DCE MRI at 3.0 Tesla in identifying "triple-negative" breast cancers.In this Institutional Review Board-approved retrospective study, DCE-MRI of 84 women presenting 88 invasive carcinomas were evaluated by a radiologist and analyzed using quantitative computer-aided techniques. Each tumor and its surrounding parenchyma were segmented semi-automatically in 3-D. A total of 85 imaging features were extracted from the two regions, including morphologic, densitometric, and statistical texture measures of enhancement. A small subset of optimal features was selected using an efficient sequential forward floating search algorithm. To distinguish triple-negative cancers from other subtypes, we built predictive models based on support vector machines. Their classification performance was assessed with the area under receiver operating characteristic curve (AUC using cross-validation.Imaging features based on the tumor region achieved an AUC of 0.782 in differentiating triple-negative cancers from others, in line with the current state of the art. When background parenchymal enhancement features were included, the AUC increased significantly to 0.878 (p<0.01. Similar improvements were seen in nearly all subtype classification tasks undertaken. Notably, amongst the most discriminating features for predicting triple-negative cancers were textures of background parenchymal enhancement.Considering the tumor as well as its surrounding parenchyma on DCE-MRI for radiomic image phenotyping provides useful information for identifying triple-negative breast cancers. Heterogeneity of background parenchymal enhancement, characterized by quantitative texture features on DCE-MRI, adds value to such differentiation models as they are strongly associated with the triple-negative subtype

Clinicopathological Characteristics of Triple-negative Breast Cancers in the Northeast Region of Turkey

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Bülent Yıldız

2014-06-01

Full Text Available Background: Triple-negative (TN breast cancer is a subtype of breast cancer characterised by a loss of estrogen receptor (ER, progesterone receptor (PR expression, and the absence of human epidermal growth factor (HER2 overexpression. Aims: To identify the relationships between clinicopathological characteristics of TN breast cancers in the northeast region of Turkey and disease free survival (DFS and overall survival (OS. Study Design: Retrospective clinical study. Methods: Seven hundred and eighty non-metastatic breast cancer patients were enrolled in this study. The relationships between TN breast cancer and other breast cancers with respect to clinicopathological characteristics, as well as DFS and OS, were studied. Results: The triple-negative phenotype was detected in 204 patients (27.1%. Patients with triple-negative breast cancer had more grade 2-3 tumours compared to those with other types of breast cancer (92.5% versus 84.3%, p=0.004. Invasive ductal carcinoma histology, on the other hand, was less prevalent in patients with TN breast cancer (77% versus 84.5%, p=0.016. No significant differences were identified between the groups in other clinicopathological variables. Relapse and mortality rates were higher in the TN group during the follow-up of both groups [57 (27.9% versus 89 (16.2%, p<0.001 for relapse; 27 (13.2% versus 37 (6.8%, p=0.005 for mortality]. The univariate analysis demonstrated shorter DFS and OS for patients with TN breast cancer compared to those with other types of breast cancer. In the multivariate analysis, patients with TN breast cancer were 2.21 times more likely to develop relapse, while the likelihood of death increased 3.21-fold (p<0.001 and p<0.001. Conclusion: Triple-negative breast cancers demonstrate a more aggressive clinical course compared to other breast cancers. More effective strategies should be developed for the treatment of this subgroup of breast cancer.

Using logistic regression to improve the prognostic value of microarray gene expression data sets: application to early-stage squamous cell carcinoma of the lung and triple negative breast carcinoma.

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Mount, David W; Putnam, Charles W; Centouri, Sara M; Manziello, Ann M; Pandey, Ritu; Garland, Linda L; Martinez, Jesse D

2014-06-10

Numerous microarray-based prognostic gene expression signatures of primary neoplasms have been published but often with little concurrence between studies, thus limiting their clinical utility. We describe a methodology using logistic regression, which circumvents limitations of conventional Kaplan Meier analysis. We applied this approach to a thrice-analyzed and published squamous cell carcinoma (SQCC) of the lung data set, with the objective of identifying gene expressions predictive of early death versus long survival in early-stage disease. A similar analysis was applied to a data set of triple negative breast carcinoma cases, which present similar clinical challenges. Important to our approach is the selection of homogenous patient groups for comparison. In the lung study, we selected two groups (including only stages I and II), equal in size, of earliest deaths and longest survivors. Genes varying at least four-fold were tested by logistic regression for accuracy of prediction (area under a ROC plot). The gene list was refined by applying two sliding-window analyses and by validations using a leave-one-out approach and model building with validation subsets. In the breast study, a similar logistic regression analysis was used after selecting appropriate cases for comparison. A total of 8594 variable genes were tested for accuracy in predicting earliest deaths versus longest survivors in SQCC. After applying the two sliding window and the leave-one-out analyses, 24 prognostic genes were identified; most of them were B-cell related. When the same data set of stage I and II cases was analyzed using a conventional Kaplan Meier (KM) approach, we identified fewer immune-related genes among the most statistically significant hits; when stage III cases were included, most of the prognostic genes were missed. Interestingly, logistic regression analysis of the breast cancer data set identified many immune-related genes predictive of clinical outcome. Stratification of

Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants.

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Pareja, Fresia; Geyer, Felipe C; Marchiò, Caterina; Burke, Kathleen A; Weigelt, Britta; Reis-Filho, Jorge S

2016-01-01

Triple-negative breast cancers (TNBCs), defined by lack of expression of estrogen receptor, progesterone receptor and HER2, account for 12-17% of breast cancers and are clinically perceived as a discrete breast cancer subgroup. Nonetheless, TNBC has been shown to constitute a vastly heterogeneous disease encompassing a wide spectrum of entities with marked genetic, transcriptional, histological and clinical differences. Although most TNBCs are high-grade tumors, there are well-characterized low-grade TNBCs that have an indolent clinical course, whose natural history, molecular features and optimal therapy vastly differ from those of high-grade TNBCs. Secretory and adenoid cystic carcinomas are two histologic types of TNBCs underpinned by specific fusion genes; these tumors have an indolent clinical behavior and lack all of the cardinal molecular features of high-grade triple-negative disease. Recent studies of rare entities, including lesions once believed to constitute mere benign breast disease (e.g., microglandular adenosis), have resulted in the identification of potential precursors of TNBC and suggested the existence of a family of low-grade triple-negative lesions that, despite having low-grade morphology and indolent clinical behavior, have been shown to harbor the complex genomic landscape of common forms of TNBC, and may progress to high-grade disease. In this review, we describe the heterogeneity of TNBC and focus on the histologic and molecular features of low-grade forms of TNBC. Germane to addressing the challenges posed by the so-called triple-negative disease is the realization that TNBC is merely a descriptive term, and that low-grade types of TNBC may be driven by distinct sets of genetic alterations.

Common breast cancer susceptibility loci are associated with triple negative breast cancer

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Stevens, Kristen N.; Vachon, Celine M.; Lee, Adam M.; Slager, Susan; Lesnick, Timothy; Olswold, Curtis; Fasching, Peter A.; Miron, Penelope; Eccles, Diana; Carpenter, Jane E.; Godwin, Andrew K.; Ambrosone, Christine; Winqvist, Robert; Schmidt, Marjanka K.; Cox, Angela; Cross, Simon S.; Sawyer, Elinor; Hartmann, Arndt; Beckmann, Matthias W.; Schulz-Wendtland, Rüdiger; Ekici, Arif B.; Tapper, William J; Gerty, Susan M; Durcan, Lorraine; Graham, Nikki; Hein, Rebecca; Nickels, Stephan; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Hans-Peter; Konstantopoulou, Irene; Fostira, Florentia; Pectasides, Dimitrios; Dimopoulos, Athanasios M.; Fountzilas, George; Clarke, Christine L.; Balleine, Rosemary; Olson, Janet E.; Fredericksen, Zachary; Diasio, Robert B.; Pathak, Harsh; Ross, Eric; Weaver, JoEllen; Rüdiger, Thomas; Försti, Asta; Dünnebier, Thomas; Ademuyiwa, Foluso; Kulkarni, Swati; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Ko, Yon-Dschun; Van Limbergen, Erik; Janssen, Hilde; Peto, Julian; Fletcher, Olivia; Giles, Graham G.; Baglietto, Laura; Verhoef, Senno; Tomlinson, Ian; Kosma, Veli-Matti; Beesley, Jonathan; Greco, Dario; Blomqvist, Carl; Irwanto, Astrid; Liu, Jianjun; Blows, Fiona M.; Dawson, Sarah-Jane; Margolin, Sara; Mannermaa, Arto; Martin, Nicholas G.; Montgomery, Grant W; Lambrechts, Diether; dos Santos Silva, Isabel; Severi, Gianluca; Hamann, Ute; Pharoah, Paul; Easton, Douglas F.; Chang-Claude, Jenny; Yannoukakos, Drakoulis; Nevanlinna, Heli; Wang, Xianshu; Couch, Fergus J.

2012-01-01

Triple negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiological factors which promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome wide association studies (GWAS) display heterogeneity of effect among breast cancer subtypes as defined by estrogen receptor (ER) and progesterone receptor (PR) status. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple negative breast cancer and 4,978 healthy controls. We identified six single nucleotide polymorphisms (SNPs) significantly associated with risk of triple negative breast cancer, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.11) and rs8100241 (19p13.11). Together, our results provide convincing evidence of genetic susceptibility for triple negative breast cancer. PMID:21844186

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer.

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Shan, Naing Lin; Wahler, Joseph; Lee, Hong Jin; Bak, Min Ji; Gupta, Soumyasri Das; Maehr, Hubert; Suh, Nanjoo

2017-10-01

Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH) 2 D 3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH) 2 D 3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest

Imaging and histologic prognostic factors in triple-negative breast cancer and carcinoma in situ as a prognostic factor.

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Sebastián Sebastián, C; García Mur, C; Cruz Ciria, S; Rosero Cuesta, D S; Gros Bañeres, B

2016-01-01

To analyze what factors in magnetic resonance imaging (MRI) and histological study of triple-negative breast cancers are related to tumor recurrence and to shorter disease-free survival. To analyze survival and recurrence in function of the presence of an in situ component. This was a retrospective study of MRI staging examinations in 122 women with triple-negative breast cancer done from 2007 through 2014. In the MRI, we evaluated morphological variables (size, margins, morphology, internal signal in T2-weighted sequences) and dynamic variables (perfusion and diffusion). In the histological study, we evaluated Ki67, p53, CK5/6, nuclear grade, and Scarff-Bloom grade, as well as the presence of an in situ component and tumor grade (high grade or not high grade). We compared the variables between patients with tumor recurrence and those without, and we conducted a survival analysis. Non-nodular enhancement was more common in patients with tumor recurrence (p=0.038) and was associated with shorter disease-free survival (p=0.023). Neither diffusion restriction (p=0.079) nor ki67 (p=0.052) was associated with a worse prognosis. An in situ component was detected in 44% of triple-negative tumors, and a greater proportion of patients in the group with tumor recurrence had an in situ component; however, the presence of an in situ component was not associated with shorter survival (p = 0.185). Non-nodular enhancement was associated with a worse prognosis. Diffusion restriction, ki67, and the presence of an in situ component were not associated with shorter disease-free survival. Copyright © 2016 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

Keratin 17 is overexpressed and predicts poor survival in estrogen receptor-negative/human epidermal growth factor receptor-2-negative breast cancer.

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Merkin, Ross D; Vanner, Elizabeth A; Romeiser, Jamie L; Shroyer, A Laurie W; Escobar-Hoyos, Luisa F; Li, Jinyu; Powers, Robert S; Burke, Stephanie; Shroyer, Kenneth R

2017-04-01

Clinicopathological features of breast cancer have limited accuracy to predict survival. By immunohistochemistry (IHC), keratin 17 (K17) expression has been correlated with triple-negative status (estrogen receptor [ER]/progesterone receptor/human epidermal growth factor receptor-2 [HER2] negative) and decreased survival, but K17 messenger RNA (mRNA) expression has not been evaluated in breast cancer. K17 is a potential prognostic cancer biomarker, targeting p27, and driving cell cycle progression. This study compared K17 protein and mRNA expression to ER/progesterone receptor/HER2 receptor status and event-free survival. K17 IHC was performed on 164 invasive breast cancers and K17 mRNA was evaluated in 1097 breast cancers. The mRNA status of other keratins (16/14/9) was evaluated in 113 ER - /HER2 - ductal carcinomas. IHC demonstrated intense cytoplasmic and membranous K17 localization in myoepithelial cells of benign ducts and lobules and tumor cells of ductal carcinoma in situ. In ductal carcinomas, K17 protein was detected in most triple-negative tumors (28/34, 82%), some non-triple-negative tumors (52/112, 46%), but never in lobular carcinomas (0/15). In ductal carcinomas, high K17 mRNA was associated with reduced 5-year event-free survival in advanced tumor stage (n = 149, hazard ratio [HR] = 3.68, P = .018), and large (n = 73, HR = 3.95, P = .047), triple-negative (n = 103, HR = 2.73, P = .073), and ER - /HER2 - (n = 113, HR = 2.99, P = .049) tumors. There were significant correlations among keratins 17, 16, 14, and 9 mRNA levels suggesting these keratins (all encoded on chromosome 17) could be coordinately expressed in breast cancer. Thus, K17 is expressed in a subset of triple-negative breast cancers, and is a marker of poor prognosis in patients with advanced stage and ER - /HER2 - breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

EGFR conjunct FSCN1 as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer.

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Wang, Chao-Qun; Li, Yang; Huang, Bi-Fei; Zhao, Yong-Ming; Yuan, Hui; Guo, Dongfang; Su, Chen-Ming; Hu, Gui-Nv; Wang, Qian; Long, Tengyun; Wang, Yan; Tang, Chih-Hsin; Li, Xiaoni

2017-11-15

Emerging evidence indicates that Fascin-1 (FSCN1) may possess a causal role in the development of several types of cancers and serves as a novel biomarker of aggressiveness in certain carcinomas. However, the regulatory mechanism of FSCN1 in triple-negative breast cancer (TNBC) cell invasion and migration is still largely unknown. In our study, we observed that the FSCN1 expression rates were significantly higher in invasive ductal carcinoma, compared with both usual ductal hyperplasia and ductal carcinoma in situ. FSCN1 expression was significantly higher in cases of TNBC compared with the non-TNBC subtype. Overexpression of FSCN1 promoted TNBC cell migration and invasion. Epidermal growth factor induced the expression of FSCN1 through activation of MAPK, which subsequently promoted cell migration and invasion. A significant decrease in FSCN1 expression following the co-treatment of FSCN1 siRNA and Gefitinib, compared with the separate treatment of FSCN1 siRNA or Gefitinib. Furthermore, we found that there was a significant association between FSCN1 expression and poor relapse-free survival and overall survival. Therefore, we suggest that co-targeting epidermal growth factor receptor and FSCN1 dual biomarker may be used as a novel therapeutic strategy for TNBC.

Detection of hepatocellular carcinoma by Gd-EOB-DTPA-enhanced liver MRI: Comparison with triple phase 64 detector row helical CT

International Nuclear Information System (INIS)

Akai, Hiroyuki; Kiryu, Shigeru; Matsuda, Izuru; Satou, Jirou; Takao, Hidemasa; Tajima, Taku; Watanabe, Yasushi; Imamura, Hiroshi; Kokudo, Norihiro; Akahane, Masaaki; Ohtomo, Kuni

2011-01-01

Purpose: To compare the diagnostic performance of Gd-EOB-DTPA-enhanced MRI with that of triple phase 64-MDCT in the detection of hepatocellular carcinoma (HCC). Patients and methods: Thirty-four patients with 52 surgically proven lesions underwent Gd-EOB-DTPA-enhanced MRI and triple phase 64-MDCT. Two observers independently evaluated MR and CT imaging on a lesion-by-lesion basis. Sensitivity, positive and negative predictive values and reproducibility were evaluated. The diagnostic accuracy of each modality was assessed with alternative-free response receiver operating characteristic (ROC) analysis. Results: Both observers showed higher sensitivity in detecting lesions with MRI compared to CT, however, only the difference between the two imaging techniques for observer 2 was significant (P = 0.034). For lesions 1 cm or smaller, MRI and CT showed equal sensitivity (both 62.5%) with one observer, and MRI proved superior to CT with the other observer (MRI 75% vs. CT 56.3%), but the latter difference was not significant (P = 0.083). The difference in positive and negative predictive value between the two imaging techniques for each observer was not significant (P > 0.05). The areas under the ROC curve for each observer were 0.843 and 0.861 for MRI vs. 0.800 and 0.833 for CT and the differences were not significant. Reproducibility was higher using MRI for both observers, but the result was not significant (MRI 32/33 vs. CT 29/33, P = 0.083). Conclusion: Gd-EOB-DTPA-enhanced MRI tended to show higher diagnostic accuracy, sensitivity and reproducibility compared to triple phase 64-MDCT in the detection of hepatocellular carcinoma, however statistical significance was not achieved.

Pre-treatment double- or triple-positive tumor markers are predictive of a poor outcome for patients undergoing radiofrequency ablation for hepatocellular carcinoma.

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Nitta, Hidetoshi; Nakagawa, Shigeki; Kaida, Takayoshi; Arima, Kota; Higashi, Takaaki; Taki, Katsunobu; Okabe, Hirohisa; Hayashi, Hiromitsu; Hashimoto, Daisuke; Chikamoto, Akira; Ishiko, Takatoshi; Beppu, Toru; Baba, Hideo

2017-03-01

We evaluated the therapeutic effect of radiofrequency ablation (RFA) on hepatocellular carcinoma (HCC) according to the number of positive tumor markers. The subjects of this study were 160 patients who underwent percutaneous and surgical RFA for HCC. Patients were divided into negative (n = 51), single- (n = 69), double- (n = 31), and triple-positive (n = 9) tumor marker groups according to the pre-treatment expression of these markers. We looked for any relationships among clinical parameters, outcomes, and tumor markers. The 3-year recurrence-free and overall survival rates of the negative, single-, double-, and triple-positive groups were 30, 19, 16, and 11 % (P = 0.02), and 94, 88, 67, and 37 % (P tumor marker profile was independently associated with local recurrence [hazard ratio (HR) 5.48, 95 % confidence interval (CI) 2.44-12.33, P tumor markers.

Targeting histone abnormality in triple negative breast cancer

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2017-08-01

clinical trials for treatment of cancers such as acute myeloid leukemia (AML) and lung cancer (http://clinicaltrials. gov). LSD2 has been linked to...The Cancer Genome Atlas; AML, acute myeloid leukemia ; DNMT, DNA methyltransferase; TNBC, triple-negative breast cancer; BCSC, breast cancer stem cell

Triple-negative breast cancer: present challenges and new perspectives

NARCIS (Netherlands)

Podo, Franca; Buydens, Lutgarde M. C.; Degani, Hadassa; Hilhorst, Riet; Klipp, Edda; Gribbestad, Ingrid S.; van Huffel, Sabine; van Laarhoven, Hanneke W. M.; Luts, Jan; Monleon, Daniel; Postma, Geert J.; Schneiderhan-Marra, Nicole; Santoro, Filippo; Wouters, Hans; Russnes, Hege G.; Sørlie, Therese; Tagliabue, Elda; Børresen-Dale, Anne-Lise

2010-01-01

Triple-negative breast cancers (TNBC), characterized by absence of estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of human epidermal growth factor receptor 2 (HER2), are typically associated with poor prognosis, due to aggressive tumor phenotype(s), only partial

[18F]fluorodeoxyglucose triple-head coincidence imaging as an adjunct to 131I scanning for follow-up of papillary thyroid carcinoma.

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Gonzalo, Irene T Gaw; Itti, Emmanuel; Mlikotic, Anton; Pham, Le H; Cesar, Romeo B; Meignan, Michel; Mishkin, Fred S

2003-01-01

To evaluate the feasibility of using [(18)F]fluorodeoxyglucose ((18)FDG) triple-head coincidence imaging as a potential cost-effective alternative to positron emission tomography in the setting of suspected recurrence of papillary thyroid carcinoma. We retrospectively studied 10 patients with suspected recurrence of papillary carcinoma of the thyroid, who underwent (18)FDG coincidence imaging,(131)I scanning, and a reference anatomic scan (computed tomography, magnetic resonance imaging, or both) within 1 year in most cases. The (131)I scan detected the recurrence in five patients (62.5%) and failed to reveal recurrent cancer in three patients (37.5%); in contrast,(18)FDG imaging detected the recurrence in eight patients (100%) and was true negative in two patients in whom the scans were performed more than 1 year after effective therapy for the recurrence. The sensitivity of detection was unrelated to lesion size. The (18)FDG imaging results led to additional radiotherapy in all (131)I-negative patients, two of whom had high thyroglobulin levels and one of whom had a low thyroglobulin concentration but the presence of antithy-roglobulin antibodies. We conclude that (18)FDG triple-head coincidence imaging is useful for routine management of patients with thyroid cancer who have no abnormalities detected on (131)I scans but have high serum thyroglobulin levels. This technique, however, may not be as sensitive as a dedicated positron emission tomographic device, particularly for the assessment of small tumors.

Clinical efficacy of local targeted chemotherapy for triple-negative breast cancer

International Nuclear Information System (INIS)

He, Jinsong; Wang, Xianming; Guan, Hong; Chen, Weicai; Wang, Ming; Wu, Huisheng; Wang, Zun; Zhou, Ruming; Qiu, Shuibo

2011-01-01

The aim of the study was to evaluate the clinical efficacy of superselective intra-arterial targeted neo-adjuvant chemotherapy in the treatment of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative (triple-negative) breast cancer. A total of 47 triple-negative breast cancer patients (29 at stage II, 13 at stage III and 5 at stage IV) were randomly assigned to two groups: targeted chemotherapy group (n=24) and control group (n=23). Patients in the targeted chemotherapy group received preoperative superselective intra-arterial chemotherapy with CEF regimen (C: cyclophosphamide [600 mg/m 2 ]; E: epirubicin [90 mg/m 2 ]; F: 5-fluorouracil [600 mg/m 2 ]), and those in the control group received routine neoadjuvant chemotherapy with CEF. The duration of the treatment, changes in lesions and the prognosis were determined. The average course of the treatment was 15 days in the targeted chemotherapy group which was significantly shorter than that in the control group (31 days) (P<0.01). The remission rate of lesions was 91.6% in the targeted chemotherapy group and 60.9% in the control group, respectively. Among these patients, 9 died within two years, including 2 (both at IV stage) in the targeted chemotherapy group and 7 (2 at stage II, 4 at stage III and 1 at stage IV) in the control group. As an neoadjuvant therapy, the superselective intra-arterial chemotherapy is effective for triple-negative breast cancer, with advantages of the short treatment course and favourable remission rates as well as prognoses

Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic options.

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Pierluigi Gasparini

Full Text Available Triple negative breast cancers are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapeutics. Androgen receptor has been associated with triple negative breast cancer pathogenesis, but its role in the different subtypes has not been clearly defined. We examined androgen receptor protein expression by immunohistochemical analysis in 678 breast cancers, including 396 triple negative cancers. Fifty matched lymph node metastases were also examined. Association of expression status with clinical (race, survival and pathological (basal, non-basal subtype, stage, grade features was also evaluated. In 160 triple negative breast cancers, mRNA microarray expression profiling was performed, and differences according to androgen receptor status were analyzed. In triple negative cancers the percentage of androgen receptor positive cases was lower (24.8% vs 81.6% of non-triple negative cases, especially in African American women (16.7% vs 25.5% of cancers of white women. No significant difference in androgen receptor expression was observed in primary tumors vs matched metastatic lesions. Positive androgen receptor immunoreactivity was inversely correlated with tumor grade (p<0.01 and associated with better overall patient survival (p = 0.032 in the non-basal triple negative cancer group. In the microarray study, expression of three genes (HER4, TNFSF10, CDK6 showed significant deregulation in association with androgen receptor status; eg CDK6, a novel therapeutic target in triple negative cancers, showed significantly higher expression level in androgen receptor negative cases (p<0.01. These findings confirm the prognostic impact of androgen receptor expression in non-basal triple negative breast cancers, and suggest targeting of new androgen receptor-related molecular pathways in patients with these cancers.

Practical consensus recommendations on management of triple-negative metastatic breast cancer

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R Rangarao

2018-01-01

Full Text Available Patients with breast cancer along with metastatic estrogen and progesterone receptor (ER/PR- and human epidermal growth factor receptor 2 (HER2-negative tumors are referred to as having metastatic triple-negative breast cancer (mTNBC disease. Resistance to current standard therapies such as anthracyclines or taxanes limits the available options for previously treated patients with metastatic TNBC to a small number of non-cross-resistant regimens, and there is currently no preferred standard chemotherapy. Clinical experience suggests that many women with triple-negative metastatic breast cancer (MBC relapse quickly. Expert oncologist discussed about new chemotherapeutic strategies and agents used in treatment of mTNBC and the expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple-Negative Breast Cancer

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2017-10-01

Award Number: W81XWH-15-1-0311 TITLE: TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple- Negative Breast Cancer PRINCIPAL...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Triple-negative breast cancers (TNBCs) represent only 10%-15% of all breast cancers ; however... cancers (TNBC) represent 10-15% of all breast cancers . While significant advances have been made for targeted therapy of ER and HER2-positive breast

Adenoid cystic carcinoma of the breast, high grade with basal phenotype, literature review

Directory of Open Access Journals (Sweden)

Enaam Junainah

Full Text Available Adenoid cystic carcinoma (ACC is a rare type of breast carcinoma resembling adenoid cystic carcinoma of other sites. this type of tumors usually characterized by the exhibiting dual cell population of luminal and basaloid with specific growth pattern Most of these sub types are triple-negative with basal-like breast features (tumors that are devoid of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, and express basal cell markers, they are usually low-grade but can be high grade, clinical behavior is indolent despite the nuclear grade, lymph node involvement or distant metastases which is rarely occur. Treatment is either simple mastectomy or lumpectomy. Chemotherapy, radiation and hormonal treatment have limited used in those cases. Keywords: Adenoid cystic carcinoma, Breast, Triple-negative and basal-like phenotype

The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer

International Nuclear Information System (INIS)

Rhee, Jiyoung; Kim, Tae-You; Han, Sae-Won; Oh, Do-Youn; Kim, Jee Hyun; Im, Seock-Ah; Han, Wonshik; Ae Park, In; Noh, Dong-Young; Bang, Yung-Jue

2008-01-01

Triple-negative (TN) breast cancer, which is defined as being negative for the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), represents a subset of breast cancer with different biologic behaviour. We investigated the clinicopathologic characteristics and prognostic indicators of lymph node-negative TN breast cancer. Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Seoul National University Hospital between Jan. 2000 and Jun. 2003. Clinicopathologic variables and clinical outcomes were evaluated. Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (< 35 y, p = 0.003), and higher histologic and nuclear grade (p < 0.001). It also correlated with a molecular profile associated with biological aggressiveness: negative for bcl-2 expression (p < 0.001), positive for the epidermal growth factor receptor (p = 0.003), and a high level of p53 (p < 0.001) and Ki67 expression (p < 0.00). The relapse rates during the follow-up period (median, 56.8 months) were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (p = 0.004). Relapse free survival (RFS) was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer (4-year RFS rate 85.5% vs. 94.2%, respectively; p = 0.001). On multivariate analysis, young age, close resection margin, and triple-negativity were independent predictors of shorter RFS. TN breast cancer had higher relapse rate and more aggressive clinicopathologic characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into the risk factor analysis for node-negative breast cancer

ADAM-17: a novel therapeutic target for triple negative breast cancer.

LENUS (Irish Health Repository)

McGowan, P M

2013-02-01

Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR\\/HER family of receptors.

Nuclear Kaiso expression is associated with high grade and triple-negative invasive breast cancer.

Directory of Open Access Journals (Sweden)

Jeroen F Vermeulen

Full Text Available Kaiso is a BTB/POZ transcription factor that is ubiquitously expressed in multiple cell types and functions as a transcriptional repressor and activator. Little is known about Kaiso expression and localization in breast cancer. Here, we have related pathological features and molecular subtypes to Kaiso expression in 477 cases of human invasive breast cancer. Nuclear Kaiso was predominantly found in invasive ductal carcinoma (IDC (p = 0.007, while cytoplasmic Kaiso expression was linked to invasive lobular carcinoma (ILC (p = 0.006. Although cytoplasmic Kaiso did not correlate to clinicopathological features, we found a significant correlation between nuclear Kaiso, high histological grade (p = 0.023, ERα negativity (p = 0.001, and the HER2-driven and basal/triple-negative breast cancers (p = 0.018. Interestingly, nuclear Kaiso was also abundant in BRCA1-associated breast cancer (p<0.001 and invasive breast cancer overexpressing EGFR (p = 0.019. We observed a correlation between nuclear Kaiso and membrane-localized E-cadherin and p120-catenin (p120 (p<0.01. In contrast, cytoplasmic p120 strongly correlated with loss of E-cadherin and low nuclear Kaiso (p = 0.005. We could confirm these findings in human ILC cells and cell lines derived from conditional mouse models of ILC. Moreover, we present functional data that substantiate a mechanism whereby E-cadherin controls p120-mediated relief of Kaiso-dependent gene repression. In conclusion, our data indicate that nuclear Kaiso is common in clinically aggressive ductal breast cancer, while cytoplasmic Kaiso and a p120-mediated relief of Kaiso-dependent transcriptional repression characterize ILC.

CCR 20th Anniversary Commentary: Triple-Negative Breast Cancer in 2015—Still in the Ballpark.

Science.gov (United States)

Narod, Steven A; Dent, Rebecca A; Foulkes, William D

2015-09-01

The research article by Dent and colleagues, which was published in the August 1, 2007, issue of Clinical Cancer Research, provided a clinical description of metastatic progression of triple-negative breast cancers. Finding successful treatment strategies for women with triple-negative breast cancer remains a challenge. ©2015 American Association for Cancer Research.

Heterogeneity of triple-negative breast cancer: mammographic, US, and MR imaging features according to androgen receptor expression

Energy Technology Data Exchange (ETDEWEB)

Bae, Min Sun; Song, Sung Eun; Kim, Won Hwa; Lee, Su Hyun; Moon, Woo Kyung [Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Park, So Yeon; Park, In-Ae [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Han, Wonshik; Noh, Dong-Young [Seoul National University College of Medicine, Department of Surgery, Seoul (Korea, Republic of)

2014-09-16

Our aim was to determine whether triple-negative breast cancers (TNBCs) with and without androgen receptor (AR) expression have distinguishing imaging features on mammography, breast ultrasound (US), and magnetic resonance (MR) imaging. AR expression was assessed immunohistochemically in 125 patients with TNBC from a consecutive series of 1,086 operable invasive breast cancers. Two experienced radiologists blinded to clinicopathological findings reviewed all imaging studies in consensus using the BI-RADS lexicon. The imaging and pathological features of 33 AR-positive TNBCs were compared with those of 92 AR-negative TNBCs. The presence of mammographic calcifications with or without a mass (p < 0.001), non-mass enhancement on MR imaging (p < 0.001), and masses with irregular shape or spiculated margins on US (p < 0.001 and p = 0.002) and MR imaging (p = 0.001 and p < 0.001) were significantly associated with AR-positive TNBC. Compared with AR-negative TNBC, AR-positive TNBC was more likely to have a ductal carcinoma in situ component (59.8 % vs. 90.9 %, p = 0.001) and low Ki-67 expression (30.4 % vs. 51.5 %, p = 0.030). AR-positive and AR-negative TNBCs have different imaging features, and certain imaging findings can be useful to predict AR status in TNBC. (orig.)

Wnt signaling in triple-negative breast cancer

Science.gov (United States)

Pohl, SÖ-G; Brook, N; Agostino, M; Arfuso, F; Kumar, A P; Dharmarajan, A

2017-01-01

Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease. PMID:28368389

Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms.

Science.gov (United States)

Milosevic Feenstra, Jelena D; Nivarthi, Harini; Gisslinger, Heinz; Leroy, Emilie; Rumi, Elisa; Chachoua, Ilyas; Bagienski, Klaudia; Kubesova, Blanka; Pietra, Daniela; Gisslinger, Bettina; Milanesi, Chiara; Jäger, Roland; Chen, Doris; Berg, Tiina; Schalling, Martin; Schuster, Michael; Bock, Christoph; Constantinescu, Stefan N; Cazzola, Mario; Kralovics, Robert

2016-01-21

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR or exon 10 of MPL or JAK2-V617F in >90% of the cases, whereas the remaining cases are termed "triple negative." We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL-S204P, a germline MPL-V285E mutation, and a germline JAK2-G571S variant. We performed Sanger sequencing of the entire coding region of MPL in 62, and of JAK2 in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPL mutation were detected. All of the identified MPL mutations were gain-of-function when analyzed in functional assays. JAK2 variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2-V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders. © 2016 by The American Society of Hematology.

The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

International Nuclear Information System (INIS)

Young, SR; DeSai, Damini; Zandvakili, Inuk; Royer, Robert; Li, Song; Narod, Steven A; Pilarski, Robert T; Donenberg, Talia; Shapiro, Charles; Hammond, Lyn S; Miller, Judith; Brooks, Karen A; Cohen, Stephanie; Tenenholz, Beverly

2009-01-01

Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2). The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT) and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE). All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer

Assessment of triple-phase CT findings for the differentiation of fat-deficient hepatic angiomyolipoma from hepatocellular carcinoma in non-cirrhotic liver

International Nuclear Information System (INIS)

Jeon, Tae Yeon; Kim, Seong Hyun; Lim, Hyo K.; Lee, Won Jae

2010-01-01

Background: To evaluate the triple-phase CT findings for the differentiation of fat-deficient angiomyolipoma from hepatocellular carcinoma in non-cirrhotic liver. Methods: We retrospectively reviewed contrast-enhanced triple-phase CT images of 10 patients with fat-deficient hepatic angiomyolipoma and 28 patients with 29 hepatocellular carcinomas in non-cirrhotic liver proved on histologic examination. The CT findings for the two types of tumors were compared using Fisher's exact test. Results: Early draining vein depicted on arterial or portal phases was seen in eight (80%) angiomyolipomas and two hepatocellular carcinomas (7%) (p < 0.001), in which the early draining vein was connected with tumoral vessels. The tumoral vessels in the angiomyolipoma were more prominent and ectatic, were distributed both centrally and peripherally, and were seen in smaller tumors than in the hepatocellular carcinoma. Tumor capsule enhancement was absent in all angiomyolipomas as compared with two (7%) hepatocellular carcinomas with no tumor capsule (p < 0.001). The other CT findings were not significantly different for the two different types of tumors. Conclusions: The presence of early draining vein connecting with prominent tumoral vessels and absent tumor capsule were useful CT findings for the differentiation of fat-deficient angiomyolipoma from hepatocellular carcinoma in non-cirrhotic liver.

A Study of Triple Negative Breast Cancer at a Tertiary Cancer Care ...

African Journals Online (AJOL)

cause of cancer deaths worldwide. It is the ... Background: Triple negative breast cancers (TNBCs) are a diverse and heterogeneous group .... nonHispanic black patients with breast cancer, at 24.6%. ... chance of breast conservation rates.

Selective androgen receptor modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

Science.gov (United States)

Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D; Yepuru, Muralimohan; Miller, Duane D; Steiner, Mitchell S; Dalton, James T

2014-01-01

The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

Selective androgen receptor modulators (SARMs negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

Directory of Open Access Journals (Sweden)

Ramesh Narayanan

Full Text Available The androgen receptor (AR is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer.Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC co-culture signaling studies were performed to understand the mechanisms of action.Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures.1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

Long-Term Complete Remission with nab-Paclitaxel, Bevacizumab, and Gemcitabine Combination Therapy in a Patient with Triple-Negative Metastatic Breast Cancer

Directory of Open Access Journals (Sweden)

Alberto Montero

2012-12-01

Full Text Available This is a case study of a 52-year-old female patient diagnosed in June 2007 with primary metastatic invasive ductal carcinoma of the left breast and synchronous metastases in the bone, lymph nodes, and lung. Biopsy results of the tumor tissue were negative for the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2. In November 2007, she participated in a phase II study of metastatic HER2-negative breast cancer. Treatment consisted of systemic chemotherapy with gemcitabine 1,500 mg/m2, nab-paclitaxel 150 mg/m2, and bevacizumab 10 mg/kg once every other week. The patient experienced pain relief in her sternum after 5 weeks of chemotherapy, and her analgesic therapy was discontinued. After 7 months, the patient achieved a complete radiographic response, which was maintained for nearly 2 additional years. She continued receiving treatment throughout this period, requiring 1 dose reduction due to fatigue. The patient experienced no other adverse events, including neuropathy, and continued working uninterrupted throughout her treatment. The patient was discontinued from the study in May 2010 after disease progression, almost a full 3 years after diagnosis. The patient showed minimal response to subsequent therapies but had disease stabilization and died from her disease in April 2012. Median overall survival for patients with metastatic triple-negative breast cancer is between 12 and 13.3 months. This patient survived nearly 5 years following diagnosis. This case exemplifies how therapy with nab-paclitaxel, bevacizumab, and gemcitabine may prolong survival, with minimal toxicity, in select patients with triple-negative metastatic breast cancer.

Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

Energy Technology Data Exchange (ETDEWEB)

Wang, Feng [Department of Gastroenterology, The Tenth People’s Hospital of Shanghai, Tongji University, Shanghai 200072 (China); Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yang, Yong, E-mail: yyang@houstonmethodist.org [Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Medicine, Weill Cornell Medical College, New York, NY 10065 (United States)

2014-11-21

Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.

Metaplastic Carcinoma with Chondroid Differentiation Arising in Microglandular Adenosis

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Ga-Eon Kim

2017-07-01

Full Text Available Microglandular adenosis (MGA of the breast is a rare, benign proliferative lesion but with a significant rate of associated carcinoma. Herein, we report an unusual case of metaplastic carcinoma with chondroid differentiation associated with typical MGA. Histologically, MGA showed a direct transition to metaplastic carcinoma without an intervening atypical MGA or ductal carcinoma in situ component. The immunohistochemical profile of the metaplastic carcinoma was mostly similar to that of MGA. In both areas, all the epithelial cells were positive for S-100 protein, but negative for estrogen receptor, progesterone receptor, HER2/neu, and epidermal growth factor receptor. An increase in the Ki-67 and p53 labelling index was observed from MGA to invasive carcinoma. To the best of our knowledge, this is the first case of metaplastic carcinoma with chondroid differentiation arising in MGA in Korea. This case supports the hypothesis that a subset of MGA may be a non-obligate morphologic precursor of breast carcinoma, especially the triple-negative subtype.

Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin

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Danica L. Rowe

2009-09-01

Full Text Available In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited.

Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer

DEFF Research Database (Denmark)

Szallasi, Zoltan Imre; Eklund, Aron Charles; Li, Qiyuan

2010-01-01

PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer...... samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller...

Clinical Initial Response of Neoadjuvant Chemotheraphy in Triple Negative, HER-2, and Luminal Types of Breast Cancer in Denpasar (A Preliminary Study

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Kristianto Yuli Yarso

2012-01-01

Full Text Available Objectives: Triple Negative, Luminal, HER-2 subtypes of breast cancer are markers to predict behavior, aggressiveness, and response to chemotherapy. The aim of this study is to understand character and response to standard neoadjuvant chemotherapy in different subtypes of breast cancer. Method: This is a descriptive study of breast cancer subtypes. From 687 patients (2003-2010 351 patients have IHC data which divided into 3 groups, Triple negative, Luminal, and HER-2. We used 10% as a cut off point for ER, PR, while 30% & positive 3 for HER-2. We determined initial clinical response after 3 cycles of neoadjuvant chemotherapy although only 77 got standard neoadjuvant chemotherapy and had clinical response data. We used 50% diameters depreciation & no metastasis as cut off point for respond group. Results: There were 116 (33% Triple Negative, 60 (17% HER-2, and 175 (50% Luminal Subtypes. The mean of age for 351 patients are 48.32 (23-82 years. In this study, it was obtained that no significant difference of means of age (p=0.24 in these 3 groups. Triple negative group significantly more advance in grade if compared with the other two groups (p=0.02. HER-2 group had highest response with standard neoadjuvant chemotherapy (50%, Luminal group had (49%, and Triple negative group had only (15% response. One pCR in HER-2 group. There were no difference ages in subtypes. Triple negative has more advances in grade. HER-2 group has highest response to standard neoadjuvant chemotherapy and Triple negative has lowest response to standard neoadjuvant chemotherapy.

Adenoid cystic carcinomas of the salivary gland, lacrimal gland, and breast are morphologically and genetically similar but have distinct microRNA expression profiles

DEFF Research Database (Denmark)

Andreasen, Simon; Tan, Qihua; Agander, Tina Klitmøller

2018-01-01

Adenoid cystic carcinoma is among the most frequent malignancies in the salivary and lacrimal glands and has a grave prognosis characterized by frequent local recurrences, distant metastases, and tumor-related mortality. Conversely, adenoid cystic carcinoma of the breast is a rare type of triple......-negative (estrogen and progesterone receptor, HER2) and basal-like carcinoma, which in contrast to other triple-negative and basal-like breast carcinomas has a very favorable prognosis. Irrespective of site, adenoid cystic carcinoma is characterized by gene fusions involving MYB, MYBL1, and NFIB, and the reason...... for the different clinical outcomes is unknown. In order to identify the molecular mechanisms underlying the discrepancy in clinical outcome, we characterized the phenotypic profiles, pattern of gene rearrangements, and global microRNA expression profiles of 64 salivary gland, 9 lacrimal gland, and 11 breast...

Cytokeratin 20-negative Merkel cell carcinoma is infrequently associated with the Merkel cell polyomavirus.

Science.gov (United States)

Miner, Andrew G; Patel, Rajiv M; Wilson, Deborah A; Procop, Gary W; Minca, Eugen C; Fullen, Douglas R; Harms, Paul W; Billings, Steven D

2015-04-01

Merkel cell carcinoma is a rare, highly aggressive cutaneous neuroendocrine carcinoma most commonly seen in sun-damaged skin. Histologically, the tumor consists of primitive round cells with fine chromatin and numerous mitoses. Immunohistochemical stains demonstrate expression of neuroendocrine markers. In addition, cytokeratin 20 (CK20) is expressed in ∼95% of cases. In 2008, Merkel cell carcinoma was shown to be associated with a virus now known as Merkel cell polyomavirus in ∼80% of cases. Prognostic and mechanistic differences between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative Merkel cell carcinoma may exist. There has been the suggestion that CK20-negative Merkel cell carcinomas less frequently harbor Merkel cell polyomavirus, but a systematic investigation for Merkel cell polyomavirus incidence in CK20-negative Merkel cell carcinoma has not been done. To test the hypothesis that Merkel cell polyomavirus is less frequently associated with CK20-negative Merkel cell carcinoma, we investigated 13 CK20-negative Merkel cell carcinomas from the files of the Cleveland Clinic and the University of Michigan for the virus. The presence or absence of Merkel cell polyomavirus was determined by quantitative PCR performed for Large T and small T antigens, with sequencing of PCR products to confirm the presence of Merkel cell polyomavirus. Ten of these (77%) were negative for Merkel cell polyomavirus and three (23%) were positive for Merkel cell polyomavirus. Merkel cell polyomavirus is less common in CK20-negative Merkel cell carcinoma. Larger series and clinical follow-up may help to determine whether CK20-negative Merkel cell carcinoma is mechanistically and prognostically unique.

ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms

OpenAIRE

Ralff, Marie D.; Kline, Christina L.B.; Küçükkase, Ozan C; Wagner, Jessica; Lim, Bora; Dicker, David T.; Prabhu, Varun V.; Oster, Wolfgang; El-Deiry, Wafik S.

2017-01-01

Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13). A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell...

Caffeic Acid Phenethyl Ester and Ethanol Extract of Propolis Induce the Complementary Cytotoxic Effect on Triple-Negative Breast Cancer Cell Lines

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Anna Rzepecka-Stojko

2015-05-01

Full Text Available Chemotherapy of breast cancer could be improved by bioactive natural substances, which may potentially sensitize the carcinoma cells’ susceptibility to drugs. Numerous phytochemicals, including propolis, have been reported to interfere with the viability of carcinoma cells. We evaluated the in vitro cytotoxic activity of ethanol extract of propolis (EEP and its derivative caffeic acid phenethyl ester (CAPE towards two triple-negative breast cancer (TNBC cell lines, MDA-MB-231 and Hs578T, by implementation of the MTT and lactate dehydrogenase (LDH assays. The morphological changes of breast carcinoma cells were observed following exposure to EEP and CAPE. The IC50 of EEP was 48.35 µg∙mL−1 for MDA-MB-23 cells and 33.68 µg∙mL−1 for Hs578T cells, whereas the CAPE IC50 was 14.08 µM and 8.01 µM for the MDA-MB-231 and Hs578T cell line, respectively. Here, we report that propolis and CAPE inhibited the growth of the MDA-MB-231 and Hs578T lines in a dose-dependent and exposure time-dependent manner. EEP showed less cytotoxic activity against both types of TNBC cells. EEP and, particularly, CAPE may markedly affect the viability of breast cancer cells, suggesting the potential role of bioactive compounds in chemoprevention/chemotherapy by potentiating the action of standard anti-cancer drugs.

Triple composite tumor of stomach: A rare combination of alpha fetoprotein positive hepatoid adenocarcinoma, tubular adenocarcinoma and large cell neuroendocrine carcinoma

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Lipika Lipi

2014-01-01

Full Text Available A 50-year-old male patient presented with pain abdomen of 6 months duration. Computed tomography scan revealed a large mass in the stomach occluding the lumen. Histopathology revealed a triple composite tumor comprising of tubular adenocarcinoma arising on a background of high-grade dysplasia, hepatoid adenocarcinoma (positive for Hep Par-1 and alpha fetoprotein and large cell neuroendocrine carcinoma (positive for synaptophysin and chromogranin with nodal metastasis.Triple composite tumors are distinctly rare with few reports in literature.

Advancement of mass spectrometry-based proteomics technologies to explore triple negative breast cancer.

Science.gov (United States)

Miah, Sayem; Banks, Charles A S; Adams, Mark K; Florens, Laurence; Lukong, Kiven E; Washburn, Michael P

2016-12-20

Understanding the complexity of cancer biology requires extensive information about the cancer proteome over the course of the disease. The recent advances in mass spectrometry-based proteomics technologies have led to the accumulation of an incredible amount of such proteomic information. This information allows us to identify protein signatures or protein biomarkers, which can be used to improve cancer diagnosis, prognosis and treatment. For example, mass spectrometry-based proteomics has been used in breast cancer research for over two decades to elucidate protein function. Breast cancer is a heterogeneous group of diseases with distinct molecular features that are reflected in tumour characteristics and clinical outcomes. Compared with all other subtypes of breast cancer, triple-negative breast cancer is perhaps the most distinct in nature and heterogeneity. In this review, we provide an introductory overview of the application of advanced proteomic technologies to triple-negative breast cancer research.

Selection of Novel Peptides Homing the 4T1 CELL Line: Exploring Alternative Targets for Triple Negative Breast Cancer.

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Vera L Silva

Full Text Available The use of bacteriophages to select novel ligands has been widely explored for cancer therapy. Their application is most warranted in cancer subtypes lacking knowledge on how to target the cancer cells in question, such as the triple negative breast cancer, eventually leading to the development of alternative nanomedicines for cancer therapeutics. Therefore, the following study aimed to select and characterize novel peptides for a triple negative breast cancer murine mammary carcinoma cell line- 4T1. Using phage display, 7 and 12 amino acid random peptide libraries were screened against the 4T1 cell line. A total of four rounds, plus a counter-selection round using the 3T3 murine fibroblast cell line, was performed. The enriched selective peptides were characterized and their binding capacity towards 4T1 tissue samples was confirmed by immunofluorescence and flow cytometry analysis. The selected peptides (4T1pep1 -CPTASNTSC and 4T1pep2-EVQSSKFPAHVS were enriched over few rounds of selection and exhibited specific binding to the 4T1 cell line. Interestingly, affinity to the human MDA-MB-231 cell line was also observed for both peptides, promoting the translational application of these novel ligands between species. Additionally, bioinformatics analysis suggested that both peptides target human Mucin-16. This protein has been implicated in different types of cancer, as it is involved in many important cellular functions. This study strongly supports the need of finding alternative targeting systems for TNBC and the peptides herein selected exhibit promising future application as novel homing peptides for breast cancer therapy.

Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells.

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Maturi, Varun; Enroth, Stefan; Heldin, Carl-Henrik; Moustakas, Aristidis

2018-05-10

Zinc finger E-box binding homeobox 1 (ZEB1) is a transcriptional regulator involved in embryonic development and cancer progression. ZEB1 induces epithelial-mesenchymal transition (EMT). Triple-negative human breast cancers express high ZEB1 mRNA levels and exhibit features of EMT. In the human triple-negative breast cancer cell model Hs578T, ZEB1 associates with almost 2,000 genes, representing many cellular functions, including cell polarity regulation (DLG2 and FAT3). By introducing a CRISPR-Cas9-mediated 30 bp deletion into the ZEB1 second exon, we observed reduced migratory and anchorage-independent growth capacity of these tumor cells. Transcriptomic analysis of control and ZEB1 knockout cells, revealed 1,372 differentially expressed genes. The TIMP metallopeptidase inhibitor 3 and the teneurin transmembrane protein 2 genes showed increased expression upon loss of ZEB1, possibly mediating pro-tumorigenic actions of ZEB1. This work provides a resource for regulators of cancer progression that function under the transcriptional control of ZEB1. The data confirm that removing a single EMT transcription factor, such as ZEB1, is not sufficient for reverting the triple-negative mesenchymal breast cancer cells into more differentiated, epithelial-like clones, but can reduce tumorigenic potential, suggesting that not all pro-tumorigenic actions of ZEB1 are linked to the EMT. © 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Targeting the androgen receptor in triple-negative breast cancer: current perspectives

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Mina A

2017-09-01

Full Text Available Alain Mina,1 Rachel Yoder,2 Priyanka Sharma1 1Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Westwood, 2University of Kansas Cancer Center, Kansas City, KS, USA Abstract: Triple-negative breast cancer (TNBC is an aggressive subtype associated with frequent recurrence and metastasis. Unlike hormone receptor-positive subtypes, treatment of TNBC is currently limited by the lack of clinically available targeted therapies. Androgen signaling is necessary for normal breast development, and its dysregulation has been implicated in breast tumorigenesis. In recent years, gene expression studies have identified a subset of TNBC that is enriched for androgen receptor (AR signaling. Interference with androgen signaling in TNBC is promising, and AR-inhibiting drugs have shown antitumorigenic activity in preclinical and proof of concept clinical studies. Recent advances in our understanding of androgenic signaling in TNBC, along with the identification of interacting pathways, are allowing development of the next generation of clinical trials with AR inhibitors. As novel AR-targeting agents are developed and evaluated in clinical trials, it is equally important to establish a robust set of biomarkers for identification of TNBC tumors that are most likely to respond to AR inhibition. Keywords: triple-negative breast cancer, androgen signaling, targeted therapy, biomarkers, prognosis 

Adenoid cystic carcinomas of the salivary gland, lacrimal gland, and breast are morphologically and genetically similar but have distinct microRNA expression profiles.

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Andreasen, Simon; Tan, Qihua; Agander, Tina Klitmøller; Steiner, Petr; Bjørndal, Kristine; Høgdall, Estrid; Larsen, Stine Rosenkilde; Erentaite, Daiva; Olsen, Caroline Holkmann; Ulhøi, Benedicte Parm; von Holstein, Sarah Linéa; Wessel, Irene; Heegaard, Steffen; Homøe, Preben

2018-02-21

Adenoid cystic carcinoma is among the most frequent malignancies in the salivary and lacrimal glands and has a grave prognosis characterized by frequent local recurrences, distant metastases, and tumor-related mortality. Conversely, adenoid cystic carcinoma of the breast is a rare type of triple-negative (estrogen and progesterone receptor, HER2) and basal-like carcinoma, which in contrast to other triple-negative and basal-like breast carcinomas has a very favorable prognosis. Irrespective of site, adenoid cystic carcinoma is characterized by gene fusions involving MYB, MYBL1, and NFIB, and the reason for the different clinical outcomes is unknown. In order to identify the molecular mechanisms underlying the discrepancy in clinical outcome, we characterized the phenotypic profiles, pattern of gene rearrangements, and global microRNA expression profiles of 64 salivary gland, 9 lacrimal gland, and 11 breast adenoid cystic carcinomas. All breast and lacrimal gland adenoid cystic carcinomas had triple-negative and basal-like phenotypes, while salivary gland tumors were indeterminate in 13% of cases. Aberrations in MYB and/or NFIB were found in the majority of cases in all three locations, whereas MYBL1 involvement was restricted to tumors in the salivary gland. Global microRNA expression profiling separated salivary and lacrimal gland adenoid cystic carcinoma from their respective normal glands but could not distinguish normal breast adenoid cystic carcinoma from normal breast tissue. Hierarchical clustering separated adenoid cystic carcinomas of salivary gland origin from those of the breast and placed lacrimal gland carcinomas in between these. Functional annotation of the microRNAs differentially expressed between salivary gland and breast adenoid cystic carcinoma showed these as regulating genes involved in metabolism, signal transduction, and genes involved in other cancers. In conclusion, microRNA dysregulation is the first class of molecules separating adenoid

Triple-negative breast cancer: new perspectives for targeted therapies

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Tomao F

2015-01-01

Full Text Available Federica Tomao,1 Anselmo Papa,2 Eleonora Zaccarelli,2 Luigi Rossi,2 Davide Caruso,2 Marina Minozzi,2 Patrizia Vici,3 Luigi Frati,4 Silverio Tomao21Department of Gynecology and Obstetrics, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, 2Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Oncology Unit, Istituto Chirurgico Ortopedico Traumatologico, Latina, 3Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy; 4Department of Molecular Medicine, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, ItalyAbstract: Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death.Keywords: basal-like breast cancer, estrogen–progesterone receptors, gene-expression microarray, human epidermal growth factor receptor 2, chemotherapy, target therapy

Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer

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Jeff C. Liu

2018-04-01

Full Text Available Summary: CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC, RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition. Minimal cooperation was observed in vitro between CDC25 antagonists and CDK1, CDK2, or CDK4/6 inhibitors, but strong synergy with WEE1 inhibition was apparent. In accordance with increased PI3K signaling following long-term CDC25 inhibition, CDC25 and PI3K inhibitors effectively synergized to suppress TNBC growth both in vitro and in xenotransplantation models. These results provide a rationale for the development of CDC25-based therapies for diverse RB1/PTEN/TP53-deficient and -proficient TNBCs. : Liu et al. report that inhibition of the protein phosphatase CDC25 kills diverse triple-negative breast cancer (TNBC cells. Moreover, CDC25 antagonists cooperate with other drugs, such as PI3K inhibitors, to efficiently suppress growth of human TNBC engrafted into mice. Keywords: triple negative breast cancer, basal-like breast cancer, therapy, RB1, PTEN, TP53, CDC25, WEE1, CHK1, checkpoint control

High infiltration of tumor-associated macrophages in triple-negative breast cancer is associated with a higher risk of distant metastasis

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Yuan ZY

2014-08-01

Full Text Available Zhong-Yu Yuan,1–3* Rong-Zhen Luo,1,2,4,* Rou-Jun Peng,1–3 Shu-Sen Wang,1–3 Cong Xue1–3 1State Key Laboratory of Oncology in South China, 2Collaborative Innovation Center for Cancer Medicine, 3Departments of Medical Oncology, Sun Yat-Sen University Cancer Center, 4Departments of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China  *These authors contributed equally to this work Background: Triple-negative breast cancer (TNBC is associated with poor prognosis and high probability of distant metastases. Tumor microenvironments play a pivotal role in tumor metastasis. Tumor-associated macrophages (TAMs are one of the main cell components, and they are correlated with increasing metastatic risk. The aim of this study is to analyze the prognostic significance of the infiltration of TAMs in patients with TNBC. Materials and methods: Immunohistochemical staining for cluster of differentiation (CD68 (a marker for macrophages was performed on tissue microarrays of operable breast cancer among 287 patients with TNBC, and the number of infiltrating TAMs was correlated with clinicopathological parameters. Results: We found that TNBC with a large number of infiltrating TAMs had a significantly higher risk of distant metastasis, as well as lower rates of disease-free survival and overall survival than those with a smaller number of infiltrating TAMs. Multivariate analysis indicated that the number of infiltrating TAMs was a significant independent prognostic factor of disease-free survival (P=0.001 in all patients. Conclusion: Our results suggested that high infiltrating TAMs are a significantly unfavorable prognostic factor for patients with TNBC, and they could become a potentially useful prognostic marker for TNBC. Keywords: breast carcinoma, triple-negative, tumor-associated macrophages, prognosis

Androgen receptor positive triple negative breast cancer: Clinicopathologic, prognostic, and predictive features.

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Kristine Astvatsaturyan

Full Text Available Overexpression of the androgen receptor (AR characterizes a distinct molecular subset of triple negative breast carcinomas (TNBC. The role of AR as a prognostic/predictive biomarker in TNBC is controversial, but increasing evidence suggests that this subset may respond to therapeutic agents targeting AR. Evaluation of AR has not been standardized, and criteria for selection of patients for antiandrogen therapy remain controversial. In this study we determine the appropriate threshold of AR immunoreactivity to define AR positive (AR+ TNBC, describe the clinicopathologic features of AR+ TNBC, and discuss the utility of AR positivity as a prognostic and predictive marker in TNBC.135 invasive TNBC processed in accordance with ASCO/CAP guidelines, were immunostained for AR. Clinicopathologic features of AR+ TNBC were analyzed and compared to AR negative (AR- TNBC. Patients' age, tumor size, tumor grade, lymph node status, proliferation rate, immunopositivity for EGFR, CK5/6, Ki-67, and disease free survival (DFS were evaluated statistically.A 1% cutpoint was confirmed as the appropriate threshold for AR positivity. Using this cutpoint 41% of 135 TNBC were AR+. AR+ TNBC occurred in older women, were larger, had lower mean proliferation rate and increased incidence of axillary metastasis than AR- TNBC. 76% of TNBC with apocrine morphology were AR+. A subset of AR+TNBC expressed basal markers (EGFR and CK5/6. A prognostic model was created.AR identifies a heterogeneous group of TNBC. Additional evaluation of EGFR expression allowed us to stratify TNBCs into 3 risk groups with significant differences in DFS and therapeutic implications: low-risk (AR+ EGFR- which represents the LAR molecular subtype with the best prognosis and may benefit the most from anti-androgen therapies; high-risk (AR- EGFR+ which represents the basal molecular subtype with the worst prognosis and may benefit the most from chemotherapy regimens; intermediate-risk (AR+EGFR+ and AR

Comparative Profiling of Triple-Negative Breast Carcinomas Tissue Glycoproteome by Sequential Purification of Glycoproteins and Stable Isotope Labeling

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Xiang Chen

2016-01-01

Full Text Available Background: Women with triple negative breast cancers (TNBCs have a poor prognosis due to lack of suitable targeted therapies. Changes in the protein glycosylation are increasingly being recognized as an important modification associated with cancer etiology. Methods: In an attempt to identify TNBC biomarkers with greater diagnostic and prognostic capabilities, hydrazide- based chemistry method combined with LC-MS/MS were used to purify and identify N-linked glycopeptides or glycoproteins of tissues from TNBC patients. Results: A total of 550 unique N-linked glycoproteins were identified, among these proteins, 72 unique N-linked glycoproteins were significantly regulated in tumor tissues, of which 56 proteins were upregulated and 16 proteins were downregulated. To assess the validity of the results, three selected proteins including Vascular endothelial growth factor receptor 1, Insulin receptor, Tissue factor pathway inhibitor were selected for western blot analysis, and these proteins were found as potential biomarkers of TNBC. The top three pathways of differentially expressed glycoproteins participated in were caveolar-mediated endocytosis signaling, agrin interactions at neuromuscular junction and LXR/RXR activation. Conclusion: This work provides potential glycoprotein markers to function as a novel tissue-based biomarker for TNBC.

Androgen receptor expression and its relationship with clinicopathological parameters in an Iranian population with invasive breast carcinoma

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Fereshteh Mohammadizadeh

2014-01-01

Conclusions: AR expression was found to be frequently present in breast carcinoma in the studied population. Since half of the ER negative and half of the triple negative tumors were found to be AR positive, AR positive cases may benefit from alternative endocrine therapeutic strategies other than the conventional endocrine-targeted medications.

Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients.

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Cabagnols, Xénia; Favale, Fabrizia; Pasquier, Florence; Messaoudi, Kahia; Defour, Jean Philippe; Ianotto, Jean Christophe; Marzac, Christophe; Le Couédic, Jean Pierre; Droin, Nathalie; Chachoua, Ilyas; Favier, Remi; Diop, M'boyba Khadija; Ugo, Valérie; Casadevall, Nicole; Debili, Najet; Raslova, Hana; Bellanné-Chantelot, Christine; Constantinescu, Stefan N; Bluteau, Olivier; Plo, Isabelle; Vainchenker, William

2016-01-21

Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in essential thrombocythemia (ET) with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L, and CALR mutations, using whole-exome sequencing and next-generation sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, 1 homozygous SH2B3 mutation, 1 MPLS505N, 1 MPLW515R, and 2 MPLS204P mutations. In the remaining patients, 4 presented a clonal and 7 a polyclonal hematopoiesis, suggesting that certain triple-negative ETs are not MPNs. NGS on 26 additional triple-negative ETs detected only 1 MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN. © 2016 by The American Society of Hematology.

Association between obesity with disease-free survival and overall survival in triple-negative breast cancer: A meta-analysis.

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Mei, Lin; He, Lin; Song, Yuhua; Lv, Yang; Zhang, Lijiu; Hao, Fengxi; Xu, Mengmeng

2018-05-01

To investigate the relationship between obesity and disease-free survival (DFS) and overall survival (OS) of triple-negative breast cancer. Citations were searched in PubMed, Cochrane Library, and Web of Science. Random effect model meta-analysis was conducted by using Revman software version 5.0, and publication bias was evaluated by creating Egger regression with STATA software version 12. Nine studies (4412 patients) were included for DFS meta-analysis, 8 studies (4392 patients) include for OS meta-analysis. There were no statistical significances between obesity with DFS (P = .60) and OS (P = .71) in triple-negative breast cancer (TNBC) patients. Obesity has no impact on DFS and OS in patients with TNBC.

Anticancer and Anti-Inflammatory Properties of Ganoderma lucidum Extract Effects on Melanoma and Triple-Negative Breast Cancer Treatment.

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Barbieri, Antonio; Quagliariello, Vincenzo; Del Vecchio, Vitale; Falco, Michela; Luciano, Antonio; Amruthraj, Nagoth Joseph; Nasti, Guglielmo; Ottaiano, Alessandro; Berretta, Massimiliano; Iaffaioli, Rosario Vincenzo; Arra, Claudio

2017-02-28

Among the most important traditional medicinal fungi, Ganoderma lucidum has been used as a therapeutic agent for the treatment of numerous diseases, including cancer, in Oriental countries. The aim of this study is to investigate the anti-inflammatory, anticancer and anti-metastatic activities of Ganoderma lucidum extracts in melanoma and triple-negative breast cancer cells. Ganoderma lucidum extracts were prepared by using common organic solvents; MDA-MB 231 and B16-F10 cell lines were adopted as cellular models for triple-negative breast cancer and melanoma and characterized for cell viability, wound-healing assay and measurement of cytokines secreted by cancer cells under pro-inflammatory conditions (incubation with lipopolysaccharide, LPS) and pretreatment with Ganoderma lucidum extract at different concentrations. Our study demonstrates, for the first time, how Ganoderma lucidum extracts can significantly inhibit the release of IL-8, IL-6, MMP-2 and MMP-9 in cancer cells under pro-inflammatory condition. Interestingly, Ganoderma lucidum extracts significantly also decrease the viability of both cancer cells in a time- and concentration-dependent manner, with abilities to reduce cell migration over time, which is correlated with a lower release of matrix metalloproteases. Taken together, these results indicate the possible use of Ganoderma lucidum extract for the therapeutic management of melanoma and human triple-negative breast cancer.

A CLDN1-negative phenotype predicts poor prognosis in triple-negative breast cancer.

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Fei Ma

Full Text Available INTRODUCTION: Triple-negative breast cancer (TNBC is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs. MATERIALS AND METHODS: The surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed. RESULTS: Positive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014. The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003. Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS in both lymph node positive (LN+ and negative (LN- cases (both P<0.001. Similarly it was also associated with shorter overall survival (OS(P = 0.003 in LN+ cases; P = 0.018 in LN- cases. In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008. Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002. However, neither CLDN4 nor CLDN7 expression was associated with survival. CONCLUSION: In TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor

Pre-menopausal triple-negative breast cancer at HAM hospital medan

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Betty; Laksmi, L. I.; Siregar, K. B.

2018-03-01

Triple-negative breast cancers (TNBC) are a type of breast cancer that does not have any or lack expression of the three receptors of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER-2). This cross-sectional study was performed on patients TNBC in HAM hospital Medan from 2013 to 2016 by immunohistochemistry stained. A total 60 invasive breast cancer samples with TNBC. The more frequent in TNBC group were 51-60 years (19 cases, 31.66%) and pre-menopause (34 cases, 57%). Tumor size T3 and T4 with staging IIIA and IIIB, histology sub-type IC-NOS and ILC with grade 2 and grade 3 of histologic was more common in TNBC.

Full Length Article Role of glypican-3 immunocytochemistry in differentiating hepatocellular carcinoma from metastatic carcinoma of the liver utilizing fine needle aspiration cytology

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Zaakook, M.; Abu Sinna, E.; Ayoub, M.; El-Sheikh, S.

2013-01-01

Purpose: Evaluation of the sensitivity and specificity of glypican3 (GPC3) in differentiating hepatocellular carcinoma (HCC) from metastatic carcinomas of the liver in cell block material. Patients and methods: Sixty cell blocks were prepared from liver FNAs performed in the radiodiagnosis department, National Cancer Institute, in the period between August 2011 and May 2012. Cases diagnosed as hepatocellular carcinoma, or metastatic carcinoma were included in the study. Cell block sections were stained with anti GPC-3. Sensitivity, specificity, and positive and negative predictive values, of GPC3 were calculated. The final diagnosis was based on the triple approach of clinical data, radiological findings, as well as cytomorphologic features aided by GPC-3 results. Results: 70% of cases were diagnosed as HCC, and 30% as metastatic carcinomas. 95.2% of HCC cases expressed GPC3. Poorly differentiated cases showed the highest GPC3 sensitivity (100%), followed by moderately differentiated cases (96.5%), while well differentiated cases expressed GPC3 in 90% of cases. 83.3% of metastatic carcinomas were negative for GPC3. In this study, sensitivity of GPC-3 in HCC was 95.2%, specificity was 83.3%, positive and negative predictive values were 93% and 88.2% respectively, and total accuracy was 91.7%. Conclusion: Immunocytochemical staining for GPC3 in cell block material is a highly sensitive and specific method capable of distinguishing HCC from the vast majority of metastatic carcinomas of the liver

Triple-negative (ER, PgR, HER-2/neu breast cancer in Indian women

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Vinayak W Patil

2011-03-01

Full Text Available Vinayak W Patil1, Rajeev Singhai1, Amit V Patil2, Prakash D Gurav21Department of Biochemistry, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, India; 2Department of Surgery, Government Medical College, Miraj, IndiaAbstract: The aim of our study was to analyze triple-negative (TN breast cancer, which is defined as being negative for the estrogen receptor (ER, the progesterone receptor (PgR, and the human epidermal growth factor receptor 2 (HER-2/neu and which represents a subset of breast cancer with different biologic behavior. We investigated the clinicopathological characteristics and prognostic indicators of lymph node-negative TN breast cancer. Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Grant Medical College and Sir JJ Group of Hospitals, Mumbai, India, from May 2007 to October 2010. Clinicopathological variables and clinical outcomes were evaluated. Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (<35 years, P = 0.003 and a higher histopathologic and nuclear grade (P < 0.001. It also correlated with a molecular profile associated with biological aggressiveness: negative for Bcl-2 expression (P < 0.001, positive for the epidermal growth factor receptor (P = 0.003, and a high level of p53 (P < 0.001 and Ki-67 expression (P < 0.00. The relapse rates during the follow-up period (median 56.8 months were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (P = 0.004. Relapse-free survival (RFS was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer: 3.5-year RFS rate 85.5% versus 94.2%, respectively; P = 0.001. On multivariate analysis, young age, close resection margin, and triple negativity were independent predictors of shorter RFS. TN breast cancer had a higher relapse rate and more aggressive clinicopathological

Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins.

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Eng, M S; Kaur, J; Prasmickaite, L; Engesæter, B Ø; Weyergang, A; Skarpen, E; Berg, K; Rosenblum, M G; Mælandsmo, G M; Høgset, A; Ferrone, S; Selbo, P K

2018-05-16

Triple-negative breast cancer (TNBC) and malignant melanoma are highly aggressive cancers that widely express the cell surface chondroitin sulfate proteoglycan 4 (CSPG4/NG2). CSPG4 plays an important role in tumor cell growth and survival and promotes chemo- and radiotherapy resistance, suggesting that CSPG4 is an attractive target in cancer therapy. In the present work, we applied the drug delivery technology photochemical internalization (PCI) in combination with the novel CSPG4-targeting immunotoxin 225.28-saporin as an efficient and specific strategy to kill aggressive TNBC and amelanotic melanoma cells. Light-activation of the clinically relevant photosensitizer TPCS2a (fimaporfin) and 225.28-saporin was found to act in a synergistic manner, and was superior to both PCI of saporin and PCI-no-drug (TPCS2a + light only) in three TNBC cell lines (MDA-MB-231, MDA-MB-435 and SUM149) and two BRAFV600E mutated malignant melanoma cell lines (Melmet 1 and Melmet 5). The cytotoxic effect was highly dependent on the light dose and expression of CSPG4 since no enhanced cytotoxicity of PCI of 225.28-saporin compared to PCI of saporin was observed in the CSPG4-negative MCF-7 cells. The PCI of a smaller, and clinically relevant CSPG4-targeting toxin (scFvMEL-rGel) validated the CSPG4-targeting concept in vitro and induced a strong inhibition of tumor growth in the amelanotic melanoma xenograft A-375 model. In conclusion, the combination of the drug delivery technology PCI and CSPG4-targeting immunotoxins is an efficient, specific and light-controlled strategy for the elimination of aggressive cells of TNBC and malignant melanoma origin. This study lays the foundation for further preclinical evaluation of PCI in combination with CSPG4-targeting.

Modeling triple-negative breast cancer heterogeneity: effects of stromal macrophages, fibroblasts and tumor vasculature.

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Norton, Kerri-Ann; Jin, Kideok; Popel, Aleksander S

2018-05-08

A hallmark of breast tumors is its spatial heterogeneity that includes its distribution of cancer stem cells and progenitor cells, but also heterogeneity in the tumor microenvironment. In this study we focus on the contributions of stromal cells, specifically macrophages, fibroblasts, and endothelial cells on tumor progression. We develop a computational model of triple-negative breast cancer based on our previous work and expand it to include macrophage infiltration, fibroblasts, and angiogenesis. In vitro studies have shown that the secretomes of tumor-educated macrophages and fibroblasts increase both the migration and proliferation rates of triple-negative breast cancer cells. In vivo studies also demonstrated that blocking signaling of selected secreted factors inhibits tumor growth and metastasis in mouse xenograft models. We investigate the influences of increased migration and proliferation rates on tumor growth, the effect of the presence on fibroblasts or macrophages on growth and morphology, and the contributions of macrophage infiltration on tumor growth. We find that while the presence of macrophages increases overall tumor growth, the increase in macrophage infiltration does not substantially increase tumor growth and can even stifle tumor growth at excessive rates. Copyright © 2018. Published by Elsevier Ltd.

Synchronous triple urogenital cancer (renal cancer, bladder cancer, prostatic cancer). A case report

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Takada, Tsuyoshi; Honda, Masahito; Momohara, Chikahiro; Komori, Kazuhiko; Fujioka, Hideki [Osaka Police Hospital (Japan)

2002-04-01

A case of synchronous triple urogenital cancer, which was comprised of renal cell carcinoma of the left kidney, transitional cell carcinoma of the urinary bladder, and adenocarcinoma of the prostate, is reported. A 72-year-old Japanese male patient was referred to our outpatient clinic with the complaint of asymptomatic hematuria. At that time, his serum of level of PSA was elevated to 20 ng/ml. Cystourethroscopy showed a papillary bladder tumor and coagula through the left urinary orifice. Ultrasonography, computed tomography and magnetic resonance imaging showed a mass lesion measuring about 6 cm by 5 cm in the left kidney. Angiography showed a hypervascular lesion measuring about 6 cm by 5 cm at the same site. Double cancer, consisting of renal cell carcinoma and transitional cell carcinoma of the urinary bladder, was suspected and we performed left total nephroureterectomy, hilar lymphadenectomy, and transurethral rection of the bladder tumor, one month later. At the same time, we performed a biopsy of the prostate. Histological diagnosis was renal cell carcinoma, clear cell carcinoma and transitional cell carcinoma of urinary bladder. Histological diagnosis of the prostate biopsy was moderately differentiated adenocarcinoma. Since this case fulfilled the criteria of Warren and Gates, it was classified as synchronous triple urogenital cancer. A review of the literature revealed 17 authentic cases of triple urogenital cancer, of which 14 and 10 cases were reported as a combination of renal cancer, bladder cancer and prostatic cancer, in the world and in Japan, respectively. Furthermore, he had been exposed to the atomic bomb explosion in Hiroshima in 1945. This carcinogenic precursor may be related to the development of the triple cancer. (author)

Synchronous triple urogenital cancer (renal cancer, bladder cancer, prostatic cancer). A case report

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Takada, Tsuyoshi; Honda, Masahito; Momohara, Chikahiro; Komori, Kazuhiko; Fujioka, Hideki

2002-01-01

A case of synchronous triple urogenital cancer, which was comprised of renal cell carcinoma of the left kidney, transitional cell carcinoma of the urinary bladder, and adenocarcinoma of the prostate, is reported. A 72-year-old Japanese male patient was referred to our outpatient clinic with the complaint of asymptomatic hematuria. At that time, his serum of level of PSA was elevated to 20 ng/ml. Cystourethroscopy showed a papillary bladder tumor and coagula through the left urinary orifice. Ultrasonography, computed tomography and magnetic resonance imaging showed a mass lesion measuring about 6 cm by 5 cm in the left kidney. Angiography showed a hypervascular lesion measuring about 6 cm by 5 cm at the same site. Double cancer, consisting of renal cell carcinoma and transitional cell carcinoma of the urinary bladder, was suspected and we performed left total nephroureterectomy, hilar lymphadenectomy, and transurethral rection of the bladder tumor, one month later. At the same time, we performed a biopsy of the prostate. Histological diagnosis was renal cell carcinoma, clear cell carcinoma and transitional cell carcinoma of urinary bladder. Histological diagnosis of the prostate biopsy was moderately differentiated adenocarcinoma. Since this case fulfilled the criteria of Warren and Gates, it was classified as synchronous triple urogenital cancer. A review of the literature revealed 17 authentic cases of triple urogenital cancer, of which 14 and 10 cases were reported as a combination of renal cancer, bladder cancer and prostatic cancer, in the world and in Japan, respectively. Furthermore, he had been exposed to the atomic bomb explosion in Hiroshima in 1945. This carcinogenic precursor may be related to the development of the triple cancer. (author)

Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer.

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Hassan, Saima; Esch, Amanda; Liby, Tiera; Gray, Joe W; Heiser, Laura M

2017-12-01

Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose-response measures of cell viability, an EC 50 value was calculated for each cellular phenotype and each PARP inhibitor. The EC 50 values for both 53BP1 metrics strongly correlated with IC 50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle-associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition. Mol Cancer Ther; 16(12); 2892-901. ©2017 AACR . ©2017 American Association for Cancer Research.

Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer

NARCIS (Netherlands)

Li, Bo; Chonghaile, Triona Ni; Fan, Yue; Madden, Stephen F.; Klinger, Rut; O'Connor, Aisling E.; Walsh, Louise; O'Hurley, Gillian; Udupi, Girish Mallya; Joseph, Jesuchristopher; Tarrant, Finbarr; Conroy, Emer; Gaber, Alexander; Chin, Suet-Feung; Bardwell, Helen A; Provenzano, Elena; Crown, John; Dubois, Thierry; Linn, Sabine; Jirstrom, Karin; Caldas, Carlos; O'Connor, Darran P; Gallagher, William M

2017-01-01

Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate

Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival.

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Maiti, Aparna; Takabe, Kazuaki; Hait, Nitai C

2017-04-01

About 40,000 American women die from metastatic breast cancer each year despite advancements in treatment. Approximately, 15% of breast cancers are triple-negative for estrogen receptor, progesterone receptor, and HER2. Triple-negative cancer is characterized by more aggressive, harder to treat with conventional approaches and having a greater possibility of recurrence. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid signaling mediator has emerged as a key regulatory molecule in breast cancer progression. Therefore, we investigated whether cytosolic sphingosine kinase type 1 (SphK1) and nuclear sphingosine kinase type 2 (SphK2), the enzymes that make S1P are critical for growth and PI3K/AKT, ERK-MAP kinase mediated survival signaling of lung metastatic variant LM2-4 breast cancer cells, generated from the parental triple-negative MDA-MB-231 human breast cancer cell line. Similar with previous report, SphKs/S1P signaling is critical for the growth and survival of estrogen receptor positive MCF-7 human breast cancer cells, was used as our study control. MDA-MB-231 did not show a significant effect of SphKs/S1P signaling on AKT, ERK, and p38 pathways. In contrast, LM2-4 cells that gained lung metastatic phenotype from primary MDA-MB-231 cells show a significant effect of SphKs/S1P signaling requirement on cell growth, survival, and cell motility. PF-543, a selective potent inhibitor of SphK1, attenuated epidermal growth factor (EGF)-mediated cell growth and survival signaling through inhibition of AKT, ERK, and p38 MAP kinase pathways mainly in LM2-4 cells but not in parental MDA-MB-231 human breast cancer cells. Moreover, K-145, a selective inhibitor of SphK2, markedly attenuated EGF-mediated cell growth and survival of LM2-4 cells. We believe this study highlights the importance of SphKs/S1P signaling in metastatic triple-negative breast cancers and targeted therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Targeting Tryptophan Catabolism: A Novel Method to Block Triple-Negative Breast Cancer Metastasis

Science.gov (United States)

2017-04-01

Negative Breast Cancer Nicholas C. D’Amato1, Thomas J. Rogers1, Michael A. Gordon1, Lisa I. Greene1, Dawn R. Cochrane1, Nicole S. Spoelstra1, Travis G...cancer progression. Biochim Biophys Acta 2013;1833:3481–98. 10. Kamarajugadda S, Stemboroski L, Cai Q, Simpson NE, Nayak S, Tan M, et al. Glucose...4664. Published OnlineFirst September 11, 2015.Cancer Res Nicholas C. D’Amato, Thomas J. Rogers, Michael A. Gordon, et al. Metastasis in Triple

MiR-34b is associated with clinical outcome in triple-negative breast cancer patients

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Svoboda Marek

2012-03-01

Full Text Available Abstract Background Breast cancer is the most common malignancy with the highest incidence rates among women worldwide. Triple-negative breast cancer (TNBC represents the major phenotype of basal-like molecular subtype of breast cancer, characterized by higher incidence in young women and a very poor prognosis. MicroRNAs (miRNAs are small non-coding RNAs playing significant role in the pathogenesis of many cancers including breast cancer. Therefore, miRNAs are also potential prognostic and/or predictive biomarkers in triple-negative breast cancer patients. Methods Thirty-nine TNBC patients with available formalin-fixed paraffin-embedded (FFPE tissues were enrolled in the study. MiR-34a, miR-34b, and miR-34c were analyzed using qRT-PCR and correlated to clinico-pathological features of TNBC patients. Results Expression levels of miR-34b significantly correlate with disease free survival (DFS (p = 0.0020, log-rank test and overall survival (OS (p = 0.0008, log-rank test of TNBC patients. No other significant associations between miR-34a, miR-34b, and miR-34c with available clinical pathological data were observed. Conclusions MiR-34b expression negatively correlates with disease free survival and overall survival in TNBC patients. Thus, miR-34b may present a new promising prognostic biomarker in TNBC patients, but independent validations are necessary.

Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle

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Zhang, Li; Varma, Nadimpalli RS; Gang, Zhang Z.; Ewing, James R.; Arbab, Ali S; Ali, Meser M

2016-01-01

There is no available targeted therapy or imaging agent for triple negative breast cancer (TNBC). We developed a small-sized dendrimer-based nanoparticle containing a clinical relevant MRI contrast agent, GdDOTA and a NIR fluorescent dye, DL680. Systemic delivery of dual-modal nanoparticles led to accumulation of the agents in a flank mouse model of TNBC that were detected by both optical and MR imaging. In-vivo fluorescence images, as well as ex-vivo fluorescence images of individual organs, demonstrated that nanoparticles accumulated into tumor selectively. A dual modal strategy resulted in a selective delivery of a small-sized (GdDOTA)42-G4-DL680 dendrimeric agent to TNBC tumors, avoiding other major organs. PMID:28018751

Next generation sequencing of Cytokeratin 20-negative Merkel cell carcinoma reveals ultraviolet-signature mutations and recurrent TP53 and RB1 inactivation.

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Harms, Paul W; Collie, Angela M B; Hovelson, Daniel H; Cani, Andi K; Verhaegen, Monique E; Patel, Rajiv M; Fullen, Douglas R; Omata, Kei; Dlugosz, Andrzej A; Tomlins, Scott A; Billings, Steven D

2016-03-01

Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin 20 (CK20) is expressed in ~95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small-cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20-negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus-independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (10 Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer-relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high-confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping genetic changes

Next Generation Sequencing of Cytokeratin 20-Negative Merkel Cell Carcinoma Reveals Ultraviolet Signature Mutations and Recurrent TP53 and RB1 Inactivation

Science.gov (United States)

Harms, Paul W.; Collie, Angela M. B.; Hovelson, Daniel H.; Cani, Andi K.; Verhaegen, Monique E.; Patel, Rajiv M.; Fullen, Douglas R.; Omata, Kei; Dlugosz, Andrzej A.; Tomlins, Scott A.; Billings, Steven D.

2016-01-01

Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin-20 (CK20) is expressed in approximately 95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20-negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus-independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (ten Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer-relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%)) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping

Cadmium promotes the proliferation of triple-negative breast cancer cells through EGFR-mediated cell cycle regulation

International Nuclear Information System (INIS)

Wei, Zhengxi; Song, Xiulong; Shaikh, Zahir A.

2015-01-01

Cadmium (Cd) is a carcinogenic metal which is implicated in breast cancer by epidemiological studies. It is reported to promote breast cancer cell growth in vitro through membrane receptors. The study described here examined Cd-mediated growth of non-metastatic human breast cancer derived cells that lack receptors for estrogen, progesterone, and HER2. Treatment of triple-negative HCC 1937 cells with 0.1–0.5 μM Cd increased cell growth by activation of AKT and ERK. Accelerated cell cycle progression was achieved by increasing the levels of cyclins A, B, and E, as well as those of CDKs 1 and 2. Although triple negative cells lack estrogen receptor, they express high levels of EGFR. Therefore, further studies on HCC 1937 and another triple-negative cell line, HCC 38, were conducted using specific siRNA and an inhibitor of EGFR to determine whether EGFR was responsible for mediating the effect of Cd. The results revealed that in both cell types EGFR was not only activated upon Cd treatment, but was also essential for the downstream activation of AKT and ERK. Based on these observations, it is concluded that, in breast cancer cells lacking estrogen receptor, sub-micromolar concentration of Cd can promote cell proliferation. Furthermore, that EGFR plays a critical role in this process. - Highlights: • Sub-micromolar concentrations of Cd promote cell growth in breast cancer cells that lack ER, PR, and HER2. • The increase in cell number is not due to reduction in apoptosis. • Growth promotion involves AKT and ERK signaling and downstream stimulation of cell cycle progression. • Initiation of cell growth by Cd occurs at the cell membrane and requires the activation of EGFR.

A case report of locally advanced triple negative breast cancer showing pathological complete response to weekly paclitaxel with bevacizumab treatment following disease progression during anthracycline-based neoadjuvant chemotherapy

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Hideo Shigematsu

2017-01-01

Conclusions: Although the addition of bevacizumab to standard adjuvant chemotherapy is not recommended in unselected triple negative breast cancer, the potent effect on tumor shrinkage should be considered in the treatment of locally advanced triple negative breast cancer showing disease progression during standard NAC.

Quantum-Dot-Based Theranostic Micelles Conjugated with an Anti-EGFR Nanobody for Triple-Negative Breast Cancer Therapy.

Science.gov (United States)

Wang, Yuyuan; Wang, Yidan; Chen, Guojun; Li, Yitong; Xu, Wei; Gong, Shaoqin

2017-09-13

A quantum-dot (QD)-based micelle conjugated with an anti-epidermal growth factor receptor (EGFR) nanobody (Nb) and loaded with an anticancer drug, aminoflavone (AF), has been engineered for EGFR-overexpressing cancer theranostics. The near-infrared (NIR) fluorescence of the indium phosphate core/zinc sulfide shell QDs (InP/ZnS QDs) allowed for in vivo nanoparticle biodistribution studies. The anti-EGFR nanobody 7D12 conjugation improved the cellular uptake and cytotoxicity of the QD-based micelles in EGFR-overexpressing MDA-MB-468 triple-negative breast cancer (TNBC) cells. In comparison with the AF-encapsulated nontargeted (i.e., without Nb conjugation) micelles, the AF-encapsulated Nb-conjugated (i.e., targeted) micelles accumulated in tumors at higher concentrations, leading to more effective tumor regression in an orthotopic triple-negative breast cancer xenograft mouse model. Furthermore, there was no systemic toxicity observed with the treatments. Thus, this QD-based Nb-conjugated micelle may serve as an effective theranostic nanoplatform for EGFR-overexpressing cancers such as TNBCs.

Distinct microbiological signatures associated with triple negative breast cancer.

Science.gov (United States)

Banerjee, Sagarika; Wei, Zhi; Tan, Fei; Peck, Kristen N; Shih, Natalie; Feldman, Michael; Rebbeck, Timothy R; Alwine, James C; Robertson, Erle S

2015-10-15

Infectious agents are the third highest human cancer risk factor and may have a greater role in the origin and/or progression of cancers, and related pathogenesis. Thus, knowing the specific viruses and microbial agents associated with a cancer type may provide insights into cause, diagnosis and treatment. We utilized a pan-pathogen array technology to identify the microbial signatures associated with triple negative breast cancer (TNBC). This technology detects low copy number and fragmented genomes extracted from formalin-fixed paraffin embedded archival tissues. The results, validated by PCR and sequencing, define a microbial signature present in TNBC tissue which was underrepresented in normal tissue. Hierarchical clustering analysis displayed two broad microbial signatures, one prevalent in bacteria and parasites and one prevalent in viruses. These signatures demonstrate a new paradigm in our understanding of the link between microorganisms and cancer, as causative or commensal in the tumor microenvironment and provide new diagnostic potential.

LOXL4 knockdown enhances tumor growth and lung metastasis through collagen-dependent extracellular matrix changes in triple-negative breast cancer.

Science.gov (United States)

Choi, Sul Ki; Kim, Hoe Suk; Jin, Tiefeng; Moon, Woo Kyung

2017-02-14

Lysyl oxidase (LOX) family genes catalyze collagen cross-link formation. To determine the effects of lysyl oxidase-like 4 (LOXL4) expression on breast tumor formation and metastasis, we evaluated primary tumor growth and lung metastasis in mice injected with LOXL4-knockdown MDA-MB-231 triple-negative human breast cancer cells. In addition, we analyzed overall survival in breast cancer patients based on LOXL4 expression using a public online database. In the mouse xenograft model, LOXL4 knockdown increased primary tumor growth and lung colonization as well as collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging revealed that LOXL4 knockdown resulted in the thickening of collagen bundles within tumors. In addition, weak LOXL4 expression was associated with poor overall survival in breast cancer patients from the BreastMark dataset, and this association was strongest in triple-negative breast cancer patients. These results demonstrate that weak LOXL4 expression leads to remodeling of the extracellular matrix through induction of collagen synthesis, deposition, and structural changes. These alterations in turn promote tumor growth and metastasis and are associated with poor clinical outcomes in triple-negative breast cancer.

Clinical and pathological factors influencing survival in a large cohort of triple-negative breast cancer patients.

Science.gov (United States)

Urru, Silvana Anna Maria; Gallus, Silvano; Bosetti, Cristina; Moi, Tiziana; Medda, Ricardo; Sollai, Elisabetta; Murgia, Alma; Sanges, Francesca; Pira, Giovanna; Manca, Alessandra; Palmas, Dolores; Floris, Matteo; Asunis, Anna Maria; Atzori, Francesco; Carru, Ciriaco; D'Incalci, Maurizio; Ghiani, Massimo; Marras, Vincenzo; Onnis, Daniela; Santona, Maria Cristina; Sarobba, Giuseppina; Valle, Enrichetta; Canu, Luisa; Cossu, Sergio; Bulfone, Alessandro; Rocca, Paolo Cossu; De Miglio, Maria Rosaria; Orrù, Sandra

2018-01-08

To provide further information on the clinical and pathological prognostic factors in triple-negative breast cancer (TNBC), for which limited and inconsistent data are available. Pathological characteristics and clinical records of 841 TNBCs diagnosed between 1994 and 2015 in four major oncologic centers from Sardinia, Italy, were reviewed. Multivariate hazard ratios (HRs) for mortality and recurrence according to various clinicopathological factors were estimated using Cox proportional hazards models. After a mean follow-up of 4.3 years, 275 (33.3%) TNBC patients had a progression of the disease and 170 (20.2%) died. After allowance for study center, age at diagnosis, and various clinicopathological factors, all components of the TNM staging system were identified as significant independent prognostic factors for TNBC mortality. The HRs were 3.13, 9.65, and 29.0, for stage II, III and IV, respectively, vs stage I. Necrosis and Ki-67 > 16% were also associated with increased mortality (HR: 1.61 and 1.99, respectively). Patients with tumor histotypes other than ductal invasive/lobular carcinomas had a more favorable prognosis (HR: 0.40 vs ductal invasive carcinoma). No significant associations with mortality were found for histologic grade, tumor infiltrating lymphocytes, and lymphovascular invasion. Among lymph node positive TNBCs, lymph node ratio appeared to be a stronger predictor of mortality than pathological lymph nodes stage (HR: 0.80 for pN3 vs pN1, and 3.05 for >0.65 vs <0.21 lymph node ratio), respectively. Consistent results were observed for cancer recurrence, except for Ki-67 and necrosis that were not found to be significant predictors for recurrence. This uniquely large study of TNBC patients provides further evidence that, besides tumor stage at diagnosis, lymph node ratio among lymph node positive tumors is an additional relevant predictor of survival and tumor recurrence, while Ki-67 seems to be predictive of mortality, but not of recurrence.

19p13.1 is a triple-negative-specific breast cancer susceptibility locus

DEFF Research Database (Denmark)

Stevens, Kristen N; Fredericksen, Zachary; Vachon, Celine M

2012-01-01

(PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly......The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor...... associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER...

Neoadjuvant treatments in triple-negative breast cancer patients: where we are now and where we are going

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Omarini C

2018-01-01

Full Text Available Claudia Omarini, Giorgia Guaitoli, Stefania Pipitone, Luca Moscetti, Laura Cortesi, Stefano Cascinu, Federico Piacentini Department of Medical and Surgical Sciences for Children & Adults, Division of Medical Oncology, University Hospital of Modena, Modena, Italy Abstract: Triple-negative breast cancer (TNBC remains the poorest-prognosis breast cancer (BC subtype. Gene expression profiling has identified at least six different triple-negative subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN tumors may justify the difficulty in treating this BC subtype. Several targeted agents have been investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic treatment is an effective option of care. The achievement of a pathological complete response represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitivity. In this review, we provide a brief description of the main predictive biomarkers for tumor response to systemic treatment. Moreover, we review the treatment strategies investigated for TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC patients may be treated on the basis of tumor molecular profile. Keywords: triple-negative breast cancer, neoadjuvant chemotherapy, BRCA, platinum, immunotherapy, PARP-1 inhibitors

Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer

International Nuclear Information System (INIS)

Sánchez-Muñoz, Alfonso; Gallego, Elena; Luque, Vanessa de; Pérez-Rivas, Luís G; Vicioso, Luís; Ribelles, Nuria; Lozano, José; Alba, Emilio

2010-01-01

Mutational analysis of the KRAS gene has recently been established as a complementary in vitro diagnostic tool for the identification of patients with colorectal cancer who will not benefit from anti-epidermal growth factor receptor (EGFR) therapies. Assessment of the mutation status of KRAS might also be of potential relevance in other EGFR-overexpressing tumors, such as those occurring in breast cancer. Although KRAS is mutated in only a minor fraction of breast tumors (5%), about 60% of the basal-like subtype express EGFR and, therefore could be targeted by EGFR inhibitors. We aimed to study the mutation frequency of KRAS in that subtype of breast tumors to provide a molecular basis for the evaluation of anti-EGFR therapies. Total, genomic DNA was obtained from a group of 35 formalin-fixed paraffin-embedded, triple-negative breast tumor samples. Among these, 77.1% (27/35) were defined as basal-like by immunostaining specific for the established surrogate markers cytokeratin (CK) 5/6 and/or EGFR. KRAS mutational status was determined in the purified DNA samples by Real Time (RT)-PCR using primers specific for the detection of wild-type KRAS or the following seven oncogenic somatic mutations: Gly12Ala, Gly12Asp, Gly12Arg, Gly12Cys, Gly12Ser, Gly12Val and Gly13Asp. We found no evidence of KRAS oncogenic mutations in all analyzed tumors. This study indicates that KRAS mutations are very infrequent in triple-negative breast tumors and that EGFR inhibitors may be of potential benefit in the treatment of basal-like breast tumors, which overexpress EGFR in about 60% of all cases

Pathologic response after neoadjuvant chemotherapy predicts locoregional control in patients with triple negative breast cancer

OpenAIRE

Chen, Victor E.; Gillespie, Erin F.; Zakeri, Kaveh; Murphy, James D.; Yashar, Catheryn M.; Lu, Sharon; Einck, John P.

2017-01-01

Purpose: Our goal was to determine the impact of pathologic response after neoadjuvant chemotherapy in triple negative breast cancer (TNBC) on the subsequent risk of locoregional recurrence (LRR) and disease-free survival (DFS) in the setting of adjuvant radiation therapy. Methods and materials: This was an institutional review board–approved retrospective chart review of patients with clinical stage I-III breast cancer treated with neoadjuvant chemotherapy, local surgery (breast conservat...

Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

Science.gov (United States)

Beg, Shaham; Siraj, Abdul K; Prabhakaran, Sarita; Jehan, Zeenath; Ajarim, Dahish; Al-Dayel, Fouad; Tulbah, Asma; Al-Kuraya, Khawla S

2015-06-01

PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.

Genomic profile of a patient with triple negative essential thrombocythemia, unresponsive to therapy: A case report and literature review

Directory of Open Access Journals (Sweden)

Uzma Zaidi

2017-07-01

Full Text Available Clonal analysis of patients with triple negative myeloproliferative neoplasm (MPN has provided evidence of additional aberrations, including epigenetic alterations. To discover such novel genetic aberrations, patients were screened through next-generation sequencing using a myeloid sequencing panel of 54 genes using a genetic analyser. Genetic variants in 28 genes, including TET2, BCOR, BCR, and ABL1 were identified in a triple negative essential thrombocythemia (ET patient. The individual role of some of these variants in disease pathogenesis has yet to be studied. Somatic mutations in the same genes have been reported with variable frequencies in myeloid malignancies. However, no pathogenic impact of these variants could be found; therefore, long-term follow up of patients with genetic analysis of a large cohort and the use of whole genome sequencing is required to assess the effects of these variants.

Correlation of primary tumor FDG uptake with clinicopathologic prognostic factors in invasive ductal carcinoma of the breast

International Nuclear Information System (INIS)

Jo, I; Kim, Sung Hoon; Kim, Hae Won; Kang, Sung Hee; Zeon, Seok Kil; Kim, Su Jin

2015-01-01

The purpose of this study was to investigate the correlation of primary tumor FDG uptake to clinicopathological prognostic factors in invasive ductal carcinoma of the breast. We retrospectively reviewed 136 of 215 female patients with pathologically proven invasive ductal breast cancer from January 2008 to December 2011 who underwent F-18 FDG PET/CT for initial staging and follow-up after curative treatment with analysis of estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (HER2). The maximum standardized uptake value (SUV max ) of the primary breast tumor was measured and compared with hormonal receptor and HER2 overexpression status. The high SUV max of primary breast tumors is significantly correlated with the clinicopathological factors: tumor size, histologic grade, TNM stage, negativity of ER, negativity of PR, HER2 overexpression and triple negativity. The recurrent group with non-triple negative cancer had a higher SUV max compared with the non-recurrent group, though no significant difference in FDG uptake was noted between the recurrence and non-recurrent groups in subjects with triple-negative cancer. Lymph node involvement was the independent risk factor for cancer recurrence in the multivariate analysis. In conclusion, high FDG uptake in primary breast tumors is significantly correlated with clinicopathological factors, such as tumor size, histologic grade, TNM stage, negativity of the hormonal receptor, HER2 overexpression and triple negativity. Therefore, FDG PET/CT is a helpful prognostic tool to direct the further management of patients with breast cancer

Male occult triple-negative breast cancer with dermatomyositis: a case report and review of the literature

Directory of Open Access Journals (Sweden)

Zhang L

2017-11-01

Full Text Available Le Zhang,1 Chenghua Zhang,2 Zhaoying Yang,1 Miao He,3 Lijuan Zhang,1 Shereen Ezzat,4 Xi Liang5 1Department of Breast Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China; 2Endoscopy Department, Jilin Cancer Hospital, Changchun, Jilin,China; 3Department of Anesthesia, The Second Hospital of Jilin University, Changchun, Jilin, China; 4Ontario Cancer Institute and The Endocrine Oncology Site Group, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; 5Department of Breast Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China Abstract: Occult breast cancer is defined by the presence of axillary metastases without an identifiable primary breast tumor. Here, we report a rare case of a male occult breast cancer with dermatomyositis. We performed a modified radical mastectomy consisting of whole breast mastectomy and axillary lymph node dissection. Immunohistochemistry and fluorescent in situ hybridization analyses demonstrated an adenocarcinoma likely of breast origin, which was an occult triple-negative breast cancer. Interestingly, the patient’s previously noted periorbital dermatomyositis resolved promptly following surgical excision. Keywords: male breast cancer, occult breast cancer, triple-negative breast cancer, dermato­myositis 

Prediction of breast cancer recurrence using lymph node metabolic and volumetric parameters from {sup 18}F-FDG PET/CT in operable triple-negative breast cancer

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Kim, Yong-il [CHA University, Department of Nuclear Medicine, CHA Bundang Medical Center, Seongnam (Korea, Republic of); Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kim, Yong Joong [Veterans Health Service Medical Center, Seoul (Korea, Republic of); Paeng, Jin Chul; Cheon, Gi Jeong; Lee, Dong Soo [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Chung, June-Key [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Kang, Keon Wook [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Biomedical Sciences, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of)

2017-10-15

Triple-negative breast cancer has a poor prognosis. We evaluated several metabolic and volumetric parameters from preoperative {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the prognosis of triple-negative breast cancer and compared them with current clinicopathologic parameters. A total of 228 patients with triple-negative breast cancer (mean age 47.0 ± 10.8 years, all women) who had undergone preoperative PET/CT were included. The PET/CT metabolic parameters evaluated included maximum, peak, and mean standardized uptake values (SUVmax, SUVpeak, and SUVmean, respectively). The volumetric parameters evaluated included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Metabolic and volumetric parameters were evaluated separately for tumor (T) and lymph nodes (N). The prognostic value of these parameters was compared with that of clinicopathologic parameters. All lymph node metabolic and volumetric parameters showed significant differences between patients with and without recurrence. However, tumor metabolic and volumetric parameters showed no significant differences. In a univariate survival analysis, all lymph node metabolic and volumetric parameters (SUVmax-N, SUVpeak-N, SUVmean-N, MTV-N, and TLG-N; all P < 0.001), T stage (P = 0.010), N stage (P < 0.001), and TNM stage (P < 0.001) were significant parameters. In a multivariate survival analysis, SUVmax-N (P = 0.005), MTV (P = 0.008), and TLG (P = 0.006) with TNM stage (all P < 0.001) were significant parameters. Lymph node metabolic and volumetric parameters were significant predictors of recurrence in patients with triple-negative breast cancer after surgery. Lymph node metabolic and volumetric parameters were useful parameters for evaluating prognosis in patients with triple-negative breast cancer by {sup 18}F-FDG PET/CT, rather than tumor parameters. (orig.)

Age-Related Frequency of Triple Negative Breast Cancer in Women

International Nuclear Information System (INIS)

Sajid, M. T.; Ahmad, M.; Mustafa, Q.; Shukr, I.; Azhar, M.

2014-01-01

Objective: To determine frequency of triple negative breast cancer (TNBC) in Pakistani women with respect to age. Study Design: Observational study. Place and Duration of Study: Armed Forces Institute of Pathology (AFIP), Rawalpindi, from July 2005 to July 2010. Methodology: Pathological records of all specimens of breast cancer were reviewed and data was obtained for estrogen receptor (ER), progesterone receptor (PR) and HER-2 neu receptor proteins. Specimens having complete record of all three proteins were included for analysis. TNBC was defined as those who were ER, PR and HER-2 neu negative. Overall frequency as well as frequency with respect to age was calculated. Descriptive and categorical variables were analyzed using SPSS version 17. Results: Eight hundred and fifteen patients out of 4715 (17.28%) were found to be TNBC. Mean age of diagnosis of TNBC was found to be 46.26 A +- 12.22 years of age while other breast cancers had a mean age 52.90 A +- 9.78 years (p 50 years while majority of patients with other breast cancers were elderly females (p < 0.001). Conclusion: TNBC comprised 17.28% of the breast cancers in Pakistani women diagnosed at the studied centre. A higher frequency of TNBC was noted in significantly younger patients. (author)

Prevalence of papillomaviruses, polyomaviruses, and herpesviruses in triple-negative and inflammatory breast tumors from algeria compared with other types of breast cancer tumors.

Directory of Open Access Journals (Sweden)

Marilys Corbex

Full Text Available The possible role of viruses in breast cancer etiology remains an unresolved question. We hypothesized that if some viruses are involved, it may be in a subgroup of breast cancers only. Epidemiological arguments drove our interest in breast cancer subgroups that are more frequent in Africa, namely inflammatory breast cancer (IBC and triple-negative breast cancer. We tested whether viral prevalence was significantly higher in these subgroups.One hundred fifty-five paraffin-embedded malignant breast tumors were randomly selected at the pathology laboratory of the University Hospital of Annaba (Algeria to include one third of IBC and two thirds of non-IBC. They were tested for the presence of DNA from 61 viral agents (46 human papillomaviruses, 10 polyomaviruses, and 5 herpesviruses using type-specific multiplex genotyping assays, which combine multiplex PCR and bead-based Luminex technology.Viral DNA was found in 22 (17.9% of 123 tumors. The most prevalent viruses were EBV1 and HPV16. IBC tumors carried significantly more viruses (any type than non-IBC tumors (30% vs. 13%, p<0.04. Similarly, triple-negative tumors displayed higher virus-positivity than non-triple-negative tumors (44% vs. 14%, p<0.009.Our results suggest an association between the presence of viral DNA and aggressive breast cancer phenotypes (IBC, triple-negative. While preliminary, they underline the importance of focusing on subgroups when studying viral etiology in breast cancer. Further studies on viruses in breast cancer should be conducted in much larger samples to confirm these initial findings.

Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

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Ye J

2016-08-01

Full Text Available Jun Ye,1,2 Xuejun Xia,1,2 Wujun Dong,1,2 Huazhen Hao,1,2 Luhua Meng,1,2 Yanfang Yang,1,2 Renyun Wang,1,2 Yuanfeng Lyu,3 Yuling Liu1,2 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, 2Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 3School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: There is no effective clinical therapy for triple-negative breast cancers (TNBCs, which have high low-density lipoprotein (LDL requirements and express relatively high levels of LDL receptors (LDLRs on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel–cholesterol complex (PTX-CH Emul was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231 and non-TNBC (MCF7 cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native

Combined calcitriol and menadione reduces experimental murine triple negative breast tumor.

Science.gov (United States)

Bohl, Luciana; Guizzardi, Solange; Rodríguez, Valeria; Hinrichsen, Lucila; Rozados, Viviana; Cremonezzi, David; Tolosa de Talamoni, Nori; Picotto, Gabriela

2017-10-01

Calcitriol (D) or 1,25(OH) 2 D 3 inhibits the growth of several tumor cells including breast cancer cells, by activating cell death pathways. Menadione (MEN), a glutathione-depleting compound, may be used to potentiate the antiproliferative actions of D on cancer cells. We have previously shown in vitro that MEN improved D-induced growth arrest on breast cancer cell lines, inducing oxidative stress and DNA damage via ROS generation. Treatment with MEN+D resulted more effective than D or MEN alone. To study the in vivo effect of calcitriol, MEN or their combination on the development of murine transplantable triple negative breast tumor M-406 in its syngeneic host. Tumor M-406 was inoculated s.c., and when tumors reached the desired size, animals were randomly assigned to one of four groups receiving daily i.p. injections of either sterile saline solution (controls, C), MEN, D, or both (MEN+D). Body weight and tumor volume were recorded three times a week. Serum calcium was determined before and at the end of the treatment, at which time tumor samples were obtained for histological examination. None of the drugs, alone or in combination, affected mice body weight in the period studied. The combined treatment reduced tumor growth rate (C vs. MEN+D, P<0.05) and the corresponding histological sections exhibited small remaining areas of viable tumor only in the periphery. A concomitant DNA fragmentation was observed in all treated groups and MEN potentiated the calcitriol effect on tumor growth. As previously observed in vitro, treatment with MEN and D delayed tumor growth in vivo more efficiently than the individual drugs, with evident signals of apoptosis induction. Our results propose an alternative protocol to treat triple negative breast cancer, using GSH depleting drugs together with calcitriol, which would allow lower doses of the steroid to maintain the antitumor effect while diminishing its adverse pharmacological effects. Copyright © 2017. Published by

(-)-Epigallocatechin 3-Gallate Synthetic Analogues Inhibit Fatty Acid Synthase and Show Anticancer Activity in Triple Negative Breast Cancer.

Science.gov (United States)

Crous-Masó, Joan; Palomeras, Sònia; Relat, Joana; Camó, Cristina; Martínez-Garza, Úrsula; Planas, Marta; Feliu, Lidia; Puig, Teresa

2018-05-11

(-)-Epigallocatechin 3-gallate (EGCG) is a natural polyphenol from green tea with reported anticancer activity and capacity to inhibit the lipogenic enzyme fatty acid synthase (FASN), which is overexpressed in several human carcinomas. To improve the pharmacological profile of EGCG, we previously developed a family of EGCG derivatives and the lead compounds G28, G37 and G56 were characterized in HER2-positive breast cancer cells overexpressing FASN. Here, diesters G28, G37 and G56 and two G28 derivatives, monoesters M1 and M2, were synthesized and assessed in vitro for their cytotoxic, FASN inhibition and apoptotic activities in MDA-MB-231 triple-negative breast cancer (TNBC) cells. All compounds displayed moderate to high cytotoxicity and significantly blocked FASN activity, monoesters M1 and M2 being more potent inhibitors than diesters. Interestingly, G28, M1, and M2 also diminished FASN protein expression levels, but only monoesters M1 and M2 induced apoptosis. Our results indicate that FASN inhibition by such polyphenolic compounds could be a new strategy in TNBC treatment, and highlight the potential anticancer activities of monoesters. Thus, G28, G37, G56, and most importantly M1 and M2, are anticancer candidates (alone or in combination) to be further characterized in vitro and in vivo.

Triple-negative breast cancer with brain metastases: a comparison between basal-like and non-basal-like biological subtypes

NARCIS (Netherlands)

A. Niwińska (Anna); W. Olszewski (Wojciech); M. Murawska (Magdalena); K. Pogoda (Katarzyna)

2011-01-01

textabstractThe aim of this study was to divide the group of triple-negative breast cancer patients with brain metastases into basal-like and non-basal-like biological subtypes in order to compare clinical features and survival rates in those two groups. A comprehensive analysis of 111 consecutive

Survival and local control rates of triple-negative breast cancer patients treated with boost-IOERT during breast-conserving surgery

Energy Technology Data Exchange (ETDEWEB)

Fastner, Gerd; Zehentmayr, Franz; Kopp, Peter; Fussl, Christoph; Sedlmayer, Felix [Landeskrankenhaus, Paracelsus Medical University, Department of Radiotherapy and Radio-Oncology, Salzburg (Austria); Hauser-Kronberger, Cornelia [Landeskrankenhaus, Paracelsus Medical University, Department of Pathology, Salzburg (Austria); Moder, Angelika [Landeskrankenhaus, Paracelsus Medical University, Institute of Inborn Errors in Metabolism, Salzburg (Austria); Reitsamer, Roland; Fischer, Thorsten [Landeskrankenhaus, Paracelsus Medical University, Department of Special Gynecology, Salzburg (Austria); Landeskrankenhaus, Paracelsus Medical University, Department of Gynecology, Salzburg (Austria); Deutschmann, Heinrich [Landeskrankenhaus, Paracelsus Medical University, Department of Radiotherapy and Radio-Oncology, Salzburg (Austria); Paracelsus Medical University, Institute for Research and Development of Advanced Radiation Technologies (radART), Salzburg (Austria)

2016-01-15

The purpose of this work was to retrospectively evaluate survival and local control rates of triple-negative breast cancer subtypes classified as five marker negative (5NP) and core basal (CB), respectively, after breast-conserving surgery and intraoperative boost radiotherapy with electrons (IOERT) followed by whole breast irradiation. A total of 71 patients with triple-negative breast cancer were enrolled, who were treated with lumpectomy, axillary lymph node dissection, and IOERT with 9.6 Gy (median D{sub max}) followed by normofractionated whole breast irradiation to median total doses of 54 Gy. Chemotherapy was applied in a neoadjuvant (12 %), adjuvant (75 %), or combinational setting (7 %). After a median follow-up of 97 months (range 4-170 months), 5 in-breast recurrences were detected (7.0 %). For all patients, 8-year actuarial rates for local control, metastases-free survival, disease-specific survival, and overall survival amounted to 89, 75, 80, and 69 %, respectively. All local recurrences occurred in grade 3 (G3) tumors irrespective of their specific immunohistochemical phenotype; thus, the local control rate for grades 1/2 (G1/2) was 100 % for both 5NP and CB, while for G3 it was 88 % for 5NP and 90 % for CB (p = 0.65 and 0.82, respectively, n.s.). For disease-specific survival, only the difference of the best-prognosis group 5-NP/G3 vs. the worst-prognosis cohort CB/G1/2 was statistically significant: 90 % vs. 54 % (p = 0.03). Boost-IOERT provides acceptable long-term in-breast control in triple negative breast cancer. The best subgroup in terms of disease-specific survival was represented by 5NP in combination with tumor grading G3. (orig.) [German] Ziel der Studie war es, im Rahmen einer retrospektiven Analyse Ueberlebens- und Lokalkontrollraten bei triple-negativen Mammakarzinomen zu untersuchen. Die Tumoren waren in 5NP(5-Marker-negative)- und CB(core basal)-Subtypen klassifiziert und die Patientinnen hatten nach brusterhaltender Operation und

Pretreatment Hematocrit Is Superior to Hemoglobin as a Prognostic Factor for Triple Negative Breast Cancer.

Science.gov (United States)

Chen, Bo; Dai, Danian; Tang, Hailin; Ai, Xiaohong; Chen, Xi; Zhang, Xiaoyan; Li, Zhiyan; Xie, Xiaoming

2016-01-01

Anemia usually refers to low hemoglobin (Hb) levels. Previous studies indicated that anemia negatively influence the survival in various cancers. Hematocrit (HCT) is the volume percentage of red blood cells in blood, which could indicate anemia in both individuals and populations. This study compared the value of HCT with that of Hb for predicting outcomes of patients who underwent treatment for triple negative breast cancer (TNBC). A retrospective study of 293 triple negative breast cancer patients, accepting treatment from January 2004 to December 2009 at Sun Yat-sen University Cancer Center, was conducted. Kaplan-Meier curves and multivariate Cox proportional models were used to calculate disease free survival (DFS) and overall survival (OS). The cut-off value of HCT was 35.9% determined by X-tile software analysis. The cut-off value of Hb was 12.0 g/dl based on the World Health Organization (WHO) criteria. In univariate analysis, low HCT and low Hb were both significantly associated with decreased DFS and OS. In multivariate analysis, HCT (HR: 0.570; 95% CI: 0.331-0.981, P = 0.042 for DFS; HR: 0.456; 95% CI: 0.256-0.813, P = 0.008 for OS) was still identified as independent predictor of outcome, but not Hb. Pretreatment low HCT is independently associated with poor prognosis in TNBC patients. However, HCT was found to be superior to Hb in terms of predicting breast cancer mortality. In the future, large-scale prospective studies or validation studies are needed to verify our findings.

Chasing down the triple-negative myeloproliferative neoplasms: Implications for molecular diagnostics.

Science.gov (United States)

Langabeer, Stephen E

2016-01-01

The majority of patients with classical myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia, and primary myelofibrosis harbor distinct disease-driving mutations within the JAK2 , CALR , or MPL genes. The term triple-negative has been recently applied to those MPN without evidence of these consistent mutations, prompting whole or targeted exome sequencing approaches to determine the driver mutational status of this subgroup. These strategies have identified numerous novel mutations that occur in alternative exons of both JAK2 and MPL , the majority of which result in functional activation. Current molecular diagnostic approaches may possess insufficient coverage to detect these alternative mutations, prompting further consideration of targeted exon sequencing into routine diagnostic practice. How to incorporate these illuminating findings into the expanding molecular diagnostic algorithm for MPN requires continual attention.

Evidence for the Existence of Triple-Negative Variants in the MCF-7 Breast Cancer Cell Population

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Euphemia Leung

2014-01-01

Full Text Available The MCF-7 line, derived in 1973 from a malignant pleural effusion, is one of the most commonly used culture models for human breast cancer. Despite its long history, MCF-7 is a surprisingly heterogeneous line. We previously showed that if MCF-7 cells were cultured for a prolonged period either in the absence of estrogen or in the presence of the antiestrogen tamoxifen, sub-lines were selected that differed from the parental line in ploidy, mean cell volume, signaling pathway usage, and drug sensitivity. This suggests a process of selection of preexisting variants rather than of adaptation of the parental line. All the sublines were estrogen receptor (ER positive, raising the question of whether MCF-7 also contains ER negative variants. Here, we have looked for such variants by culturing for a prolonged period in the presence of fulvestrant, an estrogen antagonist that has no estrogen agonist activity. Three sublines were developed, each of which was ER negative, progesterone receptor (PR negative and expressed only a low level of HER2. Each of the variants differed from the original MCF-7 line in ploidy, modal cell volume, and signaling pathway usage. Control experiments in which cells were cultured for a prolonged period in the absence of estrogen selected for variants that were ER and PR positive. The properties of the triple-negative MCF-7 were compared with those of an existing triple-negative cell line, MDA-MB-231, and human epidermal growth factor receptor 2 (HER2+ SKBr3, as well as from those of the “immortalized” breast epithelial line MCF10A. The results suggest that new variants or phenotypes of MCF-7 might be generated continuously in culture, and by implication this might apply to breast cancer development and even normal breast epithelial development in vivo.

Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.

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Paolo Cossu-Rocca

Full Text Available Triple Negative Breast Cancer (TNBC accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data.PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components.PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC.Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.

Science.gov (United States)

Cossu-Rocca, Paolo; Orrù, Sandra; Muroni, Maria Rosaria; Sanges, Francesca; Sotgiu, Giovanni; Ena, Sara; Pira, Giovanna; Murgia, Luciano; Manca, Alessandra; Uras, Maria Gabriela; Sarobba, Maria Giuseppina; Urru, Silvana; De Miglio, Maria Rosaria

2015-01-01

Triple Negative Breast Cancer (TNBC) accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data. PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components. PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC. Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

Metabolic Syndrome and Triple-Negative Breast Cancer: A New Paradigm

International Nuclear Information System (INIS)

Davis, A.A.; Kaklamani, V.G.

2012-01-01

Triple-negative breast cancers (TNBCs) are aggressive tumors with poor prognosis compared to other breast cancer subtypes. The evidence linking TNBC with the metabolic syndrome, which consists of central obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, has emerged from clinical studies and experiments using cell lines and mouse models. Epidemiological studies have associated abdominal obesity with increased incidence of TNBC. Additionally, insulin resistance, dyslipidemia, and hypertension are associated with increased incidence of breast cancer across all subtypes. The insulin-leptin-adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis. Specifically, increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation, survival, cell-cycle regulation, and angio genesis. Insulin, insulin-like growth factor I (IGF-I), and epidermal growth factor receptor (EGFR) may mediate interactions between these two hormones. Further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin-leptin-adiponectin axis for TNBC

Metabolic Syndrome and Triple-Negative Breast Cancer: A New Paradigm

Energy Technology Data Exchange (ETDEWEB)

Davis, A A; Kaklamani, V G [Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 (Ukraine)

2012-07-01

Triple-negative breast cancers (TNBCs) are aggressive tumors with poor prognosis compared to other breast cancer subtypes. The evidence linking TNBC with the metabolic syndrome, which consists of central obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, has emerged from clinical studies and experiments using cell lines and mouse models. Epidemiological studies have associated abdominal obesity with increased incidence of TNBC. Additionally, insulin resistance, dyslipidemia, and hypertension are associated with increased incidence of breast cancer across all subtypes. The insulin-leptin-adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis. Specifically, increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation, survival, cell-cycle regulation, and angio genesis. Insulin, insulin-like growth factor I (IGF-I), and epidermal growth factor receptor (EGFR) may mediate interactions between these two hormones. Further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin-leptin-adiponectin axis for TNBC

Tumor-initiating CD49f cells are a hallmark of chemoresistant triple negative breast cancer.

Science.gov (United States)

Gomez-Miragaya, Jorge; González-Suárez, Eva

2017-01-01

Taxanes are mainstay treatment of triple negative breast cancer (TNBC) patients but resistance often develops. Using TNBC patient-derived orthoxenografts (PDX) we have recently discovered that a CD49f+ chemoresistant population with tumor-initiating ability is present in sensitive tumors and expands in tumors that have acquired resistance. Importantly, sensitivity to taxanes is recovered after long-term drug interruption. The characterization of this chemoresistant CD49f+ cells provides a unique opportunity to identify novel targets for the treatment of chemoresistant TNBC.

Isolated perifacial lymph node metastasis in oral squamous cell carcinoma with clinically node-negative neck.

Science.gov (United States)

Agarwal, Sangeet Kumar; Arora, Sowrabh Kumar; Kumar, Gopal; Sarin, Deepak

2016-10-01

The incidence of occult perifacial nodal disease in oral cavity squamous cell carcinoma is not well reported. The purpose of this study was to evaluate the incidence of isolated perifacial lymph node metastasis in patients with oral squamous cell carcinoma with a clinically node-negative neck. The study will shed light on current controversies and will provide valuable clinical and pathological information in the practice of routine comprehensive removal of these lymph node pads in selective neck dissection in the node-negative neck. Prospective analysis. This study was started in August 2011 when intraoperatively we routinely separated the lymph node levels from the main specimen for evaluation of the metastatic rate to different lymph node levels in 231 patients of oral squamous cell cancer with a clinically node-negative neck. The current study demonstrated that 19 (8.22%) out of 231 patients showed ipsilateral isolated perifacial lymph node involvement. The incidence of isolated perifacial nodes did not differ significantly between the oral tongue (7.14%) and buccal mucosa (7.75%). Incidence was statistically significant in cases with lower age group (oral squamous cell carcinoma with a clinically node-negative neck. The incidence of isolated perifacial involvement is high in cases of buccal mucosal and tongue cancers. A meticulous dissection of the perifacial nodes seems prudent when treating the neck in oral cavity squamous cell carcinoma. 4 Laryngoscope, 126:2252-2256, 2016. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Circulating tumor DNA for triple-negative breast cancer diagnosis and treatment decisions.

Science.gov (United States)

Saliou, Adrien; Bidard, François-Clément; Lantz, Olivier; Stern, Marc-Henri; Vincent-Salomon, Anne; Proudhon, Charlotte; Pierga, Jean-Yves

2016-01-01

Triple-negative breast cancer (TNBC) is a highly aggressive disease characterized by a high number of relapses and poor overall survival. The heterogeneity of the disease and the limited treatment options compared to other breast cancer subtypes mainly explain these clinical outcomes. New biomarkers are urgently needed to improve the management of TNBC. Circulating tumor DNA, identified by tumor-related molecular alterations, could be used in the context of non-invasive "liquid biopsy" and help in TNBC diagnosis and treatment decisions. In this review, we discuss the key issues related to the potential of circulating tumor DNA to improve the management of this disease and the future steps to overcome before its implementation into clinical routine within the next 5 years.

(−-Epigallocatechin 3-Gallate Synthetic Analogues Inhibit Fatty Acid Synthase and Show Anticancer Activity in Triple Negative Breast Cancer

Directory of Open Access Journals (Sweden)

Joan Crous-Masó

2018-05-01

Full Text Available (−-Epigallocatechin 3-gallate (EGCG is a natural polyphenol from green tea with reported anticancer activity and capacity to inhibit the lipogenic enzyme fatty acid synthase (FASN, which is overexpressed in several human carcinomas. To improve the pharmacological profile of EGCG, we previously developed a family of EGCG derivatives and the lead compounds G28, G37 and G56 were characterized in HER2-positive breast cancer cells overexpressing FASN. Here, diesters G28, G37 and G56 and two G28 derivatives, monoesters M1 and M2, were synthesized and assessed in vitro for their cytotoxic, FASN inhibition and apoptotic activities in MDA-MB-231 triple-negative breast cancer (TNBC cells. All compounds displayed moderate to high cytotoxicity and significantly blocked FASN activity, monoesters M1 and M2 being more potent inhibitors than diesters. Interestingly, G28, M1, and M2 also diminished FASN protein expression levels, but only monoesters M1 and M2 induced apoptosis. Our results indicate that FASN inhibition by such polyphenolic compounds could be a new strategy in TNBC treatment, and highlight the potential anticancer activities of monoesters. Thus, G28, G37, G56, and most importantly M1 and M2, are anticancer candidates (alone or in combination to be further characterized in vitro and in vivo.

ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

OpenAIRE

Yuan, Xun; Kho, Dhonghyo; Xu, Jing; Gajan, Ambikai; Wu, Kongming; Wu, Gen Sheng

2017-01-01

ONC201 was previously identified as a first-in-class antitumor agent and small-molecule inducer of the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) gene that induces apoptosis in cancer cells. ONC201 has a safety profile and is currently in phase II clinical trials for the treatment of various malignancies. In the current study, we examine the effect of ONC201 on triple-negative breast cancer cells (TNBC), a subtype of breast cancer that is sensitive to TRAIL. We find that ...

Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.

Science.gov (United States)

Yamamoto, Mizuki; Sakane, Kota; Tominaga, Kana; Gotoh, Noriko; Niwa, Takayoshi; Kikuchi, Yasuko; Tada, Keiichiro; Goshima, Naoki; Semba, Kentaro; Inoue, Jun-Ichiro

2017-06-01

Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial-mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re-undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple-negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus-labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E-box-binding homeobox 1 (ZEB1) or Zinc finger protein SNAI2 (SLUG) significantly suppressed EMT but promoted partial MET, indicating that ZEB1 and SLUG are crucial to EMT and MET. We also show that primary breast cancer cells underwent EMT that correlated with changes in expression profiles of genes determining EMT status and breast cancer subtype. These changes were very similar to those observed in EMT in HCC38 cells. Consequently, we propose HCC38 as a suitable model to analyze EMT-MET dynamics that could affect the development of triple-negative breast cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Define the Twist ATX LPAR1 Signaling Axis in Promoting Obesity Associated Triple Negative Breast Cancer

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2017-05-01

with the research as presented in the original proposal and as defined in the statement of work . 6. Products We have generated mice with tissue...University of Kentucky College of Medicine 5e. TASK NUMBER E-Mail: a.j.morris@uky.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES...14. ABSTRACT Breast cancer remains the second leading cause of cancer‐related death in women worldwide. Triple negative breast cancer (TNBC) carries a

Define the Twist-ATX-LPAR1 Signaling Axis in Promoting Obesity Associated Triple Negative Breast Cancer

Science.gov (United States)

2017-05-01

original proposal and as defined in the statement of work . 6. Products We have generated mice with tissue specific inactivation of the ENPP2 gene in...Kentucky College of Medicine 5e. TASK NUMBER E-Mail: yiwei.lin@uky.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8...ABSTRACT Breast cancer remains the second leading cause of cancer‐related death in women worldwide. Triple negative breast cancer (TNBC) carries a poorer

Carnosol induces ROS-mediated beclin1-independent autophagy and apoptosis in triple negative breast cancer.

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Yusra Al Dhaheri

Full Text Available In this study we investigated the in vitro and in vivo anticancer effect of carnosol, a naturally occurring polyphenol, in triple negative breast cancer.We found that carnosol significantly inhibited the viability and colony growth induced G2 arrest in the triple negative MDA-MB-231. Blockade of the cell cycle was associated with increased p21/WAF1 expression and downregulation of p27. Interestingly, carnosol was found to induce beclin1-independent autophagy and apoptosis in MDA-MB-231 cells. The coexistence of both events, autophagy and apoptosis, was confirmed by electron micrography. Induction of autophagy was found to be an early event, detected within 3 h post-treatment, which subsequently led to apoptosis. Carnosol treatment also caused a dose-dependent increase in the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2. Moreover, we show that carnosol induced DNA damage, reduced the mitochondrial potential and triggered the activation of the intrinsic and extrinsic apoptotic pathway. Furthermore, we found that carnosol induced a dose-dependent generation of reactive oxygen species (ROS and inhibition of ROS by tiron, a ROS scavenger, blocked the induction of autophagy and apoptosis and attenuated DNA damage. To our knowledge, this is the first report to identify the induction of autophagy by carnosol.In conclusion our findings provide strong evidence that carnosol may be an alternative therapeutic candidate against the aggressive form of breast cancer and hence deserves more exploration.

Significant difference in p53 and p21 protein immunoreactivity in HPV 16 positive and HPV negative breast carcinomas

International Nuclear Information System (INIS)

Hennig, E.M.; Norwegian Radium Hospital, Oslo; Kvinnsland, S.; Holm, R.; Nesland, J.M.

1999-01-01

Human papillomavirus (HPV) 16 has previously been found in 19/41 breast carcinomas (46%) in women with a history of HPV 16 positive CIN III lesions. There was no significant difference in distribution of histological subtypes, mean or median tumour diameter or number of regional lymph node metastases in the HPV positive and HPV negative breast carcinoma groups. P53, p21 and c-erbB-2 proteins were analyzed by immunohistochemistry in the HPV 16 positive and HPV negative breast carcinomas. There was a significant difference in p53 and p21 protein immunoreactivity between HPV 16 positive and HPV negative breast carcinomas (p=0.0091 and p=0.0040), with a significant less detectable p53 and p21 protein immunoreactivity in the HPV 16 positive cases. There was also a significant difference in the coexpression of p53/p21 between the HPV 16 positive and HPV 16 negative breast carcinomas (p=0.002). No significant difference in immunostaining for c-erbB-2 protein in the two groups was found (p=0.15), or for the coexpression of p53/c-erbB-2 (p=0.19). The significantly lower expression of p53 and p21 proteins in HPV 16 positive than in HPV 16 negative breast carcinomas supports the hypothesis of inactivation and degradation of wild-type p53 proteins by HPV 16 E6 and that p53 mutation is not necessary for transformation in the HPV 16 positive cases. (orig.)

The prognostic value of Her4 receptor isoform expression in triple-negative and Her2 positive breast cancer patients

International Nuclear Information System (INIS)

Machleidt, Anna; Buchholz, Stefan; Diermeier-Daucher, Simone; Zeman, Florian; Ortmann, Olaf; Brockhoff, Gero

2013-01-01

Not only four but rather seven different human epidermal growth factor receptor related (Her) receptor tyrosine kinases (RTKs) have been described to be expressed in a variety of normal and neoplastic tissues: Her1, Her2, Her3, and additionally four Her4 isoforms have been identified. A differential expression of Her4 isoforms does not, however, play any role in either the molecular diagnostics or treatment decision for breast cancer patients. The prognostic and predictive impact of Her4 expression in breast cancer is basically unclear. We quantified the Her4 variants JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, and JM-b/CYT2 by isoform-specific polymerase chain reaction (qPCR) in (i) triple-negative, (ii) Her2 positive breast cancer tissues and (iii) in benign breast tissues. In all three tissue collectives we never found the JM-b/CYT1 or the JM-b/CYT2 isoform expressed. In contrast, the two JM-a/CYT1 and JM-a/CYT2 isoforms were always simultaneously expressed but at different ratios. We identified a positive prognostic impact on overall survival (OS) in triple-negative and event-free survival (EFS) in Her2 positive patients. This finding is independent of the absolute JM-a/CYT1 to JM-a/CYT2 expression ratio. In Her2 positive patients, Her4 expression only has a favorable effect in estrogen-receptor (ER)-positive but not in ER-negative individuals. In summary, JM-a/CYT1 and JM-a/CYT2 but not JM-b isoforms of the Her4 receptor are simultaneously expressed in both triple-negative and Her2 positive breast cancer tissues. Although different expression ratios of the two JM-a isoforms did not reveal any additional information, Her4 expression basically indicates a prolonged EFS and OFS. An extended expression analysis that takes all Her receptor homologs, including the Her4 isoforms, into account might render more precisely the molecular diagnostics required for the development of optimized targeted therapies

Sentinel lymph node biopsy in node-negative squamous cell carcinoma of the oral cavity and oropharynx.

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Burns, P

2012-02-01

OBJECTIVES: Considerable controversy exists regarding the merits of elective neck dissection in patients with early stage oral cavity and oropharyngeal squamous cell carcinoma. It is highly desirable to have a method of identifying those patients who would benefit from further treatment of the neck when they are clinically node-negative. The purpose of the present study was to examine the use of sentinel lymph node biopsy in identifying occult neck disease in a cohort of patients with node-negative oral cavity and oropharyngeal squamous cell carcinoma. DESIGN: We evaluated a total of 13 patients with oral cavity and oropharyngeal cancer who were clinically and radiologically node-negative. RESULTS: A sentinel lymph node was found in all 13 patients, revealing metastatic disease in five patients, four of whom had one or more positive sentinel lymph nodes. There was one false negative result, in which the sentinel lymph node was negative for tumour whereas histological examination of the neck dissection specimen showed occult disease. CONCLUSION: In view of these findings, we would recommend the use of sentinel lymph node biopsy in cases of oral cavity and oropharyngeal squamous cell carcinoma, in order to aid the differentiation of those patients whose necks are harbouring occult disease and who require further treatment.

Does a Negative Triple Test Reduce the Rate of Negative Appendectomy in Adults?

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Mahmoud F. Sakr

2012-08-01

Results: Sixty-seven patients (65.9% were female and 35 (34.1% were male. Their ages ranged between 16 and 49 years (mean 27.5 years. Most patients (87.3% had their symptoms for 12-36 hours before hospital admission. The mean values for TLC, NP, and CRP were 7,573/ and micro;L, 54.53%, and 0.61 mg/L, respectively. Of the 102 patients with NTT, 101 (99% proved not to have appendiceal inflammation (NPV=99%. Only 39 patients were operated upon, of whom 38 (97.4% had a normal appendix, and the remaining 63 patients were either discharged (n=47 or referred to other specialties (n=16. There were significantly more women (76.3%, 29/38 with negative appendectomy than men (24.7%, 9/38 (X2= 21.1, p=0.0001. Gynecological causes were the most common (60.5%, 23/38 and in 11 cases, the exact etiology could not be identified. Conclusions: From the data presented, it may be concluded that TLC, NP and CRP blood levels (triple test should be measured upon hospital admission of adult patients with clinically suspected acute appendicitis. If used judiciously, they may spare the group of patients with an NTT an unnecessary surgical operation, hence markedly reducing the NAR with its potential risks. [Arch Clin Exp Surg 2012; 1(4.000: 229-236

Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro

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Rodolfo Garza-Morales

2018-05-01

Full Text Available Triple-negative breast cancer (TNBC is one of the most aggressive types of cancer, and treatment is limited to chemotherapy and radiation. Oncolytic virotherapy may be a promising approach to treat TNBC. However, oncolytic adenovirus (OAd-based mono-therapeutic clinical trials have resulted in modest outcomes. The OAd potency could be increased by chemotherapy-induced autophagy, an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. In this study, the ability of alkylating agent temozolomide (TMZ-induced autophagy to increase OAd replication and oncolysis in TNBC cells was evaluated. Human TNBC MDA-MB-231 and HCC1937 cells and mouse 4T1 cells were infected with an OAd expressing the red fluorescent protein mCherry on the virus capsid (OAdmCherry alone or in combination with TMZ. TNBC cells treated with OAdmCherry/TMZ displayed greater mCherry and adenovirus (Ad early region 1A (E1A expression and enhanced cancer-cell killing compared to OAdmCherry or TMZ alone. The combined therapy-mediated cell death was associated with virus replication and accumulation of the autophagy marker light chain 3 (LC3-II. Overall, this study provides experimental evidence of TMZ’s ability to increase oncolytic virotherapy in both human and murine TNBC cells.

Del-1 Expression as a Potential Biomarker in Triple-Negative Early Breast Cancer.

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Lee, Soo Jung; Lee, Jeeyeon; Kim, Wan Wook; Jung, Jin Hyang; Park, Ho Yong; Park, Ji-Young; Chae, Yee Soo

2018-01-01

A differential diagnostic role for plasma Del-1 was proposed for early breast cancer (EBC) in our previous study. We examined tumoral Del-1 expression and analyzed its prognostic impact among patients with EBC. Del-1 mRNA expression was assessed in breast epithelial and cancer cells. Meanwhile, the tumoral expression of Del-1 was determined based on tissue microarrays and immunohistochemistry results from 440 patients. While a high Del-1 mRNA expression was found in all the breast cancer cell lines, the expression was significantly higher in MDA-MB-231. Tumoral expression of Del-1 was also significantly associated with a negative expression of estrogen receptor or progesterone receptor, and low expression of Ki-67, particularly in the case of triple-negative breast cancer (TNBC) (p breast cancer cell lines exhibited Del-1 expression, the expression rate and intensity were specifically prominent in TNBC. In addition, based on its relationship to an unfavorable histology and worse survival trend, Del-1 could act as a molecular target in TNBC patients. © 2018 S. Karger AG, Basel.

Combination therapy and evaluation of therapeutic effect in hepatocellular carcinoma cell using triple reporter genes; containing for NIS, HSV1-sr39tk and GFP

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Lee, You La; Lee, Yong Jin; Ahn, Sohn Joo; Ahn, Byeong Cheol; Lee, Sang Woo; Yoo, Jeong Soo; Lee, Jae Tae [Kyungpook National University, Daegu (Korea, Republic of)

2007-07-01

To identify therapeutic effect after combine Sodium Iodine Symporter (NIS) and Mutant Herpes-simplex virus type 1 sr39tk (HSV1-sr39tk) expression in hepatocellular carcinoma cell, we transfected triple gene and investigated the properties of these gene ability in hepatocellular carcinoma cell line. After making vector with gene encoding a fusion protein comprised of HSV1-sr39tk and green florescence protein (GFP), to make triple reporter genes NIS gene was further fused to the vector using IRES vector. The vector expressing triple reporter gene was transfected to the Huh-7 cell line using liposome. Functions of hNIS and HSV1-sr39tk expression were confirmed by radio iodine uptake with and without perchlorate and [3H]-penciclovir (3-H PCV) uptake, respectively. To evaluate therapeutic effect in vitro, GCV and I-131 was treated in Huh-7/NTG cell and dual therapy performed. An animal imaging acquired using Optix and microPET in vivo. I-125 uptake was increased up to 100-fold compare to that of non-transfected cells. The transfected cell accumulated H-3 PCV up to 53 times higher at 2 hour than that of non-transfected cells. With fluorescence microscopy, green fluorescence was detected in the transfected cell. In cytotoxic studies, the cell viability of Huh-7/NTG cell was decreased to 41 % of control cell at 10ug/ml GCV concentrations. The survival rate of the Huh-7/NTG cell treated with I-131 decreased up to 16%. In I-131 and GCV dual therapy, Huh-7/NTG cell survival rate decreased up to 4%. In animal studies, Huh-7/NTG tumors showed higher uptake of 18F-FHBG and I-124 than Huh-7 tumors. GFP signal is also higher in Huh-7/NTG tumor than control. We successfully constructed a vector with delivery two therapeutic genes and one reporter gene and transfected the vector to a Huh-7 cell. The hepatocellular carcinoma cell transfected with the vector can be treated with GCV and I-131. The effect of dual gene therapy could be easily assessed by the optical reporter gene imaging.

Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells.

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Zhou, Yan; Lin, Shuchen; Tseng, Kuo-Fu; Han, Kun; Wang, Yaling; Gan, Zhi-Hua; Min, Da-Liu; Hu, Hai-Yan

2016-10-21

Triple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP-noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism. After treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB-231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods. MiR array was used to analysis the change of miRs. We predicted and verified CUL1 is the target of miR-302a using Luciferase reporter assay. We also silenced the CUL1 by siRNA, to clarify whether CUL1 take part in the cell proliferation, migration and regulated its substrate TIMP1 and TRAF2. Moreover, after transfection, the antagomir of miR-302a and CUL1 over-expressed plasmid into HCC1937 and MDA-MB-231 cell accompanied with the Selumetinib treatment, we detected the proliferation and migration again. Selumetinib reduce the proliferation, migration, triggered apoptosis and G1 arrest in TNBC cell lines. In this process, the miR-302a was up-regulated and inhibited the CUL1 expression. The later negatively regulated the TIMP1 and TRAF2. As soon as we knockdown miR-302a and over-expression CUL1 in TNBC cells, the cytotoxicity of Selumetinib was reversed. MiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer.

Clinical characteristics of triple negative breast cancer in Egyptian women: a hospital-based experience

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Nivine Gado

2016-06-01

Full Text Available Purpose: Triple negative breast cancer (TNBC is an aggressive subtype of breast cancer with poor prognosis despite the high rates of response to chemotherapy. We aim to study the clinical features, factors influencing recurrence and survival outcomes of TNBC patients.Methods: We retrospectively studied the charts of patients with biopsy proven TNBC treated at The Clinical Oncology Department Ain-Shams University between 2009 and 2012.Results: One hundred and forty five patients fulfilled the eligibility criteria. The incidence of TNBC was 10.5% - 15% with a mean of 12% of all breast cancer patients. The follow-up duration ranged from six months to four years. The age range was 26 to 78 years. Infiltrating ductal carcinoma represented 93.1% of the pathologic types. 87% of patients were free of metastases (M0 at presentation. Clinical stages II and III represented 38 and 39.5% of the patients. 66% of patients had modified radical mastectomy. Following surgery, 77.5% of patients received adjuvant chemotherapy while 61% of the patients had adjuvant radiation therapy. Anthracyclines based chemotherapy was given to 52% of patients. Disease-free survival (DFS of the M0 patients at 20 and 30 months was 92% and 80% respectively. Relapse occurred in 23% of M0 patients. After a mean duration of DFS of 15.1 months, the most common sites of metastases for relapsed M0 patients were pulmonary (44.8%, bone (41.4%, and locoregional (13.8%. The median overall survival (ORS of patients was 18 months (1 - 45 months, whereas for the M1 group of patients the median ORS was 9 months (2 - 29 months.Conclusion: The incidence, pathological characteristics, and clinical behavior of TNBC were similar to what is mentioned in the literature. Adding taxanes to the chemotherapy protocols and using postoperative radiotherapy were both associated with a significant increase in the mean period of DFS, while did not significantly affect the ORS.

Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

Science.gov (United States)

Yano, Shuya; Takehara, Kiyoto; Miwa, Shinji; Kishimoto, Hiroyuki; Tazawa, Hiroshi; Urata, Yasuo; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

2016-01-01

We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative high-invasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)-light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model. PMID:27689331

ABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines.

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Clément Chevalier

Full Text Available The non-receptor tyrosine kinase ABL drives myeloid progenitor expansion in human chronic myeloid leukemia. ABL inhibition by the tyrosine kinase inhibitor nilotinib is a first-line treatment for this disease. Recently, ABL has also been implicated in the transforming properties of solid tumors, including triple negative (TN breast cancer. TN breast cancers are highly metastatic and several cell lines derived from these tumors display high invasive activity in vitro. This feature is associated with the activation of actin-rich membrane structures called invadopodia that promote extracellular matrix degradation. Here, we investigated nilotinib effect on the invasive and migratory properties of different TN breast cancer cell lines. Nilotinib decreased both matrix degradation and invasion in the TN breast cancer cell lines MDA-MB 231 and MDA-MB 468. However, and unexpectedly, nilotinib increased by two-fold the invasive properties of the TN breast cancer cell line BT-549 and of Src-transformed fibroblasts. Both display much higher levels of ABL kinase activity compared to MDA-MB 231. Similar effects were obtained by siRNA-mediated down-regulation of ABL expression, confirming ABL central role in this process. ABL anti-tumor effect in BT-549 cells and Src-transformed fibroblasts was not dependent on EGF secretion, as recently reported in neck and squamous carcinoma cells. Rather, we identified the TRIO-RAC1 axis as an important downstream element of ABL activity in these cancer cells. In conclusion, the observation that TN breast cancer cell lines respond differently to ABL inhibitors could have implications for future therapies.

Overexpression of ETV4 protein in triple-negative breast cancer is associated with a higher risk of distant metastasis

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Yuan ZY

2014-09-01

-overexpressed tumor had a significantly higher risk of developing distant metastasis (P<0.0001 and shorter overall survival and disease-free survival. Overexpression of ETV4 protein was an independent predictor of short disease-free survival of TNBC patients (P=0.021. Conclusion: Overexpression of ETV4 protein increases risk of developing distant metastasis and results in a poor prognosis for TNBC patients. Thus, ETV4 might be a novel target for developing an alternative therapeutic strategy for prevention of TNBC distant metastasis. Keywords: breast carcinoma, triple-negative, ETS translocation variant 4, ETV4, prognosis

Melanin-originated carbonaceous dots for triple negative breast cancer diagnosis by fluorescence and photoacoustic dual-mode imaging.

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Xiao, Wei; Li, Yuan; Hu, Chuan; Huang, Yuan; He, Qin; Gao, Huile

2017-07-01

Carbonaceous dots exhibit increasing applications in diagnosis and drug delivery due to excellent photostability and biocompatibility properties. However, relative short excitation and emission of melanin carbonaceous dots (MCDs) limit the applicability in fluorescence bioimaging. Furthermore, the generally poor spatial resolution of fluorescence imaging limits potential in vivo applications. Due to a variety of beneficial properties, in this study, MCDs were prepared exhibiting great potential in fluorescence and photoacoustic dual-mode bioimaging. The MCDs exhibited a long excitation peak at 615nm and emission peak at 650nm, further highlighting the applicability in fluorescence imaging, while the absorbance peak at 633nm renders MCDs suitable for photoacoustic imaging. In vivo, the photoacoustic signal of MCDs was linearly correlated with the concentration of MCDs. Moreover, the MCDs were shown to be taken up into triple negative breast cancer cell line 4T1 in both a time- and concentration-dependent manner. In vivo fluorescence and photoacoustic imaging of subcutaneous 4T1 tumor demonstrated that MCDs could passively target triple negative breast cancer tissue by enhanced permeability and retention effects and may therefore be used for tumor dual-mode imaging. Furthermore, fluorescence distribution in tissue slices suggested that MCDs may distribute in 4T1 tumor with high efficacy. In conclusion, the MCDs studied offer potential application in fluorescence and photoacoustic dual-mode imaging. Copyright © 2017 Elsevier Inc. All rights reserved.

Prognostic Value of Triple-Negative Phenotype at the Time of Locally Recurrent, Conservatively Treated Breast Cancer

International Nuclear Information System (INIS)

Parikh, Rahul R.; Housman, Douglas; Yang Qifeng; Toppmeyer, Deborah; Wilson, Lynn D.; Haffty, Bruce G.

2008-01-01

Purpose: To evaluate the prognostic value of triple-negative (TN) ER, PR, Her2/neu basal-like carcinoma of the breast, at the time of ipsilateral breast tumor recurrence (IBTR) after conservative surgery and radiation treatment (RT). Methods and Materials: A tissue microarray was constructed of 47 IBTR specimens of patients who experienced an IBTR after conservative surgery and RT that were processed and stained for ER, PR, and HER2/neu. Results: At a median post-recurrence follow-up of 7.5 years, the 5-year overall survival (OS) and disease metastasis-free survival (DMFS) after IBTR were 91.4% and 83.0%, respectively. Median time to tumor recurrence (TTR) and IBTR was shorter in the TN phenotype (3.88 vs. 5.00 years; p = 0.09). The TN tumors were not associated with size of local recurrence or recurrence elsewhere in the breast. Despite administration of standard chemotherapy at the time of IBTR, the 5-year DMFS and 5-year OS for the TN cohort were 48.6% and 72.7%, respectively. The 5-year DMFS was 48.6% for TN tumors and 90.8% for non-TN tumors (p < 0.01). By univariate analysis, significant factors associated with poor 5-year DMFS and OS after IBTR included: TN phenotype (p < 0.01), TTR 3 years or less (p < 0.01), local recurrence at or near the original tumor site (p = 0.08). In multivariate analysis, TN was a significant independent predictor of poorer 5-year DMFS (relative risk, 5.91; 95% confidence interval, 1.83-19.01; p < 0.01) after IBTR. Conclusions: Although patients experiencing an IBTR have a relatively favorable prognosis, those with IBTR events of the TN phenotype had a rather poor prognosis despite receiving standard chemotherapy. Strategies with novel systemic therapies to improve outcomes in patients experiencing IBTR of the TN phenotype are warranted

Clinical Characteristics in Patients with Triple Negative Breast Cancer

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Janet Yeh

2017-01-01

Full Text Available Purpose. The purpose of this study was to compare and contrast the clinical characteristics of the triple negative breast cancer (TNBC and non-TNBC patients, with a particular focus on genetic susceptibility and risk factors prior to diagnosis. Methods. Our institutional database was queried for all patients diagnosed with invasive breast cancer between January 2010 and May 2016. Results. Out of a total of 1964 patients, 190 (10% patients had TNBC. The median age for both TNBC and non-TNBC was 59 years. There was a significantly higher proportion of African American and Asian patients with TNBC (p=0.0003 compared to patients with non-TNBC. BRCA1 and BRCA2 were significantly associated with TNBC (p<0.0001, p=0.0007. A prior history of breast cancer was significantly associated with TNBC (p=0.0003. There was no relationship observed between TNBC and a history of chemoprevention or patients who had a history of AH or LCIS. Conclusions. We found that having Asian ancestry, a prior history of breast cancer, and a BRCA1 or BRCA2 mutation all appear to be positively associated with TNBC. In order to develop more effective treatments, better surveillance, and improved prevention strategies, it is necessary to improve our understanding of the population at risk for TNBC.

Identification of a rhodium(iii) complex as a Wee1 inhibitor against TP53-mutated triple-negative breast cancer cells.

Science.gov (United States)

Yang, Guan-Jun; Zhong, Hai-Jing; Ko, Chung-Nga; Wong, Suk-Yu; Vellaisamy, Kasipandi; Ye, Min; Ma, Dik-Lung; Leung, Chung-Hang

2018-03-06

The rhodium(iii) complex 1 was identified as a potent Wee1 inhibitor in vitro and in cellulo. It decreased Wee1 activity and unscheduled mitotic entry, and induced cell damage and death in TP53-mutated triple-negative breast cancer cells. 1 represents a promising scaffold for further development of more potent metal-based Wee1 antagonists.

Incidence and Outcome of BRCA Mutations in Unselected Patients with Triple Receptor-Negative Breast Cancer.

LENUS (Irish Health Repository)

Gonzalez-Angulo, Ana M

2011-03-01

To investigate the incidence of germline and somatic BRCA1\\/2 mutations in unselected patients with triple-negative breast cancer (TNBC) and determine the prognostic significance of carrying a mutation. Methods: DNA was obtained from 77 TNBC and normal tissues. BRCA1\\/2 exons\\/flanking regions were sequenced from tumor and patients classified as mutant or wild type (WT). Sequencing was repeated from normal tissue to identify germline and somatic mutations. Patient characteristics were compared with chi-square. Survival was estimated by Kaplan-Meier method and compared with log-rank. Cox proportional hazards models were fit to determine the independent association of mutation status with outcome.

Accuracy of Triple Diagnostic Test in Patients with Thyroid Nodule at Dr. Cipto Mangunkusumo General Hospital

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Diani Kartini

2017-04-01

Full Text Available The aim of the study is to evaluate the accuracy of triple diagnostic test on thyroid nodules. The data from patients’ medical records who came to Cipto Mangunkusumo General Hospital for the first time or for evaluation of thyroid nodule and patients who underwent thyroidectomy during 2010 to 2011. Clinical examination was scored by McGill Thyroid Nodule Score. ROC procedure was performed to obtain clinical cut-off scores of diagnosis of malignant. Ultrasonography (USG result was considered malignant for TIRADS 4, 5, and 6. If clinical, USG and histopathology examinations of triple diagnostic give positive results, it will be classified as concordant malignant whereas if all those three show benign results, the classification is benign. Thyroid carcinoma was found in 134 out of 161 patients with thyroid nodule. There were 84 patients with concordant results for all three elements of the triple test. Out of 84 patients with concordant triple diagnostic results, there were 53 malignant cases (32.9% and 31 benign cases (19.3%. Main histopathological findings among patients with thyroid carcinoma was papillary (90.3%, follicular (3%, medullary (0.7%, and anaplastic (6%. The sensitivity and specificity of triple diagnostic was 77% and 94%, with positive predictive value of 98%, negative predictive value of 51,6% and accuracy of 80.9%. Combination of clinical findings, USG, and FNAB gave malignant probability of 92%, better than combination of clinical findings and USG (81.6% or clinical findings and FNAB (87%. Triple diagnostic cannot be used as an ideal test to replace frozen section examination in managing thyroid nodule. However, in cases with concordant results of each triple diagnostic’s element, the positive predictive value (98% and malignant probability (92% is high. Keywords: thyroid nodule, triple diagnostic, accuracy.   Akurasi Metode Triple Diagnostic pada Pasien Nodul Tiroid  di RSUPN Dr. Cipto Mangunkusumo   Abstrak Tujuan

Triple negative breast cancers have a reduced expression of DNA repair genes.

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Enilze Ribeiro

Full Text Available DNA repair is a key determinant in the cellular response to therapy and tumor repair status could play an important role in tailoring patient therapy. Our goal was to evaluate the mRNA of 13 genes involved in different DNA repair pathways (base excision, nucleotide excision, homologous recombination, and Fanconi anemia in paraffin embedded samples of triple negative breast cancer (TNBC compared to luminal A breast cancer (LABC. Most of the genes involved in nucleotide excision repair and Fanconi Anemia pathways, and CHK1 gene were significantly less expressed in TNBC than in LABC. PARP1 levels were higher in TNBC than in LABC. In univariate analysis high level of FANCA correlated with an increased overall survival and event free survival in TNBC; however multivariate analyses using Cox regression did not confirm FANCA as independent prognostic factor. These data support the evidence that TNBCs compared to LABCs harbour DNA repair defects.

CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer.

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Xiang, Jingyu; Hurchla, Michelle A; Fontana, Francesca; Su, Xinming; Amend, Sarah R; Esser, Alison K; Douglas, Garry J; Mudalagiriyappa, Chidananda; Luker, Kathryn E; Pluard, Timothy; Ademuyiwa, Foluso O; Romagnoli, Barbara; Tuffin, Gérald; Chevalier, Eric; Luker, Gary D; Bauer, Michael; Zimmermann, Johann; Aft, Rebecca L; Dembowsky, Klaus; Weilbaecher, Katherine N

2015-11-01

The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow-disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a "chemotherapy framing" dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases. ©2015 American Association for Cancer Research.

A Novel Differentiation Therapy Approach to Reduce the Metastatic Potential of Basal, Highly Metastatic, Triple-Negative Breast Cancers

Science.gov (United States)

2012-05-01

metastatic process (Condeelis and Pollard 2006), we quantitated macrophage recruitment in the lungs of mice injected with 231-Empty or 231-GATA3 cells by...image quantitation of Ki-67 expression and H&E staining of metastatic lung lesions using Apirio Image Analysis software (Figure 9) which demonstrated...expression in MD A-MB-231 and in another triple negative breast cancer cell line, Hs578T Transient knock down of GATA3 in the lum inal GATA3 positiv

Cotargeting the lncRNA-PIP3 Interaction and AKT/PI3K Signaling Axis: A Novel Paradigm for Treating Triple-Negative Breast Cancer

Science.gov (United States)

2017-10-01

Negative Breast Cancer PRINCIPAL INVESTIGATOR: Dr. Liuqing Yang CONTRACTING ORGANIZATION: University of Texas MD Anderson Cancer Center Houston, TX...Signaling Axis: A Novel Paradigm for Treating Triple-Negative Breast Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Liuqing Yang 5d...ORGANIZATION REPORT NUMBER UNIVERSITY OF TEXAS M D ANDERSON CANCER HOUSTON TX 77030-0417 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES

Triple negative breast cancer: new therapeutic approaches and BRCA status.

Science.gov (United States)

Guney Eskiler, Gamze; Cecener, Gulsah; Egeli, Unal; Tunca, Berrin

2018-05-01

Treatment of triple negative breast cancer (TNBC) is a clinically challenging problem due to intriguing clinical and pathologic features of TNBC and natural or induced resistance to existing therapies. However, a great understanding of features of TNBC particularly associated with BRCA mutations has led to the development of different therapeutic approaches. Besides, identification of TNBC subtypes contribute to investigation of the underlying molecular differences and development of new strategies for the treatment of TNBC patients. In this review, we discussed the definition and characteristic properties of TNBC. We summarized an up-to-date description of the reported clinical trials of novel targeted strategies especially PARP inhibitors (PARPi) due to novel and highly potent for the treatment of TNBC. Additionally, we reviewed published studies which investigated the prevalence and types of BRCA1/2 mutation in breast cancer patients to assess and draw attention of association of BRCA status with TNBC. Consequently, the definition subtype of TNBC has important predictive value for the development of new therapeutic agents in the treatment of TNBC. Additionally, the incidence and types of mutations in BRCA-related pathways may be affected by ethnic origin and contribute to the risk of developing TNBC. © 2018 APMIS. Published by John Wiley & Sons Ltd.

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer.

Science.gov (United States)

Oudin, Madeleine J; Barbier, Lucie; Schäfer, Claudia; Kosciuk, Tatsiana; Miller, Miles A; Han, Sangyoon; Jonas, Oliver; Lauffenburger, Douglas A; Gertler, Frank B

2017-01-01

Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA and particularly its invasive isoform, MENA INV , are established drivers of metastasis. MENA INV expression is significantly correlated with metastasis and poor outcome in human patients with breast cancer. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENA INV confer resistance to the taxane paclitaxel, but not to the widely used DNA-damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENA INV -driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by co-treatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance. Mol Cancer Ther; 16(1); 143-55. ©2016 AACR. ©2016 American Association for Cancer Research.

Oral squamous cell carcinoma and a clinically negative neck : the value of follow-up

NARCIS (Netherlands)

Wensing, Bart M; Merkx, Matthias A W; Krabbe, Paul F M; Marres, Henri A M; Van den Hoogen, Frank J A

2011-01-01

BACKGROUND: In squamous cell carcinoma of the oral cavity (SCCOC), regular follow-up comprises 5 years of prescheduled visits, irrespective of tumor stage/classification and/or treatment. We analyzed our standard treatment and follow-up protocol in patients with a preoperative clinically negative

Integrated microRNA and mRNA signatures associated with survival in triple negative breast cancer.

Science.gov (United States)

Cascione, Luciano; Gasparini, Pierluigi; Lovat, Francesca; Carasi, Stefania; Pulvirenti, Alfredo; Ferro, Alfredo; Alder, Hansjuerg; He, Gang; Vecchione, Andrea; Croce, Carlo M; Shapiro, Charles L; Huebner, Kay

2013-01-01

Triple negative breast cancer (TNBC) is a heterogeneous disease at the molecular, pathologic and clinical levels. To stratify TNBCs, we determined microRNA (miRNA) expression profiles, as well as expression profiles of a cancer-focused mRNA panel, in tumor, adjacent non-tumor (normal) and lymph node metastatic lesion (mets) tissues, from 173 women with TNBCs; we linked specific miRNA signatures to patient survival and used miRNA/mRNA anti-correlations to identify clinically and genetically different TNBC subclasses. We also assessed miRNA signatures as potential regulators of TNBC subclass-specific gene expression networks defined by expression of canonical signal pathways.Tissue specific miRNAs and mRNAs were identified for normal vs tumor vs mets comparisons. miRNA signatures correlated with prognosis were identified and predicted anti-correlated targets within the mRNA profile were defined. Two miRNA signatures (miR-16, 155, 125b, 374a and miR-16, 125b, 374a, 374b, 421, 655, 497) predictive of overall survival (P = 0.05) and distant-disease free survival (P = 0.009), respectively, were identified for patients 50 yrs of age or younger. By multivariate analysis the risk signatures were independent predictors for overall survival and distant-disease free survival. mRNA expression profiling, using the cancer-focused mRNA panel, resulted in clustering of TNBCs into 4 molecular subclasses with different expression signatures anti-correlated with the prognostic miRNAs. Our findings suggest that miRNAs play a key role in triple negative breast cancer through their ability to regulate fundamental pathways such as: cellular growth and proliferation, cellular movement and migration, Extra Cellular Matrix degradation. The results define miRNA expression signatures that characterize and contribute to the phenotypic diversity of TNBC and its metastasis.

Lipid-rich histology in a basal-type immunoprofile breast carcinoma: histochemical and immunohistochemical analysis of a case

Directory of Open Access Journals (Sweden)

Francesco Maria Maiello

2009-12-01

Full Text Available We describe the clinicopathological and morphological features of an unusual breast carcinoma classifiable as a lipid-rich variant of ductal invasive carcinoma, with a basal-type immunohistochemical profile. Basal-type breast cancers show no hormonal receptor expression, rarely over-express HER-2 but exhibit molecular high weight cytokeratins, EGFR and c-kit positivity. Special stains and histochemistry tests were used to elucidate the nature of vescicles in the neoplastic cells. Sudan IV was performed on formalin-fixed tissue. Commercially available antibodies tested were: ER, PgR, EGFR, HER2, c-kit, high molecular weight cytokeratins. Cytoplasmic lipids were highlighted as red-orange droplets on Sudan IV staining. As for immunohistochemistry, the tumor showed no reactivity to ER, PgR and HER2 (triple negative, and diffuse and strong positivity to high weight cytokeratins, EGFR and c-kit, such as a basal-type breast carcinoma. A basaloid phenotype in a lipid-rich carcinoma has not been previously reported.

A Phenotypic Cell-Binding Screen Identifies a Novel Compound Targeting Triple-Negative Breast Cancer.

Science.gov (United States)

Chen, Luxi; Long, Chao; Youn, Jonghae; Lee, Jiyong

2018-06-11

We describe a "phenotypic cell-binding screen" by which therapeutic candidate targeting cancer cells of a particular phenotype can be isolated without knowledge of drug targets. Chemical library beads are incubated with cancer cells of the phenotype of interest in the presence of cancer cells lacking the phenotype of interest, and then the beads bound to only cancer cells of the phenotype of interest are selected as hits. We have applied this screening strategy in discovering a novel compound (LC129-8) targeting triple-negative breast cancer (TNBC). LC129-8 displayed highly specific binding to TNBC in cancer cell lines and patient-derived tumor tissues. LC129-8 exerted anti-TNBC activity by inducing apoptosis, inhibiting proliferation, reversing epithelial-mesenchymal transition, downregulating cancer stem cell activity and blocking in vivo tumor growth.

Early stage cost-effectiveness analysis of a BRCA1-like test to detect triple negative breast cancers responsive to high dose alkylating chemotherapy

NARCIS (Netherlands)

Miquel-Cases, Anna; Steuten, Lotte Maria Gertruda; Retel, Valesca P.; van Harten, Willem H.

2015-01-01

Purpose Triple negative breast cancers (TNBC) with a BRCA1-like profile may benefit from high dose alkylating chemotherapy (HDAC). This study examines whether BRCA1-like testing to target effective HDAC in TNBC patients can be more cost-effective than treating all patients with standard

Tumor-infiltrating lymphocytes and ductal carcinoma in situ of the breast: friends or foes?

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Agahozo, Marie Colombe; Hammerl, Dora; Debets, Reno; Kok, Marleen; van Deurzen, Carolien H M

2018-02-20

In the past three decades, the detection rate of ductal carcinoma in situ of the breast has dramatically increased due to breast screening programs. As a consequence, about 20% of all breast cancer cases are detected in this early in situ stage. Some ductal carcinoma in situ cases will progress to invasive breast cancer, while other cases are likely to have an indolent biological behavior. The presence of tumor-infiltrating lymphocytes is seen as a promising prognostic and predictive marker in invasive breast cancer, mainly in HER2-positive and triple-negative subtypes. Here, we summarize the current understanding regarding immune infiltrates in invasive breast cancer and highlight recent observations regarding the presence and potential clinical significance of such immune infiltrates in patients with ductal carcinoma in situ. The presence of tumor-infiltrating lymphocytes, their numbers, composition, and potential relationship with genomic status will be discussed. Finally, we propose that a combination of genetic and immune markers may better stratify ductal carcinoma in situ subtypes with respect to tumor evolution.

Two-miRNA classifiers differentiate mutation-negative follicular thyroid carcinomas and follicular thyroid adenomas in fine needle aspirations with high specificity

DEFF Research Database (Denmark)

Stokowy, Tomasz; Wojtas, Bartosz; Jarzab, Barbara

2016-01-01

Diagnosis of thyroid by fine needle aspiration is challenging for the "indeterminate" category and can be supported by molecular testing. We set out to identify miRNA markers that could be used in a diagnostic setting to improve the discrimination of mutation-negative indeterminate fine needle...... aspirations. miRNA high-throughput sequencing was performed for freshly frozen tissue samples of 19 RAS and PAX8/PPARG mutation-negative follicular thyroid carcinomas, and 23 RAS and PAX8/PPARG mutation-negative follicular adenomas. Differentially expressed miRNAs were validated by quantitative polymerase...... chain reaction in a set of 44 fine needle aspiration samples representing 24 follicular thyroid carcinomas and 20 follicular adenomas. Twenty-six miRNAs characterized by a significant differential expression between follicular thyroid carcinomas and follicular adenomas were identified. Nevertheless...

Postmastectomy radiotherapy reduces locoregional and disease recurrence in patients with stage II–III triple-negative breast cancer treated with neoadjuvant chemotherapy and mastectomy

Directory of Open Access Journals (Sweden)

Chen XX

2018-04-01

-free survival in the entire cohort as well as in patients with stage IIA disease. Our results may help in tailoring adjuvant treatment decisions for these particular patient populations. Keywords: triple-negative breast carcinoma, neoadjuvant chemotherapy, surgery, adjuvant radiation therapy, locoregional recurrence, disease recurrence

High-risk human papillomavirus (HPV) DNA sequences in metaplastic breast carcinomas of Mexican women

International Nuclear Information System (INIS)

Herrera-Goepfert, Roberto; Vela-Chávez, Teresa; Carrillo-García, Adela; Lizano-Soberón, Marcela; Amador-Molina, Alfredo; Oñate-Ocaña, Luis F; Hallmann, Rita Sotelo-Regil

2013-01-01

Metaplastic carcinoma, an uncommon subtype of breast cancer, is part of the spectrum of basal-like, triple receptor-negative breast carcinomas. The present study examined 20 surgical specimens of metaplastic breast carcinomas, for the presence of high-risk Human papillomavirus (HPV), which is suspected to be a potential carcinogenic agent for breast carcinoma. Mastectomy specimens from patients harboring metaplastic breast carcinoma, as defined by the World Health Organization (WHO), and who attended the Instituto Nacional de Cancerologia in Mexico City, were retrieved from the files of the Department of Pathology accumulated during a 16-year period (1995–2008). Demographic and clinical information was obtained from patients’ medical records. DNA was extracted from formalin-fixed, paraffin-embedded tumors and HPV type-specific amplification was performed by means of Polymerase chain reaction (PCR). Quantitative Real-time (RT) PCR was conducted in HPV positive cases. Statistically, the association of continuous or categorical variables with HPV status was tested by the Student t, the Chi square, or Fisher’s exact tests, as appropriate. High-risk HPV DNA was detected in eight (40%) of 20 metaplastic breast carcinomas: seven (87.5%) HPV-16 and one (12.5%) HPV-18. Mean age of patients with HPV-positive cases was 49 years (range 24–72 years), the same as for HPV-negative cases (range, 30–73 years). There were not striking differences between HPV + and HPV– metaplastic carcinomas regarding clinical findings. Nearly all cases were negative for estrogen, progesterone and Human epidermal growth factor receptor 2 (HER2), but positive for Epidermal growth factor receptor (EGFR). High-risk HPV has been strongly associated with conventional breast carcinomas, although the subtle mechanism of neoplastic transformation is poorly understood. In Mexican patients, the prevalence of HPV infection among metaplastic breast carcinomas is higher than in non-metaplastic ones

Management of the clinically node negative neck in squamous cell carcinoma of the maxilla

NARCIS (Netherlands)

Joosten, Michiel H M A; de Bree, Remco; Van Cann, Ellen M.

Objective: The management of the clinically node negative (N0) neck in patients with squamous cell carcinoma of the maxilla (MSCC) is a matter of debate. In this retrospective cohort study the incidence of occult metastases is determined in clinically N0 MSCCs, as well as histopathological factors

Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome

Energy Technology Data Exchange (ETDEWEB)

Doyen, J. [Department of Radiation Oncology, Centre A. Lacassagne, Nice (France); Trastour, C. [Department of Gynecology, Archet II Hospital, 06202 Nice (France); Ettore, F.; Peyrottes, I.; Toussant, N. [Department of Pathology, Centre A. Lacassagne, Nice (France); Gal, J. [Department of Medical Statistics, Centre A. Lacassagne, Nice (France); Ilc, K.; Roux, D. [Institute for Research on Cancer and Aging (IRCAN), University of Nice, Centre A. Lacassagne, 06189 Nice (France); Parks, S.K. [Centre Scientifique de Monaco (CSM) (Monaco); Ferrero, J.M. [Department of Medical Oncology, Centre A. Lacassagne, Nice (France); Pouysségur, J., E-mail: jacques.pouyssegur@unice.fr [Institute for Research on Cancer and Aging (IRCAN), University of Nice, Centre A. Lacassagne, 06189 Nice (France); Centre Scientifique de Monaco (CSM) (Monaco)

2014-08-15

Highlights: • Glycolytic markers are highly expressed in triple negative breast cancers. • Lactate/H{sup +} symporter MCT4 demonstrated the strongest deleterious impact on survival. • MCT4 should serve as a new prognostic factor in node-negative breast cancers. - Abstract: Background: {sup 18}Fluor-deoxy-glucose PET-scanning of glycolytic metabolism is being used for staging in many tumors however its impact on prognosis has never been studied in breast cancer. Methods: Glycolytic and hypoxic markers: glucose transporter (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 and 4 (MCT1, 4), MCT accessory protein basigin and lactate-dehydrogenase A (LDH-A) were assessed by immunohistochemistry in two cohorts of breast cancer comprising 643 node-negative and 127 triple negative breast cancers (TNBC) respectively. Results: In the 643 node-negative breast tumor cohort with a median follow-up of 124 months, TNBC were the most glycolytic (≈70%), followed by Her-2 (≈50%) and RH-positive cancers (≈30%). Tumoral MCT4 staining (without stromal staining) was a strong independent prognostic factor for metastasis-free survival (HR = 0.47, P = 0.02) and overall-survival (HR = 0.38, P = 0.002). These results were confirmed in the independent cohort of 127 cancer patients. Conclusion: Glycolytic markers are expressed in all breast tumors with highest expression occurring in TNBC. MCT4, the hypoxia-inducible lactate/H{sup +} symporter demonstrated the strongest deleterious impact on survival. We propose that MCT4 serves as a new prognostic factor in node-negative breast cancer and can perhaps act soon as a theranostic factor considering the current pharmacological development of MCT4 inhibitors.

Treatment of triple-negative breast cancer with Chinese herbal medicine

Science.gov (United States)

Meng, Hui; Peng, Nan; Yu, Mingwei; Sun, Xu; Ma, Yunfei; Yang, Guowang; Wang, Xiaomin

2017-01-01

Abstract Introduction: Triple-negative breast cancer (TNBC) is featured with the biological properties of strong aggressive behaviors, rapid disease progression, high risk of recurrence and metastasis, and low disease free survival. Patients with this tumor are insensitive to the endocrine therapy and target treatment for HER-2; therefore, chemotherapy is often used as routine treatment in clinical. Because of the fact that a considerable number of patients seek for Chinese herbal medicine (CHM) treatment after operation and chemotherapy and (or) radiotherapy, it is thus need to evaluate the correlation between Chinese herbal medicine treatment and prognosis. Methods and analysis: This is a multicenter, prospective cohort study started in March 2016 in Beijing. A simple of 220 participants diagnosed with TNBC were recruited from nine hospitals and are followed up every 3 to 6 months till March 2020. Detailed information of participants includes personal information, history of cancer, quality of life, symptoms of traditional Chinese medicine and fatigue status is taken face-to-face at baseline. Ethics and dissemination: The study has received ethical approval from the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University (No.2016BL-014-01). Articles summarizing the primary results and ancillary analyses will be published in peer-reviewed journals. Trial registration: Chinese Clinical Trial Registry: ChiCTR-OOC-16008246. PMID:29095272

TMEPAI genome editing in triple negative breast cancer cells

Directory of Open Access Journals (Sweden)

Bantari W.K. Wardhani

2017-05-01

Full Text Available Background: Clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9 is a powerful genome editing technique. It consists of RNA-guided DNA endonuclease Cas9 and single guide RNA (gRNA. By combining their expressions, high efficiency cleavage of the target gene can be achieved, leading to the formation of DNA double-strand break (DSB at the genomic locus of interest which will be repaired via NHEJ (non-homologous end joining or HDR (homology-directed repair and mediate DNA alteration. We aimed to apply the CRISPR/Cas9 technique to knock-out the transmembrane prostate androgen-induced protein (TMEPAI gene in the triple negative breast cancer cell line.Methods: Designed gRNA which targets the TMEPAI gene was synthesized, annealed, and cloned into gRNA expression vector. It was co-transfected into the TNBC cell line using polyethylenimine (PEI together with Cas9-GFP and puromycin resistant gene vector. At 24-hours post-transfection, cells were selected by puromycin for 3 days before they were cloned. Selected knock-out clones were subsequently checked on their protein levels by western blotting.Results: CRISPR/Cas9, a genome engineering technique successfully knocked-out TMEPAI in the Hs578T TNBC cell line. Sequencing shows a frameshift mutation in TMEPAI. Western blot shows the absence of TMEPAI band on Hs578T KO cells.Conclusion: TMEPAI gene was deleted in the TNBC cell line using the genomic editing technique CRISPR/Cas9. The deletion was confirmed by genome and protein analysis.

5-FU and ixabepilone modify the microRNA expression profiles in MDA-MB-453 triple-negative breast cancer cells

OpenAIRE

YAO, YONGSHAN; CHEN, SHENGHAN; ZHOU, XIN; XIE, LI; CHEN, AIJUN

2013-01-01

This study aimed to discover new potential mechanisms of chemotherapy with drugs used in the treatment of luminal androgen receptor (LAR)-type triple-negative breast cancer (TNBC). We examined the microRNA (miRNA) expression profiles of LAR-type TNBC in vitro, and explored the variation in miRNA expression profiles in cells when treated with the chemotherapy drugs capecitabine and ixabepilone. The present study revealed that the expression levels of the three antitumor miRNAs, miR-122a, miR-1...

Immunohistochemical Expression of Survivin in Breast Carcinoma: Relationship with Clinico pathological Parameters, Proliferation and Molecular Classification

International Nuclear Information System (INIS)

YOUSSEF, N.S.; HEWEDI, I.H.; ABD RABOH, N.M.

2008-01-01

Background and Objective: Survivin is a novel member of the inhibitor of apoptosis (IAP) gene family. It is associated with more aggressive behavior and parameters of poor prognosis in most human cancers including gastric, colorectal and bladder carcinomas. However, conflicting data exist on its prognostic effect in breast cancer. This current study is designed to assess survivin expression in breast carcinoma relating results with clinico pathological parameters, proliferation (MIB-1) and molecular classification. Material and Methods: Our retrospective study com- prised of 65 archived cases of breast carcinoma. Samples from the tumor and the adjacent normal breast tissue were immuno stained for survivin and MIB-1. Nuclear and cytoplasmic survivin expression was evaluated in normal breast tissue and carcinoma regarding both the intensity and the percentage of positive cells. ER, PR, HER2 were used as surrogate markers to classify the cases into four molecular subtypes. Results: Survivin expression was detected in 78.5% of breast carcinomas. The adjacent normal breast tissue was immuno negative. Survivin expression showed significant association with increased tumor size ( p <0.0001), high histologic grade ( p =0.04), lymph node metastases ( p <0.001), advanced tumor stage ( p <0.0001), MIB-1 expression ( p =0.02), negative estrogen receptor status ( p =0.01) and negative progesterone receptor status ( p <0.0001). The subcellular localization of survivin significantly related to histologic grade, stage and lymph node involvement. The percentage of TNP (triple negative phenotype) and HER2+/ER-PR- tumors expressing survivin were significantly higher compared to the Luminal subtypes ( p =0.01). Conclusion: Survivin expression was associated with parameters of poor prognosis in breast cancer. Moreover, the cancer-specific expression of survivin, coupled with its importance in inhibiting cell death and in regulating cell division, makes it a potential target for novel

Microglandular adenosis: a prime suspect in triple-negative breast cancer development.

Science.gov (United States)

Tsang, Julia Ys; Tse, Gary Mk

2016-06-01

Microglandular adenosis (MGA) and atypical MGA (AMGA) are unusual lesions of the breast. They were once regarded as benign proliferative lesions and innocent bystanders. Several lines of evidence suggested that they could be neoplastic, clonal lesions and a non-obligate precursor for triple-negative breast cancers (TNBC). Recent work published in The Journal of Pathology by Guerini-Rocco and colleagues provided further evidence regarding the precursor-product relationship between MGA/AMGA and TNBC. Using a massively parallel sequencing approach, they demonstrated that MGA/AMGA, particularly those associated with TNBC, could be clonal neoplastic lesions showing clonal non-synonymous mutations, but none in pure MGA. Importantly, those alterations were observed in the associated TNBC. They were also able to identify recurrent alterations in TP53 in those MGA/AMGA cases as well as their associated TNBC. The findings, in conjunction with others, underscore the significance for MGA in clinical diagnosis. The potential of a benign lesion to progress into an aggressive malignant tumour implies that modification of the current management approach may be necessary. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Integration of Genomic, Biologic, and Chemical Approaches to Target p53 Loss and Gain-of-Function in Triple Negative Breast Cancer

Science.gov (United States)

2016-09-01

in this progress report: p53 triple-negative breast cancer subtypes gene expression somatic cell genetics CRISPR / Cas 3. ACCOMPLISHMENTS Major...report, we described the creation of an isogenic p53 mutant TNBC cell line panel using CRISPR / Cas -mediated genome editing8 and the resultant...LOF null state. To validate that mutant p53 is directly responsible for this altered transcription, we will use the same CRISPR -mediated genome

Determination of HER2 and p53 Mutations by Sequence Analysis Method and EGFR/Chromosome 7 Gene Status by Fluorescence in Situ Hybridization for the Predilection of Targeted Therapy Modalities in Immunohistochemically Triple Negative Breast Carcinomas in Turkish Population.

Science.gov (United States)

Pala, Emel Ebru; Bayol, Umit; Keskin, Elif Usturali; Ozguzer, Alp; Kucuk, Ulku; Ozer, Ozge; Koc, Altug

2015-09-01

Triple negative breast cancer (TNBC), an agressive subtype accounts nearly 15 % of all breast carcinomas. Conventional chemotherapy is the only treatment modality thus new, effective targeted therapy methods have been investigated. Epidermal growth factor receptor (EGFR) inhibitors give hope according to the recent studies results. Also therapeutic agents have been tried against aberrant p53 signal activity as TNBC show high p53 mutation rates. Our aim was to detect the incidence of mutations/amplifications identified in TNBC in our population. Here we used sequence analysis to detect HER2 (exon 18-23), p53 (exon 5-8) mutations; fluorescence in situ hybridization (FISH) method to analyse EGFR/chromosome 7 centromere gene status in 82 immunohistochemically TNBC. Basaloid phenotype was identified in 49 (59.8 %) patients. EGFR amplification was noted in 5 cases (6.1 %). All EGFR amplified cases showed EGFR overexpression by immunohistochemistry (IHC). p53 mutations were identified in 33 (40.2 %) cases. Almost 60 % of the basal like breast cancer cases showed p53 mutation. Only one case showed HER2 mutation (exon 20:g.36830_3). Our results showed that gene amplification is not the unique mechanism in EGFR overexpression. IHC might be used in the decision of anti-EGFR therapy in routine practice. p53 mutation rate was lower than the rates reported in the literature probably due to ethnic differences and low sensitivity of sanger sequences in general mutation screening. We also established the rarity of HER2 mutation in TNBC. In conclusion EGFR and p53 are the major targets in TNBC also for our population.

Conditional internalization of PEGylated nanomedicines by PEG engagers for triple negative breast cancer therapy

Science.gov (United States)

Su, Yu-Cheng; Burnouf, Pierre-Alain; Chuang, Kuo-Hsiang; Chen, Bing-Mae; Cheng, Tian-Lu; Roffler, Steve R.

2017-06-01

Triple-negative breast cancer (TNBC) lacks effective treatment options due to the absence of traditional therapeutic targets. The epidermal growth factor receptor (EGFR) has emerged as a promising target for TNBC therapy because it is overexpressed in about 50% of TNBC patients. Here we describe a PEG engager that simultaneously binds polyethylene glycol and EGFR to deliver PEGylated nanomedicines to EGFR+ TNBC. The PEG engager displays conditional internalization by remaining on the surface of TNBC cells until contact with PEGylated nanocarriers triggers rapid engulfment of nanocargos. PEG engager enhances the anti-proliferative activity of PEG-liposomal doxorubicin to EGFR+ TNBC cells by up to 100-fold with potency dependent on EGFR expression levels. The PEG engager significantly increases retention of fluorescent PEG probes and enhances the antitumour activity of PEGylated liposomal doxorubicin in human TNBC xenografts. PEG engagers with specificity for EGFR are promising for improved treatment of EGFR+ TNBC patients.

A biomimetic collagen derived peptide exhibits anti-angiogenic activity in triple negative breast cancer.

Directory of Open Access Journals (Sweden)

Elena V Rosca

Full Text Available We investigated the application of a mimetic 20 amino acid peptide derived from type IV collagen for treatment of breast cancer. We showed that the peptide induced a decrease of proliferation, adhesion, and migration of endothelial and tumor cells in vitro. We also observed an inhibition of triple negative MDA-MB-231 xenograft growth by 75% relative to control when administered intraperitoneally for 27 days at 10 mg/kg. We monitored in vivo the changes in vascular properties throughout the treatment using MRI and found that the vascular volume and permeability surface area product decreased significantly. The treatment also resulted in an increase of caspase-3 activity and in a reduction of microvascular density. The multiple mode of action of this peptide, i.e., anti-angiogenic, and anti-tumorigenic, makes it a viable candidate as a therapeutic agent as a monotherapy or in combination with other compounds.

ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms.

Science.gov (United States)

Ralff, Marie D; Kline, Christina L B; Küçükkase, Ozan C; Wagner, Jessica; Lim, Bora; Dicker, David T; Prabhu, Varun V; Oster, Wolfgang; El-Deiry, Wafik S

2017-07-01

Breast cancer is a major cause of cancer-related death. TNF-related apoptosis-inducing ligand (TRAIL) has been of interest as a cancer therapeutic, but only a subset of triple-negative breast cancers (TNBC) is sensitive to TRAIL. The small-molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here, we show that ONC201 is efficacious against both TNBC and non-TNBC cells ( n = 13). A subset of TNBC and non-TNBC cells succumbs to ONC201-induced cell death. In 2 of 8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The proapoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8), ONC201 has an antiproliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G 1 phase of the cell cycle. pRb expression is associated with sensitivity to the antiproliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells ( n = 5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset ( n = 2) shows PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL independent. Our data demonstrate that ONC201 has potent antiproliferative and proapoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a preclinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. Mol Cancer Ther; 16(7); 1290-8. ©2017 AACR . ©2017 American Association for Cancer Research.

Lifeguard inhibition of Fas-mediated apoptosis: A possible mechanism for explaining the cisplatin resistance of triple-negative breast cancer cells.

Science.gov (United States)

Radin, Daniel; Lippa, Arnold; Patel, Parth; Leonardi, Donna

2016-02-01

Triple-negative breast cancer does not express estrogen receptor-α, progesterone or the HER2 receptor making hormone or antibody therapy ineffective. Cisplatin may initiate p73-dependent apoptosis in p53 mutant cell lines through Fas trimerization and Caspase-8 activation and Bax up regulation and subsequent Caspase-9 activation. The triple-negative breast cancer, MDA-MB-231, overexpresses the protein Lifeguard, which inhibits Fas-mediated apoptosis by inhibiting Caspase-8 activation after Fas trimerization. The relationship between Fas, Lifeguard and cisplatin is investigated by down regulating Lifeguard via shRNA. Results demonstrate that cisplatin's efficacy increases when Lifeguard is down regulated. Lifeguard Knockdown MDA-MB-231 continue to decrease in cell viability from 24 to 48h after cisplatin treatment while no additional decrease in viability is observed in the Wild-Type MDA over the same period. Higher Caspase-8 activity in the Lifeguard knockdown MDA after cisplatin administration could explain the significant decrease in cell viability from 24 to 48h. This cell type is also more sensitive to Fas ligand-mediated reductions in cell viability, confirming Lifeguard's anti-apoptotic function through the Fas receptor. This research suggests that the efficacy of chemotherapy acting through the Fas pathway would increase if Lifeguard were not overexpressed to inhibit Fas-mediated apoptosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer.

Science.gov (United States)

Martey, Orleans; Nimick, Mhairi; Taurin, Sebastien; Sundararajan, Vignesh; Greish, Khaled; Rosengren, Rhonda J

2017-01-01

Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71), that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA) micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks) also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg) for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles.

Ultra-microsecond pulsed curcumin for effective treatment of triple negative breast cancers.

Science.gov (United States)

Mittal, Lakshya; Raman, Vishak; Camarillo, Ignacio G; Sundararajan, Raji

2017-09-30

Triple negative breast cancer (TNBC) is difficult to treat due to lack of the three receptors, commonly used for treating breast cancers. Current standard of cure is either ineffective or refractive to many patients. Thus, there is a critical need for alternate, affordable therapies for TNBC cancers. Towards this, electrical pulse-mediated chemotherapy, known as electrochemotherapy is a viable option, because it uses the synergy of electrical pulses and the anticancer properties of chemo drug. Considering the cost and the harsh side effects of various commonly administered chemo drugs, in this study, low cost, yet effective, natural phytochemical curcumin is studied for its anticancer effect on MDA-MB-231, TNBC cells. We applied eight 10 μs, 2500 V/cm or 5000 V/cm pulses with 10 μM concentration of curcumin, and measured cell viability and cytotoxicity. Results indicate that cell survival, as low as 4% was induced by 5000 V/cm pulses, after 72 h, while it was 15% after 24 h. This demonstrates the potential of this treatment for TNBC and the transfer to clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

An overview of triple infection with hepatitis B, C and D viruses.

Science.gov (United States)

Riaz, Mehwish; Idrees, Muhamad; Kanwal, Hifza; Kabir, Firoz

2011-07-27

Viral hepatitis is one of the major health problems worldwide, particularly in South East Asian countries including Pakistan where hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are highly endemic. Hepatitis delta virus (HDV) is also not uncommon world-wide. HCV, HBV, and HDV share parallel routes of transmission due to which dual or triple viral infection can occur in a proportion of patients at the same time. HBV and HCV are important factors in the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). In addition to LC and HCC, chronic HDV infection also plays an important role in liver damage with oncogenic potential.The current article reviews the available literature about the epidemiology, pathogenesis, transmission, symptoms, diagnosis, replication, disease outcome, treatment and preventive measures of triple hepatitis infection by using key words; epidemiology of triple infection, risk factors, awareness status, treatment and replication cycle in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar. Total data from 74 different studies published from 1983 to 2010 on triple hepatitis infections were reviewed and included in this study. The present article briefly describes triple infection with HCV, HBV and HDV.

Prognostic Value of E-Cadherin and β-Catenin in Triple-Negative Breast Cancer.

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Shen, Tiansheng; Zhang, Kui; Siegal, Gene P; Wei, Shi

2016-11-01

To analyze the expression of E-cadherin and β-catenin in triple-negative breast cancer (TNBC) to assess their prognostic significance. The expression of E-cadherin and β-catenin was examined semiquantitatively and correlated with other pathologic factors and survival outcomes. Of 72 consecutive TNBCs, 56% showed reduced membranous expression of E-cadherin or β-catenin, with a strong correlation to each other. Of the clinicopathologic factors analyzed, tumor size and nodal status were significantly associated with overall survival and disease-specific survival, while the latter remained an independent factor by multivariate analysis. Reduced E-cadherin and β-catenin were both significantly associated with a poor overall survival and disease-specific survival by univariate and multivariate analyses. E-cadherin and β-catenin expression provides discriminative prognostic power independent of conventional pathologic factors, thus further reinforcing the important role of cell adhesion molecules in the process of tumor metastasis, especially in TNBC. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Esophageal squamous cell carcinoma presenting as submucosal lesion with repeatedly negative endoscopic biopsies

Directory of Open Access Journals (Sweden)

Narendra S Choudhary

2016-01-01

Full Text Available A 74-year-old male presented with dysphagia for 2 months. Computed tomography revealed irregular wall thickening of the esophagus at T3 to T5 level. He underwent gastroscopy which revealed a submucosal bulge with normal mucosa at 25 cm from incisors. Repeated biopsies were taken, all were negative for malignancy. The patient underwent endoscopic ultrasound, and fine-needle aspiration was taken which was suggestive for squamous cell carcinoma.

Identification of Novel Biomarkers and Targeting Tumor-Initiating Cell Clones of the Triple-Negative Breast Cancer Subtype

DEFF Research Database (Denmark)

Ehmsen, Sidse

Brystkræft påvirker mere end 10% af kvinderne i vestlige lande og er den hyppigste årsag til kræftrelateret dødelighed blandt kvinder på verdensplan. Den triple-negative brystkræft-subtype (TNBC, (ER-/PR-/HER2normal)) udgør ca. 10% af alle brystkræfttilfældene, samtidig er den aggressiv og forbun....... En af de nyeste strategier inden for terapi mod CSC’er er at ramme essentielle signalveje inden for selv-fornyelse of metastasering. Formålet med arbejdet præsenteret i denne afhandling er at identificere nye biomarkører, der kan undergruppere den ellers meget heterogene gruppe af TNBC...

Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression.

Science.gov (United States)

Li, Linda Xiaoyan; Zhou, Julie Xia; Calvet, James P; Godwin, Andrew K; Jensen, Roy A; Li, Xiaogang

2018-02-27

We identified SMYD2, a SMYD (SET and MYND domain) family protein with lysine methyltransferase activity, as a novel breast cancer oncogene. SMYD2 was expressed at significantly higher levels in breast cancer cell lines and in breast tumor tissues. Silencing of SMYD2 by RNAi in triple-negative breast cancer (TNBC) cell lines or inhibition of SMYD2 with its specific inhibitor, AZ505, significantly reduced tumor growth in vivo. SMYD2 executes this activity via methylation and activation of its novel non-histone substrates, including STAT3 and the p65 subunit of NF-κB, leading to increased TNBC cell proliferation and survival. There are cross-talk and synergistic effects among SMYD2, STAT3, and NF-κB in TNBC cells, in that STAT3 can contribute to the modification of NF-κB p65 subunit post-translationally by recruitment of SMYD2, whereas the p65 subunit of NF-κB can also contribute to the modification of STAT3 post-translationally by recruitment of SMYD2, leading to methylation and activation of STAT3 and p65 in these cells. The expression of SMYD2 can be upregulated by IL-6-STAT3 and TNFα-NF-κB signaling, which integrates epigenetic regulation to inflammation in TNBC development. In addition, we have identified a novel SMYD2 transcriptional target gene, PTPN13, which links SMYD2 to other known breast cancer associated signaling pathways, including ERK, mTOR, and Akt signaling via PTPN13 mediated phosphorylation.

Three-year follow-up of sentinel node-negative patients with early oral cavity squamous cell carcinoma

DEFF Research Database (Denmark)

Sebbesen, Lars; Bilde, Anders; Therkildsen, Marianne

2014-01-01

2009, 53 consecutive SNB-negative patients with oral cavity squamous cell carcinoma (SCC) T1 to T2 were accrued. Follow-up was done continuously with the most recent examination in October 2011. The location of the sentinel lymph nodes was determined using dynamic and planar lymphoscintigraphy...

The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

International Nuclear Information System (INIS)

Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.; Anderson, Redmond-Craig; Zeng, Chenbo; Xu, Kuiying; Hou, Catherine; McDonald, Elizabeth S.; Pryma, Daniel A.; Mach, Robert H.

2015-01-01

Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods: Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. - Highlights: • TNBC cells are sensitive to sigma-2 receptor targeted drug conjugate SW IV-134. • MDA-MB-231 displayed the highest amount of sigma-2 receptors and corresponded well with

The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

Energy Technology Data Exchange (ETDEWEB)

Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.; Anderson, Redmond-Craig; Zeng, Chenbo; Xu, Kuiying; Hou, Catherine; McDonald, Elizabeth S.; Pryma, Daniel A.; Mach, Robert H., E-mail: rmach@mail.med.upenn.edu

2015-11-27

Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods: Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. - Highlights: • TNBC cells are sensitive to sigma-2 receptor targeted drug conjugate SW IV-134. • MDA-MB-231 displayed the highest amount of sigma-2 receptors and corresponded well with

ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms

Science.gov (United States)

Ralff, Marie D.; Kline, Christina L.B.; Küçükkase, Ozan C; Wagner, Jessica; Lim, Bora; Dicker, David T.; Prabhu, Varun V.; Oster, Wolfgang; El-Deiry, Wafik S.

2017-01-01

Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13). A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8) ONC201 has an anti-proliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G1 phase of the cell cycle. pRb expression is associated with sensitivity to the anti-proliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n=5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n=2) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. PMID:28424227

Triple synchronous cancers. A medical and ethical problem

International Nuclear Information System (INIS)

Debevec, L.; Cesar, R.; Kern, I.

2007-01-01

In a patient with suspicious synchronous multiple tumours, there are limited possibilities for effective therapy. Therefore, the decision for invasive diagnostics and precise staging of tumours is questionable, especially in elderly patients suitable only for symptomatic therapy. A 78-year-old man with hypertension and angina pectoris was admitted to the hospital due to syncope. Two primary lung tumours and a kidney tumour were detected by imaging investigation. The patient refused invasive diagnostics and left the hospital. After 19 months he was readmitted in an impaired clinical condition and subsequently died of bronchopneumonia. The autopsy revealed squamous cell carcinoma of the right upper lobe with metastases to regional lymph nodes and to the brain, small-cell carcinoma of the left upper lobe with metastases to regional lymph nodes and to the spleen, and clear-cell kidney carcinoma with multiple metastases to the lungs. All tumours were necrotizing, and therefore we assumed that any attempt at specific therapy would have been ineffective. In an elderly patient with advanced lung tumors and suspicious synchronous triple cancers, the ''wait and see'' option can be suitable. (author)

The PIKfyve–ArPIKfyve–Sac3 triad in human breast cancer: Functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines

International Nuclear Information System (INIS)

Ikonomov, Ognian C.; Filios, Catherine; Sbrissa, Diego; Chen, Xuequn; Shisheva, Assia

2013-01-01

Highlights: •We assess PAS complex proteins and phosphoinositide levels in breast cancer cells. •Sac3 and ArPIKfyve are markedly elevated in triple-negative breast cancer cells. •Sac3 silencing inhibits proliferation in triple-negative breast cancer cell lines. •Phosphoinositide profiles are altered in breast cancer cells. •This is the first evidence linking high Sac3 with breast cancer cell proliferation. -- Abstract: The phosphoinositide 5-kinase PIKfyve and 5-phosphatase Sac3 are scaffolded by ArPIKfyve in the PIKfyve–ArPIKfyve–Sac3 (PAS) regulatory complex to trigger a unique loop of PtdIns3P–PtdIns(3,5)P 2 synthesis and turnover. Whereas the metabolizing enzymes of the other 3-phosphoinositides have already been implicated in breast cancer, the role of the PAS proteins and the PtdIns3P–PtdIns(3,5)P 2 conversion is unknown. To begin elucidating their roles, in this study we monitored the endogenous levels of the PAS complex proteins in cell lines derived from hormone-receptor positive (MCF7 and T47D) or triple-negative breast cancers (TNBC) (BT20, BT549 and MDA-MB-231) as well as in MCF10A cells derived from non-tumorigenic mastectomy. We report profound upregulation of Sac3 and ArPIKfyve in the triple negative vs. hormone-sensitive breast cancer or non-tumorigenic cells, with BT cell lines showing the highest levels. siRNA-mediated knockdown of Sac3, but not that of PIKfyve, significantly inhibited proliferation of BT20 and BT549 cells. In these cells, knockdown of ArPIKfyve had only a minor effect, consistent with a primary role for Sac3 in TNBC cell proliferation. Intriguingly, steady-state levels of PtdIns(3,5)P 2 in BT20 and T47D cells were similar despite the 6-fold difference in Sac3 levels between these cell lines. However, steady-state levels of PtdIns3P and PtdIns5P, both regulated by the PAS complex, were significantly reduced in BT20 vs. T47D or MCF10A cell lines, consistent with elevated Sac3 affecting directly or indirectly the

Standard of Care and Promising New Agents for Triple Negative Metastatic Breast Cancer

Directory of Open Access Journals (Sweden)

Patrizia Mancini

2014-10-01

Full Text Available Triple negative breast cancer (TNBC is a cluster of heterogeneous diseases, all of them sharing the lack of expression of estrogen and progesterone receptors and HER2 protein. They are characterized by different biological, molecular and clinical features, including a poor prognosis despite the increased sensitivity to the current cytotoxic therapies. Several studies have identified important molecular features which enable further subdivision of this type of tumor. We are drawing from genomics, transcription and translation analysis at different levels, to improve our knowledge of the molecular alterations along the pathways which are activated during carcinogenesis and tumor progression. How this information should be used for the rational selection of therapy is an ongoing challenge and the subject of numerous research studies in progress. Currently, the vascular endothelial growth factor (VEGF, poly (ADP-ribose polymerase (PARP, HSP90 and Aurora inhibitors are most used as targeting agents in metastatic setting clinical trials. In this paper we will review the current knowledge about the genetic subtypes of TNBC and their different responses to conventional therapeutic strategies, as well as to some new promising molecular target agents, aimed to achieve more tailored therapies.

Standard of Care and Promising New Agents for Triple Negative Metastatic Breast Cancer

Energy Technology Data Exchange (ETDEWEB)

Mancini, Patrizia, E-mail: patrizia.mancini@uniroma1.it [Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Angeloni, Antonio [Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Risi, Emanuela [Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Orsi, Errico [Department of Surgical Science, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Mezi, Silvia [Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy)

2014-10-24

Triple negative breast cancer (TNBC) is a cluster of heterogeneous diseases, all of them sharing the lack of expression of estrogen and progesterone receptors and HER2 protein. They are characterized by different biological, molecular and clinical features, including a poor prognosis despite the increased sensitivity to the current cytotoxic therapies. Several studies have identified important molecular features which enable further subdivision of this type of tumor. We are drawing from genomics, transcription and translation analysis at different levels, to improve our knowledge of the molecular alterations along the pathways which are activated during carcinogenesis and tumor progression. How this information should be used for the rational selection of therapy is an ongoing challenge and the subject of numerous research studies in progress. Currently, the vascular endothelial growth factor (VEGF), poly (ADP-ribose) polymerase (PARP), HSP90 and Aurora inhibitors are most used as targeting agents in metastatic setting clinical trials. In this paper we will review the current knowledge about the genetic subtypes of TNBC and their different responses to conventional therapeutic strategies, as well as to some new promising molecular target agents, aimed to achieve more tailored therapies.

Function of AURKA protein kinase in the formation of vasculogenic mimicry in triple-negative breast cancer stem cells

Directory of Open Access Journals (Sweden)

Liu Y

2016-06-01

Full Text Available Ying Liu,1,2,* Baocun Sun,1–3,* Tieju Liu,1,2,* Xiulan Zhao,1,2 Xudong Wang,3 Yanlei Li,1,2 Jie Meng,2 Qiang Gu,1,2 Fang Liu,1,2 Xueyi Dong,1,2 Peimei Liu,2 Ran Sun,2 Nan Zhao1 1Department of Pathology, General Hospital of Tianjin Medical University, 2Department of Pathology, Tianjin Medical University, 3Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, People’s Republic of China *These authors contributed equally to this work Abstract: Tumor cell vasculogenic mimicry (VM, a newly defined pattern of tumor blood supply, signifies the functional plasticity of aggressive cancer cells forming vascular networks. VM and cancer stem cells (CSCs have been shown to be associated with tumor growth, local invasion, and distant metastasis. In our previous study, CSCs in triple-negative breast cancer were potential to participate in VM formation. In this study, breast CSCs were isolated from the triple-negative breast cancer cell line MDA-MB-231 by using mammosphere culture. Western blotting and reverse transcription polymerase chain reaction showed that mammosphere cells displayed an increased expression of AURKA protein kinase and stem cell marker c-myc and sox2. The VM formation by mammosphere cells was inhibited by AURKA knockdown or the addition of AURKA inhibitor MLN8237. In the meantime, MLN8237 induced the increased E-cadherin and decreased c-myc, sox2, and β-catenin expressions. The function of AURKA in VM formation was further confirmed using a xenograft-murine model. The results suggested that AURKA protein kinase is involved in VM formation of CSCs and may become a new treatment target in suppressing VM and metastasis of breast cancer. Keywords: AURKA, cancer stem cells, vasculogenic mimicry, breast cancer

Granzyme B-based cytolytic fusion protein targeting EpCAM specifically kills triple negative breast cancer cells in vitro and inhibits tumor growth in a subcutaneous mouse tumor model

NARCIS (Netherlands)

Amoury, Manal; Kolberg, Katharina; Pham, Anh-Tuan; Hristodorov, Dmitrij; Mladenov, Radoslav; Di Fiore, Stefano; Helfrich, Wijnand; Kiessling, Fabian; Fischer, Rainer; Pardo, Alessa; Thepen, Theophilus; Hussain, Ahmad F.; Nachreiner, Thomas; Barth, Stefan

2016-01-01

Triple-negative breast cancer (TNBC) is associated with poor prognosis and high prevalence among young premenopausal women. Unlike in other breast cancer subtypes, no targeted therapy is currently available. Overexpression of epithelial cell adhesion molecule (EpCAM) in 60% of TNBC tumors correlates

Number of negative lymph nodes as a prognostic factor in esophageal squamous cell carcinoma.

Science.gov (United States)

Ma, Mingquan; Tang, Peng; Jiang, Hongjing; Gong, Lei; Duan, Xiaofeng; Shang, Xiaobin; Yu, Zhentao

2017-10-01

The aim of this study is to investigate the number of negative lymph nodes (NLNs) as a prognostic factor for survival in patients with resected esophageal squamous cell carcinoma. A total of 381 esophageal squamous cell carcinoma patients who had underwent surgical resection as the primary treatment was enrolled into this retrospective study. The impact of number of NLNs on patient's overall survival was assessed and compared with the factors among the current tumor-nodes-metastasis (TNM) staging system. The number of NLNs was closely related to the overall survival, and the 5-year survival rate was 45.4% for number of NLNs of >20 (142 cases) and 26.4% for NLNs ≤ 20 (239 cases) (P = 0.001). In multivariate survival analysis, the number of NLNs remained an independent prognostic factor (P = 0.002) as did the other current TNM factors. For subgroup analysis, the predictive value of number of NLNs was significant in patients with T3 or T4 disease (P = 0.001) and patients with N1 and N2-3 disease (P = 0.025, 0.043), but not in patients with T1 or T2 disease or patients with N0 disease. The number of NLNs, which represents the extent of lymphadenectomy for esophageal squamous cell carcinoma, could impact the overall survival of patients with resected esophageal squamous cell carcinoma, especially among those with nodal-positive disease and advanced T-stage tumor. © 2016 John Wiley & Sons Australia, Ltd.

Serum albumin and globulin analysis for hepatocellular carcinoma detection avoiding false-negative results from alpha-fetoprotein test negative subjects

Science.gov (United States)

Wang, Jing; Feng, Shangyuan; Lin, Juqiang; Zeng, Yongyi; Li, Ling; Huang, Zufang; Li, Buhong; Zeng, Haishan; Chen, Rong

2013-11-01

Surface-enhanced Raman spectroscopy (SERS) of serum albumin and globulin were employed to detect hepatocellular carcinoma (HCC). Tentative assignments of SERS bands show specific biomolecular changes associated with cancer development. These changes include a decrease in relative amounts of tryptophan, glutamine, glycine, and serine, indicating excessive consumption of amino acids for protein duplication. Principal component analysis was also introduced to analyze the obtained spectra, resulting in both diagnostic sensitivity and specificity of 100%. More importantly, it reveals that this method can detect HCC patients with alpha-fetoprotein negative test results, suggesting its great potential as a new alternative to detect HCC.

Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy.

Science.gov (United States)

Feng, Tingting; Cao, Wei; Shen, Wanxiang; Zhang, Liang; Gu, Xinsheng; Guo, Yang; Tsai, Hsiang-I; Liu, Xuewen; Li, Jian; Zhang, Jingxuan; Li, Shan; Wu, Fuyun; Liu, Ying

2017-01-03

Triple-negative breast cancers (TNBCs) are the most aggressive and hard-to-treat breast tumors with poor prognosis, and exploration for novel therapeutic drugs is impending. Arctigenin (Atn), a bioactive lignan isolated from seeds of Arctium lappa L, has been reported to inhibit many cancer types; however, the effect of Atn on TNBC remains unclear. In this study, we demonstrated that Atn decreased proliferation, and induced apoptosis in TNBC cells. Furthermore, we explored the underlying mechanism of Atn inhibition on TNBC cells. Computational docking and affinity assay showed that Atn bound to the SH2 domain of STAT3. Atn inhibited STAT3 binding to genomic DNA by disrupting hydrogen bond linking between DNA and STAT3. In addition, Atn augmented Taxotere®-induced TNBC cell cytotoxicity. TNBC xenograft tests also confirmed the antitumor effect of Atn in vivo. These characteristics render Atn as a promising candidate drug for further development and for designing new effective STAT3 inhibitors.

Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy

Science.gov (United States)

Shen, Wanxiang; Zhang, Liang; Gu, Xinsheng; Guo, Yang; Tsai, Hsiang-i; Liu, Xuewen; Li, Jian; Zhang, Jingxuan; Li, Shan; Wu, Fuyun; Liu, Ying

2017-01-01

Triple-negative breast cancers (TNBCs) are the most aggressive and hard-to-treat breast tumors with poor prognosis, and exploration for novel therapeutic drugs is impending. Arctigenin (Atn), a bioactive lignan isolated from seeds of Arctium lappa L, has been reported to inhibit many cancer types; however, the effect of Atn on TNBC remains unclear. In this study, we demonstrated that Atn decreased proliferation, and induced apoptosis in TNBC cells. Furthermore, we explored the underlying mechanism of Atn inhibition on TNBC cells. Computational docking and affinity assay showed that Atn bound to the SH2 domain of STAT3. Atn inhibited STAT3 binding to genomic DNA by disrupting hydrogen bond linking between DNA and STAT3. In addition, Atn augmented Taxotere®-induced TNBC cell cytotoxicity. TNBC xenograft tests also confirmed the antitumor effect of Atn in vivo. These characteristics render Atn as a promising candidate drug for further development and for designing new effective STAT3 inhibitors. PMID:27861147

Exercise and dietary advice intervention for survivors of triple-negative breast cancer: effects on body fat, physical function, quality of life, and adipokine profile.

Science.gov (United States)

Swisher, Anne K; Abraham, Jame; Bonner, Daniel; Gilleland, Diana; Hobbs, Gerald; Kurian, Sobha; Yanosik, Mary Anne; Vona-Davis, Linda

2015-10-01

Regular exercise and healthy eating are routinely recommended for breast cancer survivors, and past studies show benefits in quality of life and decreased inflammation. However, this has not been tested specifically in triple-negative breast cancer survivors. Increasing physical activity and losing body fat are thought to positively affect inflammatory biomarkers that have been associated with breast cancer. Therefore, the primary purpose of this study was to determine if participation in an exercise and dietary counseling program can improve body fat, physical function, and quality of life in survivors of this aggressive breast cancer. Secondarily, we sought to determine if participation in the program had beneficial effects on obesity-related markers of the adipokine profile. Sixty-six survivors of triple-negative breast cancer with BMI >25 were invited to participate. Twenty-eight enrolled and 23 completed the randomized, controlled trial (13 intervention, 10 control). Moderate-intensity aerobic exercise (150 min per week, for 12 weeks) and diet counseling were compared to usual care, education only. The primary outcome of interest was weight loss (body mass, BMI, % fat), and secondary outcomes included physical function (exercise capacity), quality of life (Function After Cancer Therapy-Breast (FACT-B)), cytokines (C-reactive protein (CRP), TNF-α, IL-6), and adipokine profile (leptin, adiponectin, insulin). Participants in the program lost more body fat (2.4 % loss vs. 0.4 % gain, p life (FACT-B total score +14 pts) and decreased sedentary time but did not improve peak exercise capacity. The intervention had no effect on serum cytokines and adipokines after 12 weeks in the program. However, serum leptin and adiponectin and their ratio were significantly correlated with BMI in the intervention group (p life in survivors of triple-negative breast cancer. BMI was associated with favorable changes in leptin and adiponectin which may reflect a change in adiposity

KIF14 Promotes AKT Phosphorylation and Contributes to Chemoresistance in Triple-Negative Breast Cancer

Directory of Open Access Journals (Sweden)

Stina M. Singel

2014-03-01

Full Text Available Despite evidence that kinesin family member 14 (KIF14 can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor–negative/progesterone receptor–negative/human epidermal growth factor receptor 2-negative, “triple-negative” breast cancers (TNBC. To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.

Divergent Synthesis of Chondroitin Sulfate Disaccharides and Identification of Sulfate Motifs that Inhibit Triple Negative Breast Cancer

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Wei Poh, Zhong; Heng Gan, Chin; Lee, Eric J.; Guo, Suxian; Yip, George W.; Lam, Yulin

2015-09-01

Glycosaminoglycans (GAGs) regulate many important physiological processes. A pertinent issue to address is whether GAGs encode important functional information via introduction of position specific sulfate groups in the GAG structure. However, procurement of pure, homogenous GAG motifs to probe the “sulfation code” is a challenging task due to isolation difficulty and structural complexity. To this end, we devised a versatile synthetic strategy to obtain all the 16 theoretically possible sulfation patterns in the chondroitin sulfate (CS) repeating unit; these include rare but potentially important sulfated motifs which have not been isolated earlier. Biological evaluation indicated that CS sulfation patterns had differing effects for different breast cancer cell types, and the greatest inhibitory effect was observed for the most aggressive, triple negative breast cancer cell line MDA-MB-231.

miR-367 promotes proliferation and invasion of hepatocellular carcinoma cells by negatively regulating PTEN

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Meng, Xiangrui, E-mail: mengxiangruibb2008@163.com [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Lu, Peng [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Fan, Qingxia [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China)

2016-01-29

MicroRNAs play important roles in the carcinogenesis of many types of cancers by inhibiting gene expression at posttranscriptional level. However, the roles of microRNAs in hepatocellular carcinoma, are still unclear. Here, we identified that miR-367 promotes hepatocellular carcinoma (HCC) cell proliferation by negatively regulates its target gene PTEN. The expression of miR-367 and PTEN are significantly inverse correlated in 35 HCC patients. In HCC cell line, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-367, while miR-367 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-367 mimics significantly promoted the migration and invasion of HCC cells, whereas miR-367 inhibitors significantly reduced cell migration and invasion. Luciferase assays confirmed that miR-367 directly bound to the 3'untranslated region of PTEN, and western blotting showed that miR-367 suppressed the expression of PTEN at the protein levels. This study indicated that miR-367 negatively regulates PTEN and promotes proliferation and invasion of HCC cells. Thus, miR-367 may represent a potential therapeutic target for HCC intervention. - Highlights: • miR-367 mimics promote the proliferation and invasion of HCC cells. • miR-367 inhibitors inhibit the proliferation and invasion of HCC cells. • miR-367 targets 3′UTR of PTEN in HCC cells. • miR-367 negatively regulates PTEN in HCC cells.

Triple-phase enhanced MSCT in evaluating solitary pulmonary nodules

International Nuclear Information System (INIS)

Zhang Jin'e; Zhao Zhenjun; Liang Changhong; He Hui; Zhang Jia; Ru Guangteng

2005-01-01

Objective: An evaluation of the triple-phase enhanced MSCT in the assessment of solitary pulmonary nodules (SPN). Methods: Prospective study was made on 102 SPN using triple-phase enhanced MSCT, and the net elevation of the CT value of nodules as well as the neoplastic blood vessels were assessed. In total 102 patients were enrolled, including 63 males and 39 females, aged from 17 to 87 years (57.2 years in average). The nodules sized from 2.1 to 4.0 cm (3.3cm in average). Pulmonary carcinoma was proved in 71 cases and benign SPN in 31 cases(including 11 inflammatory pseudo tumors, 6 tuberculosis, 3 inflammatory granulomas, 3 lesions of acute nonspecific inflammation, 3 hamartomas, 3 mycosis and 2 abscesses). The spiral scan was performed on an 8-row detector spiral CT (GE/light speed Qx/I Extra) with 5mm/4 slices. The scan time was 1 second per circle. The 5mm sliced imaging was done for CT value measurement and 1.25mm sliced imaging was for MPR(multiplanar reconstruction) or VR(volume rendering), 20ml Ultravist(300 mg/I) was administered at first at a rate of 4ml/s via forearm superficial vein by a power injector. The peak CT values in pulmonary artery and aorta were to determine the delay time for the acquisition in pulmonary phase and aortal phase. Then Ultravist in a volume of lml/ body kilogram was injected, followed by 50 ml of sodium chloride. Delay phase was 3 minutes. Results: The differences of net increased CT value in three phases were statistically significant respectively between lung cancer and benign nodules (F=30.668, 4.495 and 56.141, respectively, P=0.000, 0.036 and 0. 000, respectively). When the net increased CT value≥20 HU was set as a diagnostic threshold, the sensitivity, specificity, positive predict value, negative predict value and veracity were 93%, 29%, 75%, 64.3% and 73.5%. When net increased CT value ≥20 HU in aortal phase while net increased CT value < 20 HU in pulmonary phase was set as a di- agnostic threshold, those values

Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials.

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Juul, Nicolai; Szallasi, Zoltan; Eklund, Aron C; Li, Qiyuan; Burrell, Rebecca A; Gerlinger, Marco; Valero, Vicente; Andreopoulou, Eleni; Esteva, Francisco J; Symmans, W Fraser; Desmedt, Christine; Haibe-Kains, Benjamin; Sotiriou, Christos; Pusztai, Lajos; Swanton, Charles

2010-04-01

Addition of taxanes to preoperative chemotherapy in breast cancer increases the proportion of patients who have a pathological complete response (pCR). However, a substantial proportion of patients do not respond, and the prognosis is particularly poor for patients with oestrogen-receptor (ER)/progesterone-receptor (PR)/human epidermal growth factor receptor 2 (HER2; ERBB2)-negative (triple-negative) disease who do not achieve a pCR. Reliable identification of such patients is the first step in determining who might benefit from alternative treatment regimens in clinical trials. We previously identified genes involved in mitosis or ceramide metabolism that influenced sensitivity to paclitaxel, with an RNA interference (RNAi) screen in three cancer cell lines, including a triple-negative breast-cancer cell line. Here, we assess these genes as a predictor of pCR to paclitaxel combination chemotherapy in triple-negative breast cancer. We derived a paclitaxel response metagene based on mitotic and ceramide genes identified by functional genomics studies. We used area under the curve (AUC) analysis and multivariate logistic regression to retrospectively assess the metagene in six cohorts of patients with triple-negative breast cancer treated with neoadjuvant chemotherapy; two cohorts treated with paclitaxel (n=27, 30) and four treated without paclitaxel (n=88, 28, 48, 39). The metagene was associated with pCR in paclitaxel-treated cohorts (AUC 0.79 [95% CI 0.53-0.93], 0.72 [0.48-0.90]) but not in non-paclitaxel treated cohorts (0.53 [0.31-0.77], 0.59 [0.22-0.82], 0.53 [0.36-0.71], 0.64 [0.43-0.81]). In multivariate logistic regression, the metagene was associated with pCR (OR 19.92, 2.62-151.57; p=0.0039) with paclitaxel-containing chemotherapy. The paclitaxel response metagene shows promise as a paclitaxel-specific predictor of pCR in patients with triple-negative breast cancer. The metagene is suitable for development into a reverse transcription-PCR assay, for which

Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance

Institute of Scientific and Technical Information of China (English)

Tianjian Yu; Genhong Di

2017-01-01

Breast cancer has been shown to live in the tumor microenvironment,which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells.Diverse components of the breast cancer microenvironment,such as suppressive immune cells,re-programmed fibroblast cells,altered extracellular matrix (ECM) and certain soluble factors,synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis.Among these components,stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways,whereas the ECM features biochemical and biomechanical changes.However,triple-negative breast cancer (TNBC),the most aggressive subtype of this disease that lacks effective therapies available for other subtypes,is considered to feature a unique microenvironment distinct from that of other subtypes,especially compared to Luminal A subtype.Because these changes are now considered to significantly impact breast cancer development and progression,these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC.In this review,we focus on the composition of the TNBC microenvironment,concomitant distinct biological alteration,specific interplay between various cell types and TNBC cells,and the prognostic implications of these findings.

Transcriptome analysis of Wnt3a-treated triple-negative breast cancer cells.

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Sylvie Maubant

Full Text Available The canonical Wnt/β-catenin pathway is activated in triple-negative breast cancer (TNBC. The activation of this pathway leads to the expression of specific target genes depending on the cell/tissue context. Here, we analyzed the transcriptome of two different TNBC cell lines to define a comprehensive list of Wnt target genes. The treatment of cells with Wnt3a for 6h up-regulated the expression (fold change > 1.3 of 59 genes in MDA-MB-468 cells and 241 genes in HCC38 cells. Thirty genes were common to both cell lines. Beta-catenin may also be a transcriptional repressor and we found that 18 and 166 genes were down-regulated in response to Wnt3a treatment for 6h in MDA-MB-468 and HCC38 cells, respectively, of which six were common to both cell lines. Only half of the activated and the repressed transcripts have been previously described as Wnt target genes. Therefore, our study reveals 137 novel genes that may be positively regulated by Wnt3a and 104 novel genes that may be negatively regulated by Wnt3a. These genes are involved in the Wnt pathway itself, and also in TGFβ, p53 and Hedgehog pathways. Thorough characterization of these novel potential Wnt target genes may reveal new regulators of the canonical Wnt pathway. The comparison of our list of Wnt target genes with those published in other cellular contexts confirms the notion that Wnt target genes are tissue-, cell line- and treatment-specific. Genes up-regulated in Wnt3a-stimulated cell lines were more strongly expressed in TNBC than in luminal A breast cancer samples. These genes were also overexpressed, but to a much lesser extent, in HER2+ and luminal B tumors. We identified 72 Wnt target genes higher expressed in TNBCs (17 with a fold change >1.3 which may reflect the chronic activation of the canonical Wnt pathway that occurs in TNBC tumors.

Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients – a retrospective study of clinical and tumor characteristics

International Nuclear Information System (INIS)

Besic, Nikola; Satej, Nika; Ratosa, Ivica; Horvat, Andreja Gojkovic; Marinko, Tanja; Gazic, Barbara; Petric, Rok

2014-01-01

Metformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC. A chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed. Control group consisted of 320 consecutive patients with invasive BC without DM. BC subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] + and/or progesterone receptor [PR]+, HER-2-), luminal B (ER + and/or PR+, HER-2+), HER-2 (ER-, PR-, HER-2+), triple-negative/basal (ER-, PR-, HER-2-). Patients on metformin had a lower proportion of T3 or T4 tumors than patients who were not receiving metformin (16% vs. 26%; p = 0.035). No statistical difference was found between the two study groups in N stage. Patients with DM on metformin, with DM not on metformin and the control group had different molecular subtypes of BC (p = 0.01): the luminal A subtype was found in 78%, 83% and 71%, the luminal B in 12.6%, 9% and 11%, HER-2 in 0.8%, 1.6% and 8%, and the triple-negative/basal-like subtype in 8.6%, 6.4% and 10%, respectively. Our data indicate that long-term use of metformin use correlates with molecular subtype of BC in diabetics on metformin in comparison to diabetics not on metformin and patients without DM. However, most likely, different distribution of the molecular subtypes of BC in these three groups of patients was caused by other risk factors for breast carcinoma, such as age of patients or obesity

Treatment outcome in patients with triple negative early stage breast cancers compared with other molecular subtypes

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Kim, Ja Young; Chang, Sei Kyung; Lee, Bo Mi; Shin, Hyun Soo; Park, Heily

2012-01-01

To determine whether triple negative (TN) early stage breast cancers have poorer survival rates compared with other molecular types. Between August 2000 and July 2006, patients diagnosed with stage I, II early stage breast cancers, in whom all three markers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor [HER]-2) were available and treated with modified radical mastectomy or breast conserving surgery followed by radiotherapy, were retrospectively reviewed. Of 446 patients, 94 (21.1%) were classified as TN, 57 (12.8%) as HER-2 type, and 295 (66.1%) as luminal. TN was more frequently associated with young patients younger than 35 years old (p = 0.002), higher histologic grade (p 0.05). We found that patients with TN early stage breast cancers had no difference in survival rates compared with other molecular subtypes. Prospective study in homogeneous treatment group will need for a prognosis of TN early stage breast cancer.

The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor

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Kristen L. Karlin

2014-11-01

Full Text Available Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 (“STP axis” cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase βTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

MicroPET/CT Imaging of AXL Downregulation by HSP90 Inhibition in Triple-Negative Breast Cancer

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Wanqin Wang

2017-01-01

Full Text Available AXL receptor tyrosine kinase is overexpressed in a number of solid tumor types including triple-negative breast cancer (TNBC. AXL is considered an important regulator of epithelial-to-mesenchymal transition (EMT and a potential therapeutic target for TNBC. In this work, we used microPET/CT with 64Cu-labeled anti-human AXL antibody (64Cu-anti-hAXL to noninvasively interrogate the degradation of AXL in vivo in response to 17-allylamino-17-demethoxygeldanamycin (17-AAG, a potent inhibitor of HSP90. 17-AAG treatment caused significant decline in AXL expression in orthotopic TNBC MDA-MB-231 tumors, inhibited EMT, and delayed tumor growth in vivo, resulting in significant reduction in tumor uptake of 64Cu-anti-hAXL as clearly visualized by microPET/CT. Our data indicate that 64Cu-anti-hAXL can be useful for monitoring anti-AXL therapies and for assessing inhibition of HSP90 molecular chaperone using AXL as a molecular surrogate.

HN1L Promotes Triple-Negative Breast Cancer Stem Cells through LEPR-STAT3 Pathway

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Yi Liu

2018-01-01

Full Text Available Here, we show that HEMATOLOGICAL AND NEUROLOGICAL EXPRESSED 1-LIKE (HN1L is a targetable breast cancer stem cell (BCSC gene that is altered in 25% of whole breast cancer and significantly correlated with shorter overall or relapse-free survival in triple-negative breast cancer (TNBC patients. HN1L silencing reduced the population of BCSCs, inhibited tumor initiation, resensitized chemoresistant tumors to docetaxel, and hindered cancer progression in multiple TNBC cell line-derived xenografts. Additionally, gene signatures associated with HN1L correlated with shorter disease-free survival of TNBC patients. We defined HN1L as a BCSC transcription regulator for genes involved in the LEPR-STAT3 signaling axis as HN1L binds to a putative consensus upstream sequence of STAT3, LEPTIN RECEPTOR, and MIR-150. Our data reveal that BCSCs in TNBC depend on the transcription regulator HN1L for the sustained activation of the LEPR-STAT3 pathway, which makes it a potentially important target for both prognosis and BCSC therapy.

A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1).

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Bonnefoi, H; Grellety, T; Tredan, O; Saghatchian, M; Dalenc, F; Mailliez, A; L'Haridon, T; Cottu, P; Abadie-Lacourtoisie, S; You, B; Mousseau, M; Dauba, J; Del Piano, F; Desmoulins, I; Coussy, F; Madranges, N; Grenier, J; Bidard, F C; Proudhon, C; MacGrogan, G; Orsini, C; Pulido, M; Gonçalves, A

2016-05-01

Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone. Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety. One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% [95% confidence interval (CI) 7.7%-38.6%], including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%-22.1%). The median PFS was 2.8 months (95% CI 1.7%-5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2. AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment. NCT01842321. © The Author 2016

The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer.

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Huang, Shang-Pen; Liu, Pei-Yao; Kuo, Chih-Jung; Chen, Chi-Long; Lee, Wei-Jiunn; Tsai, Yu-Hui; Lin, Yuan-Feng

2017-06-02

Distant metastasis of triple-negative breast cancer (TNBC) to other organs, e.g., the lungs, has been correlated with poor survival rates among breast cancer patients. Therefore, the identification of useful therapeutic targets to prevent metastasis or even inhibit tumor growth of TNBC is urgently needed. Gαh is a novel GTP-binding protein and known as an inactive form of calcium-dependent tissue transglutaminase. However, the functional consequences of transamidating and G-protein activities of tissue transglutaminase in promoting cancer metastasis are still controversial. Kaplan-Meier analyses were performed to estimate the prognostic values of Gαh and PLCδ1 by utilizing public databases and performing immunohistochemical staining experiments. Cell-based invasion assays and in vivo lung colony-forming and orthotropic lung metastasis models were established to evaluate the effectiveness of interrupting the protein-protein interaction (PPI) between Gαh and PLCδ1 in inhibiting the invasive ability and metastatic potential of TNBC cells. Here, we showed that the increased level of cytosolic, not extracellular, Gαh is a poor prognostic marker in breast cancer patients and correlates with the metastatic evolution of TNBC cells. Moreover, clinicopathological analyses revealed that the combined signature of high Gαh/PLCδ1 levels indicates worse prognosis in patients with breast cancer and correlates with lymph node metastasis of ER-negative breast cancer. Blocking the PPI of the Gαh/PLCδ1 complex by synthetically myristoylated PLCδ1 peptide corresponding to the Gαh-binding interface appeared to significantly suppress cellular invasiveness in vitro and inhibit lung metastatic colonies of TNBC cells in vivo. This study establishes Gαh/PLCδ1 as a poor prognostic factor for patients with estrogen receptor-negative breast cancers, including TNBCs, and provides therapeutic value by targeting the PPI of the Gαh/PLCδ1 complex to combat the metastatic progression

Impact of Statin Use on Outcomes in Triple Negative Breast Cancer

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Shaitelman, Simona F.; Stauder, Michael C.; Allen, Pamela; Reddy, Sangeetha; Lakoski, Susan; Atkinson, Bradley; Reddy, Jay; Amaya, Diana; Guerra, William; Ueno, Naoto; Caudle, Abigail; Tereffe, Welela; Woodward, Wendy A.

2017-01-01

Purpose: We sought to investigate if the use of HMG Co-A reductase inhibitors (statins) has an impact on outcomes among patients with triple negative breast cancer (TNBC). Methods: We reviewed the cases of women with invasive, non-metastatic TNBC, diagnosed 1997-2012. Clinical outcomes were compared based on statin use (defined as ever use during treatment vs. never use). We identified a subset of women for whom a 5-value lipid panel (5VLP) was available, including total cholesterol, low density lipoprotein, high density lipoprotein, very low density lipoprotein, and triglycerides. The Kaplan-Meier method was used to estimate median overall survival (OS), distant metastases-free survival (DMFS), and local-regional recurrence-free survival (LRRFS). A Cox proportional hazards regression model was used to test the statistical significance of prognostic factors. Results: 869 women were identified who met inclusion criteria, with a median follow-up time of 75.1 months (range 2.4-228.9 months). 293 (33.7%) patients used statins and 368 (42.3%) had a 5VLP. OS, DMFS, and LRRFS were not significant based on statin use or type. Controlling for the 5VLP values, on multivariable analysis, statin use was significantly associated with OS (HR 0.10, 95% CI 0.01-0.76), but not with DMFS (HR 0.14, 95% CI 0.01-1.40) nor LRRFS (HR 0.10 95% CI 0.00-3.51). Conclusions: Statin use among patients with TNBC is not associated with improved OS, although it may have a benefit for a subset of patients. Prospective assessment would be valuable to better assess the potential complex correlation between clinical outcome, lipid levels, and statin use. PMID:28819403

Preoperative diagnosis of carcinoma within fibroadenoma on screening mammograms

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Borecky, N.; Rickard, M.

2008-01-01

Three cases of fibroadenoma associated with carcinoma are reported. These cases were diagnosed within a screening programme as a result of suspicious mammographic findings, and the diagnosis of malignancy was confirmed preoperatively by core biopsy in all cases. The mammographic findings suggestive of carcinoma within fibroadenoma were irregularity of margins in one case and associated new suspicious pleomorphic and linear calcifications in the two other cases. The preoperative diagnosis of carcinoma within fibroadenoma was provided by ultrasound-guided core biopsy in two cases and core biopsy under stereotactic guidance in one case. Whereas asymptomatic fibroadenoma with benign imaging appearances usually does not require further investigation, fibroadenoma with atypical imaging features requires a triple test investigation.

FOXP3 Transcription Factor: A Candidate Marker for Susceptibility and Prognosis in Triple Negative Breast Cancer

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Leandra Fiori Lopes

2014-01-01

Full Text Available Triple negative breast cancer (TNBC is a relevant subgroup of neoplasia which presents negative phenotype of estrogen and progesterone receptors and has no overexpression of the human epidermal growth factor 2 (HER2. FOXP3 (forkhead transcription factor 3 is a marker of regulatory T cells (Tregs, whose expression may be increased in tumor cells. This study aimed to investigate a polymorphism (rs3761548 and the protein expression of FOXP3 for a possible involvement in TNBC susceptibility and prognosis. Genetic polymorphism was evaluated in 50 patients and in 115 controls by allele-specific PCR (polymerase chain reaction. Protein expression was evaluated in 38 patients by immunohistochemistry. It was observed a positive association for homozygous AA (OR = 3.78; 95% CI = 1.02–14.06 in relation to TNBC susceptibility. Most of the patients (83% showed a strong staining for FOXP3 protein in the tumor cells. In relation to FOXP3-positive infiltrate, 47% and 58% of patients had a moderate or intense intratumoral and peritumoral mononuclear infiltrate cells, respectively. Tumor size was positively correlated to intratumoral FOXP3-positive infiltrate (P=0.026. In conclusion, since FOXP3 was positively associated with TNBC susceptibility and prognosis, it seems to be a promising candidate for further investigation in larger TNBC samples.

A radiologic evaluation of bladder tumors on barium air double contrast cystography and triple-fractionated cystography

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Hur, W. J.; Jang, H. Y.; Sol, C. H.; Kim, B. S.

1984-01-01

Clinically bladder tumors can be easily diagnosed on cystoscopic examination and biopsy in the patients with silent hematuria, terminal dribbling and dysuria. But for the evaluation of the extent of tumor invasion, the authors performed both barium-air double contrast and triple-fractionated cystography on 16 patients suspected to be bladder tumor on cystoscopic examination in the radiologic department of B.N.U.H. from September 1982 to August 1983. The obtained results were summarized as follows. 1. On barium-air double contrast cystography and triple-fractionated cystography, 13 cases were concluded as bladder tumor, and 3 cases were consistent with the findings of chronic inflammation out of the total 16 cases. 2. After operation of 15 cases, 12 cases were confirmed pathologically as transitional cell carcinoma, 1 case as prostatic hypertrophy, and 2 cases as chronic inflammation. Remaining one was biopsied on cystoscopic examination, and confirmed as chronic inflammation. 3. Among 9 cases of transitional cell carcinoma having the evidence of muscle invasion on triple- fractionated cystography, 8 cases were confirmed as more than stage B 1 on pathologic study, and the other as chronic inflammation. 4. In detecting multiplicity, presence of ulceration, and evaluation of nature of tumor surface, barium- air double contrast cystogrpahy was more excellent than cystoscopic results. 5. Cases presenting both ulceration and cauliflower appearance on barium- air double contrast cystography was more than grade III on microscopic evaluation. 6. In conclusion, the authors considers the barium-air double contrast and triple-fractionated cystography are easy to perform, reasonable in price and have relatively high accuracy in tumor detection, staging and grading.

Cellular responses of BRCA1-defective and triple-negative breast cancer cells and in vitro BRCA1 interactions induced by metallo-intercalator ruthenium(II) complexes containing chloro-substituted phenylazopyridine

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Nhukeaw, Tidarat; Temboot, Pornvichai; Hansongnern, Kanidtha; Ratanaphan, Adisorn

2014-01-01

Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Breast cancers with a BRCA1 mutation are also frequently triple-negative. Currently, there is a lack of effective therapies and known specific molecular targets for this aggressive breast cancer subtype. To address this concern, we have explored the cellular responses of BRCA1-defective and triple-negative breast cancer cells, and in vitro BRCA1 interactions induced by the ruthenium(II) complexes containing the bidentate ligand, 5-chloro-2-(phenylazo)pyridine. Triple-negative MDA-MB-231, BRCA1-defective HCC1937 and BRCA1-competent MCF-7 breast cancer cell lines were treated with ruthenium(II) complexes. The cytoxoxicity of ruthenium-induced breast cancer cells was evaluated by a real time cellular analyzer (RTCA). Cellular uptake of ruthenium complexes was determined by ICP-MS. Cell cycle progression and apoptosis were assessed using propidium iodide and Annexin V flow cytometry. The N-terminal BRCA1 RING protein was used for conformational and functional studies using circular dichroism and in vitro ubiquitination. HCC1937 cells were significantly more sensitive to the ruthenium complexes than the MDA-MB-231 and MCF-7 cells. Treatment demonstrated a higher degree of cytotoxicity than cisplatin against all three cell lines. Most ruthenium atoms were retained in the nuclear compartment, particularly in HCC1937 cells, after 24 h of incubation, and produced a significant block at the G2/M phase. An increased induction of apoptotic cells as well as an upregulation of p53 mRNA was observed in all tested breast cancer cells. It was of interest that BRCA1 mRNA and replication of BRCA1-defective cells were downregulated. Changes in the conformation and binding constants of ruthenium-BRCA1 adducts were observed, causing inactivation of the RING heterodimer BRCA1/BARD1-mediated E3 ubiquitin ligase activity

S100A14 is a novel independent prognostic biomarker in the triple-negative breast cancer subtype

DEFF Research Database (Denmark)

Ehmsen, Sidse; Hansen, Lea Tykgaard; Bak, Martin

2015-01-01

Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup with generally poor outcome and lack of an effective targeted therapy. Prognostic or predictive biomarkers to guide treatment decisions for this group of patients are needed. To evaluate the potential of S100A14 protein...... as a novel biomarker in TNBC, the protein expression of S100A14 was correlated with clinical outcomes in a Pilot Sample set and a Danish cohort of predominantly TNBC patients. Kaplan-Meier analysis identified a prognostic impact of S100A14 on disease-free survival and overall survival, showing that tumors......-), had equally poor outcomes as those with tumor-positive axillary lymph nodes (N+), while TNBC/N- patients with low S100A14 expression had a significantly better disease free survival (p = 0.013). Multivariate analysis revealed that S100A14 is an independent prognostic factor for TNBC patients (p = 0...

Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer

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Martey O

2017-10-01

Full Text Available Orleans Martey,1 Mhairi Nimick,1 Sebastien Taurin,1 Vignesh Sundararajan,1 Khaled Greish,2 Rhonda J Rosengren1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene-1-methylpiperidine-4-one (RL71, that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles. Keywords: curcumin derivatives, nanomedicine, EGFR, biodistribution

Spindle cell carcinoma of the breast as complex cystic lesion: a case report

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Kitada, Masahiro; Hayashi, Satoshi; Matsuda, Yoshinari; Ishibashi, Kei; Oikawa, Keisuke; Miyokawa, Naoyuki

2014-01-01

Spindle cell carcinoma of the breast is a rare tumor. This tumor can proliferate rapidly and cause cystic changes because of internal tissue necrosis. We evaluated a 54-year-old woman with right breast lump. Mammography showed a category four mass with a diameter of 2.5 cm. Ultrasonography (US) revealed a complex cystic lesion, and fine-needle aspiration (FNA) cytology demonstrated bloody fluid and malignant cells. Partial breast resection and sentinel lymph node biopsy were performed. Immunohistology revealed spindle cells with positive results for cytokeratin (AE1/AE3) and vimentin, partially positive results for s-100, and negative results for desmin and α-actin. The pathological stage was IIA, and biochemical characterization showed that the tumor was triple negative. Six courses of FEC-100 chemotherapy (5-fluorouracil 500 mg/m 2 , epirubicin 100 mg/m 2 , and cyclophosphamide 500 mg/m 2 ) were administered. Radiotherapy was performed. This case is discussed with reference to the literature

Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.

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Goh, Gerald; Walradt, Trent; Markarov, Vladimir; Blom, Astrid; Riaz, Nadeem; Doumani, Ryan; Stafstrom, Krista; Moshiri, Ata; Yelistratova, Lola; Levinsohn, Jonathan; Chan, Timothy A; Nghiem, Paul; Lifton, Richard P; Choi, Jaehyuk

2016-01-19

Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

Triple-negative breast cancer: multipronged approach, single-arm pilot phase II study

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Recchia, Francesco; Candeloro, Giampiero; Desideri, Giovambattista; Necozione, Stefano; Recchia, Cornelia O C; Cirulli, Vincenzo; Rea, Silvio

2012-01-01

Anthracyclines (A) and taxanes (T) are standard first-line chemotherapy agents for patients with advanced breast cancer. Platinum analogues have also shown activity in the triple-negative breast cancer (TNBC) histology, but clinical data are limited. Here we report the long-term follow-up of a phase II study on TNBC treated with a combined modality therapy, including induction with AT, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with concurrent radiation therapy, and a dose-dense consolidation chemotherapy (HDCT) with carboplatin (CBDCA), ifosfamide (IFX), etoposide (VP-16). Patients' median age was 44 years, with 73% premenopausal. Epirubicin 75 mg/m 2 and docetaxel 75 mg/m 2 were administered to 70 patients with TNBC: as neoadjuvant and adjuvant therapy to 12 and 58 patients, respectively. Postoperative radiation therapy, 5000 cGy, was delivered, synchronous with triweekly CMF. After radiation therapy, two courses of HDCT with CBDCA, IFX, VP-16, were given, with hematological growth factors. After a median follow-up of 81 months, all patients were evaluable for toxicity and response. Most important toxicity were grade 3 skin reaction and grade 4 hematological in 3% and 31% of patients, respectively. Pathological complete response was observed in 25% of patients receiving preoperative chemotherapy. Treatment failures were as follows: eight visceral, four contralateral breast cancer, four locoregional, and one leukemia. Five-year progression-free survival and overall survival rate were 78% and 91%, respectively. Induction chemotherapy, followed by chemoradiation therapy and HDCT, provides a prolonged disease-free period and a significant increase in overall survival in TNBC, with an acceptable toxicity profile

The exploration of contrasting pathways in Triple Negative Breast Cancer (TNBC).

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Narrandes, Shavira; Huang, Shujun; Murphy, Leigh; Xu, Wayne

2018-01-04

Triple Negative Breast Cancers (TNBCs) lack the appropriate targets for currently used breast cancer therapies, conferring an aggressive phenotype, more frequent relapse and poorer survival rates. The biological heterogeneity of TNBC complicates the clinical treatment further. We have explored and compared the biological pathways in TNBC and other subtypes of breast cancers, using an in silico approach and the hypothesis that two opposing effects (Yin and Yang) pathways in cancer cells determine the fate of cancer cells. Identifying breast subgroup specific components of these opposing pathways may aid in selecting potential therapeutic targets as well as further classifying the heterogeneous TNBC subtype. Gene expression and patient clinical data from The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used for this study. Gene Set Enrichment Analysis (GSEA) was used to identify the more active pathways in cancer (Yin) than in normal and the more active pathways in normal (Yang) than in cancer. The clustering analysis was performed to compare pathways of TNBC with other types of breast cancers. The association of pathway classified TNBC sub-groups to clinical outcomes was tested using Cox regression model. Among 4729 curated canonical pathways in GSEA database, 133 Yin pathways (FDR pathways (p-value pathway while PPARα is the top Yang pathway in TNBC. The TNBC and other types of breast cancers showed different pathways enrichment significance profiles. Using top Yin and Yang pathways as classifier, the TNBC can be further subtyped into six sub-groups each having different clinical outcomes. We first reported that the FOMX1 pathway is the most upregulated and the PPARα pathway is the most downregulated pathway in TNBC. These two pathways could be simultaneously targeted in further studies. Also the pathway classifier we performed in this study provided insight into the TNBC heterogeneity.

Gene expression in triple-negative breast cancer in relation to survival.

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Wang, Shuyang; Beeghly-Fadiel, Alicia; Cai, Qiuyin; Cai, Hui; Guo, Xingyi; Shi, Liang; Wu, Jie; Ye, Fei; Qiu, Qingchao; Zheng, Ying; Zheng, Wei; Bao, Ping-Ping; Shu, Xiao-Ou

2018-05-10

The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression. We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources. Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS. We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.

Prognostic significance of proline, glutamic acid, leucine rich protein 1 (PELP1) in triple-negative breast cancer: a retrospective study on 129 cases

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Zhang, Yanzhi; Dai, Jiali; McNamara, Keely M.; Bai, Bing; Shi, Mumu; Chan, Monica S. M.; Liu, Ming; Sasano, Hironobu; Wang, Xiuli; Li, Xiaolei; Liu, Lijuan; Ma, Ying; Cao, Shuwen; Xing, Yanchun; Zhao, Baoshan; Song, Yinli; Wang, Lin

2015-01-01

Triple-negative breast cancer (TNBC) is associated with an aggressive clinical course due to the lack of therapeutic targets. Therefore, identifying reliable prognostic biomarkers and novel therapeutic targets for patients with TNBC is required. Proline, glutamic acid, leucine rich protein 1 (PELP1) is a novel steroidal receptor co-regulator, functioning as an oncogene and its expression is maintained in estrogen receptor (ER) negative breast cancers. PELP1 has been proposed as a prognostic biomarker in hormone-related cancers, including luminal-type breast cancers, but its significance in TNBC has not been studied. PELP1 immunoreactivity was evaluated using immunohistochemistry in 129 patients with TNBC. Results were correlated with clinicopathological variables including patient’s age, tumor size, lymph node stage, tumor grade, clinical stage, histological type, Ki-67 LI, as well as clinical outcome of the patients, including disease-free survival (DFS) and overall survival (OS). PELP1 was localized predominantly in the nuclei of carcinoma cells in TNBC. With the exception of a positive correlation between PELP1 protein expression and lymph node stage (p = 0.027), no significant associations between PELP1 protein expression and other clinicopathological variables, including DFS and OS, were found. However, when PELP1 and Ki-67 LI were grouped together, we found that patients in the PELP1/Ki-67 double high group (n = 48) demonstrated significantly reduced DFS (p = 0.005, log rank test) and OS (p = 0.002, log rank test) than others (n = 81). Multivariable analysis supported PELP1/Ki-67 double high expression as an independent prognostic factor in patients with TNBC, with an adjusted hazard ratio of 2.020 for recurrence (95 % CL, 1.022–3.990; p = 0.043) and of 2.380 for death (95 % CL, 1.138–4.978; p = 0.021). We found that evaluating both PELP1 and Ki-67 expression in TNBC could enhance the prognostic sensitivity of the two biomarkers. Therefore, we propose

Highly adaptable triple-negative breast cancer cells as a functional model for testing anticancer agents.

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Balraj Singh

Full Text Available A major obstacle in developing effective therapies against solid tumors stems from an inability to adequately model the rare subpopulation of panresistant cancer cells that may often drive the disease. We describe a strategy for optimally modeling highly abnormal and highly adaptable human triple-negative breast cancer cells, and evaluating therapies for their ability to eradicate such cells. To overcome the shortcomings often associated with cell culture models, we incorporated several features in our model including a selection of highly adaptable cancer cells based on their ability to survive a metabolic challenge. We have previously shown that metabolically adaptable cancer cells efficiently metastasize to multiple organs in nude mice. Here we show that the cancer cells modeled in our system feature an embryo-like gene expression and amplification of the fat mass and obesity associated gene FTO. We also provide evidence of upregulation of ZEB1 and downregulation of GRHL2 indicating increased epithelial to mesenchymal transition in metabolically adaptable cancer cells. Our results obtained with a variety of anticancer agents support the validity of the model of realistic panresistance and suggest that it could be used for developing anticancer agents that would overcome panresistance.

ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells.

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Yuan, Xun; Kho, Dhonghyo; Xu, Jing; Gajan, Ambikai; Wu, Kongming; Wu, Gen Sheng

2017-03-28

ONC201 was previously identified as a first-in-class antitumor agent and small-molecule inducer of the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) gene that induces apoptosis in cancer cells. ONC201 has a safety profile and is currently in phase II clinical trials for the treatment of various malignancies. In the current study, we examine the effect of ONC201 on triple-negative breast cancer cells (TNBC), a subtype of breast cancer that is sensitive to TRAIL. We find that ONC201 inhibits the growth of TNBC cells including TNBC cells that have developed acquired TRAIL resistance. However, TNBC cells that have developed acquired ONC201 resistance are cross-resistant to TRAIL. Mechanistically, ONC201 triggers an integrated stress response (ISR) involving the activation of the transcription factor ATF4. Knockdown of ATF4 impairs ONC201-induced apoptosis of TNBC cells. Importantly, the activation of ATF4 is compromised in ONC201-resistant TNBC cells. Thus, our results indicate that ONC201 induces an ISR to cause TNBC cell death and suggest that TNBC patients may benefit from ONC201-based therapies.

Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations

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Pistelli, Mirco, E-mail: mirco.pistelli@alice.it; Caramanti, Miriam [Clinica di Oncologia Medica, AO Ospedali Riuniti-Ancona, Università Politecnica delle Marche, Ancona 60020 (Italy); Biscotti, Tommasina; Santinelli, Alfredo [Anatomia Patologica, AO Ospedali Riuniti-Ancona, Università Politecnica delle Marche, Ancona 60020 (Italy); Pagliacci, Alessandra; De Lisa, Mariagrazia; Ballatore, Zelmira; Ridolfi, Francesca; Maccaroni, Elena; Bracci, Raffaella; Berardi, Rossana; Battelli, Nicola; Cascinu, Stefano [Clinica di Oncologia Medica, AO Ospedali Riuniti-Ancona, Università Politecnica delle Marche, Ancona 60020 (Italy)

2014-06-27

Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001) and a lympho-vascular invasion (p = 0.01), but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72) or overall survival (p = 0.93). Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target.

Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations

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Mirco Pistelli

2014-06-01

Full Text Available Background: Triple-negative breast cancers (TNBC are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001 and a lympho-vascular invasion (p = 0.01, but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72 or overall survival (p = 0.93. Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target.

Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations

International Nuclear Information System (INIS)

Pistelli, Mirco; Caramanti, Miriam; Biscotti, Tommasina; Santinelli, Alfredo; Pagliacci, Alessandra; De Lisa, Mariagrazia; Ballatore, Zelmira; Ridolfi, Francesca; Maccaroni, Elena; Bracci, Raffaella; Berardi, Rossana; Battelli, Nicola; Cascinu, Stefano

2014-01-01

Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001) and a lympho-vascular invasion (p = 0.01), but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72) or overall survival (p = 0.93). Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target

Outcomes of Breast Cancer Patients With Triple Negative Receptor Status Treated With Accelerated Partial Breast Irradiation

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Wilkinson, J. Ben; Reid, Robert E.; Shaitelman, Simona F.; Chen, Peter Y.; Mitchell, Christine K.; Wallace, Michelle F.; Marvin, Kimberly S.; Grills, Inga S.; Margolis, Jeffrey M.; Vicini, Frank A.

2011-01-01

Purpose: Triple negative receptor status (TNRS) of patients undergoing breast-conserving therapy treated with whole-breast irradiation has been associated with increased distant metastasis and decreased disease-free and overall survival. This paper reports the outcomes of TNRS patients treated with accelerated partial breast irradiation (APBI). Methods and Materials: We studied 455 patients who received APBI at our institution, using interstitial, intracavitary, and three-dimensional conformal radiation therapy. TNRS was assigned if a patient tested negative for all three (ER [estrogen receptor], PR [progesterone receptor], and HER2/neu) receptors. Of 202 patients with all receptor results available, 20 patients were designated TNRS, and 182 patients had at least one receptor positive (RP). We analyzed ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis (DM), and overall survival (OS). Results: Mean follow-up was 4.1 years for the TNRS group and 5.1 years for the RP cohort (p = 0.11). TNRS patients had a higher histologic grade (59% TNRS vs. 13% RP; p 0.52). OS for the RP cohort was 93% at 5 years (p > 0.28). Conclusions: In our patient population, TNRS conferred a clinical outcome similar to that of patients with RP disease treated with APBI. Further investigation with larger patient populations and longer follow-up periods is warranted to confirm that APBI is a safe and effective treatment for patients with localized TNRS breast cancer.

Outcomes of breast cancer patients with triple negative receptor status treated with accelerated partial breast irradiation.

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Wilkinson, J Ben; Reid, Robert E; Shaitelman, Simona F; Chen, Peter Y; Mitchell, Christine K; Wallace, Michelle F; Marvin, Kimberly S; Grills, Inga S; Margolis, Jeffrey M; Vicini, Frank A

2011-11-01

Triple negative receptor status (TNRS) of patients undergoing breast-conserving therapy treated with whole-breast irradiation has been associated with increased distant metastasis and decreased disease-free and overall survival. This paper reports the outcomes of TNRS patients treated with accelerated partial breast irradiation (APBI). We studied 455 patients who received APBI at our institution, using interstitial, intracavitary, and three-dimensional conformal radiation therapy. TNRS was assigned if a patient tested negative for all three (ER [estrogen receptor], PR [progesterone receptor], and HER2/neu) receptors. Of 202 patients with all receptor results available, 20 patients were designated TNRS, and 182 patients had at least one receptor positive (RP). We analyzed ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis (DM), and overall survival (OS). Mean follow-up was 4.1 years for the TNRS group and 5.1 years for the RP cohort (p = 0.11). TNRS patients had a higher histologic grade (59% TNRS vs. 13% RP; p 0.52). OS for the RP cohort was 93% at 5 years (p > 0.28). In our patient population, TNRS conferred a clinical outcome similar to that of patients with RP disease treated with APBI. Further investigation with larger patient populations and longer follow-up periods is warranted to confirm that APBI is a safe and effective treatment for patients with localized TNRS breast cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing.

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Radovich, Milan; Clare, Susan E; Atale, Rutuja; Pardo, Ivanesa; Hancock, Bradley A; Solzak, Jeffrey P; Kassem, Nawal; Mathieson, Theresa; Storniolo, Anna Maria V; Rufenbarger, Connie; Lillemoe, Heather A; Blosser, Rachel J; Choi, Mi Ran; Sauder, Candice A; Doxey, Diane; Henry, Jill E; Hilligoss, Eric E; Sakarya, Onur; Hyland, Fiona C; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Badve, Sunil; Ivan, Mircea; Liu, Yunlong; Sledge, George W; Schneider, Bryan P

2014-01-01

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.

A Safety and Tolerability Study of INCAGN02385 in Select Advanced Malignancies

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2018-05-15

Cervical Cancer; Microsatellite Instability (MSI)-High Endometrial Cancer; Gastric Cancer (Including Stomach and Gastroesophageal Junction [GEJ]); Esophageal Cancer; Hepatocellular Carcinoma; Melanoma (Uveal Melanoma Excluded); Merkel Cell Carcinoma; Mesothelioma; MSI-high Colorectal Cancer; Non-small Cell Lung Cancer (NSCLC); Ovarian Cancer; Squamous Cell Carcinoma of the Head and Neck (SCCHN); Small Cell Lung Cancer (SCLC); Renal Cell Carcinoma (RCC); Triple-negative Breast Cancer; Urothelial Carcinoma; Diffuse Large B-cell Lymphoma

A genome-wide siRNA screen identifies proteasome addiction as a vulnerability of basal-like triple-negative breast cancer cells

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Petrocca, Fabio; Altschuler, Gabriel; Tan, Shen Mynn; Mendillo, Marc L.; Yan, Haoheng; Jerry, D. Joseph; Kung, Andrew L.; Hide, Winston; Ince, Tan A.; Lieberman, Judy

2013-01-01

Summary Basal-like triple negative breast cancers (TNBC) have poor prognosis. To identify basal-like TNBC dependencies, a genome-wide siRNA lethality screen compared two human breast epithelial cell lines transformed with the same genes - basal-like BPLER and myoepithelial HMLER. Expression of the screen’s 154 BPLER dependency genes correlated with poor prognosis in breast, but not lung or colon, cancer. Proteasome genes were overrepresented hits. Basal-like TNBC lines were selectively sensitive to proteasome inhibitor drugs relative to normal epithelial, luminal and mesenchymal TNBC lines. Proteasome inhibition reduced growth of established basal-like TNBC tumors in mice and blocked tumor-initiating cell function and macrometastasis. Proteasome addiction in basal-like TNBCs was mediated by NOXA and linked to MCL-1 dependence. PMID:23948298

Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials

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Juul, Nicolai Stefan; Szallasi, Zoltan Imre; Eklund, Aron Charles

2010-01-01

-negative breast cancer. METHODS: We derived a paclitaxel response metagene based on mitotic and ceramide genes identified by functional genomics studies. We used area under the curve (AUC) analysis and multivariate logistic regression to retrospectively assess the metagene in six cohorts of patients with triple......-paclitaxel treated cohorts (0.53 [0.31-0.77], 0.59 [0.22-0.82], 0.53 [0.36-0.71], 0.64 [0.43-0.81]). In multivariate logistic regression, the metagene was associated with pCR (OR 19.92, 2.62-151.57; p=0.0039) with paclitaxel-containing chemotherapy. INTERPRETATION: The paclitaxel response metagene shows promise...... as a paclitaxel-specific predictor of pCR in patients with triple-negative breast cancer. The metagene is suitable for development into a reverse transcription-PCR assay, for which clinically relevant thresholds could be established in randomised clinical trials. These results highlight the potential...

Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model

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Claudia Tulotta

2016-02-01

Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.

Somatostatin receptor scintigraphy on thyroid carcinoma

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Pan Weimin; Tan Tianzhi

2004-01-01

Purpose: To study the diagnostic value and clinical method of somatostatin receptor scintigraphy on thyroid carcinoma using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent; Methods: Somatostatin receptor scintigraphy (SRS) were performed on 25 patients with thyroid carcinoma, using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent, controlling with 131 I- whole- body- imaging(1312 -WBI). Results: Of 4 patients with MTC (medullary thyroid carcinoma), positive metastasis and primary tumour were detected on 3 patients by SRS, negative results were obtained by 131 I-WBI, the positive detective rate by SRS is 3/4; of 12 patients with PTC (papillary thyroid carcinoma), positive metastasis and primary tumour were detected on 2 patients by SRS or 131 I-WBI,1 of which only by SRS, while negative results were obtained by 131 I- WBI, the positive detective rate by SRS is 3/12; of 8 patients with FTC(follicular thyroid carcinoma), positive metastasis and primary tumour were detected on 1 patients by SRS or 131 I-WBI, and 2 positive results were obtained only by SRS, while negative by 131 I-WBI, the positive detective rate by SRS is 3/8; of 1 patients with HCC (hurthle cell carcinoma ), positive metastasis and primary tumour were detected by SRS, while negative by 131 I-WBI; Conclusions: SRS using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent has high diagnostic value on thyroid carcinoma, especially on MTC and HCC. (authors)

Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma.

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Pulitzer, Melissa P; Brannon, A Rose; Berger, Michael F; Louis, Peter; Scott, Sasinya N; Jungbluth, Achim A; Coit, Daniel G; Brownell, Isaac; Busam, Klaus J

2015-08-01

Cutaneous neuroendocrine (Merkel cell) carcinoma most often arises de novo in the background of a clonally integrated virus, the Merkel cell polyomavirus, and is notable for positive expression of retinoblastoma 1 (RB1) protein and low expression of p53 compared with the rare Merkel cell polyomavirus-negative Merkel cell carcinomas. Combined squamous and Merkel cell tumors are consistently negative for Merkel cell polyomavirus. Little is known about their immunophenotypic or molecular profile. Herein, we studied 10 combined cutaneous squamous cell and neuroendocrine carcinomas for immunohistochemical expression of p53, retinoblastoma 1 protein, neurofilament, p63, and cytokeratin 20 (CK20). We compared mutation profiles of five combined Merkel cell carcinomas and seven 'pure' Merkel cell carcinomas using targeted next-generation sequencing. Combined tumors were from the head, trunk, and leg of Caucasian males and one female aged 52-89. All cases were highly p53- and p63-positive and neurofilament-negative in the squamous component, whereas RB1-negative in both components. Eight out of 10 were p53-positive, 3/10 p63-positive, and 3/10 focally neurofilament-positive in the neuroendocrine component. Six out of 10 were CK20-positive in any part. By next-generation sequencing, combined tumors were highly mutated, with an average of 48 mutations per megabase compared with pure tumors, which showed 1.25 mutations per megabase. RB1 and p53 mutations were identified in all five combined tumors. Combined tumors represent an immunophenotypically and genetically distinct variant of primary cutaneous neuroendocrine carcinomas, notable for a highly mutated genetic profile, significant p53 expression and/or mutation, absent RB1 expression in the context of increased RB1 mutation, and minimal neurofilament expression.

Treatment of triple-negative breast cancer with Chinese herbal medicine: A prospective cohort study protocol.

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Meng, Hui; Peng, Nan; Yu, Mingwei; Sun, Xu; Ma, Yunfei; Yang, Guowang; Wang, Xiaomin

2017-11-01

Triple-negative breast cancer (TNBC) is featured with the biological properties of strong aggressive behaviors, rapid disease progression, high risk of recurrence and metastasis, and low disease free survival. Patients with this tumor are insensitive to the endocrine therapy and target treatment for HER-2; therefore, chemotherapy is often used as routine treatment in clinical. Because of the fact that a considerable number of patients seek for Chinese herbal medicine (CHM) treatment after operation and chemotherapy and (or) radiotherapy, it is thus need to evaluate the correlation between Chinese herbal medicine treatment and prognosis. This is a multicenter, prospective cohort study started in March 2016 in Beijing. A simple of 220 participants diagnosed with TNBC were recruited from nine hospitals and are followed up every 3 to 6 months till March 2020. Detailed information of participants includes personal information, history of cancer, quality of life, symptoms of traditional Chinese medicine and fatigue status is taken face-to-face at baseline. The study has received ethical approval from the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University (No.2016BL-014-01). Articles summarizing the primary results and ancillary analyses will be published in peer-reviewed journals. Chinese Clinical Trial Registry: ChiCTR-OOC-16008246.

SEMA6D Expression and Patient Survival in Breast Invasive Carcinoma

Directory of Open Access Journals (Sweden)

Dongquan Chen

2015-01-01

Full Text Available Breast cancer (BC is the second most common cancer diagnosed in American women and is also the second leading cause of cancer death in women. Research has focused heavily on BC metastasis. Multiple signaling pathways have been implicated in regulating BC metastasis. Our knowledge of regulation of BC metastasis is, however, far from complete. Identification of new factors during metastasis is an essential step towards future therapy. Our labs have focused on Semaphorin 6D (SEMA6D, which was implicated in immune responses, heart development, and neurogenesis. It will be interesting to know SEMA6D-related genomic expression profile and its implications in clinical outcome. In this study, we examined the public datasets of breast invasive carcinoma from The Cancer Genome Atlas (TCGA. We analyzed the expression of SEMA6D along with its related genes, their functions, pathways, and potential as copredictors for BC patients’ survival. We found 6-gene expression profile that can be used as such predictors. Our study provides evidences for the first time that breast invasive carcinoma may contain a subtype based on SEMA6D expression. The expression of SEMA6D gene may play an important role in promoting patient survival, especially among triple negative breast cancer patients.

Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers.

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Klimov, Sergey; Rida, Padmashree Cg; Aleskandarany, Mohammed A; Green, Andrew R; Ellis, Ian O; Janssen, Emiel Am; Rakha, Emad A; Aneja, Ritu

2017-09-05

Although distant metastasis (DM) in breast cancer (BC) is the most lethal form of recurrence and the most common underlying cause of cancer related deaths, the outcome following the development of DM is related to the site of metastasis. Triple negative BC (TNBC) is an aggressive form of BC characterised by early recurrences and high mortality. Athough multiple variables can be used to predict the risk of metastasis, few markers can predict the specific site of metastasis. This study aimed at identifying a biomarker signature to predict particular sites of DM in TNBC. A clinically annotated series of 322 TNBC were immunohistochemically stained with 133 biomarkers relevant to BC, to develop multibiomarker models for predicting metastasis to the bone, liver, lung and brain. Patients who experienced metastasis to each site were compared with those who did not, by gradually filtering the biomarker set via a two-tailed t-test and Cox univariate analyses. Biomarker combinations were finally ranked based on statistical significance, and evaluated in multivariable analyses. Our final models were able to stratify TNBC patients into high risk groups that showed over 5, 6, 7 and 8 times higher risk of developing metastasis to the bone, liver, lung and brain, respectively, than low-risk subgroups. These models for predicting site-specific metastasis retained significance following adjustment for tumour size, patient age and chemotherapy status. Our novel IHC-based biomarkers signatures, when assessed in primary TNBC tumours, enable prediction of specific sites of metastasis, and potentially unravel biomarkers previously unknown in site tropism.

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer.

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Telli, M L; Stover, D G; Loi, S; Aparicio, S; Carey, L A; Domchek, S M; Newman, L; Sledge, G W; Winer, E P

2018-05-07

Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy

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Castaneda, Carlos A; Mittendorf, Elizabeth; Casavilca, Sandro; Wu, Yun; Castillo, Miluska; Arboleda, Patricia; Nunez, Teresa; Guerra, Henry; Barrionuevo, Carlos; Dolores-Cerna, Ketty; Belmar-Lopez, Carolina; Abugattas, Julio; Calderon, Gabriela; De La Cruz, Miguel; Cotrina, Manuel; Dunstan, Jorge; Gomez, Henry L; Vidaurre, Tatiana

2016-01-01

AIM To determine influence of neoadjuvant-chemotherapy (NAC) over tumor-infiltrating-lymphocytes (TIL) in triple-negative-breast-cancer (TNBC). METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays (TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response (pCR) (P = 0.0251) and outcome (P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections (ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. Post-NAC lesions with pCR had similar TIL levels than those without pCR (P = 0.6331). NAC produced a TIL decrease in full-face sections (P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival (DFS). Higher counts of CD3 in pre-NAC samples had longer overall-survival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR. CONCLUSION TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related. PMID:27777881

Elucidation of epithelial-mesenchymal transition-related pathways in a triple-negative breast cancer cell line model by multi-omics interactome analysis

DEFF Research Database (Denmark)

Pauling, Josch K; Christensen, Anne G; Batra, Richa

2014-01-01

exhibiting epithelial-like and mesenchymal-like morphology, respectively. Here we identified altered protein signaling activity in a complex biologically relevant network, related to focal adhesion and migration of breast cancer cells. We found dysregulated functional network modules revealing altered...... obtained from a triple-negative breast cancer cell line model, combining data sets of gene and protein expression as well as protein phosphorylation. We focus on alterations associated with the phenotypical differences arising from epithelial-mesenchymal transition in two breast cancer cell lines...... with generation of biological networks. This allows identification of intrinsic patterns in the data and their linkage to a specific context such as cellular compartments, diseases or functions. Identification of aberrant pathways by traditional approaches is often limited to biological networks based on either...

Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast Cancer.

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Traina, Tiffany A; Miller, Kathy; Yardley, Denise A; Eakle, Janice; Schwartzberg, Lee S; O'Shaughnessy, Joyce; Gradishar, William; Schmid, Peter; Winer, Eric; Kelly, Catherine; Nanda, Rita; Gucalp, Ayca; Awada, Ahmad; Garcia-Estevez, Laura; Trudeau, Maureen E; Steinberg, Joyce; Uppal, Hirdesh; Tudor, Iulia Cristina; Peterson, Amy; Cortes, Javier

2018-03-20

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.

Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences.

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Stewart, Delisha A; Winnike, Jason H; McRitchie, Susan L; Clark, Robert F; Pathmasiri, Wimal W; Sumner, Susan J

2016-09-02

To date, no targeted therapies are available to treat triple negative breast cancer (TNBC), while other breast cancer subtypes are responsive to current therapeutic treatment. Metabolomics was conducted to reveal differences in two hormone receptor-negative TNBC cell lines and two hormone receptor-positive Luminal A cell lines. Studies were conducted in the presence and absence of paclitaxel (Taxol). TNBC cell lines had higher levels of amino acids, branched-chain amino acids, nucleotides, and nucleotide sugars and lower levels of proliferation-related metabolites like choline compared with Luminal A cell lines. In the presence of paclitaxel, each cell line showed unique metabolic responses, with some similarities by type. For example, in the Luminal A cell lines, levels of lactate and creatine decreased while certain choline metabolites and myo-inositol increased with paclitaxel. In the TNBC cell lines levels of glutamine, glutamate, and glutathione increased, whereas lysine, proline, and valine decreased in the presence of drug. Profiling secreted inflammatory cytokines in the conditioned media demonstrated a greater response to paclitaxel in the hormone-positive Luminal cells compared with a secretion profile that suggested greater drug resistance in the TNBC cells. The most significant differences distinguishing the cell types based on pathway enrichment analyses were related to amino acid, lipid and carbohydrate metabolism pathways, whereas several biological pathways were differentiated between the cell lines following treatment.

Locoregional recurrence in patients suffering from a triple-negative breast cancer: interest of a systematic adjuvant ganglionary irradiation; Recidives locoregionales chez les patientes atteintes d'un cancer du sein triple-negatif: interet d'une irradiation ganglionnaire adjuvante systematique?

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Clerc, J.; Sunyach, M.P.; Duruisseaux, M.; Mignotte, H.; Bajard, A.; Tredan, O.; Carrie, C.; Arnaud, A. [Centre Leon-Berard, Lyon (France)

2011-10-15

The authors report the assessment of locoregional recurrence percentage within women suffering from a triple-negative breast cancer without ganglionary attack, in order to examine the interest of a systematic adjuvant ganglionary irradiation. Nearly 250 women have been treated for a breast cancer between 1999 and 2009 in the Leon-Berard Centre in Lyons. All had surgery followed or not by a chemotherapy and/or a radiotherapy. The locoregional recurrence rate is not very high, but the authors cannot yet be sure to systematically propose this treatment. Short communication

Double-membrane triple-electrolyte redox flow battery design

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Yushan, Yan; Gu, Shuang; Gong, Ke

2018-03-13

A redox flow battery is provided having a double-membrane (one cation exchange membrane and one anion exchange membrane), triple-electrolyte (one electrolyte in contact with the negative electrode, one electrolyte in contact with the positive electrode, and one electrolyte positioned between and in contact with the two membranes). The cation exchange membrane is used to separate the negative or positive electrolyte and the middle electrolyte, and the anion exchange membrane is used to separate the middle electrolyte and the positive or negative electrolyte. This design physically isolates, but ionically connects, the negative electrolyte and positive electrolyte. The physical isolation offers great freedom in choosing redox pairs in the negative electrolyte and positive electrolyte, making high voltage of redox flow batteries possible. The ionic conduction drastically reduces the overall ionic crossover between negative electrolyte and positive one, leading to high columbic efficiency.

Questioning triple rice intensification on the Vietnamese mekong delta floodplains

NARCIS (Netherlands)

Tran, Dung Duc; Halsema, van Gerardo; Hellegers, Petra J.G.J.; Ludwig, Fulco; Wyatt, Andrew

2018-01-01

Large areas of the Vietnamese Mekong Delta floodplains (VMDF) are protected by high dikes to facilitate three rice crops per year. While this has increased rice production, there is evidence that triple rice systems have negative long-term effects, both environmental and economic. Double rice

[Vulvar squamous cell carcinoma in young women with HPV negative].

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Gómez-Alarcon, A; Gómez-García, M T; García-de la-Torre, J P; Del Valle-Morón, M; Arones-Collantes, M A; González-de Merlo, G

2016-03-01

The vulvar cancer is the fourth more frequent neoplasia after the endometrial, cervix and ovarian cancer. Normally, it has been related to old women of ages from 70 to 80 years old. Rarely, it has been detected cases in adult or young women. However, its incidence has been increased in the last years and in more early years. It is for this change in the incidence and its appearance in early years why a possible etiology has been looked for, opening different hypothesis that go from that related to the HPV to those that study an inflammatory chronic process as the basis for the carcinogenesis. In this article, it has been presented the case of a woman who is 34 years old with negative VPH that made her debut with epidermoid carcinoma of the vulva moderately different and on purpose of the case, we do a revision of the literature existent. Vulvar cancer diagnosed in young women as in older, but with different trends, risk factors and natural history. The case reported here escapes the theories studied so far so needed new lines of inquiry to investigate this form of presentation young woman, without HPV infection.

Pilot Study on MAGE-C2 as a Potential Biomarker for Triple-Negative Breast Cancer

Directory of Open Access Journals (Sweden)

Qian Zhao

2016-01-01

Full Text Available Objective. In the current study, we measured the expression status of melanoma antigen gene c2 (MAGE-C2 in triple-negative breast cancer (TNBC and analyzed its prognostic with the clinical pathological features of patients with TNBC. Methods. The expressions statuses of MAGE-C2 were detected in TNBC tissues and paracarcinoma tissues by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR, and western blotting. Then, we investigated the relationship of MAGE-C2 expression status and clinicopathological parameters of TNBC patients by the chi-squared test. Finally, we discussed the relations of MAGE-C2 expression state and prognosis of patients with TNBC by Kaplan-Meier method and Cox proportional hazards model. Results. High MAGE-C2 expression was found in 38.18% (42/110 of TNBC tissues. In adjacent tissues it was 9.09% (10/110. High MAGE-C2 expression in TNBC patients was closely associated with lymph node status, tumor node metastasis (TNM stage, and lymphovascular invasion (P<0.001. TNBC patients with high MAGE-C2 expression had significantly shorter survival time than low expression patients. We also found that age, lymph node status, TNM stage, lymphovascular invasion, and MAGE-C2 expression status were closely associated with overall survival of TNBC patients (P<0.05. Conclusion. High MAGE-C2 expression may serve as an independent prognostic factor for TNBC patients.

[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo.

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Martin, Ana Carolina B M; Fuzer, Angelina M; Becceneri, Amanda B; da Silva, James Almada; Tomasin, Rebeka; Denoyer, Delphine; Kim, Soo-Hyun; McIntyre, Katherine A; Pearson, Helen B; Yeo, Belinda; Nagpal, Aadya; Ling, Xiawei; Selistre-de-Araújo, Heloisa S; Vieira, Paulo Cézar; Cominetti, Marcia R; Pouliot, Normand

2017-09-22

There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin ( Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo . We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro . In addition, [10]-gingerol is well tolerated in vivo , induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients.

Small cell type neuroendocrine carcinoma colliding with squamous cell carcinoma at esophagus

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Yang, Luoluo; Sun, Xun; Zou, Yabin; Meng, Xiangwei

2014-01-01

Collision tumor is an extremely rare tumor which defined as the concrescence of two distinct primaries neoplasms. We report here a case of collision tumor at lower third esophagus composed of small cell type neuroendocrine carcinoma (NEC), which is an very rare, highly aggressive and poorly prognostic carcinoma and squamous cell carcinoma (SqCC). In our case, pathologically, the small cell carcinoma display the characteristic of small, round, ovoid or spindle-shaped tumor cells with scant cytoplasm, which colliding with a moderately differentiated squamous cell carcinoma. Immunohistochemical staining demonstrated positive activities for CD56, synaptophysin, 34βE12, CK 5/6, ki-67 (70%-80%), but negative for CD99, chromogranin A, and TTF-1. Accurate diagnosis was made base on these findings. PMID:24817981

G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer

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Hollmén, Maija; Karaman, Sinem; Schwager, Simon; Lisibach, Angela; Christiansen, Ailsa J.; Maksimow, Mikael; Varga, Zsuzsanna; Jalkanen, Sirpa; Detmar, Michael

2016-01-01

ABSTRACT Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor (ER)-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response to co-culture with several breast cancer cell lines (T47D, MCF-7, BT-474, SKBR-3, Cal-51 and MDA-MB-231) and found that high granulocyte colony-stimulating factor (G-CSF) secretion by the triple-negative breast cancer (TNBC) cell line MDA-MB-231 gave rise to immunosuppressive HLA-DRlo macrophages that promoted migration of breast cancer cells via secretion of TGF-α. In human breast cancer samples (n = 548), G-CSF was highly expressed in TNBC (p CSF blockade in the 4T1 mammary tumor model promoted maturation of MHCIIhi blood monocytes and TAMs and significantly reduced lung metastasis, anti-CSF-1R treatment promoted MHCIIloF4/80hiMRhi anti-inflammatory TAMs and enhanced lung metastasis in the presence of high G-CSF levels. Combined anti-G-CSF and anti-CSF-1R therapy significantly increased lymph node metastases, possibly via depletion of the so-called “gate-keeper” subcapsular sinus macrophages. These results indicate that G-CSF promotes the anti-inflammatory phenotype of tumor-induced macrophages when CSF-1R is inhibited and therefore caution against the use of M-CSF/CSF-1R targeting agents in tumors with high G-CSF expression. PMID:27141367

Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

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Conde, João; Oliva, Nuria; Atilano, Mariana; Song, Hyun Seok; Artzi, Natalie

2016-03-01

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs--a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)--provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

The Critical, Clinical Role of Interferon-Beta in Regulating Cancer Stem Cell Properties in Triple-Negative Breast Cancer.

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Doherty, Mary R; Jackson, Mark W

2018-05-11

Triple-negative breast cancer (TNBC) the deadliest form of this disease currently lacks a targeted therapy and is characterized by increased risk of metastasis and presence of therapeutically resistant cancer stem cells (CSC). Recent evidence has demonstrated that the presence of an interferon (IFN)/signal transducer of activated transcription 1 (STAT1) gene signature correlates with improved therapeutic response and overall survival in TNBC patients. In agreement with these clinical observations, our recent work has demonstrated, in a cell model of TNBC that CSC have intrinsically repressed IFN signaling. Administration of IFN-β represses CSC properties, inducing a less aggressive non-CSC state. Moreover, an elevated IFN-β gene signature correlated with repressed CSC-related genes and an increased presence of tumor-infiltrating lymphocytes in TNBC specimens. We therefore propose that IFN-β be considered as a potential therapeutic option in the treatment of TNBC, to repress the CSC properties responsible for therapy failure. Future studies aim to improve methods to target delivery of IFN-β to tumors, to maximize therapeutic efficacy while minimizing systemic side effects.

The prognostic value of peripheral CD4+CD25+ T lymphocytes among early stage and triple negative breast cancer patients receiving dendritic cells-cytokine induced killer cells infusion.

Science.gov (United States)

Song, Qing-Kun; Ren, Jun; Zhou, Xin-Na; Wang, Xiao-Li; Song, Guo-Hong; Di, Li-Jun; Yu, Jing; Hobeika, Amy; Morse, Michael A; Yuan, Yan-Hua; Yang, Hua-Bing; Lyerly, Herbert Kim

2015-12-01

This study aimed to assess the prognostic value of CD4+CD25+ T lymphocyte in peripheral blood among breast cancer patients treated with adoptive T lymphocytes immunotherapy. 217 patients participated in the follow-up study. CD4+CD25+ proportion was measured by flow cytometry in peripheral T cells. The median survival was estimated by Kaplan-Meier curve, Log-rank test and Cox hazard proportion regression model, between groups of CD4+CD25+ proportion more than 5% and less than or equal to 5% in peripheral T cells. Peripheral CD4+CD25+ T lymphocytes had not a relationship with progression-free survival. It was featured that above 5% peripheral CD4+CD25+ proportion of T cells was related with the median overall survival by a shorten of 51 months (p < 0.05) with the HR 1.65 (95%CI 1.04, 2.62). Above 5% CD4+CD25+proportion of T cells produced the HR to be 1.76 (95%CI 1.07, 2.87) In stage 0-II patients, and 3.59 (95%CI 1.05, 12.29) in triple negative breast cancer patients. Cellular immunity restoration recovered by adoptive T cell infusions which resulted in less proportion of peripheral CD4+CD25+T lymphocytes could be a potential prognostic indicator among early stage and triple negative patients.

Rationale for immune-based therapies in Merkel polyomavirus-positive and -negative Merkel cell carcinomas.

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Vandeven, Natalie; Nghiem, Paul

2016-07-01

Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer that is typically caused by the Merkel cell polyomavirus (MCPyV). Polyomavirus T-antigen oncoproteins are persistently expressed in virus-positive MCCs (˜80% of cases), while remarkably high numbers of tumor-associated neoantigens are detected in virus-negative MCCs, suggesting that both MCC subsets may be immunogenic. Here we review mechanisms by which these immunogenic tumors evade multiple levels of host immunity. Additionally, we summarize the exciting potential of diverse immune-based approaches to treat MCC. In particular, agents blocking the PD-1 axis have yielded strikingly high response rates in MCC as compared with other solid tumors, highlighting the potential for immune-mediated treatment of this disease.

Microinvasive lobular carcinoma arising in a fibroadenoma.

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Hayes, Brian D; Quinn, Cecily M

2013-08-01

A 51-year-old woman had a 35 mm circumscribed calcified lesion identified on screening mammography, designated R4. Excision showed a fibroadenoma with multiple foci of lobular neoplasia (atypical lobular hyperplasia and classical lobular carcinoma in situ [LCIS]). A focus of microinvasive lobular carcinoma (MILC) was also present, confirmed on immunohistochemistry. The MILC cells were ER positive, Her-2-negative, and e-cadherin negative. Microinvasive carcinoma, defined as "invasive carcinoma with no focus measuring >1 mm" (TNM UICC 7th edition) is usually encountered in ductal carcinoma in situ but may occur with classical, florid, or pleomorphic LCIS. In one series MILC constituted 0.4% of all invasive lobular carcinomas and was present in 0.4% of all LCIS. MILC is a histologically subtle lesion, the identification of which lends further weight to the concept of lobular neoplasia as a precursor lesion. MILC has been observed in hamartoma but, to our knowledge, has not previously been reported in fibroadenoma.

A prognostic gene signature for metastasis-free survival of triple negative breast cancer patients.

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Lee, Unjin; Frankenberger, Casey; Yun, Jieun; Bevilacqua, Elena; Caldas, Carlos; Chin, Suet-Feung; Rueda, Oscar M; Reinitz, John; Rosner, Marsha Rich

2013-01-01

Although triple negative breast cancers (TNBC) are the most aggressive subtype of breast cancer, they currently lack targeted therapies. Because this classification still includes a heterogeneous collection of tumors, new tools to classify TNBCs are urgently required in order to improve our prognostic capability for high risk patients and predict response to therapy. We previously defined a gene expression signature, RKIP Pathway Metastasis Signature (RPMS), based upon a metastasis-suppressive signaling pathway initiated by Raf Kinase Inhibitory Protein (RKIP). We have now generated a new BACH1 Pathway Metastasis gene signature (BPMS) that utilizes targets of the metastasis regulator BACH1. Specifically, we substituted experimentally validated target genes to generate a new BACH1 metagene, developed an approach to optimize patient tumor stratification, and reduced the number of signature genes to 30. The BPMS significantly and selectively stratified metastasis-free survival in basal-like and, in particular, TNBC patients. In addition, the BPMS further stratified patients identified as having a good or poor prognosis by other signatures including the Mammaprint® and Oncotype® clinical tests. The BPMS is thus complementary to existing signatures and is a prognostic tool for high risk ER-HER2- patients. We also demonstrate the potential clinical applicability of the BPMS as a single sample predictor. Together, these results reveal the potential of this pathway-based BPMS gene signature to identify high risk TNBC patients that can respond effectively to targeted therapy, and highlight BPMS genes as novel drug targets for therapeutic development.

A prognostic gene signature for metastasis-free survival of triple negative breast cancer patients.

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Unjin Lee

Full Text Available Although triple negative breast cancers (TNBC are the most aggressive subtype of breast cancer, they currently lack targeted therapies. Because this classification still includes a heterogeneous collection of tumors, new tools to classify TNBCs are urgently required in order to improve our prognostic capability for high risk patients and predict response to therapy. We previously defined a gene expression signature, RKIP Pathway Metastasis Signature (RPMS, based upon a metastasis-suppressive signaling pathway initiated by Raf Kinase Inhibitory Protein (RKIP. We have now generated a new BACH1 Pathway Metastasis gene signature (BPMS that utilizes targets of the metastasis regulator BACH1. Specifically, we substituted experimentally validated target genes to generate a new BACH1 metagene, developed an approach to optimize patient tumor stratification, and reduced the number of signature genes to 30. The BPMS significantly and selectively stratified metastasis-free survival in basal-like and, in particular, TNBC patients. In addition, the BPMS further stratified patients identified as having a good or poor prognosis by other signatures including the Mammaprint® and Oncotype® clinical tests. The BPMS is thus complementary to existing signatures and is a prognostic tool for high risk ER-HER2- patients. We also demonstrate the potential clinical applicability of the BPMS as a single sample predictor. Together, these results reveal the potential of this pathway-based BPMS gene signature to identify high risk TNBC patients that can respond effectively to targeted therapy, and highlight BPMS genes as novel drug targets for therapeutic development.

Phospho-kinase profile of triple negative breast cancer and androgen receptor signaling

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Cuenca-López, María D; Montero, Juan C; Morales, Jorge C; Prat, Aleix; Pandiella, Atanasio; Ocana, Alberto

2014-01-01

The androgen receptor (AR) plays a central role in the oncogenesis of different tumors, as is the case in prostate cancer. In triple negative breast cancer (TNBC) a gene expression classification has described different subgroups including a luminal androgen subtype. The AR can be controlled by several mechanisms like the activation of membrane tyrosine kinases and downstream signaling pathways. However little is known in TNBC about how the AR is modulated by these mechanisms and the potential therapeutic strategists to inhibit its expression. We used human samples to evaluate the expression of AR by western-blot and phospho-proteomic kinase arrays that recognize membrane tyrosine kinase receptors and downstream mediators. Western-blots in human cell lines were carried out to analyze the expression and activation of individual proteins. Drugs against these kinases in different conditions were used to measure the expression of the androgen receptor. PCR experiments were performed to assess changes in the AR gene after therapeutic modulation of these pathways. AR is present in a subset of TNBC and its expression correlates with activated membrane receptor kinases-EGFR and PDGFRβ in human samples and cell lines. Inhibition of the PI3K/mTOR pathway in TNBC cell lines decreased notably the expression of the AR. Concomitant administration of the anti-androgen bicalutamide with the EGFR, PDGFRβ and Erk1/2 inhibitors, decreased the amount of AR compared to each agent given alone, and had an additive anti-proliferative effect. Administration of dihydrotestosterone augmented the expression of AR that was not modified by the inhibition of the PI3K/mTOR or Erk1/2 pathways. AR expression was posttranscriptionally regulated by PI3K or Erk1/2 inhibition. Our results describe the expression of the AR in TNBC as a druggable target and further suggest the combination of bicalutamide with inhibitors of EGFR, PDGFRβ or Erk1/2 for future development

Global trends in nanomedicine research on triple negative breast cancer: a bibliometric analysis.

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Teles, Ramon Handerson Gomes; Moralles, Herick Fernando; Cominetti, Márcia Regina

2018-01-01

Nanotechnology has emerged as a promising tool in the clinic to combat several difficult-to-manage diseases, such as cancer, which is the second leading cause of death worldwide. Chemotherapeutic drugs present several limitations such as undesired side effects, low specificity, resistance, and high relapse rates. Triple negative breast cancer (TNBC) is caused by cells that lack specific receptors in their membrane, such as estrogen (ER+) and progesterone (PR+) receptors, or by cells that do not express the amplification of human epidermal growth factor receptor-2 (HER-2+). This cancer type has poor prognosis, high relapse rates, and no targeted therapies. Thus, this study aimed to investigate the trends of nanotechnology research in TNBC and compare the contribution of research from different regions, institutions, and authors. A search of the studies published between 2012 and 2017, related to nanotechnology and TNBC, with different keyword combinations, was performed in the Scopus database. The keywords found in this search were grouped into four clusters, in which "breast cancer" was the most mentioned (1,133 times) and the word "MCF-7 cell line" is one of the latest hotspots that appeared in the year 2016. A total of 1,932 articles, which were cited 26,450 times, were identified. The USA accounted for 28.36% of the articles and 27.61% of the citations; however, none of its centers appeared in the list of 10 most productive ones in terms of publications. The journals Biomaterials and International Journal of Nanomedicine had the highest number of publications. The USA and China had the highest number of articles produced and cited; however, the highest average citation per article was from Singapore. The studies focused on the research of antineoplastic agents in animal models and cell culture, and these were the most used topics in research with nanotechnology and TNBC.

Overweight as a Prognostic Factor for Triple-Negative Breast Cancers in Chinese Women.

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Shuang Hao

Full Text Available Obesity is associated with poorer outcomes in patients with hormone receptor-positive breast cancers, but this association is not well established for women with triple-negative breast cancers (TNBC. Here, we investigated the prognostic effects of body mass index (BMI on clinical outcomes in patients with TNBC.We identified 1106 patients with TNBC who met the inclusion criteria and were treated between January 2002 and June 2012. Clinical and biological features were collected to evaluate the relation between BMI and breast cancer-specific survival (BCSS and overall survival (OS after controlling for other clinically significant variables.Of 1106 patients, 656 (59.3% were normal weight (BMI ≤24 and 450 patients (40.7% were overweight(BMI>24. Median follow-up time was 44.8 months. Breast cancer specific death was observed in 140 patients. After adjusting for clinicopathologic risk factors, overweight was associated with OS (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 1.04-2.06, P =0.028 but not BCSS (HR: 1.34, 95% CI: 0.90-2.01, P =0.15in all the patients with TNBC. When stratified with menopausal status, overweight was associated with BCSS and OS (HR: 2.27, 95% CI: 1.11-4.63, P = 0.024 and HR: 2.16, 95% CI: 1.21-3.87, P = 0.010, respectively in premenopausal women. BMI was not associated with BCSS or OS in postmenopausal women.Overweight is an independent prognostic factor of OS in all women with TNBC, and menopause status may be a mitigating factor. Among premenopausal women, overweight women are at a greater risk of poor prognosis than normal weight women. If validated, these findings should be considered in developing preventive programs.

Triple helical DNA in a duplex context and base pair opening

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Esguerra, Mauricio; Nilsson, Lennart; Villa, Alessandra

2014-01-01

It is fundamental to explore in atomic detail the behavior of DNA triple helices as a means to understand the role they might play in vivo and to better engineer their use in genetic technologies, such as antigene therapy. To this aim we have performed atomistic simulations of a purine-rich antiparallel triple helix stretch of 10 base triplets flanked by canonical Watson–Crick double helices. At the same time we have explored the thermodynamic behavior of a flipping Watson–Crick base pair in the context of the triple and double helix. The third strand can be accommodated in a B-like duplex conformation. Upon binding, the double helix changes shape, and becomes more rigid. The triple-helical region increases its major groove width mainly by oversliding in the negative direction. The resulting conformations are somewhere between the A and B conformations with base pairs remaining almost perpendicular to the helical axis. The neighboring duplex regions maintain a B DNA conformation. Base pair opening in the duplex regions is more probable than in the triplex and binding of the Hoogsteen strand does not influence base pair breathing in the neighboring duplex region. PMID:25228466

Outcome disparities in African American women with triple negative breast cancer: a comparison of epidemiological and molecular factors between African American and Caucasian women with triple negative breast cancer

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Sturtz, Lori A; Melley, Jen; Mamula, Kim; Shriver, Craig D; Ellsworth, Rachel E

2014-01-01

Although diagnosed less often, breast cancer in African American women (AAW) displays different characteristics compared to breast cancer in Caucasian women (CW), including earlier onset, less favorable clinical outcome, and an aggressive tumor phenotype. These disparities may be attributed to differences in socioeconomic factors such as access to health care, lifestyle, including increased frequency of obesity in AAW, and tumor biology, especially the higher frequency of triple negative breast cancer (TNBC) in young AAW. Improved understanding of the etiology and molecular characteristics of TNBC in AAW is critical to determining whether and how TNBC contributes to survival disparities in AAW. Demographic, pathological and survival data from AAW (n = 62) and CW (n = 98) with TNBC were analyzed using chi-square analysis, Student’s t-tests, and log-rank tests. Frozen tumor specimens were available from 57 of the TNBC patients (n = 23 AAW; n = 34 CW); RNA was isolated after laser microdissection of tumor cells and was hybridized to HG U133A 2.0 microarrays. Data were analyzed using ANOVA with FDR <0.05, >2-fold difference defining significance. The frequency of TNBC compared to all BC was significantly higher in AAW (28%) compared to CW (12%), however, significant survival and pathological differences were not detected between populations. Gene expression analysis revealed the tumors were more similar than different at the molecular level, with only CRYBB2P1, a pseudogene, differentially expressed between populations. Among demographic characteristics, AAW consumed significantly lower amounts of caffeine and alcohol, were less likely to breastfeed and more likely to be obese. These data suggest that TNBC in AAW is not a unique disease compared to TNBC in CW. Rather, higher frequency of TNBC in AAW may, in part, be attributable to the effects of lifestyle choices. Because these risk factors are modifiable, they provide new opportunities for the development of risk

Negative regulation of retrovirus expression in embryonal carcinoma cells mediated by an intragenic domain.

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Loh, T P; Sievert, L L; Scott, R W

1988-11-01

An intragenic region spanning the tRNA primer binding site of a Moloney murine leukemia virus recombinant retrovirus was found to restrict expression specifically in embryonal carcinoma (EC) cells. When the inhibitory domain was present, the levels of steady-state RNA synthesized from integrated recombinant templates in stable cotransformation assays were reduced 20-fold in EC cells but not in C2 myoblast cells. Transient-cotransfection assays showed that repression of a template containing the EC-specific inhibitory component was relieved by an excess of specific competitor DNA. In addition, repression mediated by the inhibitory component was orientation independent. This evidence demonstrates the presence of a saturable, trans-acting negative regulatory factor(s) in EC cells and suggests that the interaction of the factor(s) with the intragenic inhibitory component occurs at the DNA level.

p120-Catenin Is Critical for the Development of Invasive Lobular Carcinoma in Mice.

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Tenhagen, Milou; Klarenbeek, Sjoerd; Braumuller, Tanya M; Hofmann, Ilse; van der Groep, Petra; Ter Hoeve, Natalie; van der Wall, Elsken; Jonkers, Jos; Derksen, Patrick W B

2016-12-01

Loss of E-cadherin expression is causal to the development of invasive lobular breast carcinoma (ILC). E-cadherin loss leads to dismantling of the adherens junction and subsequent translocation of p120-catenin (p120) to the cytosol and nucleus. Although p120 is critical for the metastatic potential of ILC through the regulation of Rock-dependent anoikis resistance, it remains unknown whether p120 also contributes to ILC development. Using genetically engineered mouse models with mammary gland-specific inactivation of E-cadherin, p120 and p53, we demonstrate that ILC formation induced by E-cadherin and p53 loss is severely impaired upon concomitant inactivation of p120. Tumors that developed in the triple-knockout mice were mostly basal sarcomatoid carcinomas that displayed overt nuclear atypia and multinucleation. In line with the strong reduction in ILC incidence in triple-knockout mice compared to E-cadherin and p53 double-knockout mice, no functional redundancy of p120 family members was observed in mouse ILC development, as expression and localization of ARVCF, p0071 or δ-catenin was unaltered in ILCs from triple-knockout mice. In conclusion, we show that loss of p120 in the context of the p53-deficient mouse models is dominant over E-cadherin inactivation and its inactivation promotes the development of basal, epithelial-to-mesenchymal-transition (EMT)-type invasive mammary tumors.

The dog as a naturally-occurring model for insulin-like growth factor type 1 receptor-overexpressing breast cancer: an observational cohort study

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Jaillardon, Laetitia; Abadie, Jérome; Godard, Tiffanie; Campone, Mario; Loussouarn, Delphine; Siliart, Brigitte; Nguyen, Frédérique

2015-01-01

Dogs spontaneously develop invasive mammary carcinoma with a high prevalence of the triple-negative (TN) subtype (lack of ER-Estrogen Receptor and PR-Progesterone Receptor expression, lack of HER2-Human Epidermal Growth Factor Receptor 2 overexpression), making this animal model relevant for investigating new therapeutic pathways. Insulin-like growth factor Type-1 receptor (IGF1R) is frequently overexpressed in primary human breast cancers, with a growing role in the TN phenotype. The purpose of this study was to investigate the Dog as a candidate model for IGF1R-overexpressing mammary carcinoma. 150 bitches with canine mammary carcinoma (CMC) and a known 2-year follow-up were retrospectively included. IGF1R expression was assessed by immunohistochemistry (IHC) using a similar scoring system as for HER2 in breast cancer. The prognostic value of the IGF1R expression was assessed in terms of overall and specific survival as well as disease-free interval (DFI). 47 CMC (31 %) were classified as luminal and 103 (69 %) as triple-negative (TN-CMC). 41 % of CMC overexpressed IGF1R (IHC score 3+) of which 76 % were TN-CMC and 62 % grade III. IGF1R overexpression was associated with aggressive features including lymphovascular invasion, histological grade III, low ER expression and the TN phenotype. Univariate and multivariate analyses revealed that IGF1R overexpression was associated with shorter overall and specific survivals and shorter DFI in TN-CMC. IGF1R overexpression is common and related to a poor outcome in canine invasive mammary carcinoma, particularly in the triple negative subtype, as in human breast cancer. Preclinical studies using the Dog as a spontaneous animal model could be considered to investigate new therapies targeting IGF1R in triple-negative breast cancer. The online version of this article (doi:10.1186/s12885-015-1670-6) contains supplementary material, which is available to authorized users

Mitochondrial pyruvate carrier function is negatively linked to Warburg phenotype in vitro and malignant features in esophageal squamous cell carcinomas

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Li, Yaqing; Li, Xiaoran; Kan, Quancheng; Zhang, Mingzhi; Li, Xiaoli; Xu, Ruiping; Wang, Junsheng; Yu, Dandan; Goscinski, Mariusz Adam; Wen, Jian-Guo; Nesland, Jahn M.; Suo, Zhenhe

2017-01-01

Aerobic glycolysis is one of the emerging hallmarks of cancer cells. In this study, we investigated the relationship between blocking mitochondrial pyruvate carrier (MPC) with MPC blocker UK5099 and the metabolic alteration as well as aggressive features of esophageal squamous carcinoma. It was found that blocking pyruvate transportation into mitochondria attenuated mitochondrial oxidative phosphorylation (OXPHOS) and triggered aerobic glycolysis, a feature of Warburg effect. In addition, the HIF-1α expression and ROS production were also activated upon UK5099 application. It was further revealed that the UK5099-treated cells became significantly more resistant to chemotherapy and radiotherapy, and the UK5099-treated tumor cells also exhibited stronger invasive capacity compared to the parental cells. In contrast to esophageal squamous epithelium cells, decreased MPC protein expression was observed in a series of 157 human squamous cell carcinomas, and low/negative MPC1 expression predicted an unfavorable clinical outcome. All these results together revealed the potential connection of altered MPC expression/activity with the Warburg metabolic reprogramming and tumor aggressiveness in cell lines and clinical samples. Collectively, our findings highlighted a therapeutic strategy targeting Warburg reprogramming of human esophageal squamous cell carcinomas. PMID:27911865

Preoperative F-18-FDG PET for the detection of metastatic cervical lymph nodes in recurrent papillary thyroid carcinoma patients with negative I-131 whole body scans

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Byun, Byung Hyun; Urn, Sang Moo; Cheon, Gi Jeong; Choi, Chang Woon; Lee, Byeong Cheol; Lee, Guk Haeng; Lee, Yong Sik; Shim, Youn Sang

2007-01-01

We evaluated the diagnostic performance of FDG-PET for the detection of metastatic cervical lymph nodes in recurrent papillary thyroid carcinoma patients with negative I-131 scan. All patients had total thyroidectomy and following I-131 ablation therapy. In the follow-up period, FDG-PET showed suspected cervical lymph nodes metastases and neck dissection was performed within 3 months after FDG-PET. It had shown for all patients the negative I-131 scan within 3 months before FDG-PET or negative I-131 scan during the period of cervical lymph nodes metastases suspected on the basis of FDG-PET, CT, or ultrasonography until the latest FDG-PET. Preoperative FDG-PET results were compared with the pathologic findings of lymph nodes specimens of 19 papillary thyroid carcinoma patients. Serum Tg, TSH, and Tg antibody levels at the time of latest I-131 scan were reviewed. The size of lymph node was measured by preoperative CT or ultrasonography. In 45 cervical lymph node groups dissected, 31 lymph node groups revealed metastasis. The sensitivity and specificity of FDG-PET for metastasis were 74.2% (23 of 31) and 50.0% (7 of 14), respectively. Except for patients with elevated Tg antibody levels, all patients showed the elevated serum Tg levels than normal limits at the TSH of =30uIU/ml. 8 lesions without suspected metastatic findings on FDG-PET revealed metastasis (false negative), and none of them exceeded 8mm in size (4 to 8mm, median= 6mm). On the other hand, 23 true positive lesions on FDG-PET were variable in size (6 to 17mm, median=9mm). FDG-PET is suitable for the detection of metastatic cervical lymph nodes in patients with recurrent papillary thyroid carcinoma. However, false positive or false negative should be considered according to the size of lymph node

Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer.

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Hiraki, Masayuki; Maeda, Takahiro; Mehrotra, Neha; Jin, Caining; Alam, Maroof; Bouillez, Audrey; Hata, Tsuyoshi; Tagde, Ashujit; Keating, Amy; Kharbanda, Surender; Singh, Harpal; Kufe, Donald

2018-01-01

B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial-mesenchymal transition (EMT) and promotes anti-cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression. The results show that MUC1-C activates the BCL2A1 gene by an NF-κB p65-mediated mechanism, linking this pathway with the induction of EMT. The MCL-1 anti-apoptotic protein is also of importance for the survival of TNBC cells and is an attractive target for drug development. We found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1-C→NF-κB→BCL2A1 pathway. In addition, selection of TNBC cells for resistance to ABT-737, which inhibits BCL-2, BCL-xL and BCL-W but not MCL-1 or BCL2A1, is associated with the upregulation of MUC1-C and BCL2A1 expression. Targeting MUC1-C in ABT-737-resistant TNBC cells suppresses BCL2A1 and induces death, which is of potential therapeutic importance. These findings indicate that MUC1-C is a target for the treatment of TNBCs unresponsive to agents that inhibit anti-apoptotic members of the BCL-2 family.

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A.

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Huang, Qiuyue; Qin, Shanshan; Yuan, Xiaoning; Zhang, Liang; Ji, Juanli; Liu, Xuewen; Ma, Wenjing; Zhang, Yunfei; Liu, Pengfei; Sun, Zhiting; Zhang, Jingxuan; Liu, Ying

2017-07-01

We have shown that a novel STAT3 inhibitor arctigenin (Atn) induces significant cytotoxicity in triple-negative breast cancer (TNBC) cells. This study further delineated molecular mechanisms where by Atn triggered cytotoxicity in TNBC cells. We found Atn can also inhibit metastasis in TNBC cells through cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. CIP2A is an endogenous inhibitor of protein phosphatase 2A (PP2A), which can increase the migration and invasion of various cancer cells. PP2A is a tumor suppressor, which is functionally defective in various cancers. Atn-induced metastasis inhibition was associated with reactivation of PP2A, downregulation of CIP2A and Akt phosphorylation. Silencing CIP2A enhanced Atn-induced metastasis inhibition and apoptosis in TNBCs. Furthermore, ectopic expression of CIP2A or inhibition of PP2A in TNBC cells abolished the effects of Atn. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A, at least in part, promotes the anti-metastasis effect induced by Atn. Our findings disclose the novel therapeutic mechanism of this targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.

The interface of mental health and human rights in Indigenous peoples: triple jeopardy and triple opportunity.

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Tarantola, Daniel

2007-01-01

Insufficient understanding of the reciprocal interactions between health and human rights, mental health and human rights and the realization of all human rights by Indigenous peoples constitute a triple jeopardy in how these topics are currently being addressed and/or openly antagonized. This paper will attempt to show how a combined health and human rights approach to mental health in Indigenous peoples can transform a triple jeopardy into a triple opportunity. The vast and growing body of literature on mental health, health as a whole, and human rights as these relate to health and to Indigenous peoples will be used to frame the discussion. Attention to the complex interactions of health and human rights can guide policy formulation and action by offering a method of analysis, a process of participatory decision and a framework for accountability. In addition, mental health can find its rightful place in the health and human rights discourse through efforts to help policymakers and practitioners broaden their vision of mental illness to holistically encompass aspects of physical, social, emotional and cultural wellbeing. Finally, connecting the role that rights realization plays in determining health and wellbeing will add power to the rightful claims by Indigenous peoples to the promotion and protection of all their human rights--civil, political, economic, social and cultural. Broadening the research agenda by applying systematically a health and human rights analytical framework to the understanding of social determinants of health would minimize the risk of assigning health outcome merely to behaviours, practices and lifestyles, uncovering structural determinants of holistic health entrenched in policies and governmental conduct. Building the evidence of the negative impact of human rights violation on health and the negative impact of ill-health on the fulfilment of other human rights can help in designing comprehensive interventions, building on the

Elevated serum levels of Chromogranin A in hepatocellular carcinoma.

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Biondi, Antonio; Malaguarnera, Giulia; Vacante, Marco; Berretta, Massimiliano; D'Agata, Velia; Malaguarnera, Michele; Basile, Francesco; Drago, Filippo; Bertino, Gaetano

2012-01-01

During the past three decades, the incidence of hepatocellular carcinoma in the United States has tripled. The neuroendocrine character has been observed in some tumor cells within some hepatocellular carcinoma nodules and elevated serum chromogranin A also been reported in patients with hepatocellular carcinoma. The aim of this work was to investigate the role of serum concentration of chromogranin A in patients with hepatocellular carcinoma at different stages. The study population consisted of 96 patients (63 males and 33 females age range 52-84) at their first hospital admission for hepatocellular carcinoma. The control group consisted of 35 volunteers (20 males and 15 females age range 50-80). The hepatocellular carcinoma patients were stratified according the Barcelona-Clinic Liver Cancer classification. Venous blood samples were collected before treatment from each patients before surgery, centrifuged to obtain serum samples and stored at -80° C until assayed. The chromogranin A serum levels were elevated (> 100 ng/ml) in 72/96 patients with hepatocellular carcinoma. The serum levels of chromogranin A were significantly correlated (p<0.05) with alpha-fetoprotein. In comparison with controls, the hepatocellular carcinoma patients showed a significant increase (p<0.001) vs controls. The chromogranin A levels in the Barcelona staging of hepatocellular carcinoma was higher in stage D compared to stage C (p<0.01), to stage B (p<0.001), and to stage A (p<0.001). Molecular markers, such as chromogranin A, could be very useful tools for hepatocellular carcinoma diagnosis. However the molecular classification should be incorporated into a staging scheme, which effectively separated patients into groups with homogeneous prognosis and response to treatment, and thus serves to aid in the selection of appropriate therapy.

CLINICAL RELEVANCE OF COEXISTENCE OF DUCTAL CA IN SITU AND INVASIVE DUCTAL CARCINOMA OF BREAST

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Kirithiga Ramalingam

2017-06-01

Full Text Available BACKGROUND There are many studies reported in the literature with respect to the Ductal Carcinoma in Situ (DCIS progressing into Invasive Ductal Carcinoma (IDC of the breast. However, there is hardly any study on the coexistence of both and its clinical significance. The aim of the study is to analyse the clinical and pathological parameters of synchronous DCIS and IDC to predict the prognostic factors. MATERIALS AND METHODS 42 patients with a final pathological diagnosis of synchronous DCIS and IDC diagnosed in 2009-11 were included in the study. Statistical analysis was done using SPSS software utilising the appropriate analytical methods. RESULTS Majority of the patients in this study group presented with early breast cancer (64.3%. Forty eight percent were Her2 subtype (ER, PR negative and HER2/neu-positive and 31% were triple negative. Eighty one percent of the IDC associated histology was Not Otherwise Specified (NOS type. Grade 3 lesions were more common (57%. Recurrence of the disease occurred in 66% of patients during a mean duration of follow up of 3.6 years with predominance of visceral metastasis (51.5%. Recurrence was more common in node positive disease (59.5%, those with lymphovascular emboli (59.5% and perinodal spread (76% on histopathological examination. CONCLUSION Synchronous DCIS and IDC disease entity appears to have an aggressive nature compared to the course of IDC alone entity. Prognostic factors relating to IDC appears to correlate well with recurrence than that of the prognostic factors of DCIS component in such synchronous setting.

Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

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Cecília P Popolin

Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1 [Ru(SO4(dppb(bipy], (2 [Ru(CO3(dppb(bipy], (3 [Ru(C2O4(dppb(bipy] and (4 [Ru(CH3CO2(dppb(bipy]PF6 [where dppb = 1,4-bis(diphenylphosphinobutane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231, estrogen-dependent breast tumor cells (MCF-7 and a non-tumor breast cell line (MCF-10A. Complex (4 was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4 was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4 was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4 should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.

Palliative surgery for pancreatic carcinoma

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Khan, I.M.; Aurangzeb, M.

2010-01-01

To evaluate the role of palliative surgical treatment in patients with advanced pancreatic carcinoma. Study Design: Case series. Place and Duration of Study: Surgical Ward of Khyber Teaching Hospital, Peshawar, from January 2005 to January 2009. Methodology: The study included patients with pancreatic carcinoma admitted with advanced, unresectable carcinoma of the pancreas. Patients with resectable tumours and with previous history of gastric or biliary surgery were excluded. Palliative procedures were performed after assessment of the tumour and its confirmation as unresectable on ultrasound and CT scan + ERCP. Postoperatively all patients were referred to oncologist. Complications and mortality were noted. Results: There were 40 patients, including 24 males and 16 females with mean age 58.72 +- 6.42 years. The most common procedure performed was triple bypass in 21 (52.50%) patients followed by choledocho-, cholecysto-, hepaticoand gastro-jejunostomy in various combinations. Wound infection occurred in 7 patients and was more common in patients with co-morbidities. Biliary leakage occurred in 03 patients. Postoperative cholangitis occurred in 3 patients while 7 patients had minor leak from the drain site. Four patients developed UTI, while 5 patients had signs of delayed gastric emptying. Two patients had upper gastrointestinal bleeding. Three patients died due to septicemia and multiple organs failure. Rest of the patients were discharged in stable state. The mean hospital stay was 8.40 +- 3.48 days and median survival was 7.72 +- 2.39 months. Conclusion: Surgical palliation for the advanced carcinoma pancreas can improve the quality of life of patients and is associated with minimum morbidity and mortality. (author)

Expression of MLH1 and MSH2 in urothelial carcinoma of the renal pelvis.

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Ehsani, Laleh; Osunkoya, Adeboye O

2014-09-01

In this study, we investigated microsatellite instability in urothelial carcinoma of the renal pelvis by lack of immunohistochemical staining for MLH1 and MSH2. The study included 44 cases of urothelial carcinoma of the renal pelvis obtained from radical nephroureterectomy specimens at our institution. We evaluated the loss of nuclear immunohistochemical staining of MLH1 and MSH2. Eight of 44 (18 %) patients had negative MLH1 expression and 25/44 (57 %) patients had negative MSH2 expression. Six of 8 (75 %) patients with negative MLH1 expression were male and 2/8 (25 %) patients were female. Nineteen of 25 (75 %) patients with negative MSH2 expression were male, and 6/25 (24 %) patients were female. Seven of 8 (88 %) cases with negative MLH1 expression were high-grade urothelial carcinoma, and 21/25 (84 %) cases with negative MSH2 expression were high-grade urothelial carcinoma. Twenty-one of 44 (48 %) cases had an inverted growth pattern, of which 3/21 (14 %) cases had negative MLH1 expression and 14/21 (67 %) cases had negative MSH2 expression. Our study showed that microsatellite instability based on negative expression of MLH1 and MSH2 was more common in male patients with high-grade urothelial carcinoma. There is a strong correlation between inverted growth pattern and negative MSH2 expression. Microsatellite instability testing should be performed in patients with upper urinary tract carcinoma and may have prognostic value.

Midkine Increases Diagnostic Yield in AFP Negative and NASH-Related Hepatocellular Carcinoma.

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Roslyn Vongsuvanh

Full Text Available Robust biomarkers for population-level hepatocellular carcinoma (HCC surveillance are lacking. We compared serum midkine (MDK, dickkopf-1 (DKK1, osteopontin (OPN and AFP for HCC diagnosis in 86 HCC patients matched to 86 cirrhotics, 86 with chronic liver disease (CLD and 86 healthy controls (HC. Based on the performance of each biomarker, we assessed a separate longitudinal cohort of 28 HCC patients, at and before cancer diagnosis. Serum levels of MDK and OPN were higher in HCC patients compared to cirrhosis, CLD and HC groups. DKK1 was not different between cases and controls. More than half of HCC patients had normal AFP. In this AFP-negative HCC cohort, 59.18% (n = 29/49 had elevated MDK, applying the optimal cut-off of 0.44 ng/ml. Using AFP ≥ 20 IU/ml or MDK ≥ 0.44 ng/ml, a significantly greater number (76.7%; n = 66/86 of HCC cases were detected. The area under the receiver operating curve for MDK was superior to AFP and OPN in NASH-HCC diagnosis. In the longitudinal cohort, MDK was elevated in 15/28 (54% of HCC patients at diagnosis, of whom 67% had elevated MDK 6 months prior.AFP and MDK have a complementary role in HCC detection. MDK increases the diagnostic yield in AFP-negative HCC and has greater diagnostic performance than AFP, OPN and DKK-1 in the diagnosis of NASH-HCC. Additionally, MDK has a promising role in the pre-clinical diagnosis of HCC.

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.

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Tingting Jiang

2016-12-01

Full Text Available Triple negative breast cancer (TNBC is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR from standard-of-care anthracycline/taxane (ACT chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC selected because they had either pCR (n = 18 or extensive residual disease (n = 11 after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144 and METABRIC (n = 278 cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02 and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05. Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021, and they had significantly higher mutation burden (p < 0.001 and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009. As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort

Is triple contrast computed tomographic scanning useful in the selective management of stab wounds to the back?

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McAllister, E; Perez, M; Albrink, M H; Olsen, S M; Rosemurgy, A S

1994-09-01

We devised a protocol to prospectively manage stab wounds to the back with the hypothesis that the triple contrast computed tomographic (CT) scan is an effective means of detecting occult injury in these patients. All wounds to the back in hemodynamically stable adults were locally explored. All patients with muscular fascial penetration underwent triple contrast CT scanning utilizing oral, rectal, and IV contrast. Patients did not undergo surgical exploration if their CT scan was interpreted as negative or if the CT scan demonstrated injuries not requiring surgical intervention. Fifty-three patients were entered into the protocol. The time to complete the triple contrast CT scan ranged from 3 to 6 hours at a cost of $1050 for each scan. In 51 patients (96%), the CT scan either had negative findings (n = 31) or showed injuries not requiring exploration (n = 20). These patients did well with nonsurgical management. Two CT scans documented significant injury and led to surgical exploration and therapeutic celiotomies. Although triple contrast CT scanning was able to detect occult injury in patients with stab wounds to the back it did so at considerable cost and the results rarely altered clinical care. Therefore, its routine use in these patients is not recommended.

Discovery of N-(Naphtho[1,2-b]Furan-5-Yl Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC

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Ya Chen

2018-03-01

Full Text Available Any type of breast cancer not expressing genes of the estrogen receptor (ER, progesterone receptor (PR, or human epidermal growth factor receptor 2 (HER2 is referred to as triple-negative breast cancer (TNBC. Accordingly, TNBCs do not respond to hormonal therapies or medicines targeting the ER, PR, or HER2. Systemic chemotherapy is therefore the only treatment option available today and prognoses remain poor. We report the discovery and characterization of N-(naphtho[1,2-b]furan-5-ylbenzenesulfonamides as selective inhibitors of TNBCs. These inhibitors were identified by virtual screening and inhibited different TNBC cell lines with IC50 values of 2–3 μM. The compounds did not inhibit normal (i.e. MCF-7 and MCF-10A cells in vitro, indicating their selectivity against TNBC cells. Considering the selectivity of these inhibitors for TNBC, these compounds and analogs can serve as a promising starting point for further research on effective TNBC inhibitors.

Almost convergence of triple sequences

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Ayhan Esi; M.Necdet Catalbas

2013-01-01

In this paper we introduce and study the concepts of almost convergence and almost Cauchy for triple sequences. Weshow that the set of almost convergent triple sequences of 0's and 1's is of the first category and also almost everytriple sequence of 0's and 1's is not almost convergent.Keywords: almost convergence, P-convergent, triple sequence.

EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours.

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Toosi, Behzad M; El Zawily, Amr; Truitt, Luke; Shannon, Matthew; Allonby, Odette; Babu, Mohan; DeCoteau, John; Mousseau, Darrell; Ali, Mohsin; Freywald, Tanya; Gall, Amanda; Vizeacoumar, Frederick S; Kirzinger, Morgan W; Geyer, C Ronald; Anderson, Deborah H; Kim, TaeHyung; Welm, Alana L; Siegel, Peter; Vizeacoumar, Franco J; Kusalik, Anthony; Freywald, Andrew

2018-04-27

Triple-negative breast cancer (TNBC) tumours that lack expression of oestrogen, and progesterone receptors, and do not overexpress the HER2 receptor represent the most aggressive breast cancer subtype, which is characterised by the resistance to therapy in frequently relapsing tumours and a high rate of patient mortality. This is likely due to the resistance of slowly proliferating tumour-initiating cells (TICs), and understanding molecular mechanisms that control TICs behaviour is crucial for the development of effective therapeutic approaches. Here, we present our novel findings, indicating that an intrinsically catalytically inactive member of the Eph group of receptor tyrosine kinases, EPHB6, partially suppresses the epithelial-mesenchymal transition in TNBC cells, while also promoting expansion of TICs. Our work reveals that EPHB6 interacts with the GRB2 adapter protein and that its effect on enhancing cell proliferation is mediated by the activation of the RAS-ERK pathway, which allows it to elevate the expression of the TIC-related transcription factor, OCT4. Consistent with this, suppression of either ERK or OCT4 activities blocks EPHB6-induced pro-proliferative responses. In line with its ability to trigger propagation of TICs, EPHB6 accelerates tumour growth, potentiates tumour initiation and increases TIC populations in xenograft models of TNBC. Remarkably, EPHB6 also suppresses tumour drug resistance to DNA-damaging therapy, probably by forcing TICs into a more proliferative, drug-sensitive state. In agreement, patients with higher EPHB6 expression in their tumours have a better chance for recurrence-free survival. These observations describe an entirely new mechanism that governs TNBC and suggest that it may be beneficial to enhance EPHB6 action concurrent with applying a conventional DNA-damaging treatment, as it would decrease drug resistance and improve tumour elimination.

Outcome of triple negative breast cancer: comparison of sporadic and BRCA1-associated cancers.

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Tung, Nadine; Gaughan, Elizabeth; Hacker, Michele R; Lee, Larissa J; Alexander, Brian; Poles, Emily; Schnitt, Stuart J; Garber, Judy E

2014-07-01

The majority of breast cancers developing in BRCA1 mutation carriers are triple negative breast cancers (TNBC), an aggressive subtype that accounts for 15-20 % of sporadic breast cancer. We compare the clinical outcome and sites of relapse of TNBC in BRCA1 mutation carriers and non-carriers who received adjuvant chemotherapy. Women with stage I-III TNBC who had BRCA1 testing within 36 months of diagnosis and received adjuvant chemotherapy were identified from clinical databases at two academic institutions. Sites of relapse, freedom from distant metastasis (FFDM), and breast cancer-specific survival (BCSS) were determined. RCA1 carriers (n = 89) were significantly younger at diagnosis (P < 0.0001) than non-carriers (n = 175). FFDM at 5 years was 80.5 % for carriers and 76.9 % for non-carriers; with median follow-up of 55 months, hazard ratio (HR) was 0.90, P = 0.71. Sites of recurrence, including brain, did not differ significantly. BCSS at 5 years was 88.1 % for carriers and 81.4 % for non-carriers; HR 0.60; P = 0.15 at 55 months follow-up. BRCA1 carriers who underwent oophorectomy had a significantly lower rate of death from TNBC, with an adjusted HR of 0.30 (95 % CI 0.10-0.94). Adjusting for age, oophorectomy, and prophylactic mastectomy, BRCA1 mutation status was not an independent predictor of survival (HR 2.1; P = 0.13). BRCA1 mutation carriers with TNBC had similar survival rates and sites of recurrence to non-carriers after treatment with conventional chemotherapy. Carriers who underwent oophorectomy had a significantly lower rate of breast cancer-related death; this finding should be studied further in all women with TNBC.

Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

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Riva, Francesca; Bidard, Francois-Clement; Houy, Alexandre; Saliou, Adrien; Madic, Jordan; Rampanou, Aurore; Hego, Caroline; Milder, Maud; Cottu, Paul; Sablin, Marie-Paule; Vincent-Salomon, Anne; Lantz, Olivier; Stern, Marc-Henri; Proudhon, Charlotte; Pierga, Jean-Yves

2017-03-01

In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery. Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 ( TP53 ) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS). Forty-six patients with nonmetastatic TNBC were enrolled. TP53 mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS ( r = 0.99), specificity (≥2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index ( P = 0.003), tumor grade ( P = 0.003), and stage ( P = 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free ( P < 0.001) and overall ( P = 0.006) survival. Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival. © 2016 American Association for Clinical Chemistry.

Bridging disparate symptoms of schizophrenia: a Triple network dysfunction theory

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Tereza eNekovarova

2014-05-01

Full Text Available Schizophrenia is a complex neuropsychiatric disorder with variable symptomatology, traditionally divided into positive and negative symptoms, and cognitive deficits. Yet, the etiology of this disorder has yet to be fully understood.Recent findings suggest that alteration of the basic sense of self-awareness may be an essential distortion of schizophrenia spectrum disorders. In addition, extensive research of social and mentalizing abilities has stressed the role of distortion of social skills in schizophrenia.This article aims to propose and support a concept of triple brain network model of the dysfunctional switching between default mode and central executive network related to the aberrant activity of salience network. This model could represent a unitary mechanism of a wide array of symptom domains present in schizophrenia including the deficit of SELF (self-awareness and self-representation and theory of mind (ToM dysfunctions along with the traditional positive, negative and cognitive domains. We review previous studies which document the dysfunctions of SELF and ToM in schizophrenia together with neuroimaging data elucidating the triple brain network model as a common neuronal substrate of this dysfunction.

Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.

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Brian D Lehmann

Full Text Available Triple-negative breast cancer (TNBC is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype, with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM and mesenchymal stem-like (MSL subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype into four (TNBCtype-4 tumor-specific subtypes (BL1, BL2, M and LAR and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50 or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; [33, 51], [9, 28], [17, 41], respectively. Collectively, we provide pre-clinical data that could inform

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

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Tang, X; Ding, C-K; Wu, J; Sjol, J; Wardell, S; Spasojevic, I; George, D; McDonnell, D P; Hsu, D S; Chang, J T; Chi, J-T

2017-07-27

Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable. To identify such a nutrient, we performed a nutrigenetic screen by removing individual amino acids to identify possible addictions across a panel of breast cancer cells. This screen revealed that cystine deprivation triggered rapid programmed necrosis, but not apoptosis, in the basal-type breast cancer cells mostly seen in TNBC tumors. In contrast, luminal-type breast cancer cells are cystine-independent and exhibit little death during cystine deprivation. The cystine addiction phenotype is associated with a higher level of cystine-deprivation signatures noted in the basal type breast cancer cells and tumors. We found that the cystine-addicted breast cancer cells and tumors have strong activation of TNFα and MEKK4-p38-Noxa pathways that render them susceptible to cystine deprivation-induced necrosis. Consistent with this model, silencing of TNFα and MEKK4 dramatically reduces cystine-deprived death. In addition, the cystine addiction phenotype can be abrogated in the cystine-addictive cells by miR-200c, which converts the mesenchymal-like cells to adopt epithelial features. Conversely, the introduction of inducers of epithelial-mesenchymal transition (EMT) in cystine-independent breast cancer cells conferred the cystine-addiction phenotype by modulating the signaling components of cystine addiction. Together, our data reveal that cystine-addiction is associated with EMT in breast cancer during tumor progression. These findings provide the genetic and

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

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Lehmann, Brian D.; Bauer, Joshua A.; Chen, Xi; Sanders, Melinda E.; Chakravarthy, A. Bapsi; Shyr, Yu; Pietenpol, Jennifer A.

2011-01-01

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies. PMID:21633166

Targeted Nanoparticles for Image-guided Treatment of Triple Negative Breast Cancer: Clinical Significance and Technological Advances

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Miller-Kleinhenz, Jasmine M.; Bozeman, Erica N.

2015-01-01

Effective treatment of triple negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and non-invasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise towards the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug-resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention (EPR) effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor associated endothelial cells, stromal fibroblasts and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as others and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic. PMID:25966677

Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency.

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Masahito Kawazu

2017-06-01

Full Text Available Triple-negative breast cancer (TNBC cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2, or NOTCH3 and affected tumor suppressor genes including RB1, PTEN, and KMT2C. Furthermore, we identified putative TGFA enhancer regions. Recurrent SVs that affected the TGFA enhancer region led to enhanced expression of the TGFA oncogene that encodes one of the high affinity ligands for epidermal growth factor receptor. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblasts, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC with clinically important implications.

Patients with a negative cystoscopy and negative Nmp22® Bladderchek® test are at low risk of missed transitional cell carcinoma of the bladder: a prospective evaluation

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John D. Terrell

2011-12-01

Full Text Available OBJECTIVES: Urine based tumor markers have uncertain utility in diagnosis or surveillance of patients with bladder cancer while cytology is commonly used. We evaluated whether cytology provides additional diagnostic information in patients with a negative NMP22® BladderChek® test (BladderChek and negative cystoscopy. MATERIALS AND METHODS: We performed subset analyses of 2 large prospective multi-center databases evaluating BladderChek for UCB detection and surveillance. These cohorts were analyzed for presence of cancer and result of urine cytology in setting of a negative cystoscopy and negative BladderChek. Subsequently, we prospectively performed cystoscopy, cytology and BladderChek on 434 patients at our institution being evaluated for UCB. RESULTS: In the detection database (n = 1331, 1065 patients had a negative cystoscopy and BladderChek. There were 3 cancers (stages Ta, Tis and T1 and cytology was atypical in one and reactive in two. In the surveillance cohort (n = 668 patients, 437 patients had negative cystoscopy and BladderChek. Cancer was found in 2 patients (stages Tis and Ta. The patient with Tis has dysplastic cytology and Ta tumor had reactive cytology. In our cohort of 434 patients, 288 pts had negative cystoscopy and BladderChek. One cancer was missed, a Ta ureteral urothelial carcinoma with a reactive cytology. CONCLUSIONS: In patients with negative cystoscopy and BladderChek, very few cancers are missed and cytology was not effective in detection. Use of a point-of-care test in conjunction with cystoscopy in lieu of cytology could decrease cost, provide immediate results, improve negative predictive value and reduce the uncertainty that results from inconclusive cytologic results.

Gene Expression Profiling Reveals a Massive, Aneuploidy-Dependent Transcriptional Deregulation and Distinct Differences between Lymph Node–Negative and Lymph Node–Positive Colon Carcinomas

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Grade, Marian; Hörmann, Patrick; Becker, Sandra; Hummon, Amanda B.; Wangsa, Danny; Varma, Sudhir; Simon, Richard; Liersch, Torsten; Becker, Heinz; Difilippantonio, Michael J.; Ghadimi, B. Michael; Ried, Thomas

2016-01-01

To characterize patterns of global transcriptional deregulation in primary colon carcinomas, we did gene expression profiling of 73 tumors [Unio Internationale Contra Cancrum stage II (n = 33) and stage III (n = 40)] using oligonucleotide microarrays. For 30 of the tumors, expression profiles were compared with those from matched normal mucosa samples. We identified a set of 1,950 genes with highly significant deregulation between tumors and mucosa samples (P 5-fold average expression difference between normal colon mucosa and carcinomas, including up-regulation of MYC and of HMGA1, a putative oncogene. Furthermore, we identified 68 genes that were significantly differentially expressed between lymph node–negative and lymph node–positive tumors (P deregulated genes were validated using quantitative real-time reverse transcription-PCR in >40 tumor and normal mucosa samples with good concordance between the techniques. Finally, we established a relationship between specific genomic imbalances, which were mapped for 32 of the analyzed colon tumors by comparative genomic hybridization, and alterations of global transcriptional activity. Previously, we had conducted a similar analysis of primary rectal carcinomas. The systematic comparison of colon and rectal carcinomas revealed a significant overlap of genomic imbalances and transcriptional deregulation, including activation of the Wnt/β-catenin signaling cascade, suggesting similar pathogenic pathways. PMID:17210682

Biologic Roles of Estrogen Receptor-β and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer

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Nalo Hamilton

2015-01-01

Full Text Available Triple-negative breast cancer (TNBC occurs in 10–15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERα may be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβ expression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβ protein. To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion. In vivo, insulin-like growth factor-2 (IGF-2, along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.

A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

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Siraj M. Ali

2016-02-01

Full Text Available After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC. We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%. A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

Geodynamical simulation of the RRF triple junction

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Wang, Z.; Wei, D.; Liu, M.; Shi, Y.; Wang, S.

2017-12-01

Triple junction is the point at which three plate boundaries meet. Three plates at the triple junction form a complex geological tectonics, which is a natural laboratory to study the interactions of plates. This work studies a special triple junction, the oceanic transform fault intersects the collinear ridges with different-spreading rates, which is free of influence of ridge-transform faults and nearby hotspots. First, we build 3-D numerical model of this triple junction used to calculate the stead-state velocity and temperature fields resulting from advective and conductive heat transfer. We discuss in detail the influence of the velocity and temperature fields of the triple junction from viscosity, spreading rate of the ridge. The two sides of the oceanic transform fault are different sensitivities to the two factors. And, the influence of the velocity mainly occurs within 200km of the triple junction. Then, we modify the model by adding a ridge-transform fault to above model and directly use the velocity structure of the Macquarie triple junction. The simulation results show that the temperature at both sides of the oceanic transform fault decreases gradually from the triple junction, but the temperature difference between the two sides is a constant about 200°. And, there is little effect of upwelling velocity away from the triple junction 100km. The model results are compared with observational data. The heat flux and thermal topography along the oceanic transform fault of this model are consistent with the observed data of the Macquarie triple junction. The earthquakes are strike slip distributed along the oceanic transform fault. Their depths are also consistent with the zone of maximum shear stress. This work can help us to understand the interactions of plates of triple junctions and help us with the foundation for the future study of triple junctions.

Hep par-1: a novel immunohistochemical marker for differentiating hepatocellular carcinoma from metastatic carcinoma

International Nuclear Information System (INIS)

Hanif, R.

2014-01-01

To evaluate the diagnostic utility of Hep par-1 in differentiating hepatocellular carcinoma from metastatic carcinoma taking histopathology as a gold standard. Study Design: Comparative cross-sectional study. Place and Duration of Study: Pathology Department, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from April 2007 to February 2008. Methodology: Hep par-1 immunohistochemical stain was performed on 60 cases of liver carcinoma, 30 cases each of metastatic and hepatocellular carcinoma. Information regarding patient age, gender, sign and symptoms, radiographic findings, histological grade of tumour, and expression of Hep par-1 on hepatocellular and metastatic carcinoma were recorded on proforma sheet. Sensitivity, specificity, positive and negative predictive values, and accuracy of Hep par-1 were calculated using the formulas. Results: Hep par-1 expression was noted in 25 out of 30 cases of hepatocellular carcinoma (83%). Out of 30 cases of metastatic carcinoma, only one case expressed staining in < 5% tumour cells and remaining 29 cases showed no reactivity. The age of the patients with hepatocellular carcinoma ranged from 40 to 76 years with a median age of 60.5 years and 40 - 75 years for metastatic carcinomas with a median age of 57.5 years. Conclusion: Hep par-1 is a reliable immunohistochemical marker for cases of hepatocellular carcinoma (HCC). It can be used along with other markers in morphologically difficult cases when differential diagnosis lies between poorly differentiated HCC and metastatic carcinoma of liver. (author)

Simulation of triple coincidences in PET

International Nuclear Information System (INIS)

Cal-González, J; Herranz, E; Vicente, E; Udias, J M; Lage, E; Dave, S R; Parot, V; Herraiz, J L; Moore, S C; Park, M-A

2015-01-01

Although current PET scanners are designed and optimized to detect double coincidence events, there is a significant amount of triple coincidences in any PET acquisition. Triple coincidences may arise from causes such as: inter-detector scatter (IDS), random triple interactions (R T ), or the detection of prompt gamma rays in coincidence with annihilation photons when non-pure positron-emitting radionuclides are used (β + γ events). Depending on the data acquisition settings of the PET scanner, these triple events are discarded or processed as a set of double coincidences if the energy of the three detected events is within the scanner’s energy window. This latter option introduces noise in the data, as at most, only one of the possible lines-of-response defined by triple interactions corresponds to the line along which the decay occurred. Several novel works have pointed out the possibility of using triple events to increase the sensitivity of PET scanners or to expand PET imaging capabilities by allowing differentiation between radiotracers labeled with non-pure and pure positron-emitting radionuclides. In this work, we extended the Monte Carlo simulator PeneloPET to assess the proportion of triple coincidences in PET acquisitions and to evaluate their possible applications. We validated the results of the simulator against experimental data acquired with a modified version of a commercial preclinical PET/CT scanner, which was enabled to acquire and process triple-coincidence events. We used as figures of merit the energy spectra for double and triple coincidences and the triples-to-doubles ratio for different energy windows and radionuclides. After validation, the simulator was used to predict the relative quantity of triple-coincidence events in two clinical scanners assuming different acquisition settings. Good agreement between simulations and preclinical experiments was found, with differences below 10% for most of the observables considered. For

Immunohistochemical expression profiles of mucin antigens in salivary gland mucoepidermoid carcinoma: MUC4- and MUC6-negative expression predicts a shortened survival in the early postoperative phase.

Science.gov (United States)

Honjo, Kie; Hiraki, Tsubasa; Higashi, Michiyo; Noguchi, Hirotsugu; Nomoto, Mitsuharu; Yoshimura, Takuya; Batra, Surinder K; Yonezawa, Suguru; Semba, Ichiro; Nakamura, Norifumi; Tanimoto, Akihide; Yamada, Sohsuke

2018-02-01

In mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6-negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase.

Targeted nanoparticles for image-guided treatment of triple-negative breast cancer: clinical significance and technological advances.

Science.gov (United States)

Miller-Kleinhenz, Jasmine M; Bozeman, Erica N; Yang, Lily

2015-01-01

Effective treatment of triple-negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and noninvasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise toward the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle-based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor-associated endothelial cells, stromal fibroblasts, and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in-depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as by others, and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic. © 2015 Wiley Periodicals, Inc.

Apoptosis induction by 7-chloroquinoline-1,2,3-triazoyl carboxamides in triple negative breast cancer cells.

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Begnini, Karine Rech; Duarte, Wladimir R; da Silva, Liziane Pereira; Buss, Julieti H; Goldani, Bruna S; Fronza, Mariana; Segatto, Natália Vieira; Alves, Diego; Savegnago, Lucielli; Seixas, Fabiana Kömmling; Collares, Tiago

2017-07-01

Breast cancer is a major public health burden in both developed and developing countries and there is still a need to screen new molecules with different modes of actions. The aims of this study were to evaluate the selectivity profile, apoptotic cell death and cell cycle arrest induced by 7-chloroquinoline-1,2,3-triazoyl carboxamides derivatives in hormonal-dependent and hormonal-independent breast cancer cells. Results showed significantly decreased MCF-7 and MDA-MB-231 cells viability in vitro in a dose dependent manner after treatment with 7-chloroquinoline derivatives QTCA-1, QTCA-2 and QTCA-3. QTCA-1 displayed the highest cytotoxic activity from all the tested compounds in MDA-MB-231 with IC50 values of 20.60, 20.42 and 19.91μM in 24, 48 and 72h of treatment respectively. Apoptosis induction was also significantly higher in the hormonal-independent breast cancer cells, with 80.4% of dead cells in MDA-MB-231 and only 16.8% of dead in MCF-7 cells. As a result, G0/G1 cycle arrest was observed in MCF-7 cells and no cell cycle arrest at all was observed in MDA-MB-231 cells. Molecular docking showed a high affinity of QTCA-1 to PARP-1, Scr and PI3K/mTOR targets. These results suggest a strong activity of the 7-chloroquinoline derivative QTCA-1 in independent-hormonal cells and suggest selectivity for triple negative cells. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Development of biodegradable PLGA nanoparticles surface engineered with hyaluronic acid for targeted delivery of paclitaxel to triple negative breast cancer cells.

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Cerqueira, Brenda Brenner S; Lasham, Annette; Shelling, Andrew N; Al-Kassas, Raida

2017-07-01

This study aimed at development of poly (lactic-co-glycolic acid) (PLGA) nanoparticles embedded with paclitaxel and coated with hyaluronic acid (HA-PTX-PLGA) to actively target the drug to a triple negative breast cancer cells. Nanoparticles were successfully fabricated using a modified oil-in-water emulsion method. The effect of various formulations parameters on the physicochemical properties of the nanoparticles was investigated. SEM imaging confirmed the spherical shape and nano-scale size of the nanoparticles. A sustained drug release profile was obtained and enhanced PTX cytotoxicity was observed when MDA-MB-231 cells were incubated with the HA-PTX-PLGA formulation compared to cells incubated with the non-HA coated nanoparticles. Moreover, HA-PLGA nanoparticles exhibited improved cellular uptake, based on a possible receptor mediated endocytosis due to interaction of HA with CD44 receptors when compared to non-coated PLGA nanoparticles. The non-haemolytic potential of the nanoparticles indicated the suitability of the developed formulation for intravenous administration. Copyright © 2017 Elsevier B.V. All rights reserved.

Wakeless triple soliton accelerator

International Nuclear Information System (INIS)

Mima, K.; Ohsuga, T.; Takabe, H.; Nishihara, K.; Tajima, T.; Zaidman, E.; Horton, W.

1986-09-01

We introduce and analyze the concept of a wakeless triple soliton accelerator in a plasma fiber. Under appropriate conditions the triple soliton with two electromagnetic and one electrostatic waves in the beat-wave resonance propagates with velocity c leaving no plasma wake behind, while the phase velocity of the electrostatic wave is made also c in the fiber

Molecular alterations in early gastric carcinomas. No apparent correlation with Helicobacter pylori status

NARCIS (Netherlands)

Blok, P.; Craanen, M. E.; Offerhaus, G. J.; Dekker, W.; Kuipers, E. J.; Meuwissen, S. G.; Tytgat, G. N.

1999-01-01

Data on the differences in molecular profile between H pylori-positive and H pylori-negative early gastric carcinomas, if any, are almost nonexistent. We therefore investigated whether molecular differences can be observed between H pylori-positive and H pylori-negative early gastric carcinomas.

Immunotherapy, an evolving approach for the management of triple negative breast cancer: Converting non-responders to responders.

Science.gov (United States)

Tolba, Mai F; Omar, Hany A

2018-02-01

Immunotherapy comprises a promising new era in cancer therapy. Immune checkpoint inhibitors targeting either the programmed death (PD)-1 receptor or its ligand PD-L1 were first approved by the Food and Drug Administration (FDA) for the management of metastatic melanoma in 2011. The approval of this class is being extended to include other types of immunogenic tumors. Although breast cancer (BC) was first categorized as non-immunogenic tumor type, there are certain subsets of BC that showed a high level of tumor infiltrating lymphocytes (TILs). Those subsets include the triple negative breast cancer (TNBC) and HER-2 positive breast tumors. Preliminary data from clinical trials presented promising outcomes for patients with advanced stage/metastatic TNBC. While the objective response rate (ORR) was relatively low, it is still promising because of the observation that the patients who respond to the treatment with immune checkpoint blockade have favorable prognosis and often show a significant increase in the overall survival. Therefore, the main challenge is to find ways to enhance the tumor response to such therapy and to convert the non-responders to responders. This will consequently bring new hopes for patients with advanced stage metastatic TNBC and help to decrease death tolls from this devastating disease. In the current review, we are highlighting and discussing the up-to-date strategies adopted at either the preclinical or the clinical settings to enhance tumor responsiveness to immunotherapy. Copyright © 2018 Elsevier B.V. All rights reserved.

H-Ferritin Enriches the Curcumin Uptake and Improves the Therapeutic Efficacy in Triple Negative Breast Cancer Cells.

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Pandolfi, Laura; Bellini, Michela; Vanna, Renzo; Morasso, Carlo; Zago, Andrea; Carcano, Sofia; Avvakumova, Svetlana; Bertolini, Jessica Armida; Rizzuto, Maria Antonietta; Colombo, Miriam; Prosperi, Davide

2017-10-09

Triple negative breast cancer (TNBC) is a highly aggressive, invasive, and metastatic tumor. Although it is reported to be sensitive to cytotoxic chemotherapeutics, frequent relapse and chemoresistance often result in treatment failure. In this study, we developed a biomimetic nanodrug consisting of a self-assembling variant (HFn) of human apoferritin loaded with curcumin. HFn nanocage improved the solubility, chemical stability, and bioavailability of curcumin, allowing us to reliably carry out several experiments in the attempt to establish the potential of this molecule as a therapeutic agent and elucidate the mechanism of action in TNBC. HFn biopolymer was designed to bind selectively to the TfR1 receptor overexpressed in TNBC cells. HFn-curcumin (CFn) proved to be more effective in viability assays compared to the drug alone using MDA-MB-468 and MDA-MB-231 cell lines, representative of basal and claudin-low TNBC subtypes, respectively. Cellular uptake of CFn was demonstrated by flow cytometry and label-free confocal Raman imaging. CFn could act as a chemosensitizer enhancing the cytotoxic effect of doxorubicin by interfering with the activity of multidrug resistance transporters. In addition, CFn exhibited different cell cycle effects on these two TNBC cell lines, blocking MDA-MB-231 in G0/G1 phase, whereas MDA-MB-468 accumulated in G2/M phase. CFn was able to inhibit the Akt phosphorylation, suggesting that the effect on the proliferation and cell cycle involved the alteration of PI3K/Akt pathway.

Age/race differences in HER2 testing and in incidence rates for breast cancer triple subtypes: a population-based study and first report.

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Lund, Mary Jo; Butler, Ebonee N; Hair, Brionna Y; Ward, Kevin C; Andrews, Judy H; Oprea-Ilies, Gabriella; Bayakly, A Rana; O'Regan, Ruth M; Vertino, Paula M; Eley, J William

2010-06-01

Although US year 2000 guidelines recommended characterizing breast cancers by human epidermal growth factor receptor 2 (HER2), national cancer registries do not collect HER2, rendering a population-based understanding of HER2 and clinical "triple subtypes" (estrogen receptor [ER] / progesterone receptor [PR] / HER2) largely unknown. We document the population-based prevalence of HER2 testing / status, triple subtypes and present the first report of subtype incidence rates. Medical records were searched for HER2 on 1842 metropolitan Atlanta females diagnosed with breast cancer during 2003-2004. HER2 testing/status and triple subtypes were analyzed by age, race/ethnicity, tumor factors, socioeconomic status, and treatment. Age-adjusted incidence rates were calculated. Over 90% of cases received HER2 testing: 12.6% were positive, 71.7% negative, and 15.7% unknown. HER2 testing compliance was significantly better for women who were younger, of Caucasian or African-American descent, or diagnosed with early stage disease. Incidence rates (per 100,000) were 21.1 for HER2+ tumors and 27.8 for triple-negative tumors, the latter differing by race (36.3 and 19.4 for black and white women, respectively). HER2 recommendations are not uniformly adhered to. Incidence rates for breast cancer triple subtypes differ by age/race. As biologic knowledge is translated into the clinical setting eg, HER2 as a biomarker, it will be incumbent upon national cancer registries to report this information. Incidence rates cautiously extrapolate to an annual burden of 3000 and 17,000 HER2+ tumors for black and white women, respectively, and triple-negative tumors among 5000 and 16,000 respectively. Testing, rate, and burden variations warrant population-based in-depth exploration and clinical translation. (c) 2010 American Cancer Society.

Genetic Ancestry using Mitochondrial DNA in patients with Triple-negative breast cancer (GAMiT study).

Science.gov (United States)

Rao, Roshni; Rivers, Aeisha; Rahimi, Asal; Wooldridge, Rachel; Rao, Madhu; Leitch, Marilyn; Euhus, David; Haley, Barbara B

2017-01-01

Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns. Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected. A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; Pancestry and haplogroups A, U, H, or B to be the most common mtDNA patterns. Twelve discordances (13%) between mtDNA analysis and self-described ethnicity were identified among the 92 patients. The highest discordance (26%; 8 patients) was noted in self-described Hispanic patients: 3 had Nigerian ancestry, and 1 individual demonstrated haplogroup K mtDNA (Ashkenazi Jewish ancestry). Discordance between self-reported ethnicity and mtDNA analysis was identified in 13% of patients with TNBC. The identification of mtDNA patterns with a predisposition toward TNBC may allow for risk stratification. Cancer 2017;107-113. © 2016 American Cancer Society. © 2016 American Cancer

Caveolin-1 expression as a prognostic marker in triple negative breast cancers of Asian women.

Science.gov (United States)

Yeong, Joe; Thike, Aye Aye; Ikeda, Murasaki; Lim, Jeffrey Chun Tatt; Lee, Bernett; Nakamura, Seigo; Iqbal, Jabed; Tan, Puay Hoon

2018-02-01

Triple-negative breast cancers (TNBCs) are defined by their lack of oestrogen receptor, progesterone receptor and epidermal growth factor receptor 2. Although heterogeneous, the majority are aggressive and treatment options are limited. Caveolin acts as tumour suppressor or promoter depending on the cancer type. In this study, we aimed to determine if the expression levels of the candidate biomarker caveolin-1 on stromal or tumour cells were associated with clinicopathological parameters and disease outcomes in TNBCs from an ethnically diverse cohort of Asian women. Tumour specimens from 699 women with TNBC were subjected to immunohistochemical analysis of the frequency and intensity of caveolin-1 expression in tumour and stromal cells. A subset of 141 tumour samples also underwent Nanostring measurement of CAV1 mRNA. Results were correlated with clinicopathological parameters and disease outcomes. Expression of caveolin-1 in stromal cells was observed in 14.4% of TNBC cases. TNBCs of the basal-like phenotype (85% of samples) were significantly more likely to exhibit stromal cell caveolin-1 expression (p=0.028), as were those with a trabecular growth pattern (p=0.007). Lack of stromal caveolin-1 expression in both TNBCs and those with the basal-like phenotype was significantly associated with worse overall survival (p=0.009 and p=0.026, respectively): accordingly, increasing mRNA levels of CAV1 in TNBC samples predicted better overall survival. Caveolin-1 expression on TNBC tumour cells was not associated with clinical outcome. Stromal, but not tumoural, caveolin-1 expression is significantly associated with survival in Asian women with TNBC. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Wnt modulates MCL1 to control cell survival in triple negative breast cancer

International Nuclear Information System (INIS)

Yang, Lixin; Zhang, Hang; Zheng, Shu; Liu, Zheng; Ann, David; Yen, Yun; Perez, Aldwin Apollo; Fujie, Sayuri; Warden, Charles; Li, Jie; Wang, Yafan; Yung, Bryan; Chen, Yun-Ru; Liu, Xiyong

2014-01-01

Triple negative breast cancer (TNBC) has higher rates of recurrence and distant metastasis, and poorer outcome as compared to non-TNBC. Aberrant activation of WNT signaling has been detected in TNBC, which might be important for triggering oncogenic conversion of breast epithelial cell. Therefore, we directed our focus on identifying the WNT ligand and its underlying mechanism in TNBC cells. We performed large-scale analysis of public microarray data to screen the WNT ligands and the clinical significance of the responsible ligand in TNBC. WNT5B was identified and its overexpression in TNBC was confirmed by immunohistochemistry staining, Western blot and ELISA. ShRNA was used to knockdown WNT5B expression (shWNT5B). Cellular functional alteration with shWNT5B treatment was determined by using wound healing assay, mammosphere assay; while cell cycle and apoptosis were examined by flowcytometry. Mitochondrial morphology was photographed by electron microscope. Biological change of mitochondria was detected by RT-PCR and oxygen consumption assay. Activation of WNT pathway and its downstream targets were evaluated by liciferase assay, immunohistochemistry staining and immunoblot analysis. Statistical methods used in the experiments besides microarray analysis was two-tailed t-test. WNT5B was elevated both in the tumor and the patients’ serum. Suppression of WNT5B remarkably impaired cell growth, migration and mammosphere formation. Additionally, G0/G1 cell cycle arrest and caspase-independent apoptosis was observed. Study of the possible mechanism indicated that these effects occurred through suppression of mitochondrial biogenesis, as evidenced by reduced mitochondrial DNA (MtDNA) and compromised oxidative phosphorylation (OXPHOS). In Vivo and in vitro data uncovered that WNT5B modulated mitochondrial physiology was mediated by MCL1, which was regulated by WNT/β-catenin responsive gene, Myc. Clinic data analysis revealed that both WNT5B and MCL1 are associated with

BRCAness and Prognosis in Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

Directory of Open Access Journals (Sweden)

Hirokazu Tanino

Full Text Available BRCAness is defined as the set of traits in which BRCA1 dysfunction, arising from gene mutation, methylation or deletion, results in DNA repair deficiency. In the present study, we addressed BRCAness, therapeutic efficacy, recurrence, and survival in patients with triple negative breast cancer (TNBC who were treated with neoadjuvant chemotherapy at Kitasato University Hospital, Japan, between April 2006 and October 2012. BRCAness was determined by preoperative core needle biopsy (CNB specimens and surgical specimens. Assay was performed using Multiplex Ligation-dependent Probe Amplification (MLPA with P376-B2 BRCA1ness probemix (MRC-Holland, Amsterdam, The Netherlands. The relative copy number ratio of each sample was compared to Human Genomic DNA (Promega, Madison, WI, USA as reference samples was calculated with Coffalyser.NET default settings. The BRCAness score was calculated with the relative copy number ratio of various DNA sequences. Values of 0.5 or more were determined as the BRCA1-like Type (BRCAness and those of less than 0.5 as the Sporadic Type to analyze pathological complete response (pCR rate, recurrence, and survival. pCR (ypT0/Tis/N0 was observed in 15 patients (pCR rate: 37.5%. These patients had no recurrence. Twelve patients recurred, 8 died from breast cancer. The BRCA1-like Type were 22 and Sporadic Type were 18 in CNB specimens. No major differences were observed between the BRCA1-like Type and Sporadic Type with pCR rate, recurrence rate and survival. Twenty four surgical specimens of non-pCR patients were available and 9 were BRCA1-like Type, who had more recurrences (7/9 vs. 5/15, and their relapse-free survival was also lower (p<0.05 than that of Sporadic Type. Seven BRCA1-like Type patients remained BRCA1-like Type in surgical specimens, were worse in recurrence (p<0.01 and survival (p<0.05 compared with 6 patients whose BRCA status in surgical specimens turned to Sporadic Type. New clinical trials assessing the true

NIM Realization of the Gallium Triple Point

Science.gov (United States)

Xiaoke, Yan; Ping, Qiu; Yuning, Duan; Yongmei, Qu

2003-09-01

In the last three years (1999 to 2001), the gallium triple-point cell has been successfully developed, and much corresponding research has been carried out at the National Institute of Metrology (NIM), Beijing, China. This paper presents the cell design, apparatus and procedure for realizing the gallium triple point, and presents studies on the different freezing methods. The reproducibility is 0.03 mK, and the expanded uncertainty of realization of the gallium triple point is evaluated to be 0.17 mK (p=0.99, k=2.9). Also, the reproducibility of the gallium triple point was compared with that of the triple point of water.

Stimuli-Responsive Mesoporous Silica NPs as Non-viral Dual siRNA/Chemotherapy Carriers for Triple Negative Breast Cancer

Directory of Open Access Journals (Sweden)

Behrad Darvishi

2017-06-01

Full Text Available Triple negative breast cancer (TNBC is the most aggressive and lethal subtype of breast cancer. It is associated with a very poor prognosis and intrinsically resistant to several conventional and targeted chemotherapy agents and has a 5-year survival rate of less than 25%. Because the treatment options for TNBC are very limited and not efficient enough for achieving minimum desired goals, shifting toward a new generation of anti-cancer agents appears to be very critical. Among recent alternative approaches being proposed, small interfering RNA (siRNA gene therapy can potently suppress Bcl-2 proto-oncogene and p-glycoprotein gene expression, the most important chemotherapy resistance inducers in TNBC. When resensitized, primarily ineffective chemotherapy drugs turn back into valuable sources for further intensive chemotherapy. Regrettably, siRNA’s poor stability, rapid clearance in the circulatory system, and poor cellular uptake mostly hampers the beneficial outcomes of siRNA therapy. Considering these drawbacks, dual siRNA/chemotherapy drug encapsulation in targeted delivery vehicles, especially mesoporous silica nanoparticles (MSNs appears to be the most reasonable solution. The literature is full of reports of successful treatments of multi-drug-resistant cancer cells by administration of dual drug/siRNA-loaded MSNs. Here we tried to answer the question of whether application of a similar approach with identical delivery devices in TNBC is rational.

Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells

Directory of Open Access Journals (Sweden)

Kyung-Min Yang

2017-12-01

Full Text Available Summary: Triple-negative breast cancer (TNBC is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2, which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region. BAG2 regulates pro-cathepsin B/annexin II complex formation and facilitates the trafficking of pro-cathespin-B-containing TGN38-positive vesicles toward the cell periphery, leading to the secretion of pro-cathepsin B, which induces metastasis. Collectively, our results uncover BAG2 as a regulator of the oncogenic function of pro-cathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer. : The mechanisms controlling the pro- and anti-oncogenic roles of cathepsin B are unclear. Yang et al. find that BAG2 is a regulator of the dual functions of its client protein, CTSB, facilitating the progression of TNBC. Keywords: BAG2, cathepsin B, TNBC, tumorigenesis, metastasis, breast cancer, TGN38

Clinical importance of technetium-99m-methoxyisobutylisonitrile (MIBI) scintigraphy in differentiated thyroid carcinoma patients with elevated thyroglobulin levels and negative I-131 scanning results

International Nuclear Information System (INIS)

Kuecuek, N.O.; Kulak, H.A.; Aras, G.

2006-01-01

The aim of this study was to evaluate the potential contribution of Tc-99m-MIBI scintigraphy to the follow-up of patients with differentiated thyroid carcinoma, who had elevated Tg levels and negative I-131 whole-body scan (WBS) results. In this retrospective study, we evaluated 28 patients with differentiated thyroid carcinoma, who had total or near total thyroidectomy followed by an ablative dose of I-131 at various time intervals (15 women, 13 men; mean age 43±17 years). All patients were treated with T4 suppression. After a mean follow-up period of 6.1 years (range 3-15) all patients were determined to have a high serum Tg concentrations (>2 ng/ml) and previous negative I-131 WBS results. All patients were examined for metastatic sites using Tc-99m-MIBI scan. Scans were visually evaluated for detecting lymph node metastases and/or local recurrence, lung metastases and skeletal metastases. Tc-99m-MIBI scan demonstrated lesions in 23 patients (83.3%). In five patients with negative Tc-99m-MIBI scan findings (FN results): Chest CT showed small-sized mediastinal LN metastases in 2 patients and lung metastases in another 2 patients (<1 cm); Neck CT showed small-sized cervical LN involvement in 1 patient. The sensitivity of detection for neck was 94.4%, for lung 63.6%, and for bone lesions 100%. For all scan sites taken together, the sensitivity of disease detection was 83.3%, the specificity was 50%, positive predictive value (PPV) was 96.2%, and finally negative predictive value (NPV) was 16.7%. We concluded that Tc-99m-MIBI scan should be considered as a supplementary scintigraphic method for the follow-up of patients with high serum Tg levels and negative I-131 WBS results, and it can help clinicians in making the decision to treat these patients. (author)

Nanobiopolymer for direct targeting and inhibition of EGFR expression in triple negative breast cancer.

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Satoshi Inoue

Full Text Available Treatment options for triple negative breast cancer (TNBC are generally limited to cytotoxic chemotherapy. Recently, anti-epidermal growth factor receptor (EGFR therapy has been introduced for TNBC patients. We engineered a novel nanobioconjugate based on a poly(β-L-malic acid (PMLA nanoplatform for TNBC treatment. The nanobioconjugate carries anti-tumor nucleosome-specific monoclonal antibody (mAb 2C5 to target breast cancer cells, anti-mouse transferrin receptor (TfR antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide (AON to inhibit EGFR synthesis. The nanobioconjugates variants were: (1 P (BioPolymer with AON, 2C5 and anti-TfR for tumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR, and (2 P with AON and 2C5 (P/AON/2C5. Controls included (3 P with 2C5 but without AON (P/2C5, (4 PBS, and (5 P with PEG and leucine ester (LOEt for endosomal escape (P/mPEG/LOEt. Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissue accumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detected by western blotting. In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFR synthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation. Significant tumor growth inhibition was observed in mice treated with the lead nanobioconjugate (1 [P = 0.03 vs. controls; P<0.05 vs. nanobioconjugate variant (2]. Lead nanobioconjugate (1 also showed stronger inhibition of EGFR expression and Akt phosphorylation than other treatments. Treatment of TNBC with the new nanobioconjugate results in tumor growth arrest by inhibiting EGFR and its downstream signaling intermediate, phosphorylated Akt. The nanobioconjugate

Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT

Directory of Open Access Journals (Sweden)

Zhen-Yu He

2017-02-01

Full Text Available Triple-negative breast cancer (TNBC was regarded as the most aggressive and mortal subtype of breast cancer (BC since the molecular subtype system has been established. Abundant studies have revealed that epithelial-mesenchymal transition (EMT played a pivotal role during breast cancer metastasis and progression, especially in TNBC. Herein, we showed that inhibition the expression of replication factor C subunit 3 (RFC3 significantly attenuated TNBC metastasis and progression, which was associated with EMT signal pathway. In TNBC cells, knockdown of RFC3 can down-regulate mesenchymal markers and up-regulate epithelial markers, significantly attenuated cell proliferation, migration and invasion. Additionally, silencing RFC3 expression can decrease nude mice tumor volume, weight and relieve lung metastasis in vivo. Furthermore, we also demonstrated that overexpression of RFC3 in TNBC showed increased metastasis, progression and poor prognosis. We confirmed all of these results by immunohistochemistry analysis in 127 human TNBC tissues and found that RFC3 expression was significantly associated with poor prognosis in TNBC. Taken all these findings into consideration, we can conclude that up-regulation of RFC3 promotes TNBC progression through EMT signal pathway. Therefore, RFC3 could be an independent prognostic factor and therapeutic target for TNBC.

Recurrent/metastatic thyroid carcinomas false negative for serum thyroglobulin but positive by posttherapy I-131 whole body scans

International Nuclear Information System (INIS)

Park, Eun-Kyung; Lee, Dong Soo; Lee, Myung Chul; Chung, June-Key; Lim, Il Han; Park, Do Joon; Cho, Bo Youn

2009-01-01

Serum Tg and I-131 WBS have been used to detect recurrent and metastatic thyroid cancers postoperatively. Tg is known to be more sensitive than I-131 WBS, and therefore, false-negative WBS cases with elevated Tg levels are frequently found. However, the clinical characteristics of false-negative Tg cases with positive WBS have not been clarified. The authors evaluated 824 postoperative patients with differentiated thyroid carcinoma who underwent post-ablation/therapy I-131 WBS. Tg negativity was defined as a Tg level of ≤2 ng/mL without TgAb under thyroid-stimulating hormone stimulation. Remission, recurrence, and metastasis were confirmed using pathologic or clinically findings. Fifty-two patients (6.3%) with functioning metastasis and negativity for TgAb were Tg-negative and posttherapy I-131 WBS-positive (TgN group), and 128 patients with functioning metastases were Tg positive and WBS positive (TgP group). The TgN group consisted of 45 cases of cervical/mediastinal lymph node metastases (86.5%) and seven cases of distant metastasis to lung or bone by follow-up WBS. The TgN group demonstrated significantly higher profiles of regional involvement than the TgP group (P < 0.029). In 47 patients in the TgN group, metastatic uptake disappeared in 33, ameliorated in four, and persisted in ten during follow-up. A significant number of differentiated thyroid cancer patients were Tg-/TgAb-negative despite a positive WBS finding. Cervical and mediastinal lymph nodes were predominant sites of metastasis in the TgN group. WBS should be undertaken routinely as a complementary modality to detect functioning recurrence and metastasis regardless of serum Tg results. (orig.)

Effect of Pretreatment with Lactobacillus delbrueckii and Streptococcus thermophillus on Tailored Triple Therapy for Helicobacter pylori Eradication: A Prospective Randomized Controlled Clinical Trial.

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Tongtawee, Taweesak; Dechsukhum, Chavaboon; Leeanansaksiri, Wilairat; Kaewpitoon, Soraya; Kaewpitoon, Natthawut; Loyd, Ryan A; Matrakool, Likit; Panpimanmas, Sukij

2015-01-01

Helicobacter pylori plays an important role in gastric cancer and typical eradication regimens are no longer effective in many countries, including Thailand. The aim of our study was to compare the effect of Lactobacillus delbrueckii and Streptococcus thermophillus on tailored triple therapy for Helicobacter pylori eradication. This prospective single-center study was conducted in Thailand. Helicobacter pylori associated gastritis patients were randomized to 2 groups: group 1 (n=100) was tailored triple therapy with placebo (esomeprazole 20 mg bid, clarithromycin 500 mg bid or metronidazole 400 mg tid if clarithromycin resistance and amoxicillin 1000 mg bid), and group 2 was tailored triple therapy plus pretreatment with probiotic containing yogurt. Successful eradication was defined as both negative histology and negative rapid urease test at four weeks after treatment. A total of 200 infected patients were enrolled. PP analysis involved 194 patients: 96 in the tailored triple therapy with placebo group (group 1) and 98 the in tailored triple therapy plus pretreatment with probiotic containing yogurt group (group 2). Successful eradication was observed in 170 (87.6%) patients; by PP analysis, the eradication rate was significantly higher in group 2 (P=0.04, 95%CI; 0.02-0.13) than in group 1. ITT analysis also showed that the value was significantly higher in the tailored triple threapy plus pretreatment with probiotic containing yogurt group (group 2) (89/100; 89%) than in the tailored triple therapy with placebo group (group 1) (P=0.01, 95%CI; 0.04-0.15). In terms of adverse events, there was no significant difference between the two groups. Pretreatment with probiotic containing yogurt can improve Helicobacter pylori eradication rates with tailored triple therapy. Adding probiotics does not reduce adverse effects of the medication.

Harmonic analysis on triple spaces

DEFF Research Database (Denmark)

Danielsen, Thomas Hjortgaard

In this thesis we study examples of triple spaces, both their structure theory, their invariant differential operators as well as analysis on them. The first major results provide us with some examples of triple spaces which are strongly spherical, i.e. satisfy some conditions reminiscent...

Acid sphingomyelinase activity as an indicator of the cell stress in HPV-positive and HPV-negative head and neck squamous cell carcinoma.

Science.gov (United States)

Gerle, Mirko; Medina, Tuula Peñate; Gülses, Aydin; Chu, Hanwen; Naujokat, Hendrik; Wiltfang, Jörg; Açil, Yahya

2018-03-21

Human papillomavirus (HPV) infection, especially HPV-16 and HPV-18, has been increasingly associated with head and neck squamous cell carcinoma. The treatment of HPV-positive squamous cell carcinoma has a better response to both radiotherapy and chemotherapy and presents a better prognosis for the patient. Defining the underlying mechanism of the difference might help in developing future treatment options and could be an important factor in personal therapy planning. Endogenously secreted acid sphingomyelinase (ASMase) levels in the cellular stress caused by irradiation and cisplatin were investigated. MTT assay was performed to evaluate the viability of the treated cells. Keratinocytes were used to evaluate the effects of radiation on normal tissues. Irradiation caused a dose-dependent increase in ASMase activity in both SCC9 HPV-negative, and UDSCC2 HPV-positive cells. ASMase activity in UDSCC2 cells was significantly higher than that in SCC9 cells. UDSCC cells were more sensitive to cisplatin treatment than SCC cells, and the dose-response in the activity was observed in long-time treatments when high doses of cisplatin were used. The results of the current study have clearly showed that HPV positivity should be considered as one of the determinative factors which should be considered when tumor treatments are planned. However, further studies are needed to determine the differences in cellular responses and pathways among HPV-negative and HPV-positive cells.

Lactoferrin- Endothelin-1 Axis Contributes to the Development and Invasiveness of Triple Negative Breast Cancer Phenotypes

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Ha, Ngoc-Han; Nair, Vasudha; Reddy, Divijendra Natha Sirigiri; Mudvari, Prakriti; Ohshiro, Kazufumi; Ghanta, Krishna Sumanth; Pakala, Suresh B.; Li, Da-Qiang; Costa, Luis; Lipton, Allan; Badwe, Rajendra A.; Fuqua, Suzanne; Wallon, Margaretha; Prendergast, George C.; Kumar, Rakesh

2013-01-01

Triple-negative breast cancer (TNBC) is characterized by the lack of expression of ERα, PR and HER-2 receptors and the pathway(s) responsible for this downregulation and thus aggressiveness, remains unknown. Here we discovered that lactoferrin (Lf) efficiently downregulates the levels of ERα, PR and HER-2 receptors in a proteasome-dependent manner in breast cancer cells, and accounts for the loss of responsiveness to ER- or HER-2- targeted therapies. Further we found that Lf increases migration and invasiveness of both non-TNBC and TNBC cell lines. We discovered that Lf directly stimulates the transcription of endothelin-1 (ET-1), a secreted pro-invasive polypeptide that acts through a specific receptor ET(A)R, leading to secretion of bioactive ET-1 peptide. Interestingly, a therapeutic ET-1 receptor antagonist drug completely blocked Lf-dependent motility and invasiveness of breast cancer cells. Physiologic significance of this newly discovered Lf-ET-1 axis in the manifestation of TNBC phenotypes is revealed by elevated plasma and tissue Lf and ET-1 levels in TNBC patients as compared to those in ER+ cases. These findings describe the first physiologically relevant polypeptide as a functional determinant of downregulating all three therapeutic receptors in breast cancer which utilizes another secreted ET-1 system to confer invasiveness. Results presented here provide proof-of-principle evidence in support of therapeutic effectiveness of ET-1 receptor antagonist to completely block the Lf-induced motility and invasiveness of the TNBC as well as non-TBNC cells, and thus, opening a remarkable opportunity to treat TNBC by targeting the Lf-ET-1 axis using an approved developmental drug. PMID:22006997

331 cases of clinically node-negative supraglottic carcinoma of the larynx: a study of a modest size fixed field radiotherapy approach

International Nuclear Information System (INIS)

Sykes, Andrew J.; Slevin, Nicholas J.; Gupta, Nirmal K.; Brewster, Allison E.

2000-01-01

Purpose: For node-negative supraglottic carcinoma of the larynx, radiotherapy with surgery in reserve commonly provides very good results in terms of both local control and survival, while preserving function. However uncertainty exists over the treatment of the node-negative neck. Elective whole neck radiotherapy, while effective, may be associated with significant morbidity. The purpose of this study was to examine our practice of treating a modest size, fixed field to a high biologically effective dose and compare it with the patterns of recurrence from other centers that use different dose/volume approaches. Methods and Materials: Over a 10-year period 331 patients with node-negative supraglottic carcinoma of the larynx were treated with radiotherapy at the Christie Hospital Manchester. Patients were treated with doses of 50-55 Gy in 16 fractions over 3 weeks. Data were collected retrospectively for local and regional control, survival, and morbidity. Results: Overall local control, after surgical salvage in 17 cases, was 79% (T1-92%, T2-81%, T3-67%, T4-73%). Overall regional lymph node control, after surgical salvage in 13 cases, was 84% (T1-91%, T2-88%, T3-81%, T4-72%). Five-year crude survival was 50%, but after correcting for intercurrent deaths was 70% (T1-83%, T2-78%, T3-53%, T4-61%). Serious morbidity requiring surgery was seen in 7 cases (2.1%) and was related to prescribed dose (50 Gy-0%, 52.5 Gy-1.3%, 55 Gy-3.4%). Discussion: Our results confirm that treating a modest size, fixed field to a high biologically effective dose is highly effective. It enables preservation of the larynx in most cases, with acceptable regional control and no loss of survival compared to whole neck radiotherapy regimes

Thyroid carcinoma in children

International Nuclear Information System (INIS)

Akhzari, F.

2002-01-01

Thyroid cancer is rare in children, with only 3-6% of thyroid malignancies occurring in children, and constitutes but 6% of head and neck tumors. Over 95% thyroid cancer are differentiated, and 10% of these occur in children of adolescents. Any of the histologic types that occur in adults may be in children, but they are most often differentiated thyroid carcinomas. The etiologies of thyroid carcinoma are unknown, but factors considered in pathogenesis include irradiation, sex and age. The incandesce of thyroid carcinoma in a solitary coddle in a child has been described as high as 70%. History and /or physical examination alone are unlikely to advance the diagnosis, and with exception of plasma CT in medullary thyroid carcinoma, blood studies are unhelpful in the diagnosis of thyroid carcinoma. Radiographs and ultrasound imaging are helpful in planning treatment and follow-up, but are unlikely to be needed for initial diagnosis. One of the main indication of thyroid scan in the pediatric group is thyroid nodule. FNAB is established as the most effective method of diagnosis in adults, although in children it may be less reliable. While radionuclide scintigraphy may be considered for initial screening, FNAB is well established and its specificity allows it to negate the need for a substantial number of operation. Treatment of differentiated thyroid carcinoma in children is more controversial. Some authors maintain that modified or subtotal thyroidectomy is appropriation this disease, others maintain that total thyroidectomy is required Nevertheless, radioiodine therapy is considered to be standard in the treatment of iodine-avid thyroid carcinomas for ablation of the thyroid remnant following surgery and for treatment of iodine-avid distant diseases. The front-line treatment of medullary thyroid carcinoma is aggressive surgery. Total thyroidectomy is indicated, In general treatment with chemotherapy, extemal radiation and I-131 are not helpful, however radioactive

The Centroid of a Lie Triple Algebra

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Xiaohong Liu

2013-01-01

Full Text Available General results on the centroids of Lie triple algebras are developed. Centroids of the tensor product of a Lie triple algebra and a unitary commutative associative algebra are studied. Furthermore, the centroid of the tensor product of a simple Lie triple algebra and a polynomial ring is completely determined.

BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer.

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Shields, Sarah; Conroy, Emer; O'Grady, Tony; McGoldrick, Alo; Connor, Kate; Ward, Mark P; Useckaite, Zivile; Dempsey, Eugene; Reilly, Rebecca; Fan, Yue; Chubb, Anthony; Matallanas, David Gomez; Kay, Elaine W; O'Connor, Darran; McCann, Amanda; Gallagher, William M; Coppinger, Judith A

2018-03-20

Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.

Teaching Triple Science: GCSE Chemistry

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Learning and Skills Network (NJ3), 2007

2007-01-01

The Department for Children, Schools and Families (DCSF) has contracted with the Learning and Skills Network to support awareness and take-up of Triple Science GCSEs through the Triple Science Support Programme. This publication provides an introduction to teaching and learning approaches for the extension topics within GCSE Chemistry. It…

Recovery and normalization of triple coincidences in PET.

Science.gov (United States)

Lage, Eduardo; Parot, Vicente; Moore, Stephen C; Sitek, Arkadiusz; Udías, Jose M; Dave, Shivang R; Park, Mi-Ae; Vaquero, Juan J; Herraiz, Joaquin L

2015-03-01

Triple coincidences in positron emission tomography (PET) are events in which three γ-rays are detected simultaneously. These events, though potentially useful for enhancing the sensitivity of PET scanners, are discarded or processed without special consideration in current systems, because there is not a clear criterion for assigning them to a unique line-of-response (LOR). Methods proposed for recovering such events usually rely on the use of highly specialized detection systems, hampering general adoption, and/or are based on Compton-scatter kinematics and, consequently, are limited in accuracy by the energy resolution of standard PET detectors. In this work, the authors propose a simple and general solution for recovering triple coincidences, which does not require specialized detectors or additional energy resolution requirements. To recover triple coincidences, the authors' method distributes such events among their possible LORs using the relative proportions of double coincidences in these LORs. The authors show analytically that this assignment scheme represents the maximum-likelihood solution for the triple-coincidence distribution problem. The PET component of a preclinical PET/CT scanner was adapted to enable the acquisition and processing of triple coincidences. Since the efficiencies for detecting double and triple events were found to be different throughout the scanner field-of-view, a normalization procedure specific for triple coincidences was also developed. The effect of including triple coincidences using their method was compared against the cases of equally weighting the triples among their possible LORs and discarding all the triple events. The authors used as figures of merit for this comparison sensitivity, noise-equivalent count (NEC) rates and image quality calculated as described in the NEMA NU-4 protocol for the assessment of preclinical PET scanners. The addition of triple-coincidence events with the authors' method increased peak

Recovery and normalization of triple coincidences in PET

Energy Technology Data Exchange (ETDEWEB)

Lage, Eduardo, E-mail: elage@mit.edu; Parot, Vicente; Dave, Shivang R.; Herraiz, Joaquin L. [Madrid-MIT M+Visión Consortium, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 (United States); Moore, Stephen C.; Sitek, Arkadiusz; Park, Mi-Ae [Division of Nuclear Medicine, Department of Radiology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts 02115 (United States); Udías, Jose M. [Grupo de Física Nuclear, Departamento de Física Atómica Molecular y Nuclear, Universidad Complutense de Madrid, CEI Moncloa, Madrid 28040 (Spain); Vaquero, Juan J. [Departamento de Ingeniería Biomédica e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Leganés 28911 (Spain)

2015-03-15

Purpose: Triple coincidences in positron emission tomography (PET) are events in which three γ-rays are detected simultaneously. These events, though potentially useful for enhancing the sensitivity of PET scanners, are discarded or processed without special consideration in current systems, because there is not a clear criterion for assigning them to a unique line-of-response (LOR). Methods proposed for recovering such events usually rely on the use of highly specialized detection systems, hampering general adoption, and/or are based on Compton-scatter kinematics and, consequently, are limited in accuracy by the energy resolution of standard PET detectors. In this work, the authors propose a simple and general solution for recovering triple coincidences, which does not require specialized detectors or additional energy resolution requirements. Methods: To recover triple coincidences, the authors’ method distributes such events among their possible LORs using the relative proportions of double coincidences in these LORs. The authors show analytically that this assignment scheme represents the maximum-likelihood solution for the triple-coincidence distribution problem. The PET component of a preclinical PET/CT scanner was adapted to enable the acquisition and processing of triple coincidences. Since the efficiencies for detecting double and triple events were found to be different throughout the scanner field-of-view, a normalization procedure specific for triple coincidences was also developed. The effect of including triple coincidences using their method was compared against the cases of equally weighting the triples among their possible LORs and discarding all the triple events. The authors used as figures of merit for this comparison sensitivity, noise-equivalent count (NEC) rates and image quality calculated as described in the NEMA NU-4 protocol for the assessment of preclinical PET scanners. Results: The addition of triple-coincidence events with the

Are the uterine serous carcinomas underdiagnosed? Histomorphologic and immunohistochemical correlates and clinical follow up in high-grade endometrial carcinomas initially diagnosed as high-grade endometrioid carcinoma.

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Hu, Shaomin; Hinson, Jeff L; Matnani, Rahul; Cibull, Michael L; Karabakhtsian, Rouzan G

2018-02-01

Histologic subclassification of high-grade endometrial carcinomas can sometimes be a diagnostic challenge when based on histomorphology alone. Here we utilized immunohistochemical markers to determine the immunophenotype in histologically ambiguous high-grade endometrial carcinomas that were initially diagnosed as pure or mixed high-grade endometrioid carcinoma, aiming to determine the utility of selected immunohistochemical panel in accurate classification of these distinct tumor types, while correlating these findings with the clinical outcome. A total of 43 high-grade endometrial carcinoma cases initially classified as pure high-grade endometrioid carcinoma (n=32), mixed high-grade endometrioid carcinoma/serous carcinoma (n=9) and mixed high-grade endometrioid carcinoma/clear cell carcinoma (n=2) were retrospectively stained with a panel of immunostains, including antibodies for p53, p16, estrogen receptor, and mammaglobin. Clinical follow-up data were obtained, and stage-to-stage disease outcomes were compared for different tumor types. Based on aberrant staining for p53 and p16, 17/43 (40%) of the high-grade endometrial carcinoma cases initially diagnosed as high-grade endometrioid carcinoma were re-classified as serous carcinoma. All 17 cases showed negative staining for mammaglobin, while estrogen receptor was positive in only 6 (35%) cases. The remaining 26 cases of high-grade endometrioid carcinoma showed wild-type staining for p53 in 25 (96%) cases, patchy staining for p16 in 20 (77%) cases, and were positive for mammaglobin and estrogen receptor in 8 (31%) and 19 (73%) cases, respectively, thus the initial diagnosis of high-grade endometrioid carcinoma was confirmed in these cases. In addition, the patients with re-classified serous carcinoma had advanced clinical stages at diagnosis and poorer overall survival on clinical follow-up compared to that of the remaining 26 high-grade endometrioid carcinoma cases. These results indicate that selected

Negative correlation of LIV-1 and E-cadherin expression in hepatocellular carcinoma cells.

Directory of Open Access Journals (Sweden)

Rongxi Shen

Full Text Available LIV-1, a zinc transporter, is a mediator downstream of STAT3 both in zebrafish and mammalian cells, and is involved in epithelial-mesenchymal transition (EMT. Despite LIV-1 participates in cancer growth and metastasis, little is known about the association of LIV-1 with human liver cancer development. Therefore, the expression of LIV-1 mRNA was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR in 4 cultured cell lines (3 carcinoma and 1 normal liver cell lines, and the localization of LIV-1 protein was investigated by immunohistochemistry. Expression of LIV-1 protein was analyzed by Western blot both in 4 cultured cell lines and 120 liver tissues (100 carcinoma and 20 histologically normal tissues, and the relationship between its expression and clinicopathological finding was investigated in 100 hepatocellular carcinoma(HCC tissues. Then stable siRNA expressing Hep-G2 cells were generated to assess the function of LIV-1 in liver cancer cells. We found that LIV-1 mRNA was more highly expressed in liver cancer cell lines compared to normal liver cell line. Western blot showed the expression of LIV-1 was higher in 61% liver carcinoma tissues than that in normal liver tissues. Down-regulated LIV-1 cells showed significant inhibition of proliferation in vitro and reduction of tumor growth in vivo. Furthermore, E-cadherin expression increased in LIV-1 siRNA expressing Hep-G2. These findings indicated that LIV-1 may induce the EMT in HCC cells.

False-negative contrast-enhanced spectral mammography: use of more than one imaging modality and application of the triple test avoids misdiagnosis.

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Taylor, Donna; O'Hanlon, Susan; Latham, Bruce

2017-03-31

A 50-year-old woman presented with chest tenderness. On examination, both breasts were lumpy. Bilateral mammography showed heterogeneously dense parenchyma, with possible stromal distortion laterally on the right at the 0900 position. On ultrasound (US), a corresponding 13×9×10 mm irregular hypoechoic mass with internal vascularity was noted and both breasts had a complex heterogeneous fibroglandular background pattern. US-guided core biopsy with marker clip insertion was performed with the diagnosis of a grade 2 invasive ductal carcinoma (IDC). In view of the parenchymal pattern on mammography and US, contrast-enhanced spectral mammography (CESM) was performed for local staging. Mild background enhancement was noted, but there was no enhancement at the lesion site. The patient elected to have bilateral mastectomies and sentinel node biopsies. Final histopathology showed a node negative 11 mm grade 2 oestrogen and progesterone receptor positive, IDC. 2017 BMJ Publishing Group Ltd.

Metabolic profiles of triple-negative and luminal A breast cancer subtypes in African-American identify key metabolic differences.

Science.gov (United States)

Tayyari, Fariba; Gowda, G A Nagana; Olopade, Olufunmilayo F; Berg, Richard; Yang, Howard H; Lee, Maxwell P; Ngwa, Wilfred F; Mittal, Suresh K; Raftery, Daniel; Mohammed, Sulma I

2018-02-20

Breast cancer, a heterogeneous disease with variable pathophysiology and biology, is classified into four major subtypes. While hormonal- and antibody-targeted therapies are effective in the patients with luminal and HER-2 subtypes, the patients with triple-negative breast cancer (TNBC) subtype do not benefit from these therapies. The incidence rates of TNBC subtype are higher in African-American women, and the evidence indicates that these women have worse prognosis compared to women of European descent. The reasons for this disparity remain unclear but are often attributed to TNBC biology. In this study, we performed metabolic analysis of breast tissues to identify how TNBC differs from luminal A breast cancer (LABC) subtypes within the African-American and Caucasian breast cancer patients, respectively. We used High-Resolution Magic Angle Spinning (HR-MAS) 1H Nuclear magnetic resonance (NMR) to perform the metabolomic analysis of breast cancer and adjacent normal tissues (total n=82 samples). TNBC and LABC subtypes in African American women exhibited different metabolic profiles. Metabolic profiles of these subtypes were also distinct from those revealed in Caucasian women. TNBC in African-American women expressed higher levels of glutathione, choline, and glutamine as well as profound metabolic alterations characterized by decreased mitochondrial respiration and increased glycolysis concomitant with decreased levels of ATP. TNBC in Caucasian women was associated with increased pyrimidine synthesis. These metabolic alterations could potentially be exploited as novel treatment targets for TNBC.

Merkel cell carcinoma: is this a true carcinoma?

Science.gov (United States)

Jankowski, Marek; Kopinski, Piotr; Schwartz, Robert; Czajkowski, Rafal

2014-11-01

Recent years have brought an enhanced understanding of Merkel cell carcinoma (MCC) biology, especially with regard to the Merkel cell polyoma virus as a causative agent. Differences between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative MCC in morphology; gene expression, miRNA profiles and prognosis have been reported. Origin of MCC is controversial. Presence of neurosecretory granules has suggested that these carcinomas originate from one of the neurocrest derivatives, most probably Merkel cells; the name Merkel cell carcinoma is now widely accepted. Expression of PGP 9.5, chromogranin A and several neuropeptides, initially regarded as specific markers for neural and neuroendocrine cells, has recently been shown in a subset of lymphomas. MCC commonly expresses terminal deoxynucleotidyl transferase and PAX5. Their co-expression under physiologic circumstances is restricted to pro/pre-B cells and pre-B cells. These findings lead to the hypothesis by zur Hausen et al. that MCC originates from early B cells. This review was intended to critically appraise zur Hausen's hypothesis and discuss the possibility that MCC is a heterogenous entity with distinct subtypes. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lactate dehydrogenase downregulation mediates the inhibitory effect of diallyl trisulfide on proliferation, metastasis, and invasion in triple-negative breast cancer.

Science.gov (United States)

Cheng, Shi-Yann; Yang, Yao-Chih; Ting, Kuan-Lun; Wen, Su-Ying; Viswanadha, Vijaya Padma; Huang, Chih-Yang; Kuo, Wei-Wen

2017-04-01

The Warburg effect plays a critical role in tumorigenesis, suggesting that specific agents targeting Warburg effect key proteins may be a promising strategy for cancer therapy. Previous studies have shown that diallyl trisulfide (DATS) inhibits proliferation of breast cancer cells by inducing apoptosis in vitro and in vivo. However, whether the Warburg effect is involved with the apoptosis-promoting action of DATS is unclear. Here, we show that the action of DATS is associated with downregulation of lactate dehydrogenase A (LDHA), an essential protein of the Warburg effect whose upregulation is closely related to tumorigenesis. Interestingly, inhibition of the Warburg effect by DATS in breast cancer cells did not greatly affect normal cells. Furthermore, DATS inhibited growth of breast cancer cells, particularly in MDA-MB-231, a triple-negative breast cancer (TNBC) cell, and reduced proliferation and migration; invasion was reversed by over-expression of LDHA. These data suggest that DATS inhibits breast cancer growth and aggressiveness through a novel pathway targeting the key enzyme of the Warburg effect. Our study shows that LDHA downregulation is involved in the apoptotic effect of DATS on TNBC. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1390-1398, 2017. © 2016 Wiley Periodicals, Inc.

MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer.

Science.gov (United States)

Xu, Xin; Zhang, Yun; Jasper, Jeff; Lykken, Erik; Alexander, Peter B; Markowitz, Geoffrey J; McDonnell, Donald P; Li, Qi-Jing; Wang, Xiao-Fan

2016-04-12

Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis and could serve as biomarkers for diagnostic purposes. To identify miRNAs that functionally suppress metastasis of TNBC, we employed a concerted approach with selecting miRNAs that display differential expression profiles from bioinformatic analyses of breast cancer patient databases and validating top candidates with functional assays using breast cancer cell lines and mouse models. We have found that miR-148a exhibits properties as a tumor suppressor as its expression is inversely correlated with the ability of both human and mouse breast cancer cells to colonize the lung in mouse xenograft tumor models. Mechanistically, miR-148a appears to suppress the extravasation process of cancer cells, likely by targeting two genes WNT1 and NRP1 in a cell non-autonomous manner. Importantly, lower expression of miR-148a is detected in higher-grade tumor samples and correlated with increased likelihood to develop metastases and poor prognosis in subsets of breast cancer patients, particularly those with TNBC. Thus, miR-148a is functionally defined as a suppressor of breast cancer metastasis and may serve as a prognostic biomarker for this disease.

Reevaluation and reclassification of resected lung carcinomas originally diagnosed as squamous cell carcinoma using immunohistochemical analysis

Science.gov (United States)

Kadota, Kyuichi; Nitadori, Jun-ichi; Rekhtman, Natasha; Jones, David R.; Adusumilli, Prasad S.; Travis, William D.

2015-01-01

Currently, non-small cell lung carcinomas are primarily classified by light microscopy. However, recent studies have shown that poorly-differentiated tumors are more accurately classified by immunohistochemistry. In this study, we investigated the use of immunohistochemical analysis in reclassifying lung carcinomas that were originally diagnosed as squamous cell carcinoma. Tumor slides and blocks were available for histologic evaluation, and tissue microarrays were constructed from 480 patients with resected lung carcinomas originally diagnosed as squamous cell carcinoma between 1999 and 2009. Immunohistochemistry for p40, p63, thyroid transcription factor-1 (TTF-1; clone SPT24 and 8G7G3/1), Napsin A, Chromogranin A, Synaptophysin, and CD56 were performed. Staining intensity (weak, moderate, or strong) and distribution (focal or diffuse) were also recorded. Of all, 449 (93.5%) patients were confirmed as having squamous cell carcinomas; the cases were mostly diffusely positive for p40 and negative for TTF-1 (8G7G3/1). Twenty cases (4.2%) were reclassified as adenocarcinoma since they were positive for TTF-1 (8G7G3/1 or SPT24) with either no or focal p40 expression, and all of them were poorly-differentiated with squamoid morphology. In addition, 1 case was reclassified as adenosquamous carcinoma, 4 cases as large cell carcinoma, 4 cases as large cell neuroendocrine carcinoma, and 2 cases as small cell carcinoma. In poorly-differentiated non-small cell lung carcinomas, an accurate distinction between squamous cell carcinoma and adenocarcinoma cannot be reliably determined by morphology alone and requires immunohistochemical analysis, even in resected specimens. Our findings suggest that TTF-1 8G7G3/1 may be better suited as the primary antibody in differentiating adenocarcinoma from squamous cell carcinoma. PMID:25871623

Integrative analysis of lncRNAs and miRNAs with coding RNAs associated with ceRNA crosstalk network in triple negative breast cancer

Directory of Open Access Journals (Sweden)

Yuan NJ

2017-12-01

Full Text Available Naijun Yuan,1,* Guijuan Zhang,2,* Fengjie Bie,1 Min Ma,1 Yi Ma,3 Xuefeng Jiang,1 Yurong Wang,1,* Xiaoqian Hao1 1College of Traditional Chinese Medicine of Jinan University, Institute of Integrated Traditional Chinese and Western Medicine of Jinan University, 2The First Affiliated Hospital of Jinan University, 3Department of Cellular Biology, Guangdong Province Key Lab of Bioengineering Medicine, Institute of Biomedicine, Jinan University, Guangdong, China *These authors contributed equally to this work Abstract: Triple negative breast cancer (TNBC is a particular subtype of breast malignant tumor with poorer prognosis than other molecular subtypes. Currently, there is increasing focus on long non-coding RNAs (lncRNAs, which can act as competing endogenous RNAs (ceRNAs and suppress miRNA functions involved in post-transcriptional regulatory networks in the tumor. Therefore, to investigate specific mechanisms of TNBC carcinogenesis and improve treatment efficiency, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 116 TNBC tissues and 11 normal tissues from The Cancer Genome Atlas. As a result, we selected the threshold with |log2FC|>2.0 and an adjusted p-value >0.05 to obtain the differentially expressed mRNAs, miRNAs and lncRNAs. Hereafter, weighted gene co-expression network analysis was performed to identify the expression characteristics of dysregulated genes. We obtained five co-expression modules and related clinical feature. By means of correlating gene modules with protein–protein interaction network analysis that had identified 22 hub mRNAs which could as hub target genes. Eleven key dysregulated differentially expressed micro RNAs (DEmiRNAs were identified that were significantly associated with the 22 hub potential target genes. Moreover, we found that 14 key differentially expressed lncRNAs could interact with the key DEmiRNAs. Then, the ceRNA crosstalk network of TNBC was

Mortality risk from comorbidities independent of triple-negative breast cancer status: NCI-SEER-based cohort analysis.

Science.gov (United States)

Swede, Helen; Sarwar, Amna; Magge, Anil; Braithwaite, Dejana; Cook, Linda S; Gregorio, David I; Jones, Beth A; R Hoag, Jessica; Gonsalves, Lou; L Salner, Andrew; Zarfos, Kristen; Andemariam, Biree; Stevens, Richard G; G Dugan, Alicia; Pensa, Mellisa; A Brockmeyer, Jessica

2016-05-01

A comparatively high prevalence of comorbidities among African-American/Blacks (AA/B) has been implicated in disparate survival in breast cancer. There is a scarcity of data, however, if this effect persists when accounting for the adverse triple-negative breast cancer (TNBC) subtype which occurs at threefold the rate in AA/B compared to white breast cancer patients. We reviewed charts of 214 white and 202 AA/B breast cancer patients in the NCI-SEER Connecticut Tumor Registry who were diagnosed in 2000-2007. We employed the Charlson Co-Morbidity Index (CCI), a weighted 17-item tool to predict risk of death in cancer populations. Cox survival analyses estimated hazard ratios (HRs) for all-cause mortality in relation to TNBC and CCI adjusting for clinicopathological factors. Among patients with SEER local stage, TNBC increased the risk of death (HR 2.18, 95 % CI 1.14-4.16), which was attenuated when the CCI score was added to the model (Adj. HR 1.50, 95 % CI 0.74-3.01). Conversely, the adverse impact of the CCI score persisted when controlling for TNBC (Adj. HR 1.49, 95 % CI 1.29-1.71; per one point increase). Similar patterns were observed in SEER regional stage, but estimated HRs were lower. AA/B patients with a CCI score of ≥3 had a significantly higher risk of death compared to AA/B patients without comorbidities (Adj. HR 5.65, 95 % CI 2.90-11.02). A lower and nonsignificant effect was observed for whites with a CCI of ≥3 (Adj. HR 1.90, 95 % CI 0.68-5.29). comorbidities at diagnosis increase risk of death independent of TNBC, and AA/B patients may be disproportionately at risk.

CALR, JAK2 and MPL mutation status in Argentinean patients with BCR-ABL1- negative myeloproliferative neoplasms.

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Ojeda, Mara Jorgelina; Bragós, Irma Margarita; Calvo, Karina Lucrecia; Williams, Gladis Marcela; Carbonell, María Magdalena; Pratti, Arianna Flavia

2018-05-01

To establish the frequency of JAK2, MPL and CALR mutations in Argentinean patients with BCR-ABL1-negative  myeloproliferative neoplasms (MPN) and to compare their clinical and haematological features. Mutations of JAK2V617F, JAK2 exon 12, MPL W515L/K and CALR were analysed in 439 Argentinean patients with BCR-ABL1-negative MPN, including 176 polycythemia vera (PV), 214 essential thrombocythemia (ET) and 49 primary myelofibrosis (PMF). In 94.9% of PV, 85.5% ET and 85.2% PMF, we found mutations in JAK2, MPL or CALR. 74.9% carried JAK2V617F, 12.3% CALR mutations, 2.1% MPL mutations and 10.7% were triple negative. In ET, nine types of CALR mutations were identified, four of which were novel. PMF patients were limited to types 1 and 2, type 2 being more frequent. In ET, patients with CALR mutation were younger and had higher platelet counts than those with JAK2V617F and triple negative. In addition, JAK2V617F patients had high leucocyte and haemoglobin values compared with CALR-mutated and triple-negative patients. In PMF, patients with mutant CALR were associated with higher platelet counts. Our study underscores the importance of JAK2, MPL and CALR genotyping for accurate diagnosis of patients with BCR-ABL1-negative MPN.

Neuroendocrine and squamous colonic composite carcinoma: Case report with molecular analysis

Institute of Scientific and Technical Information of China (English)

Sabrina C Wentz; Cindy Vnencak-Jones; William V Chopp

2011-01-01

Composite colorectal carcinomas are rare. There are a modest number of cases in the medical literature, with even fewer cases describing composite carcinoma with neuroendocrine and squamous components. There are to our knowledge no reports of composite carcinoma molecular alterations. We present a case of composite carcinoma of the splenic flexure in a 33 year-old Cau casian male to investigate the presence and prognos tic significance of molecular alterations in rare colonic carcinoma subtypes. Formalin-fixed paraffin-embedded (FFPE) tissue was hematoxylin and eosin- and mucicar-mine-stained according to protocol, and immuno-stained with cytokeratin (CK)7, CK20, CDX2, AE1/AE3, chromo-granin-A and synaptophysin. DNA was extracted from FFPE tissues and molecular analyses were performedaccording to lab-developed methods, followed by capil lary electrophoresis. Hematoxylin and eosin staining showed admixed neuroendocrine and keratinized squa mous cells. Positive nuclear CDX2 expression confirmed intestinal derivation. CK7 and CK20 were negative. Neuroendocrine cells stained positively for synaptophy sin and AE1/AE3 and negatively for chromogranin and mucicarmine. Hepatic metastases showed a similar im munohistochemical profile. Molecular analysis revealed a G13D KRAS mutation. BRAF mutational testing was negative and microsatellite instability was not detected. The patient had rapid disease progression on chemo therapy and died 60 d after presentation. Although the G13D KRAS mutation normally predicts an intermediate outcome, the aggressive tumor behavior suggests other modifying factors in rare types of colonic carcinomas.

Hepatocellular Carcinoma with Foamy Histiocyte-Like Appearance: A Deceptively Clear Cell Carcinoma Appearing Variant

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Takuji Noro

2010-08-01

Full Text Available Hepatocellular carcinoma (HCC shows many pathological features, and it varies architecturally and cytologically. There have been many reports and discussions of the morphological features of HCC. A 63-year-old man was found to have a solitary tumor in liver segment 7 that was diagnosed as HCC. A partial resection of liver segment 7 was performed. Microscopically, the tumor lesion showed a moderately differentiated HCC. There was also a lesion with foamy histiocyte-like cells corresponding to the white lesion in the face of the cut tumor. Immunohistochemical staining showed that they were negative for CD68, S-100, vimentin, and HMB-45. The cytoplasm itself was negative on periodic acid Schiff (PAS and Sudan staining. Without immunohistological analysis, it is difficult to distinguish this HCC variant from clear cell carcinoma or metastases of renal cell carcinoma. It is important to recognize this type as a specific cytological variant of HCC that requires confirmation by immunohistochemistry. This report describes the case of a patient with a morphologically distinctive pattern of HCC with prominent cell cytoplasm that had a foamy histiocyte-like appearance. To the best of our knowledge, this is the first report of this HCC variant.

BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer.

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Hitomi Mori

Full Text Available Triple-negative breast cancer (TNBC is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases.The BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA. The tumor subtypes were determined immunohistochemically using resected specimens.Of the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4% tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003. There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter recurrence-free survival (RFS compared with the non-BRCAness group (P = 0.04 and had a shorter overall survival (OS although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS. Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC.The 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs.

Differentially expressed miRNAs in triple negative breast cancer between African-American and non-Hispanic white women.

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Sugita, Bruna; Gill, Mandeep; Mahajan, Akanskha; Duttargi, Anju; Kirolikar, Saurabh; Almeida, Rodrigo; Regis, Kenny; Oluwasanmi, Olusayo L; Marchi, Fabio; Marian, Catalin; Makambi, Kepher; Kallakury, Bhaskar; Sheahan, Laura; Cavalli, Iglenir J; Ribeiro, Enilze M; Madhavan, Subha; Boca, Simina; Gusev, Yuriy; Cavalli, Luciane R

2016-11-29

Triple Negative Breast Cancer (TNBC), a clinically aggressive subtype of breast cancer, disproportionately affects African American (AA) women when compared to non-Hispanic Whites (NHW). MiRNAs(miRNAs) play a critical role in these tumors, through the regulation of cancer driver genes. In this study, our goal was to characterize and compare the patterns of miRNA expression in TNBC of AA (n = 27) and NHW women (n = 30). A total of 256 miRNAs were differentially expressed between these groups, and distinct from the ones observed in their respective non-TNBC subtypes. Fifty-five of these miRNAs were mapped in cytobands carrying copy number alterations (CNAs); 26 of them presented expression levels concordant with the observed CNAs. Receiving operating characteristic (ROC) analysis showed a good power (AUC ≥ 0.80; 95% CI) for over 65% of the individual miRNAs and a high combined power with superior sensitivity and specificity (AUC = 0.88 (0.78-0.99); 95% CI) of the 26 miRNA panel in discriminating TNBC between these populations. Subsequent miRNA target analysis revealed their involvement in the interconnected PI3K/AKT, MAPK and insulin signaling pathways. Additionally, three miRNAs of this panel were associated with early age at diagnosis. Altogether, these findings indicated that there are different patterns of miRNA expression between TNBC of AA and NHW women and that their mapping in genomic regions with high levels of CNAs is not merely physical, but biologically relevant to the TNBC phenotype. Once validated in distinct cohorts of AA women, this panel can potentially represent their intrinsic TNBC genome signature.

The time domain triple probe method

International Nuclear Information System (INIS)

Meier, M.A.; Hallock, G.A.; Tsui, H.Y.W.; Bengtson, R.D.

1994-01-01

A new Langmuir probe technique based on the triple probe method is being developed to provide simultaneous measurement of plasma temperature, potential, and density with the temporal and spatial resolution required to accurately characterize plasma turbulence. When the conventional triple probe method is used in an inhomogeneous plasma, local differences in the plasma measured at each probe introduce significant error in the estimation of turbulence parameters. The Time Domain Triple Probe method (TDTP) uses high speed switching of Langmuir probe potential, rather than spatially separated probes, to gather the triple probe information thus avoiding these errors. Analysis indicates that plasma response times and recent electronics technology meet the requirements to implement the TDTP method. Data reduction techniques of TDTP data are to include linear and higher order correlation analysis to estimate fluctuation induced particle and thermal transport, as well as energy relationships between temperature, density, and potential fluctuations

Outcomes in Young Women With Breast Cancer of Triple-Negative Phenotype: The Prognostic Significance of CK19 Expression

International Nuclear Information System (INIS)

Parikh, Rahul R.; Yang Qifeng; Higgins, Susan A.; Haffty, Bruce G.

2008-01-01

Purpose: Basal-like carcinoma of the breast is associated with genetic instability and aggressive behavior. In this study, we evaluated the luminal cytokeratin marker CK-19 in young women with breast cancer treated with conservative surgery and radiation therapy (CS+RT). Methods: Primary tumor specimens from a cohort of 158 young premenopausal women (range, 25-49 years) treated with CS+RT with a median follow-up of 6.25 years were constructed into a tissue microarray. The array was stained for ER, PR, HER2, CK19, and p53. The molecular profiles were correlated with clinical-pathologic factors, overall, local, and distant relapse-free survival. The association between CK19, other co-variables, and outcome was assessed in a multivariate model. Results: Positive expression of ER, PR, HER-2/neu, CK19, and p53 were 33.1%, 34.5%, 10.0%, 79.5%, and 20.9%, respectively. With 20 local relapses and 38 distant metastases, the 10-year overall, breast relapse-free, and distant relapse-free survival were 79.65%, 87.29%, and 67.35%, respectively. Tumor stage and nodal status were associated with distant relapse-free and overall survival. In multivariate analysis, CK19 negativity was a predictor poor local (RR, 3.54; 95% CI, 1.87-7.65; p < 0.01) distant (RR, 1.44; 95% CI, 0.86-2.70; p = 0.17), and overall survival (RR, 1.89; 95% CI, 1.04-3.55; p = 0.03). Conclusions: Lack of CK19 expression identifies a subset of patients with a significantly higher risk of local relapse. Distant relapse and overall survival rates also correlated with CK19 negativity. Further evaluation of the prognostic significance of basal and luminal cytokeratins in young women with breast cancer is warranted

Theoretical investigation of compounds with triple bonds

International Nuclear Information System (INIS)

Devarajan, Deepa

2011-01-01

In this thesis, compounds with potential triple-bonding character involving the heavier main-group elements, Group 4 transition metals, and the actinides uranium and thorium were studied by using molecular quantum mechanics. The triple bonds are described in terms of the individual orbital contributions (σ, π parallel , and π perpendicular to ), involving electron-sharing covalent or donor-acceptor interactions between the orbitals of two atoms or fragments. Energy decomposition, natural bond orbital, and atoms in molecules analyses were used for the bonding analysis of the triple bonds. The results of this thesis suggest that the triple-bonding character between the heavier elements of the periodic table is important and worth further study and exploration.

Triple products of Eisenstein series

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Venkatesh, Anil

In this thesis, we construct a Massey triple product on the Deligne cohomology of the modular curve with coefficients in symmetric powers of the standard representation of the modular group. This result is obtained by constructing a Massey triple product on the extension groups in the category of admissible variations of mixed Hodge structure over the modular curve, which induces the desired construction on Deligne cohomology. The result extends Brown's construction of the cup product on Deligne cohomology to a higher cohomological product. Massey triple products on Deligne cohomology have been previously investigated by Deninger, who considered Deligne cohomology with trivial real coefficients. By working over the reals, Deninger was able to compute cohomology exclusively with differential forms. In this work, Deligne cohomology is studied over the rationals, which introduces an obstruction to applying Deninger's results. The obstruction arises from the fact that the integration map from the de Rham complex to the Eilenberg-MacLane complex of the modular group is not an algebra homomorphism. We compute the correction terms of the integration map as regularized iterated integrals of Eisenstein series, and show that these integrals arise in the cup product and Massey triple product on Deligne cohomology.

Accuracy of doppler ultrasound in diagnosis of endometrial carcinoma

International Nuclear Information System (INIS)

Batool, S.; Raza, S.; Manzur, S.

2013-01-01

Objective: To determine the accuracy of Doppler ultrasound in the diagnosis of endometrial carcinoma in patients presenting with post-menopausal bleeding while taking histopathological findings as the gold standard. Methods: The cross-sectional study was done at the Department of Radiology, Bahawal Victoria Hospital, Bahawalpur, from April 1 to September 30, 2009, and comprised 128 patients above 50 years of age having history of post-menopausal bleeding and who were referred to the department. Name, age and hospital registration number were recorded on a proforma. Doppler ultrasound was performed and endometrial thickness and uterine artery resistive index were recorded on transabdominal ultrasonography. Patients with endometrial thickness of more than 5mm and uterine artery resistive index of less than 0.7 were considered to be having endometrial carcinoma. Histopathology findings were also recorded using the hospital registration number of the patient. The findings of Doppler ultrasound scan were validated with the findings of histopathology. Results: Of the 128 patients, 48 (37.5%) were between the ages of 51 and 55 years; 46 (35.93%) were in the 56-60 age group; and 34 (26.57%) were over 65 years. On the basis of Doppler ultrasound findings, 106 (82.8%) patients were diagnosed as having endometrial carcinoma, while 22 (17.19%) were declared negative. Ultrasonography results were compared with histopathology findings. The percentages of true positive, true negative, false positive and false negative were calculated. There were 103 (80.47%) true positive; 12 (9.37%) false positive; 10 (7.81%) true negative; and 3 (2.35%) false negative. Specificity, sensitivity, positive predictive value and negative predictive value were found to be 97.16%, 76%, 89.56% and 76.92% respectively. Conclusion: The use of Doppler ultrasonography in non-invasive diagnosis of endometrial carcinoma in patients presenting with post-menopausal bleeding was quite useful with good

Verrucous carcinoma of the middle ear.

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Woodson, G E; Jurco, S; Alford, B R; McGavran, M H

1981-01-01

A case of a highly destructive, cytologically nondysplastic squamous epithelial lesion of the middle ear is presented. The cranial nerve involvement and bone destruction are more extensive than has been seen in cholesteatoma. Cultures are negative for Pseudomonas, and the patient does not have the reported diathesis for malignant otitis externa. The gross and microscopic features are those of verrucous carcinoma. To our knowledge, the middle ear has not been previously reported as a site of involvement by verrucous carcinoma.

Mucinous carcinoma of the breast: mammographic features with histologic correlation

International Nuclear Information System (INIS)

Cui Chunyan; Zhang Ling; Wu Yaopan; Li Shuqin

2011-01-01

Objective: To correlate the mammographic findings of mucinous carcinoma with histologic features. Methods: Retrospective analysis of the mammographic and pathologic findings of 37 patients with mucinous carcinomas of the breasts was performed. Results: Mammograms of ten (52.6%) women with mucinous carcinomas showed masses with well-defined, lobu-lated margins correlating well with the pure histologic type. Thirteen (81.3%) mixed type of mucinous carcinomas demonstrated poorly defined or spiculated margins (P<0.05). Most of the pure type carcinomas were hyperdense similar to most of mixed type carcinomas (P<0.05). Of 34 mucinous carcinomas tested, there were 25 ER-positive, 29 PR-positive, 24 C-erbB-2 negative expressions with pure type carcinomas accounting for 78.9%, 89.5% and 78.9%, respectively. Conclusion: The mammographic features of pure type are different from those of mixed type of mucinous breast carcinomas. The most common mammographic appearance of pure mucinous carcinoma is a well-defined mass without calcification whereas the mixed type carcinomas have more aggressive imaging characteristics. (authors)

Triple synchronous primary lung cancer: a case report and review of the literature.

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Kashif, Muhammad; Ayyadurai, Puvanalingam; Thanha, Luong; Khaja, Misbahuddin

2017-09-01

Multiple primary lung cancer may present in synchronous or metachronous form. Synchronous multiple primary lung cancer is defined as multiple lung lesions that develop at the same time, whereas metachronous multiple primary lung cancer describes multiple lung lesions that develop at different times, typically following treatment of the primary lung cancer. Patients with previously treated lung cancer are at risk for developing metachronous lung cancer, but with the success of computed tomography and positron emission tomography, the ability to detect both synchronous and metachronous lung cancer has increased. We present a case of a 63-year-old Hispanic man who came to our hospital for evaluation of chest pain, dry cough, and weight loss. He had recently been diagnosed with adenocarcinoma in the right upper lobe, with a poorly differentiated carcinoma favoring squamous cell cancer based on bronchoalveolar lavage of the right lower lobe for which treatment was started. Later, bronchoscopy incidentally revealed the patient to have an endobronchial lesion that turned out to be mixed small and large cell neuroendocrine lung cancer. Our patient had triple synchronous primary lung cancers that histologically were variant primary cancers. Triple synchronous primary lung cancer management continues to be a challenge. Our patient's case suggests that multiple primary lung cancers may still occur at a greater rate than can be detected by high-resolution computed tomography.

Biological characteristics and clinical outcome of triple negative primary breast cancer in older women - comparison with their younger counterparts.

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Binafsha M Syed

Full Text Available Triple negative (ER, PgR and HER2 negative breast cancers (TNBCs are often considered as a poor prognostic phenotype. There is dearth of evidence showing the prevalence and biological behaviour of TNBCs in older women. This study aimed to analyse their biological characteristics in comparison with a well characterised younger series from a single centre with long term clinical follow-up. Over 37 years (1973-2010, 1,758 older (≥70 years women with early operable (<5 cm primary breast cancer were managed in a dedicated clinic and have complete clinical information available. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray analysis using indirect immunohistochemistry. A total of 127 patients (22.1% had TNBCs and full biological analysis of 15 biomarkers was performed. The results were compared with those of their younger (<70 years counterparts 342 (18.9% from a previously characterised, consecutive series of primary breast cancer treated in the same unit (1986-1998. The 127 older patients with TNBCs showed lower rates of Ki67 and CK 7/8 positivity and high rates of bcl2 and CK18 positivity when compared with their younger counterparts (p<0.05. There was no significant difference in the long term clinical outcome between the two age groups, despite the fact that 47% of the younger patients had adjuvant chemotherapy, while none in the older cohort received such treatment. EGFR, axillary stage and pathological size showed prognostic significance in older women with TNBCs on univariate analysis. Despite not having received adjuvant chemotherapy, the older series had clinical outcome similar to the younger patients almost half of whom had chemotherapy. This appears to be related to other biomarkers (in addition to ER/PgR/HER2 eg Ki67, bcl2 and cytokeratins which have different expression patterns influencing prognosis.

Oral verrucous carcinoma. Treatment with radiotherapy

International Nuclear Information System (INIS)

Nair, M.K.; Sankaranarayanan, R.; Padmanabhan, T.K.; Madhu, C.S.

1988-01-01

Fifty-two cases of oral verrucous carcinoma treated with radiotherapy at the Regional Cancer Centre, Trivandrum, Kerala, India in 1982 were evaluated to determine the distribution within the oral cavity, clinical extent, and effectiveness of radiotherapy in controlling the disease. The most common site was the buccal mucosa. Fifty percent of the patients had clinically negative regional lymph nodes and 33% were in earlier stages (T1, T2, N0, and M0). The overall 3-year no evidence of disease (NED) survival rate was 44%. The 3-year NED survival rate with radium implant was 86%. We cannot comment on anaplastic transformation after radiotherapy because our treatment failures have not been subjected for biopsy concerning this matter. Because the results are comparable with those of well-differentiated squamous cell carcinoma, we think that the treatment policies advocated for oral squamous cell carcinoma are also applicable to oral verrucous carcinoma

AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial–mesenchymal transition in triple-negative breast cancer

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Qiao, Yichun; Shiue, Chiou-Nan; Zhu, Jian; Zhuang, Ting; Jonsson, Philip; Wright, Anthony P.H.; Zhao, Chunyan; Dahlman-Wright, Karin

2015-01-01

The molecular determinants of malignant cell behaviour in triple-negative breast cancer (TNBC) are poorly understood. Recent studies have shown that regulators of epithelial-mesenchymal transition (EMT) are potential therapeutic targets for TNBC. In this study, we demonstrate that the inflammatory cytokine TNFα induces EMT in TNBC cells via activation of AP-1 signaling and subsequently induces expression of the EMT regulator ZEB2. We also show that TNFα activates both the PI3K/Akt and MAPK/ERK pathways, which act upstream of AP-1. We further investigated in detail AP-1 regulation of ZEB2 expression. We show that two ZEB2 transcripts derived from distinct promoters are both expressed in breast cancer cell lines and breast tumor samples. Using the chromosome conformation capture assay, we demonstrate that AP-1, when activated by TNFα, binds to a site in promoter 1b of the ZEB2 gene where it regulates the expression of both promoter 1b and 1a, the latter via mediating long range chromatin interactions. Overall, this work provides a plausible mechanism for inflammation-induced metastatic potential in TNBC, involving a novel regulatory mechanism governing ZEB2 isoform expression. PMID:25762639

Correlation between {sup 18}F-FDG uptake on PET/CT and prognostic factors in triple-negative breast cancer

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Koo, Hye Ryoung [Seoul National University College of Medicine, Department of Radiology, 28 Yongon-dong, Chongno-gu, Seoul (Korea, Republic of); Hanyang University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Park, Jeong Seon [Hanyang University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Kang, Keon Wook [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Han, Wonshik [Seoul National University College of Medicine, Department of Surgery, Seoul (Korea, Republic of); Park, In Ae [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Moon, Woo Kyung [Seoul National University College of Medicine, Department of Radiology, 28 Yongon-dong, Chongno-gu, Seoul (Korea, Republic of)

2015-11-15

The purpose of this study was to investigate whether a correlation exists between {sup 18}F-fluorodeoxyglucose (FDG) uptake and prognostic factors in triple-negative breast cancer (TNBC). Between January 2009 and December 2013, 103 patients (mean age, 50.6 years) with primary TNBC (mean, 2.6 cm; range, 1.0-6.5 cm) underwent {sup 18}F-FDG PET/CT for initial staging. Correlations between maximum standardized uptake value (SUV{sub max}) on PET/CT and prognostic factors including tumour size, nodal status, histological grade, Ki-67 proliferation index, tumour suppressor p53, and 'basal-like' markers (epidermal growth factor receptor and CK 5/6) were assessed. The mean SUV{sub max} of the 103 tumours was 10.94 ± 5.25 (range: 2-32.8). There was a positive correlation between SUV{sub max} and Ki-67 (Spearman's rho = 0.29, P = 0.003) and tumour size (Spearman's rho = 0.27, P = 0.006), whereas this relationship was not observed in the nodal status, histological grade, p53 status and 'basal-like' phenotypes. In a multivariate regression analysis, Ki-67 (P < 0.001) and tumour size (P = 0.009) were significantly associated with SUV{sub max} in TNBCs. Increased {sup 18}F-FDG uptake on PET/CT was correlated with a high Ki-67 proliferation index and larger tumour size in TNBC. These results suggest a potential role of {sup 18}F-FDG PET/CT in identifying TNBC with more aggressive behaviour. (orig.)

Hermitian (ϵ,δ)-Freudenthal-Kantor Triple Systems and Certain Applications of *-Generalized Jordan Triple Systems to Field Theory

International Nuclear Information System (INIS)

Kamiya, Noriaki; Sato, Matsuo

2014-01-01

We define Hermitian (ϵ,δ)-Freudenthal-Kantor triple systems and prove a structure theorem. We also give some examples of triple systems that are generalizations of the u(N)⊕u(M) and sp(2N)⊕u(1) Hermitian 3-algebras. We apply a *-generalized Jordan triple system to a field theory and obtain a Chern-Simons gauge theory. We find that the novel Higgs mechanism works, where the Chern-Simons gauge theory reduces to a Yang-Mills theory in a certain limit

Squamous Cell Carcinoma In Situ Overlying Merkel Cell Carcinoma.

Science.gov (United States)

McGowan, Maria A; Helm, Matthew F; Tarbox, Michelle B

2016-11-01

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neoplasm that has exhibited an exponential increase in incidence in the past 3 decades. Combined MCC and cutaneous squamous cell carcinoma (SCC/MCC) is an uncommon variant of MCC that exhibits worse prognosis than pure MCC. To describe the clinical presentation, dermoscopy, and histology of an unusual subtype of combined SCC/MCC. A 73-year-old white woman presented with an ulcerated and violaceous 10-mm plaque on her right jawline that had been present for 2 to 3 months. On dermoscopy, the lesion was predominantly milky pink to red with peripheral crusting and large-caliber polymorphous vessels. Histology revealed SCC in situ above and adjacent to MCC. The tumor was excised with clear margins, and sentinel lymph node scintography was negative for nodal involvement. © The Author(s) 2016.

Warps, grids and curvature in triple vector bundles

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Flari, Magdalini K.; Mackenzie, Kirill

2018-06-01

A triple vector bundle is a cube of vector bundle structures which commute in the (strict) categorical sense. A grid in a triple vector bundle is a collection of sections of each bundle structure with certain linearity properties. A grid provides two routes around each face of the triple vector bundle, and six routes from the base manifold to the total manifold; the warps measure the lack of commutativity of these routes. In this paper we first prove that the sum of the warps in a triple vector bundle is zero. The proof we give is intrinsic and, we believe, clearer than the proof using decompositions given earlier by one of us. We apply this result to the triple tangent bundle T^3M of a manifold and deduce (as earlier) the Jacobi identity. We further apply the result to the triple vector bundle T^2A for a vector bundle A using a connection in A to define a grid in T^2A . In this case the curvature emerges from the warp theorem.

Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer.

Science.gov (United States)

Sun, Dejuan; Zhu, Lingjuan; Zhao, Yuqian; Jiang, Yingnan; Chen, Lixia; Yu, Yang; Ouyang, Liang

2018-04-01

Triple negative breast cancer (TNBC) is a complex and intrinsically aggressive tumour with poor prognosis, and the discovery of targeted small-molecule drugs for TNBC treatment still remains in its infancy. In this study, we aimed to discover a small-molecule agent for TNBC treatment and illuminate its potential mechanisms. Cell viability was detected by using methylthiazoltetrazolium (MTT) assay. Electron microscopy, GFP-LC3 transfection, monodansylcadaverine staining and apoptosis assay were performed to determine Fluoxetine-induced autophagy and apoptosis. Western blotting and siRNA transfection were carried out to investigate the mechanisms of Fluoxetine-induced autophagy. iTRAQ-based proteomics analysis was used to explore the underlying mechanisms. We have demonstrated that Fluoxetine had remarkable anti-proliferative activities and induced autophagic cell death in MDA-MB-231 and MDA-MB-436 cells. The mechanism for Fluoxetine-induced autophagic cell death was associated with inhibition of eEF2K and activation of AMPK-mTOR-ULK complex axis. Further iTRAQ-based proteomics and network analyses revealed that Fluoxetine-induced mechanism was involved in BIRC6, BNIP1, SNAP29 and Bif-1. These results demonstrate that Fluoxetine induces apoptosis and autophagic cell death in TNBC, which will hold a promise for the future TNBC therapy. © 2017 John Wiley & Sons Ltd.

Radiation sterilization of triple sugar iron agar

International Nuclear Information System (INIS)

Altmann, G.; Eisenberg, E.; Bogokowsky, B.

1979-01-01

Triple sugar iron agar (TSI), a medium used for the identification of enteric bacteria, was sterilized by gamma radiation using radiation doses of 750-2000 krad. The radio-sterilized medium, slightly modified by increasing its Phenol Red content, performed well when tested with different enterobacteriaceae and other gram negative bacteria. Growth, change of indicator reaction in slant and butt and formation of gas and H 2 S were equal in irradiated and autoclaved TSI. Slants of irradiated TSI in stoppered plastic tubes kept their diagnostic properties during storage for at least 4 months. Gamma irradiation appears to be an attractive and economical method of sterilising nutrient media in sealed tubes or other containers, avoiding the risk of contamination during processing. (author)

Triple approach for diagnosing breast lesions-experience at a Tertiary Care Hospital

Directory of Open Access Journals (Sweden)

Ritu Mehta

2017-01-01

Full Text Available Background: Breast lesions are always a diagnostic challenge and range from benign to malignant. Fine-Needle Aspiration Cytology (FNAC is done in patients with breast lesions. However, to get an accurate and diagnostic yield is difficult at times. Aims: The aim of this study is to highlight the role of triple approach in diagnosing breast lesions. Design and Setting: This is an observational prospective study carried out in the Department of Pathology at a tertiary care hospital over 2 years. Materials and Methods: One hundred and fifty cases of breast lump were studied. Clinical findings, imaging findings, and cytology along with histopathological findings were correlated. Results: Cytological findings were benign in 102 out of 107 patients, who were otherwise clinically and radiologically benign. In rest five patients, Breast Imaging Reporting and Data Systems (BIRADS BIRADS II category was given on mammography. In four of these five patients, there was cytological atypia. Biopsy in these four patients showed features of fibroadenoma with mild cytological atypia and one patient showed infiltrating duct carcinoma. Mammography was suggestive of malignant breast lump in 43 patients. In three patients, breast lump was diagnosed as benign on cytological examination. However, histopathological examination confirmed the mammography findings of malignancy. Conclusion: FNAC is a well-established procedure for diagnosing breast lesion but has got many pitfalls. Hence for diagnosis a breast lesion, the triple approach consisting of histopathological examination in addition to mammography and FNAC, should be considered.

Epidemiology and survival of HPV-related tonsillar carcinoma

International Nuclear Information System (INIS)

Psychogios, Georgios; Alexiou, Christoph; Agaimy, Abba; Brunner, Kathrin; Koch, Michael; Mantsopoulos, Konstantinos; Tomppert, Andrea; Iro, Heinrich

2014-01-01

The aim of this study was to determine the proportion of human papilloma virus (HPV)-positive cases in tonsillar carcinomas and investigate its development over the last decade. Further aim was to show the oncologic results in accord to HPV status and various treatment modalities. A retrospective study was conducted between 2000 and 2012 and included 275 patients treated for tonsillar carcinoma. P16 immunohistochemistry was used as a surrogate marker for HPV-associated carcinogenesis. A total of 101 (36.7%) patients proved to be p16 positive and 174 p16 negative. 80.2% of the p16-positive cases presented with T1-2 tumor. Of the early-stage patients, 79% of the p16-positive and 52.3% of the p16-negative presented with lymph node metastases. The percentage of p16-positive patients increased from 23.2% in the period 2005–2007 to 58.6% in the period 2010–2012 in the whole population and from 30.9% to 76.9% in T1-2 carcinomas. Early T-category p16-positive carcinomas had significantly better disease-specific survival (92.4% vs. 75.5%, P = 0.007) and overall survival (OS, 79.6% vs. 54.3%, P < 0.001) compared to p16-negative tumors. This study showed an increase in the percentage of p16-positive patients in tonsillar carcinoma from 23.2% in the years between 2005 and 2007 to 58.6% between 2010 and 2012. The majority (80.2%) of p16-positive patients presented with early T-category tumor but most of these (79.0%) had also lymph node metastases. Nevertheless, p16-positive patients had excellent oncologic results after surgery and adjuvant radiotherapy and could be considered for de-escalation of treatment

Breast carcinomas: variations in sonoelastographic appearance

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Fleury E

2014-08-01

Full Text Available Eduardo de Faria Castro Fleury,1 Maria do Carmo Guedes Alcoforado Assunção-Queiros,2 Decio Roveda Jr1 1Faculdade de Cências Médicas da Santa Casa de São Paulo, São Paulo, Brazil; 2Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil Background: This study assessed factors influencing the sonoelastographic presentation of breast carcinoma. Methods: A prospective collaborative study was conducted by the Santa Casa de São Paulo and CTC-Center, on 540 breast lesions in women referred for percutaneous breast biopsy. Eighty-four carcinomas showing lesions on ultrasonography were included. These lesions were classified into four sonoelastographic scores, where scores of 1, 2, and 3 were considered false-negative, and a score of 4 was considered true-positive. Scores were compared against histopathologic results, which were divided into two groups, ie, soft lesions (group 1 and hard lesions (group 2. False-negative and true-positive results were also assessed for variation according to patient age and mean lesion diameter. Results: Of the 84 lesions studied, nine yielded false-negative results on sonoelastography and 75 yielded true-positive results. In terms of histopathologic classification, eight were assigned to group 1 and 76 to group 2. The chi-squared test showed a correlation between sonoelastographic scores and histopathologic lesion type. No statistically significant differences were observed according to patient age or largest lesion diameter. Conclusion: Our results revealed an association between sonoelastographic presentation of breast lesions and histology. False-negative results on sonoelastography were influenced by histologic type of lesion and not by lesion size or patient age. Keywords: ultrasound, breast, carcinoma, elastography

Treatment outcomes of breast carcinoma in a resource-limited ...

African Journals Online (AJOL)

negative tumours larger than 2 cm and only 3 out of 14 patients (21.4%) with 1 - 2 cm node-negative .... Three patients had stage IV disease and no biopsy or surgery was done ... between white women and black women with breast carcinoma.

Novel cancer gene variants and gene fusions of triple-negative breast cancers (TNBCs) reveal their molecular diversity conserved in the patient-derived xenograft (PDX) model.

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Jung, Jaeyun; Jang, Kiwon; Ju, Jung Min; Lee, Eunji; Lee, Jong Won; Kim, Hee Jung; Kim, Jisun; Lee, Sae Byul; Ko, Beom Seok; Son, Byung Ho; Lee, Hee Jin; Gong, Gyungyup; Ahn, Sei Yeon; Choi, Jung Kyoon; Singh, Shree Ram; Chang, Suhwan

2018-04-20

Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challenge due to lack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify novel druggable targets and to understand its unique biology, we tried to implement 24 patient-derived xenografts (PDXs) of TNBC. The overall success rate of PDX implantation was 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2 negativity (with two exceptions) between the original and PDX tumors. Genomic analysis of 10 primary tumor-PDX pairs with Ion AmpliSeq CCP revealed high degree of variant conservation (85.0% to 96.9%) between primary and PDXs. Further analysis showed 44 rare variants with a predicted high impact in 36 genes including Trp53, Pten, Notch1, and Col1a1. Among them, we confirmed frequent Notch1 variant. Furthermore, RNA-seq analysis of 24 PDXs revealed 594 gene fusions, of which 163 were in-frame, including AZGP1-GJC3 and NF1-AARSD1. Finally, western blot analysis of oncogenic signaling proteins supporting molecular diversity of TNBC PDXs. Overall, our report provides a molecular basis for the usefulness of the TNBC PDX model in preclinical study. Copyright © 2018. Published by Elsevier B.V.

Characterization of Epstein Barr virus latency pattern in Argentine breast carcinoma.

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Mario A Lorenzetti

Full Text Available INTRODUCTION: Epstein-Barr virus (EBV-associated tumors show different expression patterns of latency genes. Since in breast carcinoma this pattern is not yet fully described, our aim was to characterize EBV latency pattern in our EBV positive breast carcinoma series. METHODS: The study was conducted on 71 biopsies of breast carcinoma and in 48 non-neoplastic breast controls. EBNA1, LMP2A and LMP1 expression was assessed by immunohistochemistry with monoclonal antibodies, while viral genomic DNA and EBERs RNA transcripts expression was performed by in situ hybridization. EBV presence was confirmed by PCR. RESULTS: EBV genomic DNA and EBNA1 expression were detected in 31% (22/71 of patients specifically restricted to tumor epithelial cells in breast carcinoma while all breast control samples were negative for both viral DNA and EBNA1 protein. LMP2A was detected in 73% of EBNA1 positive cases, none of which expressed either LMP1 protein or EBERs transcripts. CONCLUSIONS: These findings suggest that EBV expression pattern in the studied biopsies could be different from those previously observed in breast carcinoma cell lines and lead us to suggest a new, EBNA1, LMP2A positive and LMP1 and EBERs negative latency profile in breast carcinoma in our population.

Thyroid carcinoma

International Nuclear Information System (INIS)

Lambertini, Roberto; Dalurzo, Liliana; Jaen, Ana del V.

2008-01-01

In this document the case of a 66-year old woman is presented, with record of multi nodular goiter of 5 year of evolution, which is derived to scan ultrasound office to make a puncture-aspiration with thin needle because of the growth of nodular thyroid injuries. The ultrasound scan examination made before the puncture determine multiple dominant nodules of hyperplasia aspect between 15 and 25 mm of diameter and a small nodule of 6 mm suspected proliferate process. Despite its size, it was decided to include small nodule in injuries to a biopsy. The cytological study reveals nodular hyperplasia with carcinoma in the small nodule of 6 mm. A thyroidectomy is practiced on the patient. The deferred histological study of the thyroid gland confirms the finding of multi-nodular goiter with a small focus of papillar carcinoma. The ganglions examined were negative in the deferred examination [es

"MONOCLONAL ANTIBODY HBME-1 USEFULNESS IN DIFFERENTIATION OF BENIGN NEOPLASM AND DIFFERENTIATED THYROID CARCINOMA"

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M. Mokhtari

2005-05-01

Full Text Available HBME-l is an antimesothelial monoclonal antibody that recognizes an unknown antigen on microvilli of mesothelial cells. The antibody is only relatively specific for mesothelium and is used in the differential diagnosis of mesothelioma and adenocarcinoma within the context of an appropriate immuno-histochemical panel. HBME-l has also been reported to strongly and uniformly stain papillary and follicular carcinoma of the thyroid while benign disorders have been usually negative. We studied the immunoreactivity of HBME-l in 90 cases of benign and malignant thyroid lesions. We found strong positive staining in the majority of papillary carcinomas (28/31, in some of follicular carcinomas (4/6,and in a few follicular adenomas (2/17. Negative staining was found in oxyphilic cell adenoma (0/4, nodular goiter (0/13 and undifferentiated carcinoma. The results suggest that monoclonal antibody HBME-l is useful in differentiating papillary and follicular carcinoma of the thyroid from benign lesions, especially in more differentiated lesions. Strong and generalized immunoreactivity for HBME-l in a follicular lesion should raise the suspicion of malignancy, but negative staining specially in poorly differentiated lesion does not rule out malignancy.

Aldehyde dehydrogenase 1 (ALDH1) expression is an independent prognostic factor in triple negative breast cancer (TNBC).

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Ma, Fei; Li, Huihui; Li, Yiqun; Ding, Xiaoyan; Wang, Haijuan; Fan, Ying; Lin, Chen; Qian, Haili; Xu, Binghe

2017-04-01

Triple negative breast cancer (TNBC) is a subset of breast cancer that is highly aggressive and has a poor prognosis. Meanwhile, cancer stem cells (CSCs) are also characterized by a strong tumorigenic potential, which might be partly responsible for the aggressive behavior of TNBC. We previously showed that CSCs are enriched in TNBC cell lines and tissues. Further experiments in animal models revealed higher tumorigenicity of CSCs sorted from TNBC cell lines. In this study, we aimed to determine the clinical relationship between CSCs and TNBC by exploring the expression of aldehyde dehydrogenase 1 (ALDH1), which is a putative marker of breast CSCs, in TNBC tissues.ALDH1 levels in paraffin-embedded tumor tissues from 158 TNBC patients were evaluated by immunohistochemistry staining using an ALDH1A1 primary antibody. Staining evaluation was performed independently by two pathologists, and the expression level of ALDH1 was evaluated in terms of the percentage and intensity of positive cells. The association of immunohistochemistry staining of ALDH1 expression with clinical parameters was also analyzed.ALDH1 expression in tumor cells was observed in 88 out of 158 cases (55.7%). Analysis of clinicopathological parameters showed that the immunohistochemistry staining of ALDH1 was significantly correlated with tumor size (P = 0.02) and stage (P = 0.04). Survival analysis in patients with ALDH1 expression demonstrated shorter relapse-free survival (RFS) and overall survival (OS) times (P = 0.01; P = 0.001). Moreover, Cox multivariate analysis revealed that ALDH1 expression was an independent prognostic indicator of RFS and OS (P = 0.04; P = 0.04).Immunohistochemistry staining of ALDH1 in tumor cells is an independent prognostic indicator of RFS and OS in TNBC patients.

Mortality Risk from Co-Morbidities independent of Triple-Negative Breast Cancer Status: NCI SEER-based Cohort Analysis

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Swede, Helen; Sarwar, Amna; Magge, Anil; Braithwaite, Dejana; Cook, Linda S.; Gregorio, David I.; Jones, Beth A; Hoag, Jessica; Gonsalves, Lou; Salner, Andrew; Zarfos, Kristen; Andemariam, Biree; Stevens, Richard G; Dugan, Alicia; Pensa, Mellisa; Brockmeyer, Jessica

2017-01-01

Purpose A comparatively high prevalence of co-morbidities among African-American/Blacks (AA/B) has been implicated in disparate survival in breast cancer. There is a scarcity of data, however, if this effect persists when accounting for the adverse triple-negative breast cancer (TNBC) subtype which occurs at three-fold the rate in AA/B compared to white breast cancer patients. Methods We reviewed charts of 214 white and 202 AA/B breast cancer patients in the NCI-SEER Connecticut Tumor Registry who were diagnosed in 2000-07. We employed the Charlson Co-Morbidity Index (CCI), a weighted 17-item tool to predict risk of death in cancer populations. Cox Survival Analyses estimated hazard ratios (HR) for all-cause mortality in relation to TNBC and CCI adjusting for clinicopathological factors. Results Among patients with SEER-Local Stage, TNBC increased the risk of death (HR=2.18, 95% CI 1.14-4.16), which was attenuated when the CCI score was added to the model (Adj. HR=1.50, 95% CI 0.74-3.01). Conversely, the adverse impact of the CCI score persisted when controlling for TNBC (Adj. HR=1.49, 95% CI 1.29-1.71; per one point increase). Similar patterns were observed in SEER-Regional Stage but estimated HRs were lower. AA/B patients with a CCI score of ≥3 had a significantly higher risk of death compared to AA/B patients without comorbidities (Adj. HR=5.65, 95% CI 2.90-11.02). A lower and non-significant effect was observed for whites with a CCI of ≥3 (Adj. HR=1.90, 95% CI 0.68-5.29). Conclusions Co-morbidities at diagnosis increase risk of death independent of TNBC, and AA/B patients may be disproportionately at risk. PMID:27000206

Adenoid cystic carcinoma of the breast, 20 years of experience in a single center with review of literature.

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Treitl, Daniela; Radkani, Pejman; Rizer, Magda; El Hussein, Siba; Paramo, Juan C; Mesko, Thomas W

2018-01-01

Adenoid cystic carcinoma (ACC) of the breast is a rare type of breast cancer, which presents inconsistencies in the optimal management strategy. A retrospective review of prospectively collected data, spanning the last 20 years, was performed using the cancer registry database at our institution. Six patients were diagnosed with ACC of the breast, out of 5,813 total patients diagnosed with breast cancer (0.1%). Our identified patients had a median age of 66, all with the early stage cancer (Stage I/II). The average size of the breast lesion was 1.62 cm, and nodal status was negative for all cases. All patients had resection as primary therapy (partial or total mastectomy), with one patient also undergoing external beam radiation and tamoxifen hormonal therapy. Median follow-up was 85 months, with all patients being disease-free at last follow-up. ACC of the breast has an indolent course, despite triple negative status. Our study suggests that radiation may not be warranted and confirms the rarity of axillary node metastases, indicating that sentinel node excision may also not be necessary. Ultimately, the hope is that our findings along with the reviewed literature will aid in determining the most appropriate options for management of ACC of the breast.

Early onset sebaceous carcinoma

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Kaltreider Sara A

2011-09-01

Full Text Available Abstract Background Ocular sebaceous carcinoma can masquerade as benign lesions resulting in delay of diagnosis. Early recognition is even more difficult in young patients where the disease rarely occurs. Here, we provide a clinicopathological correlation of ocular sebaceous carcinoma in a young individual lacking history of hereditary cancer or immunosuppression. Findings A detailed histopathological study including p53 DNA sequencing was performed on an aggressive sebaceous carcinoma presenting in a healthy 32 year-old Caucasian woman. She had no history of retinoblastoma, evidence for a hereditary cancer syndrome, or radiation therapy. However, she potentially was at risk for excessive UV light exposure. A detailed review of the literature is also provided. A moderately well differentiated sebaceous carcinoma was established histopathologically arising from the meibomian gland of the upper eyelid. In most areas, the cytoplasm contained small but distinct Oil-red-O positive vacuoles. Direct sequencing of p53 identified a G:C→A:T mutation at a dipyrimidine site. The mutation results in substitution of arginine for the highly conserved glycine at residue 199 located at the p53 dimer-dimer interface. Energy minimization structural modeling predicts that G199R will neutralize negative charges contributed by nearby inter- and intramonomeric glutamate residues. Discussion This study points to the importance of recognizing that sebaceous carcinoma can occur in young patients with no evidence for hereditary cancer risk or radiation therapy. The G199R substitution is anticipated to alter the stability of the p53 tetrameric complex. The role of UV light in the etiology of sebaceous carcinoma deserves further study. Our findings, taken together with those of others, suggest that different environmental factors could lead to the development of sebaceous carcinoma in different patients.

Alpha-fetoprotein-L3 and Golgi protein 73 may serve as candidate biomarkers for diagnosing alpha-fetoprotein-negative hepatocellular carcinoma

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Zhang ZG

2015-12-01

Full Text Available Zhiguo Zhang,1 Yanying Zhang,2 Yeying Wang,1 Lingling Xu,3 Wanju Xu3 1Department of Clinical Laboratory, Zhangqiu Maternity and Child Care Hospital, Zhangqiu, 2Department of Clinical Laboratory, Zaozhuang City Wangkai Infection Hospital, Zaozhuang, 3Department of Clinical Laboratory, Qianfoshan Hospital, Jinan, People’s Republic of China Abstract: Currently, there is no reliable biomarker for use in diagnosing alpha-fetoprotein (AFP-negative hepatocellular carcinoma (HCC. Such a biomarker would aid in making an early diagnosis of AFP-negative HCC, ensuring the timely initiation of treatment. This study examined AFP-L3 and Golgi protein 73 (GP73 as candidate biomarkers for AFP-negative HCC. The affinity adsorption method and enzyme-linked immunoassays were separately used to determine serum levels of AFP-L3 and GP73 in 50 patients with AFP-negative HCC, 30 non-HCC patients, and 50 healthy subjects. Fifty percent of patients with AFP-negative HCC tested positive for AFP-L3, while 3.33% of non-HCC patients and 2.00% of healthy subjects were AFP-L3 positive. Patients with AFP-negative HCC had significantly higher serum levels of AFP-L3 compared to non-HCC patients and healthy individuals; however, there was no significant difference in the AFP-L3 levels of non-HCC patients and healthy subjects. Sixty-six percent of patients with AFP-negative HCC tested positive for GP73, while 10% of non-HCC patients and 0% of healthy subjects were GP73-positive. Patients with AFP-negative HCC had significantly higher serum levels of GP73 compared to non-HCC patients and healthy subjects, but there was no significant difference between the GP73 levels of non-HCC patients and healthy individuals. Moreover, 20 patients with AFP-negative HCC were both AFP-L3- and GP73-positive, while no non-HCC patients or healthy subjects tested positive for both markers. Either AFP-L3 or GP73 may be used as a biomarker for diagnosing AFP-negative HCC, while their combined use

High resolution CT for localization of early hilar lung carcinoma

International Nuclear Information System (INIS)

Minami, Yuko; Ishikawa, Shigemi; Saida, Yukihisa; Kajitani, Motomasa; Yamamoto, Tatsuo; Sato, Yukio; Onizuka, Masataka; Sakakibara, Yuzuru; Noguchi, Masayuki

2002-01-01

The purpose of this study was to analyse the usefulness of high resolution CT (HRCT) for the diagnosis and localization of roentgenographically occult lung cancer. HRCT was performed prospectively on chest X-ray negative patients with bloody sputum or suspicious or positive cells on sputum cytology between 1998 and 2000. After the HRCT scan, white light bronchoscopy and autofluorescence bronchoscopy were performed. HRCT depicted 19 hilar bronchial lesions in 13 cases out of 19 patients, of which 9 lesions were confirmed by white light broncoscope. Of 8 hilar squamous cell carcinomas diagnosed in this study, 7 lesions (87.5%) were depicted by HRCT. One CT-negative case (12.5%) was an in situ carcinoma in left B 1+2 . Four out of 20 lesions which showed bronchoscopic abnormality, could not be depicted by HRCT. HRCT could prospectively detect 80% of the bronchoscopic abnormalities and 87.5% of the hilar squamous cell carcinomas of the tracheobronchial lesions of the lung. Therefore, HRCT can be an effective supplemental means for screening for hilar squamous cell carcinoma. (author)

Tumour 18 F-FDG Uptake on preoperative PET/CT may predict axillary lymph node metastasis in ER-positive/HER2-negative and HER2-positive breast cancer subtypes

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Kim, Jin You; Lee, Suck Hong; Kim, Suk [Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Department of Radiology, Seo-gu, Busan (Korea, Republic of); Kang, Taewoo [Pusan National University Hospital, Busan Cancer Center, Busan (Korea, Republic of); Bae, Young Tae [Pusan National University Hospital, Department of Surgery, Busan (Korea, Republic of)

2015-04-01

To evaluate the association between tumour FDG uptake on preoperative PET/CT and axillary lymph node metastasis (ALNM) according to breast cancer subtype. The records of 671 patients with invasive breast cancer who underwent {sup 18} F-FDG PET/CT and surgery were reviewed. Using immunohistochemistry, tumours were divided into three subtypes: oestrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HER2-positive, and triple-negative. Tumour FDG uptake, expressed as maximum standardized uptake value (SUV{sub max}), and clinicopathological variables were analysed. ALNM was present in 187 of 461 ER-positive/HER2-negative, 54 of 97 HER2-positive, and 38 of 113 triple-negative tumours. On multivariate analysis, high tumour SUV{sub max} (≥4.25) (P < 0.001), large tumour size (>2 cm) (P = 0.003) and presence of lymphovascular invasion (P < 0.001) were independent variables associated with ALNM. On subset analyses, tumour SUV{sub max} maintained independent significance for predicting ALNM in ER-positive/HER2-negative (adjusted odds ratio: 3.277, P < 0.001) and HER2-positive tumours (adjusted odds ratio: 14.637, P = 0.004). No association was found for triple-negative tumours (P = 0.161). Tumour SUV{sub max} may be an independent prognostic factor for ALNM in patients with invasive breast cancer, especially in ER-positive/HER2-negative and HER2-positive subtypes, but not in those with triple-negative subtype. (orig.)

Berberine Suppresses Cell Motility Through Downregulation of TGF-β1 in Triple Negative Breast Cancer Cells

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Sangmin Kim

2018-01-01

Full Text Available Background/Aims: Transforming growth factor-beta proteins (TGF-βs are multifunctional growth factors and powerful modulators of the epithelial-mesenchymal transition (EMT in a variety of cancer types including breast and lung cancer cells. Here, we demonstrated the inhibitory effect of berberine (BBR on tumor growth and metastasis of triple negative breast cancer (TNBC cells via suppression of TGF-β1 expression. Methods: The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-β1 protein expression were analyzed by zymography and confocal microscopy, respectively. Cell migration was analyzed by wound healing assay. Tumorigenicity of TNBC cells such as tumor growth and metastasis was analyzed using xenograft models. Results: In a clinical data set, aberrant TGF-β1 expression was associated with poor prognosis of breast cancer patients. Our in vitro results using TNBC cells showed that the expression levels of matrix metalloproteinase (MMP-2 and MMP-9 and the capacity for cell migration were increased by TGF-β1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-β receptor I inhibitor, SB431542. In addition, TGF-β1–induced MMP-2 and MMP-9 expression and cell migration were decreased by SB431542. Interestingly, we showed for the first time that BBR decreased the level of TGF-β1, but not TGF-β2, in TNBC cells. Furthermore, BBR significantly decreased the level of MMP-2 expression as well as the capacity for cell migration in TNBC cells. Finally, we examined the effect of BBR on in vivo tumor growth and lung metastasis in MDA-MB231 and 4T1 breast cancer xenograft models and showed that both were significantly decreased following BBR treatment. Conclusion: BBR suppresses tumorigenicity of TNBC cells through inhibition of TGF-β1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC.

Increased macroH2A1.1 expression correlates with poor survival of triple-negative breast cancer patients.

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Anne-Claire Lavigne

Full Text Available PURPOSE: Epithelial-Mesenchymal Transition (EMT features appear to be key events in development and progression of breast cancer. Epigenetic modifications contribute to the establishment and maintenance of cancer subclasses, as well as to the EMT process. Whether histone variants contribute to these transformations is not known. We investigated the relative expression levels of histone macroH2A1 splice variants and correlated it with breast cancer status/prognosis/types. METHODS: To detect differential expression of macroH2A1 variant mRNAs in breast cancer cells and tumor samples, we used the following databases: GEO, EMBL-EBI and publisher databases (may-august 2012. We extracted macroH2A1.1/macroH2A1 mRNA ratios and performed correlation studies on intrinsic molecular subclasses of breast cancer and on molecular characteristics of EMT. Associations between molecular and survival data were determined. RESULTS: We found increased macroH2A1.1/macroH2A1 mRNA ratios to be associated with the claudin-low intrinsic subtype in breast cancer cell lines. At the molecular level this association translates into a positive correlation between macroH2A1 ratios and molecular characteristics of the EMT process. Moreover, untreated Triple Negative Breast Cancers presenting a high macroH2A1.1 mRNA ratio exhibit a poor outcome. CONCLUSION: These results provide first evidence that macroH2A1.1 could be exploited as an actor in the maintenance of a transient cellular state in EMT progress towards metastatic development of breast tumors.

Relationship Between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple Negative Breast Cancer

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Sparano, Joseph A.; Goldstein, Lori J.; Childs, Barrett H.; Shak, Steven; Brassard, Diana; Badve, Sunil; Baehner, Frederick L.; Bugarini, Roberto; Rowley, Steve; Perez, Edith; Shulman, Lawrence N.; Martino, Silvana; Davidson, Nancy E.; Kenny, Paraic A.; Sledge, George W.; Gray, Robert

2012-01-01

Purpose To perform an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy. Experimental design RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative RT-PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests. Results GRB7 was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn’s adjusted p value=0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR 2.31, p=0.04 using the median as the split). The 5-year recurrence rates were 10.5% (95% confidence intervals [CI] 7.8%, 14.1%) in the low and 20.4% (95% CI 16.5%, 25.0%) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy. Conclusions GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered. PMID:21933890

Relationship between quantitative GRB7 RNA expression and recurrence after adjuvant anthracycline chemotherapy in triple-negative breast cancer.

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Sparano, Joseph A; Goldstein, Lori J; Childs, Barrett H; Shak, Steven; Brassard, Diana; Badve, Sunil; Baehner, Frederick L; Bugarini, Roberto; Rowley, Steve; Perez, Edith A; Shulman, Lawrence N; Martino, Silvana; Davidson, Nancy E; Kenny, Paraic A; Sledge, George W; Gray, Robert

2011-11-15

To conduct an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy. RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative reverse transcriptase PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests. Growth factor receptor bound protein 7 (GRB7) was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn's adjusted P value = 0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR = 2.31; P = 0.04 using the median as the split). The 5-year recurrence rates were 10.5% [95% confidence intervals (CI), 7.8-14.1] in the low and 20.4% (95% CI, 16.5-25.0) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy. GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered.

Simultaneous determination of triple therapy for Helicobacter pylori in human plasma by reversed phase chromatography with online wavelength switching

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Ahmed, Sameh; Atia, Noha N.

2015-02-01

The infection of gastric mucosa by Helicobacter pylori (HP) is an essential cofactor in the aetiology of gastroduodenal ulcer and gastric carcinoma. Because of the bacterial resistance, combination therapy containing omeprazole (OME), tinidazole (TNZ) and clarithromycin (CLA) is commonly used for eradication of HP. However, the simultaneous determination of the triple therapy in human plasma was not reported. A simple, reproducible, and selective HPLC method was developed for the simultaneous determination of the triple therapy mixture used for management of HP infections in human plasma. An HPLC procedure based on a liquid-liquid extraction, enrichment of the analytes and subsequent reversed-phase chromatography with UV detection was used. To enable sensitive and selective detection, the method involved the use of online wavelength switching detection, with two different detection wavelengths; 280 nm for detection of OME and TNZ and 210 nm for detection of CLA. Separations were performed on C18 analytical column with acetonitrile-10 mM phosphate buffer of pH = 3.0 at flow rate of 1.0 mL min-1. The linear ranges in human plasma were 0.05-10 μg mL-1 with correlation coefficients >0.9990. The detection limits in human plasma were 0.02-0.07 μg mL-1. Validation parameters were assessed in compliance with US-FDA guidelines. The method proved to be valuable for the therapeutic drug monitoring after oral administration of triple therapy tablets.

GNAq mutations are not identified in papillary thyroid carcinomas and hyperfunctioning thyroid nodules.

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Cassol, Clarissa A; Guo, Miao; Ezzat, Shereen; Asa, Sylvia L

2010-12-01

Activating mutations of GNAq protein in a hotspot at codon 209 have been recently described in uveal melanomas. Since these neoplasms share with thyroid carcinomas a high frequency of MAP kinase pathway-activating mutations, we hypothesized whether GNAq mutations could also play a role in the development of thyroid carcinomas. Additionally, activating mutations of another subtype of G protein (GNAS1) are frequently found in hyperfunctioning thyroid adenomas, making it plausible that GNAq-activating mutations could also be found in some of these nodules. To investigate thyroid papillary carcinomas and thyroid hyperfunctioning nodules for GNAq mutations in exon 5, codon 209, a total of 32 RET/PTC, BRAF, and RAS negative thyroid papillary carcinomas and 13 hyperfunctioning thyroid nodules were evaluated. No mutations were identified. Although plausible, GNAq mutations seem not to play an important role in the development of thyroid follicular neoplasms, either benign hyperfunctioning nodules or malignant papillary carcinomas. Our results are in accordance with the literature, in which no GNAq hotspot mutations were found in thyroid papillary carcinomas, as well as in an extensive panel of other tumors. The molecular basis for MAP-kinase pathway activation in RET-PTC/BRAF/RAS negative thyroid carcinomas remains to be determined.

Radiotherapy and verrucous carcinoma of the oral cavity

International Nuclear Information System (INIS)

Vidyasagar, M.S.; Fernandes, D.J.; Pai Kasturi, D.; Akhileshwaran, R.; Rao, K.; Rao, S.; Rao, R.V.; Solomon, J.G.R.

1992-01-01

One hundred and seven cases of oral verrucous carcinoma treated with radiotherapy at Kasturba Hospital, Manipal, India between 1977 and 1987 were analysed concerning location within the oral cavity, clinical extent, and effectiveness of radiotherapy. The most common site was the buccal mucosa followed by the buccogingival sulcus. Only 13.2% of the patients presented with T1 or T2 tumours and 32.7% had clinically negative nodes. Biopsy had to be repeated more than once in 22 patients to get confirmation in invasive carcinoma. The 5-year survival rate was 35% for stage III and 26% for stage IV. The treatment results with radiotherapy were comparable with those for ordinary squamous cell carcinoma of the oral cavity. It is felt that the treatment policy for verrucous carcinoma can be the same as for ordinary squamous cell carcinoma. In order to prevent delay in diagnosis and treatment, proper cooperation between the treating oncologist and the pathologist is essential. (orig.)

Dermatomyositis with anti-TIF-1γ antibodies as a presenting symptom of underlying triple-negative breast cancer: a case report

International Nuclear Information System (INIS)

Kubeček, Ondřej; Soukup, Tomáš; Paulík, Adam; Kopecký, Jindřich

2016-01-01

Dermatomyositis is an autoimmune myopathy characterized by proximal muscle weakness, muscle inflammation, and typical skin findings. It is a rare disease with an incidence of ~1/100 000. About 15–30 % of adult-onset cases are caused by underlying malignancy and dermatomyositis can be the first symptom of undiagnosed cancer, mainly in the case of anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies presence. TIF-1γ is a transcriptional cofactor which is implicated in TGFβ signaling pathway that controls cell proliferation, differentiation, apoptosis, and tumorigenesis. Its expression was shown to be associated with younger age, higher tumor grade, more estrogen receptor negativity, tumors larger than 2 cm, and tendency towards poor outcome in early breast cancer. No association between anti-TIF-1γ antibodies and prognosis has been proposed yet. We report a case of a 43-year-old premenopausal woman presenting with the symptoms of systemic rheumatic disease, the most prominent being a typical skin rash and muscle pain. After a series of investigations, the patient was diagnosed with anti-TIF-1γ positive dermatomyositis and concurrent triple-negative breast cancer (cT1c N3c M0) as an underlying cause. Immediate intravenous corticosteroid therapy relieved the symptoms and enabled anticancer therapy to be commenced. Considering the tumor stage, neoadjuvant therapy with 4 courses of AC (Doxorubicin/Cyclophosphamide) followed by 4 courses of Paclitaxel/Carboplatin was administered. However, no tumor regression was documented and radiotherapy was chosen as the definitive treatment. Early detection of anti-TIF-1γ autoantibodies can contribute to a rapid diagnosis of tumor-associated dermatomyositis and enable immediate anticancer treatment. We demonstrate the emerging role of anti-TIF-1γ antibodies in the diagnostics of tumor-associated dermatomyositis. Furthermore, we propose a potential role of anti-TIF-1γ antibodies as a prognostic marker in early

On Pythagoras Theorem for Products of Spectral Triples

OpenAIRE

D'Andrea, Francesco; Martinetti, Pierre

2013-01-01

We discuss a version of Pythagoras theorem in noncommutative geometry. Usual Pythagoras theorem can be formulated in terms of Connes' distance, between pure states, in the product of commutative spectral triples. We investigate the generalization to both non pure states and arbitrary spectral triples. We show that Pythagoras theorem is replaced by some Pythagoras inequalities, that we prove for the product of arbitrary (i.e. non-necessarily commutative) spectral triples, assuming only some un...

GATA3 expression in advanced breast cancer: prognostic value and organ-specific relapse.

Science.gov (United States)

McCleskey, Brandi C; Penedo, Thuy L; Zhang, Kui; Hameed, Omar; Siegal, Gene P; Wei, Shi

2015-11-01

GATA3 is a transcription factor regulating luminal cell differentiation in the mammary glands and has been implicated in the luminal types of breast carcinoma. The prognostic significance of GATA3 in breast cancer remains controversial. In this study, we assessed the prognostic value of the molecule in a subset of 62 advanced breast cancers and 10 control breast cancers (no metastasis after follow-up). GATA3 expression levels in luminal tumors of advanced stage were significantly higher than that of the human epidermal growth factor receptor 2 (HER2) subtype and triple-negative carcinomas, as expected, but were similar to those of the luminal controls. Furthermore, 88% of nonluminal tumors showed variable GATA3 expression, for which the HER2 subtype had significantly higher GATA3 expression than that of the triple-negative carcinomas. Interestingly, GATA3 levels were significantly lower in carcinomas with lung relapse compared to those with metastatic recurrence to other organs, thus reflecting the findings in animal models. No significant difference was observed between tumors with bone relapse and those metastasized to nonskeletal sites. Moreover, high GATA3 expression was significantly associated with favorable relapse-free survival and overall survival. These findings suggest that GATA3 may not act solely as a luminal differentiation marker, and further uncovering the molecular pathways by which GATA3 regulates the downstream targets will be crucial to our understanding of breast cancer dissemination. Copyright© by the American Society for Clinical Pathology.

Prognostic Significance of N-Glycolyl GM3 Ganglioside Expression in Non-Small Cell Lung Carcinoma Patients: New Evidences

Science.gov (United States)

Blanco, Rancés; Domínguez, Elizabeth; Morales, Orlando; Blanco, Damián; Martínez, Darel; Rengifo, Charles E.; Viada, Carmen; Cedeño, Mercedes; Rengifo, Enrique; Carr, Adriana

2015-01-01

The prognostic role of N-glycolyl GM3 ganglioside (NeuGcGM3) expression in non-small cell lung carcinoma (NSCLC) still remains controversial. In this study, the NeuGcGM3 expression was reevaluated using an increased number of NSCLC cases and the 14F7 Mab (a highly specific IgG1 raised against NeuGcGM3). An immunohistochemical score integrating the percentage of 14F7-positive cells and the intensity of reaction was applied to reassess the relationship between NeuGcGM3 expression, some clinicopathological features, and the overall survival (OS) of NSCLC patients. The double and the triple expression of NeuGcGM3 with the epidermal growth factor receptor (EGFR) and/or its ligand, the epidermal growth factor (EGF), were also evaluated. NeuGcGM3 expression correlates with both S-Phase fraction (p = 0.006) and proliferation index (p = 0.000). Additionally, NeuGcGM3 expression was associated with a poor OS of patients in both univariate (p = 0.020) and multivariate (p = 0.010) analysis. Moreover, the double and/or the triple positivity of tumors to NeuGcGM3, EGFR, and/or EGF permitted us to identify phenotypes of NSCLC with a more aggressive biological behavior. Our results are in agreement with the negative prognostic significance of NeuGcGM3 expression in NSCLC patients. However, standardization of techniques to determine the expression of NeuGcGM3 in NSCLC as well as the implementation of a universal scoring system is recommended. PMID:26634172

Reproducibility and predictive value of scoring stromal tumour infiltrating lymphocytes in triple-negative breast cancer: a multi-institutional study.

Science.gov (United States)

O'Loughlin, Mark; Andreu, Xavier; Bianchi, Simonetta; Chemielik, Ewa; Cordoba, Alicia; Cserni, Gábor; Figueiredo, Paulo; Floris, Giuseppe; Foschini, Maria P; Heikkilä, Päivi; Kulka, Janina; Liepniece-Karele, Inta; Regitnig, Peter; Reiner, Angelika; Ryska, Ales; Sapino, Anna; Shalaby, Aliaa; Stovgaard, Elisabeth Specht; Quinn, Cecily; Walsh, Elaine M; Zolota, Vicky; Glynn, Sharon A; Callagy, Grace

2018-05-17

Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95% CI 0.601-0.767, p-value value value values (Spearman ρ = 0.727); fair for sTILs ≥ 25% (κ = 0.53) and for LPBC (κ = 0.49), but poor for sTILs as 10% increments (κ = 0.24). Increasing sTILs was significantly associated with an increased likelihood of a pathological complete response (pCR) on multivariable analysis. Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.

Holonomy loops, spectral triples and quantum gravity

DEFF Research Database (Denmark)

Johannes, Aastrup; Grimstrup, Jesper Møller; Nest, Ryszard

2009-01-01

We review the motivation, construction and physical interpretation of a semi-finite spectral triple obtained through a rearrangement of central elements of loop quantum gravity. The triple is based on a countable set of oriented graphs and the algebra consists of generalized holonomy loops...

Multicentricidade no carcinoma diferenciado da tireóide Multicentricity in the thyroid differentiated carcinoma

Directory of Open Access Journals (Sweden)

José Francisco Salles Chagas

2009-02-01

, complications, histopathological analysis and invasion of the contralateral lobe were analyzed. Patients' ages varied from 17 to 89; the most frequent histopathological pattern was the classical papillary carcinoma (18 cases, followed by follicular carcinoma (6; the follicular variant of the papillary carcinoma (2 and the Hürthle cell carcinoma (1. Twenty-one patients underwent full thyroidectomies, from 15 to 30 days after the first intervention. RESULTS: the contralateral lobe analysis was negative for carcinoma in 16 (76.5% and positive in the other 5 (23.8% patients. The complications observed were temporary dysphonia (3 cases and hypoparathyroidism (2 cases, one permanent. CONCLUSIONS: total thyroidectomy is important in the treatment of differentiated thyroid carcinomas, because there is a high contralateral spread rate (23.8%. It is a procedure without mortality, which bears few complications.

Reduced risk of axillary lymphatic spread in triple-negative breast cancer

DEFF Research Database (Denmark)

Holm-Rasmussen, Emil Villiam; Jensen, Maj-Britt; Balslev, Eva

2015-01-01

We examined the association between the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of women with primary breast cancer and the risk of axillary lymph node (ALN) involvement at the time of diagnosis. Information on 20,009 women diagnosed with primary breast...... cancer between 2008 and 2012 was retrieved from the Danish Breast Cancer Cooperative Group database. The associations between clinical and pathological variables and ALN involvement at the time of diagnosis were evaluated in univariate and multivariate regression analyses, as well as the significance......-negative breast cancer (TNBC) patients showed a significantly reduced risk of ALN involvement at the time of diagnosis compared to patients with HR-positive/HER2-negative tumors (OR 0.55; 95 % CI 0.49-0.62; P

Identification of new negative-parity levels in 152,154Nd

International Nuclear Information System (INIS)

Zhang, X.Q.; Hamilton, J.H.; Ramayya, A.V.; Peker, L.K.; Hwang, J.K.; Jones, E.F.; Komicki, J.; Beyer, C.J.; Gore, P.M.; Babu, B.R.; Ginter, T.N.; Ter-Akopian, G.M.; Daniel, A.V.; Asztalos, S.J.; Chu, S.Y.; Gregorich, K.E.; Lee, I.Y.; Macchiavelli, A.O.; Macleod, R.W.; Rasmussen, J.O.; Gilat, J.; Ter-Akopian, G.M.; Oganessian, Y.T.; Daniel, A.V.; Ter-Akopian, G.M.; Daniel, A.V.; Ma, W.C.; Varmette, P.G.; Cole, J.D.; Aryaeinejad, R.; Butler-Moore, K.; Dardenne, Y.X.; Drigert, M.W.; Stoyer, M.A.; Wild, J.F.; Becker, J.A.; Bernstein, L.A.; Lougheed, R.W.; Moody, K.J.; Donangelo, R.; Prussin, S.G.; Griffin, H.C.

1998-01-01

From an experiment with Gammasphere and a 252 Cf spontaneous fission source, a new negative-parity band in 154 Nd and new negative-parity levels in 152 Nd were identified and the yrast bands were extended to 18 + in 154 Nd and 20 + in 152 Nd in a triple gamma coincidence study. These new negative-parity bands are consistent with octupole vibrational mode. There is a constant difference as a function of spin between the J 1 values for the negative-parity band in 152 Nd and J 1 for the similar negative-parity band in 154 Nd, however, their J 2 values are essentially identical. These bands indicate a new kind of identical band. copyright 1998 The American Physical Society

Transforming growth factor β-activated kinase 1 inhibitor suppresses the proliferation in triple-negative breast cancer through TGF-β/TGFR pathway.

Science.gov (United States)

Zhang, Liangyu; Fu, Zelong; Li, Xia; Tang, Haitao; Luo, Jiesi; Zhang, Dehui; Zhuang, Yongzhi; Han, Zhiyang; Yin, Mingzhu

2017-09-01

Breast cancer is one of the most invasive cancer types in female population. The functional activity of Transforming growth factor β-activated kinase 1 (TAK1) in breast cancer progression increasingly attracts attention as it provides a potential target for antibreast cancer drug development. However, the fundamental role of TAK1 for triple-negative breast cancer (TNBC) progression and the effect of potential anti-TAK1 drug candidate needs to be further evaluated. Herein, we focused on the role of TAK1 in human breast cancer cells, and we hypothesized that the inhibition of TAK1 activation can repress the growth of human TNBC cells. We found that the TAK1 is robustly activated within cancer cell population of clinic-derived TNBC samples and the human breast cancer cell lines in culture. Furthermore, we determined the effect of 5Z-7-oxozeaenol (5Z-O), a TAK1-specific small molecule inhibitor, on proliferation of human TNBC cell line. 5Z-O treatment significantly suppressed the proliferation of human TNBC cells. Collectively, these demonstrate the role of TAK1 in human breast cancer and the antiproliferate effect of TAK1 inhibitor. Our study sets the stage for further research on TAK1 as a promising target for development of anti-TNBC drugs and therapeutic strategies. © 2017 John Wiley & Sons A/S.

Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration.

Science.gov (United States)

Muller, Marie; Guillaud-Bataille, Marine; Salleron, Julia; Genestie, Catherine; Deveaux, Sophie; Slama, Abdelhamid; de Paillerets, Brigitte Bressac; Richard, Stéphane; Benusiglio, Patrick R; Ferlicot, Sophie

2018-02-06

Hereditary leiomyomatosis and renal cell carcinoma syndrome is characterized by an increased risk of agressive renal cell carcinoma, often of type 2 papillary histology, and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and 2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors are often FH-negative and S-(2-succino)-cysteine (2SC) positive. We performed a pathology review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type 2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary, and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas were either FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%, respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal

Normalization for triple-target microarray experiments

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Magniette Frederic

2008-04-01

Full Text Available Abstract Background Most microarray studies are made using labelling with one or two dyes which allows the hybridization of one or two samples on the same slide. In such experiments, the most frequently used dyes are Cy3 and Cy5. Recent improvements in the technology (dye-labelling, scanner and, image analysis allow hybridization up to four samples simultaneously. The two additional dyes are Alexa488 and Alexa494. The triple-target or four-target technology is very promising, since it allows more flexibility in the design of experiments, an increase in the statistical power when comparing gene expressions induced by different conditions and a scaled down number of slides. However, there have been few methods proposed for statistical analysis of such data. Moreover the lowess correction of the global dye effect is available for only two-color experiments, and even if its application can be derived, it does not allow simultaneous correction of the raw data. Results We propose a two-step normalization procedure for triple-target experiments. First the dye bleeding is evaluated and corrected if necessary. Then the signal in each channel is normalized using a generalized lowess procedure to correct a global dye bias. The normalization procedure is validated using triple-self experiments and by comparing the results of triple-target and two-color experiments. Although the focus is on triple-target microarrays, the proposed method can be used to normalize p differently labelled targets co-hybridized on a same array, for any value of p greater than 2. Conclusion The proposed normalization procedure is effective: the technical biases are reduced, the number of false positives is under control in the analysis of differentially expressed genes, and the triple-target experiments are more powerful than the corresponding two-color experiments. There is room for improving the microarray experiments by simultaneously hybridizing more than two samples.

{sup 18}F-FDG-PET/CT for systemic staging of newly diagnosed triple-negative breast cancer

Energy Technology Data Exchange (ETDEWEB)

Ulaner, Gary A.; Castillo, Raychel; Riedl, Christopher C.; Jochelson, Maxine S. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Weill Cornell Medical College, Department of Radiology, New York, NY (United States); Goldman, Debra A.; Goenen, Mithat [Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Wills, Jonathan [Memorial Sloan Kettering Cancer Center, Department of Information Systems, New York, NY (United States); Pinker-Domenig, Katja [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States)

2016-10-15

National Comprehensive Cancer Network guidelines recommend {sup 18}F-FDG-PET/CT, in addition to standard staging procedures, for systemic staging of newly diagnosed stage III breast cancer patients. However, factors in addition to stage may influence PET/CT utility. As breast cancers that are negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (triple-negative breast cancer, or TNBC) are more aggressive and metastasize earlier than other breast cancers, we hypothesized that receptor expression may be one such factor. This study assesses {sup 18}F-FDG-PET/CT for systemic staging of newly diagnosed TNBC. In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with TNBC who underwent {sup 18}F-FDG-PET/CT in 2007-2013 prior to systemic or radiation therapy. Initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery, if performed prior to {sup 18}F-FDG-PET/CT. {sup 18}F-FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases, as well as unsuspected synchronous malignancies. Kaplan Meier survival estimates were calculated for initial stage IIB patients stratified by whether or not stage 4 disease was detected by {sup 18}F-FDG-PET/CT. A total of 232 patients with TNBC met inclusion criteria. {sup 18}F-FDG-PET/CT revealed unsuspected distant metastases in 30 (13 %): 0/23 initial stage I, 4/82 (5 %) stage IIA, 13/87 (15 %) stage IIB, 4/23 (17 %) stage IIIA, 8/14 (57 %) stage IIIB, and 1/3 (33 %) stage IIIC. Twenty-six of 30 patients upstaged to IV by {sup 18}F-FDG-PET/CT were confirmed by pathology, with the remaining four patients confirmed by follow-up imaging. In addition, seven unsuspected synchronous malignancies were identified in six patients. Initial stage 2B patients who were upstaged to 4 by {sup 18}F-FDG-PET/CT had significantly shorter survival compared to

Drop evaporation and triple line dynamics

Science.gov (United States)

Sobac, Benjamin; Brutin, David; Gavillet, Jerome; Université de Provence Team; Cea Liten Team

2011-03-01

Sessile drop evaporation is a phenomenon commonly came across in nature or in industry with cooling, paintings or DNA mapping. However, the evaporation of a drop deposited on a substrate is not completely understood due to the complexity of the problem. Here we investigate, with several nano-coating of the substrate (PTFE, SiOx, SiOc and CF), the influence of the dynamic of the triple line on the evaporation process. The experiment consists in analyzing simultaneously the motion of the triple line, the kinetics of evaporation, the internal thermal motion and the heat and mass transfer. Measurements of temperature, heat-flux and visualizations with visible and infrared cameras are performed. The dynamics of the evaporative heat flux appears clearly different depending of the motion of the triple line

Spectral triples and the geometry of fractals

DEFF Research Database (Denmark)

Christensen, Erik; Ivan, Cristina; Schroe, Elmar

2012-01-01

It is shown that one can construct a spectral triple for the Sierpinski gasket such that it represents any given K-homology class, On the other hand if the geodesic distance and the dimension has to be part of the data from the triple, there are certain restriction....

miRNA-135b Contributes to Triple Negative Breast Cancer Molecular Heterogeneity: Different Expression Profile in Basal-like Versus non-Basal-like Phenotypes.

Science.gov (United States)

Uva, Paolo; Cossu-Rocca, Paolo; Loi, Federica; Pira, Giovanna; Murgia, Luciano; Orrù, Sandra; Floris, Matteo; Muroni, Maria Rosaria; Sanges, Francesca; Carru, Ciriaco; Angius, Andrea; De Miglio, Maria Rosaria

2018-01-01

The clinical and genetic heterogeneity of Triple Negative Breast Cancer (TNBC) and the lack of unambiguous molecular targets contribute to the inadequacy of current therapeutic options for these variants. MicroRNAs (miRNA) are a class of small highly conserved regulatory endogenous non-coding RNA, which can alter the expression of genes encoding proteins and may play a role in the dysregulation of cellular pathways. Our goal was to improve the knowledge of the molecular pathogenesis of TNBC subgroups analyzing the miRNA expression profile, and to identify new prognostic and predictive biomarkers. We conducted a human miRNome analysis by TaqMan Low Density Array comparing different TNBC subtypes, defined by immunohistochemical basal markers EGFR and CK5/6. RT-qPCR confirmed differential expression of microRNAs. To inspect the function of the selected targets we perform Gene Ontology and KEGG enrichment analysis. We identified a single miRNA signature given by miR-135b expression level, which was strictly related to TNBC with basal-like phenotype. miR-135b target analysis revealed a role in the TGF-beta, WNT and ERBB pathways. A significant positive correlation was identified between neoplastic proliferative index and miR-135b expression. These findings confirm the oncogenic roles of miR-135b in the pathogenesis of TNBC expressing basal markers. A potential negative prognostic role of miR-135b overexpression might be related to the positive correlation with high proliferative index. Our study implies potential clinical applications: miR-135b could be a potential therapeutic target in basal-like TNBCs.

Metastatic Breast Carcinoma to the Prostate Gland

Directory of Open Access Journals (Sweden)

Meghan E. Kapp

2016-01-01

Full Text Available Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903 and no expression of P501S. The patient’s previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors.

Metaplastic carcinoma of the breast: multimodality imaging and histopathologic assessment

International Nuclear Information System (INIS)

Choi, Bo Bae; Shu, Kwang Sun

2012-01-01

Background Metaplastic carcinomas are ductal carcinomas that display metaplastic transformation of the glandular epithelium to non-glandular mesenchymal tissue. Metaplastic carcinoma has a poorer prognosis than most other breast cancers, so the differential diagnosis is important. Although many clinical and pathologic findings have been reported, to our knowledge, few imaging findings related to metaplastic carcinoma have been reported. Purpose To investigate whole-breast imaging findings, including mammography, sonography, MRI, and pathologic findings, including immunohistochemical studies of metaplastic carcinomas of the breast. Material and Methods We analyzed 33 cases of metaplastic carcinoma between January 2001 and January 2011. Mammography, ultrasonography, and MRI were recorded retrospectively using the American College of Radiology (ACR) breast imaging reporting and data system (BI-RADS) lexicon. Immunohistochemical studies of estrogen receptor (ER), progesterone receptor (PR), p53, and C-erbB-2 were performed. Results The most common mammographic findings were oval shape (37%), circumscribed margin (59%), and high density (74%). The most common sonogfindings were irregular shape (59.4%), microlobulated margin (41%), complex echogenicity (81%), parallel orientation (97%), and posterior acoustic enhancement (50%). Axillary lymph node metastases were noted for 25% of the sonographic examinations. On MRI, the most common findings of margin and shape were irregularity (57% and 52.4%, respectively). High signal intensity was the most common finding on T2-weighted images (57%). Immunohistochemical profile was negative for ER (91%, 29/32) and PR (81%, 26/32). Conclusion Metaplastic carcinomas might display more benign features and less axillary lymph node metastasis than IDC. High signal intensity on T2 MRI images and hormone receptor negativity would be helpful in differentiating this tumor from other breast cancers

Improving Ambiguity Resolution for Medium Baselines Using Combined GPS and BDS Dual/Triple-Frequency Observations.

Science.gov (United States)

Gao, Wang; Gao, Chengfa; Pan, Shuguo; Wang, Denghui; Deng, Jiadong

2015-10-30

The regional constellation of the BeiDou navigation satellite system (BDS) has been providing continuous positioning, navigation and timing services since 27 December 2012, covering China and the surrounding area. Real-time kinematic (RTK) positioning with combined BDS and GPS observations is feasible. Besides, all satellites of BDS can transmit triple-frequency signals. Using the advantages of multi-pseudorange and carrier observations from multi-systems and multi-frequencies is expected to be of much benefit for ambiguity resolution (AR). We propose an integrated AR strategy for medium baselines by using the combined GPS and BDS dual/triple-frequency observations. In the method, firstly the extra-wide-lane (EWL) ambiguities of triple-frequency system, i.e., BDS, are determined first. Then the dual-frequency WL ambiguities of BDS and GPS were resolved with the geometry-based model by using the BDS ambiguity-fixed EWL observations. After that, basic (i.e., L1/L2 or B1/B2) ambiguities of BDS and GPS are estimated together with the so-called ionosphere-constrained model, where the ambiguity-fixed WL observations are added to enhance the model strength. During both of the WL and basic AR, a partial ambiguity fixing (PAF) strategy is adopted to weaken the negative influence of new-rising or low-elevation satellites. Experiments were conducted and presented, in which the GPS/BDS dual/triple-frequency data were collected in Nanjing and Zhengzhou of China, with the baseline distance varying from about 28.6 to 51.9 km. The results indicate that, compared to the single triple-frequency BDS system, the combined system can significantly enhance the AR model strength, and thus improve AR performance for medium baselines with a 75.7% reduction of initialization time on average. Besides, more accurate and stable positioning results can also be derived by using the combined GPS/BDS system.

Metastatic carcinoma of the urinary bladder in a 67-year-old female with underlying triple primary cancers

Directory of Open Access Journals (Sweden)

Chia-Yen Hung

2016-06-01

A 67-year-old Taiwanese female presented to our institution in November 1997 with gastric signet ring cell carcinoma, pT2N0M0, status post subtotal gastrectomy. In February 2003 she was diagnosed with left breast invasive lobular carcinoma status post modified radical mastectomy, pT2N2M0. Further examination in January 2005 revealed proximal transverse colon cancer, Dukes' C2, with status post right hemicolectomy. She achieved disease-free status from all three malignancies after surgical resection and adjuvant chemotherapy for breast and colon cancers sequentially. In November 2011, she complained about sudden onset of gross hematuria for several days. Diagnostic cystoscopy showed a mass lesion over her urinary bladder. Cystoscope-assisted biopsy showed metastatic poorly differentiated adenocarcinoma with signet ring appearance. Herein we have discussed the pathologic role in the diagnosis of metastatic tumor involving a patient with multiple primary cancers. We also explored the epidemiologic risk and potential causal mechanism of patients with multiple primary cancers.

Prognostic significance of surgical extranodal extension in head and neck squamous cell carcinoma patients.

Science.gov (United States)

Matsumoto, Fumihiko; Mori, Taisuke; Matsumura, Satoko; Matsumoto, Yoshifumi; Fukasawa, Masahiko; Teshima, Masanori; Kobayashi, Kenya; Yoshimoto, Seiichi

2017-08-01

Lymph node metastasis with extranodal extension represents one of the most important adverse prognostic factors for survival in patients with head and neck squamous cell carcinoma. We propose that extranodal extension occurs to differing extents. The aim of this study was to determine the prognostic significance of extranodal extension in patients with head and neck squamous cell carcinoma. Two hundred and ninety-eight patients with head and neck squamous cell carcinoma who underwent surgical resection and neck dissection were included. Cervical lymph nodes were classified into four categories: (i) pathological N negative, (ii) extranodal extension negative, (iii) non-surgical extranodal extension and (iv) surgical extranodal extension. Lymph node metastases were detected in 67.1% of laryngeal/hypopharyngeal cancer patients and 52.7% of oral cancer patients. The 3-year disease-specific survival rates for patients in the pathological N negative, extranodal extension negative, non-surgical extranodal extension and surgical extranodal extension groups were 90.9%, 79.6%, 63.8% and 48.3%, respectively. In laryngeal/hypopharyngeal cancer patients, surgical extranodal extension was associated with a significantly poorer disease-specific survival than a pathological N negative, extranodal extension negative or non-surgical extranodal extension status. In oral cancer patients, no significant differences were observed between the non-surgical and surgical extranodal extension groups. However, non-surgical extranodal extension was associated with a poorer disease-specific survival than a pathological N negative or extranodal extension negative status. Surgical extranodal extension was a poor prognostic factor in patients with head and neck squamous cell carcinoma. The prognostic significance of surgical extranodal extension differed between laryngeal/hypopharyngeal and oral cancer patients. The clinical significance of surgical extranodal extension was much greater for

Human Papilloma Virus Associated Squamous Cell Carcinoma of the Head and Neck

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Ajila, Vidya; Shetty, Harish; Babu, Subhas; Shetty, Veena; Hegde, Shruthi

2015-01-01

Oral cancer is one of the commonest causes for mortality and morbidity with squamous cell carcinoma being the sixth most frequent malignant tumour worldwide. In addition to tobacco and alcohol, human papilloma virus (HPV) is associated with a proportion of head and neck cancers. As in cervical cancers, HPV types 16 and 18 are the cause of malignant transformation. HPV-positive cancers of head and neck have unique characteristics such as occurrence in a younger age group, distinct clinical and molecular features, and better prognosis as compared to HPV-negative carcinomas. They also possess the potential for prevention by using vaccination. The present review describes in detail the salient features of HPV associated oral squamous cell carcinoma (OSCC), its differences from HPV-negative OSCC, diagnostic features, and recent strategies in prevention and management. PMID:26483987

Human Papilloma Virus Associated Squamous Cell Carcinoma of the Head and Neck.

Science.gov (United States)

Ajila, Vidya; Shetty, Harish; Babu, Subhas; Shetty, Veena; Hegde, Shruthi

2015-01-01

Oral cancer is one of the commonest causes for mortality and morbidity with squamous cell carcinoma being the sixth most frequent malignant tumour worldwide. In addition to tobacco and alcohol, human papilloma virus (HPV) is associated with a proportion of head and neck cancers. As in cervical cancers, HPV types 16 and 18 are the cause of malignant transformation. HPV-positive cancers of head and neck have unique characteristics such as occurrence in a younger age group, distinct clinical and molecular features, and better prognosis as compared to HPV-negative carcinomas. They also possess the potential for prevention by using vaccination. The present review describes in detail the salient features of HPV associated oral squamous cell carcinoma (OSCC), its differences from HPV-negative OSCC, diagnostic features, and recent strategies in prevention and management.

Local high voltage radiotherapy with curative intent for prostatic carcinoma

International Nuclear Information System (INIS)

Jacobi, G.H.; Kurth, K.H.; Hohenfellner, R.

1979-01-01

In a 10-year interval 179 patients with prostatic carcinoma were treated by cobalt-60 teletherapy (7600 R). A selected group of 47 patients with localized disease and irradiated with curative intent had serial prostatic biopsies and were analized after a minimum follow-up of 1 year. Biopsies of half of the patients rendered definitively negative, on an average 14 months after radiotherapy. 8 patients with initial negative biopsy changed to positive secondarily. In one third of the patients histological conversion was missed, considered as radiation persister. Persistent carcinoma were of predominant low grade. 5 patients developed distant metastases 30 months after irradiation on an average. These patients had persistent positive tissue studies. Over all cumulative 5-years survival was 89%. In patients with prostatic carcinoma and local high voltage radiotherapy with curative intent (stage A through C) serial prostatic biopsies to document therapy effect seen mandatory. (orig.) 891 AJ/orig. 892 BRE [de

Stellar evolution and the triple-α reactions

International Nuclear Information System (INIS)

Suda, Takuma

2014-01-01

Nuclear reaction rates play a crucial role in the evolution of stars. For low-mass stars, the triple-α reaction controls the helium burning stars in the red giant and asymptotic giant branch (AGB) phase. More importantly, the cross section of the triple-α reaction has a great impact on the helium ignition at the center of the electron degenerate helium core of red giants and on the helium shell flashes of AGB stars. It is to be noted that stellar evolution models are influenced not only by the value of the cross section, but also by the temperature dependence of the reaction rate. In this paper, I present the impact of the triple-α reaction rates on the evolution of low-mass metal-free stars and intermediate-mass AGB stars. According to the previous study, the constraint on the triple-α reaction rate is derived based on stellar evolution theory. It is found that the recent revisions of the rate proposed by nuclear physics calculations satisfy the condition for the ignition of the helium core flash in low-mass stars

Squamous Cell Carcinoma of the Hilar Bile Duct

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Ippei Yamana

2011-08-01

Full Text Available We herein report a rare case of squamous cell carcinoma of the hilar bile duct. A 66-year-old Japanese male patient was admitted to our hospital because of appetite loss and jaundice. Abdominal computed tomography revealed an enhanced mass measuring 10 × 30 mm in the hilar bile duct region. After undergoing biliary drainage, the patient underwent extended right hepatic lobectomy with regional lymph nodes dissection. The tumor had invaded the right portal vein. Therefore, we also performed resection and reconstruction of the portal vein. Histopathologically, the carcinoma cells exhibited a solid structure with differentiation to squamous cell carcinoma with keratinization and intercellular bridges. Immunohistochemical staining of the tumor cells revealed positive cytokeratin staining and negative CAM 5.2 staining. Based on these findings, a definitive diagnosis of well-differentiated squamous cell carcinoma of the hilar bile duct was made.

On Pythagoras Theorem for Products of Spectral Triples

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D'Andrea, Francesco; Martinetti, Pierre

2013-05-01

We discuss a version of Pythagoras theorem in noncommutative geometry. Usual Pythagoras theorem can be formulated in terms of Connes' distance, between pure states, in the product of commutative spectral triples. We investigate the generalization to both non-pure states and arbitrary spectral triples. We show that Pythagoras theorem is replaced by some Pythagoras inequalities, that we prove for the product of arbitrary (i.e. non-necessarily commutative) spectral triples, assuming only some unitality condition. We show that these inequalities are optimal, and we provide non-unital counter-examples inspired by K-homology.

Development of 600 kV triple resonance pulse transformer.

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Li, Mingjia; Zhang, Faqiang; Liang, Chuan; Xu, Zhou

2015-06-01

In this paper, a triple-resonance pulse transformer based on an air-core transformer is introduced. The voltage across the high-voltage winding of the air-core transformer is significantly less than the output voltage; instead, the full output voltage appears across the tuning inductor. The maximum ratio of peak load voltage to peak transformer voltage is 2.77 in theory. By analyzing pulse transformer's lossless circuit, the analytical expression for the output voltage and the characteristic equation of the triple-resonance circuit are presented. Design method for the triple-resonance pulse transformer (iterated simulation method) is presented, and a triple-resonance pulse transformer is developed based on the existing air-core transformer. The experimental results indicate that the maximum ratio of peak voltage across the load to peak voltage across the high-voltage winding of the air-core transformer is approximately 2.0 and the peak output voltage of the triple-resonance pulse transformer is approximately 600 kV.

[Care pathway of patients with hepatocellular carcinoma in France: State of play in 2017].

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Costentin, Charlotte; Ganne-Carrié, Nathalie; Rousseau, Benoit; Gérolami, René; Barbare, Jean-Claude

2017-09-01

Hepatocellular carcinoma is a major public health problem with one of the highest overall mortality compared to other cancers. The median overall survival in France in a hospital population with hepatocellular carcinoma is 9.4 months. Several publications reported a positive impact of hepatocellular carcinoma screening on diagnosis at an early-stage, eligibility for curative treatment and overall survival. However, the identification of patients to be included in a hepatocellular carcinoma screening program and the application of screening recommendations are not optimal. Other studies suggest a potentially negative impact of delayed diagnosis or treatment initiation on the patient's prognosis. Finally, marked variations between French regions and departments have been described in terms of access to curative treatment and overall survival. In this review article, we propose a state of play of the hepatocellular carcinoma patient's care pathway in France with the aim of identifying potential breaking points with negative impact on prognosis and of developing proposals for improvement. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment

International Nuclear Information System (INIS)

Shi, Sixiang; Hong, Hao; Orbay, Hakan; Yang, Yunan; Ohman, Jakob D.; Graves, Stephen A.; Nickles, Robert J.; Liu, Bai; Wong, Hing C.; Cai, Weibo

2015-01-01

To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and 64 Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of 64 Cu-NOTA-ALT-836-Fab. ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of 64 Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. 64 Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management. (orig.)

ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment.

Science.gov (United States)

Shi, Sixiang; Hong, Hao; Orbay, Hakan; Graves, Stephen A; Yang, Yunan; Ohman, Jakob D; Liu, Bai; Nickles, Robert J; Wong, Hing C; Cai, Weibo

2015-07-01

To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and (64)Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of (64)Cu-NOTA-ALT-836-Fab. ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of (64)Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. (64)Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management.

ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment

Energy Technology Data Exchange (ETDEWEB)

Shi, Sixiang [University of Wisconsin, Materials Science Program, Madison, WI (United States); Hong, Hao; Orbay, Hakan; Yang, Yunan; Ohman, Jakob D. [University of Wisconsin, Department of Radiology, Madison, WI (United States); Graves, Stephen A.; Nickles, Robert J. [University of Wisconsin, Department of Medical Physics, Madison, WI (United States); Liu, Bai; Wong, Hing C. [Altor BioScience, Miramar, FL (United States); Cai, Weibo [University of Wisconsin, Materials Science Program, Madison, WI (United States); University of Wisconsin, Department of Radiology, Madison, WI (United States); University of Wisconsin, Department of Medical Physics, Madison, WI (United States); University of Wisconsin Carbone Cancer Center, Madison, WI (United States); University of Wisconsin, Departments of Radiology and Medical Physics, Madison, WI (United States)

2015-07-15

To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and {sup 64}Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of {sup 64}Cu-NOTA-ALT-836-Fab. ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of {sup 64}Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. {sup 64}Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management. (orig.)

THE PROGNOSIS SIGNIFICANCE OF CATHEPSIN-D EXPRESSION IN THE DIFFERENT LOCATIONS IN AXILLARY NODES NEGATIVE CARCINOMA

Institute of Scientific and Technical Information of China (English)

无

2001-01-01

Objective: The aim of this study was to investigate Cathepsin-D (Cath-D) expression in different location and its relationship with prognosis in the axillary lymph nodes negative (ANN) breast cancer patients. Methods: Cath-D expression in 192 cases of breast carcinoma were examined by immunohistochemistry. Depending on different parts of expression, three evaluating methods were used, compared and analysed. Results: The positive rate of Cath-D expression in ANN breast cancer with poor prognosis group and axillary nodes positive (ANP) group were significantly higher than that in ANN breast cancer with good prognosis group (x2=23.20, P0.05). Cath-D expression in stromal cells had no statistical difference among the three groups (x2=1.56, P>0.05). When the Cath-D expression in cancer and stromal cells were counted into the positive rate, it was near the same (u1=0.47, u2=1.41, P>0.05). Conclusion: These results suggest that Cath-D expression is one of the powerful prognostic markers in ANN breast cancer. It's a reliable, practical, and convenient method to observe and evaluate Cath-D expression in cancer cells.

Pursuing the Triple Aim: The First 7 Years.

Science.gov (United States)

Whittington, John W; Nolan, Kevin; Lewis, Ninon; Torres, Trissa

2015-06-01

POLICY POINTS: In 2008, researchers at the Institute for Healthcare Improvement (IHI) proposed the Triple Aim, strategic organizing principles for health care organizations and geographic communities that seek, simultaneously, to improve the individual experience of care and the health of populations and to reduce the per capita costs of care for populations. In 2010, the Triple Aim became part of the US national strategy for tackling health care issues, especially in the implementation of the Patient Protection and Affordable Care Act (ACA) of 2010. Since that time, IHI and others have worked together to determine how the implementation of the Triple Aim has progressed. Drawing on our 7 years of experience, we describe 3 major principles that guided the organizations and communities working on this endeavor: creating the right foundation for population management, managing services at scale for the population, and establishing a learning system to drive and sustain the work over time. In 2008, researchers at the Institute for Healthcare Improvement (IHI) described the Triple Aim as simultaneously "improving the individual experience of care; improving the health of populations; and reducing the per capita costs of care for populations." IHI and its close colleagues had determined that both individual and societal changes were needed. In 2007, IHI began recruiting organizations from around the world to participate in a collaborative to implement what became known as the Triple Aim. The 141 participating organizations included health care systems, hospitals, health care insurance companies, and others closely tied to health care. In addition, key groups outside the health care system were represented, such as public health agencies, social services groups, and community coalitions. This collaborative provided a structure for observational research. By noting the contrasts between the contexts and structures of those sites in the collaborative that progressed and

Evaluation of inadequate, indeterminate, false-negative and false-positive cases in cytological examination for breast cancer according to histological type

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Yamaguchi Rin

2012-05-01

Full Text Available Abstract Background We previously investigated the current status of breast cytology cancer screening at seven institutes in our area of southern Fukuoka Prefecture, and found some differences in diagnostic accuracy among the institutions. In the present study, we evaluated the cases involved and noted possible reasons for their original cytological classification as inadequate, indeterminate, false-negative and false-positive according to histological type. Methods We evaluated the histological findings in 5693 individuals who underwent cytological examination for breast cancer (including inadequate, indeterminate, false-negative and false-positive cases, to determine the most common histological types and/or features in these settings and the usefulness/limitations of cytological examination for the diagnosis of breast cancer. Results Among 1152 cytologically inadequate cases, histology revealed that 75/173 (43.6% cases were benign, including mastopathy (fibrocystic disease in 38.6%, fibroadenoma in 24.0% and papilloma in 5.3%. Ninety-five of 173 (54.9% cases were histologically malignant, with scirrhous growing type, invasive ductal carcinoma (SIDC being significantly more frequent (49.5% than papillotubular growing type (Papi-tub (P P = 0.0001 and ductal carcinoma in situ (DCIS (P = 0.0001. Among 458 indeterminate cases, 54/139 (38.8% were histologically benign (mastopathy, 30.0%; fibroadenoma, 27.8%; papilloma, 26.0% and 73/139 (52.5% were malignant, with SIDC being the most frequent malignant tumor (37.0%. Among 52 false-negative cases, SIDC was significantly more frequent (42.3% than DCIS (P = 0.0049 and Papi-tub (P = 0.001. There were three false-positive cases, with one each of fibroadenoma, epidermal cyst and papilloma. Conclusions The inadequate, indeterminate, false-negative and false-positive cases showed similar histological types, notably SIDC for malignant tumors, and mastopathy, fibroadenoma and papilloma for

Lymphovascular invasion, ureteral reimplantation and prior history of urothelial carcinoma are associated with poor prognosis after partial cystectomy for muscle-invasive bladder cancer with negative pelvic lymph nodes.

Science.gov (United States)

Ma, B; Li, H; Zhang, C; Yang, K; Qiao, B; Zhang, Z; Xu, Y

2013-10-01

To identify predictive factors underlying recurrence and survival after partial cystectomy for pelvic lymph node-negative muscle-invasive bladder cancer (MIBC) (urothelial carcinoma) and to report the results of partial cystectomy among select patients. We retrospectively reviewed 101 cases that received partial cystectomy for MIBC (pT2-3N0M0) between 2000 and 2010. The log-rank test and a Cox regression analyses were performed to identify factors that were predictive of recurrence and survival. With a median follow-up of 53.0 months (range 9-120), the 5-year overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) rates were 58%, 65% and 50%, respectively. A total of 33 patients died of bladder cancer and 52 patients survived with intact bladder. Of the 101 patients included, 55 had no recurrence, 12 had non-muscle-invasive recurrence in the bladder that was treated successfully, and 34 had recurrence with advanced disease. The multivariate analysis showed that prior history of urothelial carcinoma (PH.UC) was associated with both CSS and RFS and weakly associated with OS; lymphovascular invasion (LVI) and ureteral reimplantation (UR) were associated with OS, CSS and RFS. Among patients with pelvic lymph node-negative MIBC, PH.UC and UR should be considered as contraindications for partial cystectomy, and LVI is predictive of poor outcomes after partial cystectomy. Highly selective partial cystectomy is a rational alternative to radical cystectomy for the treatment of MIBC with negative pelvic lymph nodes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Polyomavirus-Negative Merkel Cell Carcinoma: A More Aggressive Subtype Based on Analysis of 282 Cases Using Multimodal Tumor Virus Detection.

Science.gov (United States)

Moshiri, Ata S; Doumani, Ryan; Yelistratova, Lola; Blom, Astrid; Lachance, Kristina; Shinohara, Michi M; Delaney, Martha; Chang, Oliver; McArdle, Susan; Thomas, Hannah; Asgari, Maryam M; Huang, Meei-Li; Schwartz, Stephen M; Nghiem, Paul

2017-04-01

Previous studies have reached conflicting conclusions regarding the proportion of Merkel cell carcinomas (MCCs) that contain the Merkel cell polyomavirus (MCPyV) and the clinical significance of tumor viral status. To address these controversies, we detected MCPyV large T antigen using immunohistochemistry with two distinct antibodies and MCPyV DNA using quantitative PCR. Tumors were called MCPyV-positive if two or more of these three assays indicated presence of this virus. A total of 53 of 282 (19%) MCC tumors in this cohort were virus-negative using this multimodal system. Immunohistochemistry with the CM2B4 antibody had the best overall performance (sensitivity = 0.882, specificity = 0.943) compared with the multimodal classification. Multivariate analysis including age, sex, and immunosuppression showed that, relative to MCC patients with virus-positive tumors, virus-negative MCC patients had significantly increased risk of disease progression (hazard ratio = 1.77, 95% confidence interval = 1.20-2.62) and death from MCC (hazard ratio = 1.85, 95% confidence interval = 1.19-2.89). We confirm that approximately 20% of MCCs are not driven by MCPyV and that such virus-negative MCCs, which can be quite reliably identified by immunohistochemistry using the CM2B4 antibody alone, represent a more aggressive subtype that warrants closer clinical follow-up. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Metastatic Carcinoma Occurring in a Gastric Hyperplastic Polyp Mimicking Primary Gastric Cancer: The First Reported Case

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Gabriel M. Groisman

2014-01-01

Full Text Available Hyperplastic polyps of the stomach are regarded as benign. However, in rare cases they may contain incipient primary carcinomas. To our knowledge, breast carcinoma metastatic to a gastric hyperplastic polyp has not yet been reported. We describe the case of a 69-year-old woman to whom a gastric polyp was endoscopically excised. The patient had previously undergone a right mastectomy for mixed, invasive ductal and lobular carcinoma 5 years earlier. Histological sections from the gastric lesion showed typical features of hyperplastic polyp with foci of poorly differentiated adenocarcinoma including signet ring cells infiltrating the lamina propria. The histologic findings were consistent with a primary gastric cancer. However, the carcinoma cells were immunopositive for estrogen and progesterone receptors and GATA3 and negative for CDX2, Hep Par 1, and MUC5AC. E-cadherin showed membranous reactivity in some of the carcinoma cells while in others it was negative. Accordingly, metastatic mixed, lobular and ductal breast carcinoma was diagnosed. We conclude that metastatic adenocarcinoma mimicking primary gastric cancer can be rarely encountered in hyperplastic gastric polyps.

Spontaneous squamous cell carcinoma of the tongue and multiple bronchioloalveolar carcinomas in a Virginia opossum (Didelphis virginiana).

Science.gov (United States)

Kim, D Y; Mitchell, M A; De las Heras, M; Taylor, H W; Cho, D-Y

2002-01-01

Two primary tumours, squamous cell carcinoma of the tongue and multiple bronchioloalveolar carcinomas, were diagnosed in a Virginia opossum (Didelphis virginiana). Two oral masses were located in the right ventrolateral surface of the tongue, near the frenulum, and the lungs contained multiple, widely distributed, nodular masses. Microscopically, the oral masses were composed of invasive cords of pleomorphic, polyhedral cells, typical of squamous cells. The multiple pulmonary masses consisted of non-ciliated, cuboidal, columnar, or occasionally polyhedral cells arranged in an alveolar pattern with multifocal areas of necrosis. This is the first report of spontaneous oropharyngeal squamous cell carcinoma in the Virginia opossum. However, multiple pulmonary adenomas have been reported previously in this species, the lesions being similar to those in sheep pulmonary adenomatosis (jaagsiekte). In the present study, immunohistochemical examination of the pulmonary tumours with a rabbit polyclonal antiserum to jaagsiekte retroviral capsid protein proved negative. Copyright Harcourt Publishers Ltd.

Primary signet-ring cell carcinoma of vermiform appendix clinically and pathologically presenting as acute appendicitis

Directory of Open Access Journals (Sweden)

Tadashi Terada, MD, PhD

2014-03-01

Full Text Available Primary signet-ring cell carcinoma (SRCC of vermiform appendix is extremely rare; only three cases have been reported in the English literature. An 89-year-old man suddenly presented right lower abdominal pain, and transferred to a hospital, where he was diagnosed with acute appendicitis by physical data, blood data, and CT. He was further transferred to our hospital for emergency operation. Physical examination showed positive abdominal pain, Blunberg sign, and Rosenstein sign. Blood test showed leukocytosis and increased C-reactive protein. An appendectomy was performed. Gross examination during operation showed inflamed appendix, appendiceal adhesion, and acute peritonitis. Gross pathological examination showed no apparent tumor, but the proximal appendix showed wall thickening and luminal occlusion. The appendix was cut into three sections, and was observed under microscopically. Nests of carcinoma cells were seen in the proximal appendix. The carcinoma was composed of SRCC (70% and mucinous carcinoma (30%. The size of carcinoma was 6 × 7 mm. The carcinoma cells invaded into muscular layer. No lymphovascular permeation was seen. The cut margins were negative for carcinoma cells. Immunohistochemically, SRCC cells were positive for cytokeratin (CK AE1/3, CK CAM5.2, CK8, CK18, CK19, CK20, EMA, CEA, CA19-9, p53, Ki-67 (labeling = 30%, CDX2, MUC2, and MUC5AC. They were negative for CK34PE1, CK5/6, CK7, CK14, p63, vimentin, TTF-1, MUC1, MUC 5AC, NSE, synaptophysin, chromogranin, and CD56. No further treatments were performed, because the appendiceal carcinoma was small, the surgical margins were negative and the patient was very old. He was followed up by various imaging modalities. No recurrence or metastasis is found 17 months after the operation.

Triple axis spectrometers

International Nuclear Information System (INIS)

Clausen, K.N.

1997-01-01

Conventional triple-axis neutron spectroscopy was developed by Brockhouse over thirty years ago' and remains today a versatile and powerful tool for probing the dynamics of condensed matter. The original design of the triple axis spectrometer is technically simple and probes momentum and energy space on a point-by-point basis. This ability to systematically probe the scattering function in a way which only requires a few angles to be moved under computer control and where the observed data in general can be analysed using a pencil and graph paper or a simple fitting routine, has been essential for the success of the method. These constraints were quite reasonable at the time the technique was developed. Advances in computer based data acquisition, neutron beam optics, and position sensitive area detectors have been gradually implemented on many triple axis spectrometer spectrometers, but the full potential of this has not been fully exploited yet. Further improvement in terms of efficiency (beyond point by point inspection) and increased sensitivity (use of focusing optics whenever the problem allows it) could easily be up to a factor of 10-20 over present instruments for many problems at a cost which is negligible compared to that of increasing the flux of the source. The real cost will be in complexity - finding the optimal set-up for a given scan and interpreting the data as the they are taken. On-line transformation of the data for an appropriate display in Q, ω space and analysis tools will be equally important for this task, and the success of these new ideas will crucially depend on how well we solve these problems. (author)

Triple correlation in temporomandibular joint dysfunction: MR imaging with arthrography, arthroscopy, and open surgery

International Nuclear Information System (INIS)

Rao, V.M.; Farole, A.; Karasick, D.

1988-01-01

Triple correlation of MR imaging with arthrography, arthroscopy, and open surgery was performed in 24 patients (34 temporomandibular joints) with ages ranging from 17 to 66 years. MR imaging showed disk position and morphologic features accurately in 30 joints (88%). It was false negative in one joint and false positive in three joints (9%). Degenerative changes were accurately detected with MR imaging, arthrography, and arthroscopy. Adhesions were diagnosed with arthrography in eight joints, arthroscopy in 14, and MR imaging in none. Disk perforations seen at open surgery were not detected with MR imaging. In conclusion, there is an overlap of information presented by various modalities. MR imaging is better than arthrography detecting disk morphologic features and displacement. Arthrography may add information by showing meniscal dynamics. Arthroscopy entails direct observation of superior joint space only and can detect adhesions and perforations better, but it may alter disk position and dynamics. In the more difficult cases, triple correlation may be needed, as modalities can be complementary

TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma.

Science.gov (United States)

Mao, Liping; Wang, Yueguo; Wang, Delin; Han, Gang; Fu, Shouzhong; Wang, Jianxin

2017-01-01

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is prevalent worldwide. Despite its limitations, serum alpha-fetoprotein (AFP) remains the most widely-used biomarker for the diagnosis of HCC. This study aimed to assess whether measurement of peripheral plasma Dickkopf-1 (DKK1) and Tie2-expressing monocytes (TEMs) could overcome the limitations of AFP and improve the diagnostic accuracy of HCC. Plasma DKK1 level and the percentage of TEMs in peripheral CD14+CD16+ monocytes from HCC patients (n = 82), HBV-related liver cirrhosis (LC) patients (n = 29), chronic hepatitis B (CHB) infected patients (n = 28) and healthy volunteers (n = 31) were analyzed by ELISA and flow cytometry. Receiver operating characteristic (ROC) curves were used to analyze a single biomarker, or a combination of two or three biomarkers. Univariate and multivariate analyses were performed to assess the significance of each marker in prediction of HCC and AFP-negative HCC from LC patients. The percentage of TEMs in peripheral CD14+CD16+ monocytes and plasma level of DKK1 in HCC group were significantly higher than those in LC, CHB and healthy control groups (all P-values TEMs alone was also significantly higher in AFP-negative HCC group than that in LC, CHB and healthy control groups (all P-values TEMs. There was no significant difference in AUC of DKK1, TEMs and AFP in HCC diagnosis between the four groups (all P>0.05). A combination of DKK1, TEMs and AFP measurements increased the AUC for HCC diagnosis as compared with either marker alone (0.833; 95%CI 0.768-0.886). The AUC for TEMs was 0.692 (95% CI 0.564-0.819) in differentiating AFP-negative HCC from LC, with a sensitivity of 80.0% and a specificity of 65.52%. Only TEMs prevailed as a significant predictor for AFP-negative HCC differentiating from LC patients in univariate and multivariate analyses (P = 0.016, P = 0.023). TEMs and DKK1 may prove to be potential complementary biomarkers for AFP in the diagnosis of HCC. TEMs

TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma.

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Liping Mao

Full Text Available Hepatitis B virus (HBV-related hepatocellular carcinoma (HCC is prevalent worldwide. Despite its limitations, serum alpha-fetoprotein (AFP remains the most widely-used biomarker for the diagnosis of HCC. This study aimed to assess whether measurement of peripheral plasma Dickkopf-1 (DKK1 and Tie2-expressing monocytes (TEMs could overcome the limitations of AFP and improve the diagnostic accuracy of HCC.Plasma DKK1 level and the percentage of TEMs in peripheral CD14+CD16+ monocytes from HCC patients (n = 82, HBV-related liver cirrhosis (LC patients (n = 29, chronic hepatitis B (CHB infected patients (n = 28 and healthy volunteers (n = 31 were analyzed by ELISA and flow cytometry. Receiver operating characteristic (ROC curves were used to analyze a single biomarker, or a combination of two or three biomarkers. Univariate and multivariate analyses were performed to assess the significance of each marker in prediction of HCC and AFP-negative HCC from LC patients.The percentage of TEMs in peripheral CD14+CD16+ monocytes and plasma level of DKK1 in HCC group were significantly higher than those in LC, CHB and healthy control groups (all P-values 0.05. A combination of DKK1, TEMs and AFP measurements increased the AUC for HCC diagnosis as compared with either marker alone (0.833; 95%CI 0.768-0.886. The AUC for TEMs was 0.692 (95% CI 0.564-0.819 in differentiating AFP-negative HCC from LC, with a sensitivity of 80.0% and a specificity of 65.52%. Only TEMs prevailed as a significant predictor for AFP-negative HCC differentiating from LC patients in univariate and multivariate analyses (P = 0.016, P = 0.023.TEMs and DKK1 may prove to be potential complementary biomarkers for AFP in the diagnosis of HCC. TEMs rather than DKK1 could serve as a complementary biomarker for AFP in the differential diagnosis of AFP-negative HCC versus LC patients.

Anogenital squamous cell carcinoma in neglected patient.

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Svecova, D; Havrankova, M; Weismanova, E; Babal, P

2012-01-01

Skin squamous cell carcinomas (SCCs) are arguably the second most common carcinoma of the skin and are responsible for the majority of non-melanoma skin cancer deaths. Gynecologist treated a Caucasian 56-years old female patient for genital wart with podophyllotoxin cream. She did not achieve complete response and therefore she has interrupted the therapy and the collaboration with the gynecologist. At the time of evaluation the lesion had a size of man's palm in anogenital region and showed characteristic features of neoplasm. The regional lymph nodes have produced infiltrated painful bubo. PCR analysis for HPV proved negative. Histopathology revealed well-differentiated squamous cell keratinizing carcinoma from the tumor as well as from the regional lymph node packet. Staging computed tomography scans proved negative and pelvis scans disclosed regional lymphadenopathy underlying the tumor. Palliative radiation therapy (by linear accelerator) was administered for the oversized tumor to the total TD 50.0Gy. The patient died 6 months after diagnostic assessment from cardio-respiratory failure. Staging computed tomography before her death did not disclose distinct metastases in her inner organs. Well-differentiated squamous cell keratinizing carcinoma could be growing endophytically affecting the underlying adipose tissue and musculature, with spreading into the regional lymph nodes. The rate of metastases into inner organs seems to vary according to the aggressiveness and metastatic behavior of each SCC. The case report calls for attention to the importance of collaboration among various specialists assisting in the diagnosis and management of skin neoplasm (Fig. 5, Ref. 12). Full Text in PDF www.elis.sk.

Triple shape memory polymers by 4D printing

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Bodaghi, M.; Damanpack, A. R.; Liao, W. H.

2018-06-01

This article aims at introducing triple shape memory polymers (SMPs) by four-dimensional (4D) printing technology and shaping adaptive structures for mechanical/bio-medical devices. The main approach is based on arranging hot–cold programming of SMPs with fused decomposition modeling technology to engineer adaptive structures with triple shape memory effect (SME). Experiments are conducted to characterize elasto-plastic and hyper-elastic thermo-mechanical material properties of SMPs in low and high temperatures at large deformation regime. The feasibility of the dual and triple SMPs with self-bending features is demonstrated experimentally. It is advantageous in situations either where it is desired to perform mechanical manipulations on the 4D printed objects for specific purposes or when they experience cold programming inevitably before activation. A phenomenological 3D constitutive model is developed for quantitative understanding of dual/triple SME of SMPs fabricated by 4D printing in the large deformation range. Governing equations of equilibrium are established for adaptive structures on the basis of the nonlinear Green–Lagrange strains. They are then solved by developing a finite element approach along with an elastic-predictor plastic-corrector return map procedure accomplished by the Newton–Raphson method. The computational tool is applied to simulate dual/triple SMP structures enabled by 4D printing and explore hot–cold programming mechanisms behind material tailoring. It is shown that the 4D printed dual/triple SMPs have great potential in mechanical/bio-medical applications such as self-bending gripers/stents and self-shrinking/tightening staples.

Role of collagen triple helix repeat containing-1 in tumor and inflammatory diseases

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Qian Wu

2017-01-01

Full Text Available Initially, collagen triple helix repeat containing-1 (CTHRC1 is expressed mainly in adventitial fibroblasts and neointimal smooth muscle cells of balloon-injured vessels, and increases cell migration, promotes tissue repair in response to injury. A variety of studies demonstrated that over-expression of CTHRC1 in solid tumors results in enhancement of migration and invasion of tumor cells, and is associated with decreased overall survival and disease-free survival. CTHRC1 expression is elevated in hepatitis B virus-infected patients and highly correlated with hepatocellular carcinoma progression as well. Furthermore, CTHRC1 plays a pivotal role in a great many fields, including increases bone mass, prevents myelination, reverses collagen synthesis in keloid fibroblasts, and increases fibroblast-like synoviocytes migration speed and abundant production of arthritic pannus in rheumatoid arthritis. Therefore, it will provide new insight into the pathogenesis of tumor and autoimmune diseases, and will shed new light on the therapy of related clinical diseases.

Government and Governance of Regional Triple Helix Interactions

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Danson, Mike; Todeva, Emanuela

2016-01-01

This conceptual paper contributes to the discussion of the role of regional government and regional Triple Helix constellations driving economic development and growth within regional boundaries. The impact of regionalism and subsidiarity on regional Triple Helix constellations, and the questions of governmentality, governance and institutional…

[Esophageal sarcomatoid carcinoma: report of a case with morphological, immunohistochemical and molecular study].

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Regragui, Asmaa; Lakhdar, Hind; Abderrahman Alaoui Belabbas, Moulay; Amrani, Meryem; Gamra, Lamia; Alaoui Belabbas, Mohamed

2004-05-01

Sarcomatoïd carcinoma is a rare tumor of the esophagus, characterized macroscopically by a polypoid aspect and histologically by the association of spindle cell carcinoma with sarcomatous pleomorphic component. We report here a case of esophagus sarcomatoïd carcinoma. Diagnosis was based on immunohistochemical analysis of tIssue samples. Human papillomavirus (HVP) detection by PCR amplification of DNA extracted from tumoral tIssue was negative, ruling out the role of HPV infection in this tumor.

Distinct choline metabolic profiles are associated with differences in gene expression for basal-like and luminal-like breast cancer xenograft models

International Nuclear Information System (INIS)

Moestue, Siver A; Borgan, Eldrid; Huuse, Else M; Lindholm, Evita M; Sitter, Beathe; Børresen-Dale, Anne-Lise; Engebraaten, Olav; Mælandsmo, Gunhild M; Gribbestad, Ingrid S

2010-01-01

Increased concentrations of choline-containing compounds are frequently observed in breast carcinomas, and may serve as biomarkers for both diagnostic and treatment monitoring purposes. However, underlying mechanisms for the abnormal choline metabolism are poorly understood. The concentrations of choline-derived metabolites were determined in xenografted primary human breast carcinomas, representing basal-like and luminal-like subtypes. Quantification of metabolites in fresh frozen tissue was performed using high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS). The expression of genes involved in phosphatidylcholine (PtdCho) metabolism was retrieved from whole genome expression microarray analyses. The metabolite profiles from xenografts were compared with profiles from human breast cancer, sampled from patients with estrogen/progesterone receptor positive (ER+/PgR+) or triple negative (ER-/PgR-/HER2-) breast cancer. In basal-like xenografts, glycerophosphocholine (GPC) concentrations were higher than phosphocholine (PCho) concentrations, whereas this pattern was reversed in luminal-like xenografts. These differences may be explained by lower choline kinase (CHKA, CHKB) expression as well as higher PtdCho degradation mediated by higher expression of phospholipase A2 group 4A (PLA2G4A) and phospholipase B1 (PLB1) in the basal-like model. The glycine concentration was higher in the basal-like model. Although glycine could be derived from energy metabolism pathways, the gene expression data suggested a metabolic shift from PtdCho synthesis to glycine formation in basal-like xenografts. In agreement with results from the xenograft models, tissue samples from triple negative breast carcinomas had higher GPC/PCho ratio than samples from ER+/PgR+ carcinomas, suggesting that the choline metabolism in the experimental models is representative for luminal-like and basal-like human breast cancer. The differences in choline metabolite

Ocular Problems in Triple-A Syndrome and Their Management

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Seydi Okumuş

2012-12-01

Full Text Available Triple-A syndrome (Allgrove syndrome, is a rare autosomal recessive syndrome that is characterized by adrenal insufficiency, alacrimia and achalasia. In this report, we present a case of triple-A syndrome and discuss the ocular manifestations of the diseases along with evaluation of the therapeutic options. In addition to the classic triad of triple-A syndrome, our patient had intermittent exotropia. The patient was receiving oral steroids for adrenal insufficiency and artificial tear drops for eye dryness. Surgery was planned for exotropia. Punctum plug insertion was made simultaneously with bilateral lateral rectus recessions. Postoperative follow-up revealed near and distant horizontal deviation at the interval of ±10 PD. The patient’s complaints about eyes regressed significantly as well. Triple-A syndrome is a life threatening and rare disorder that could be fatal when undiagnosed. Punctum plugs are convenient therapy option for the treatment of xerophthalmia encountered in triple-A syndrome. With strabismus surgery including punctum plug insertion, any other surgery can be simultaneously carried out during a single session of general anesthesia. (Turk J Ophthalmol 2012; 42: 492-4

Cancer stage and pack-years, but not p16 or HPV, are relevant for survival in hypopharyngeal and laryngeal squamous cell carcinomas.

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Dahm, Valerie; Haitel, Andrea; Kaider, Alexandra; Stanisz, Isabella; Beer, Andrea; Lill, Claudia

2018-05-09

Recently, p16 has been included in the TNM guideline for oropharyngeal carcinomas. The role of HPV and p16 in hypopharyngeal and laryngeal carcinomas has not yet been established sufficiently. Hundred and thirty-four patients with hypopharyngeal and laryngeal carcinomas were included in this retrospective analysis. Only patients with known HPV status were eligible for the investigation. Survival probabilities were estimated for different risk factors. Eighty-five patients presented with laryngeal carcinoma and 49 patients with hypopharyngeal carcinoma. 8% were HPV positive (10.6% laryngeal, 4.1% hypopharyngeal carcinoma). Median follow-up time was 58 months. We observed a significantly better overall survival for patients with an early tumor stage compared to advanced carcinoma. One of the hypopharyngeal HPV positive carcinomas was also p16 positive and one was p16 negative. Of the nine HPV positive laryngeal carcinomas, four were p16 positive and five p16 negative. Neither patients who were HPV positive nor patients positive for p16 showed a significantly better outcome than HPV or p16 negative patients. In contrast, nicotine pack-years showed a highly significant correlation with survival in our patient collective. The data suggest that tumor stage and nicotine exposure seem to have the highest impact on survival in hypopharyngeal and laryngeal squamous cell carcinoma patients. There is no evidence for a better survival for p16 positive or HPV positive patients with hypopharyngeal or laryngeal squamous cell carcinoma. HPV seems to play a minor role in these entities of head and neck carcinoma.

Analysis of false positive and false negative cytological diagnosis of breast lesions

International Nuclear Information System (INIS)

Jamal, Awtif A.; Mansoor, I.

2001-01-01

To study the reasons for interpretive errors in false negative and false positive diagnosis of breast carcinoma on fine needle aspiration cytology material. We reviewed only those cases in which cytohistological discrepancies were found, where the cytologic material was abnormal and to some extent misinterpreted or both. There was only one false negative case (false negative fraction 0.32%) proved histologically as ductal carcinoma and four false positive cases (false positive fraction 1.2%); 2 fibroadenoma; 1 fibrocystic disease; and 1 stromal fibrosis. Smears of the two false positive fibroadenoma cases showed very high cellularity, overcrowded clusters and frequent stripped nuclei. The fibrocystic case showed tight clusters of apocrine cells and sheets of loosely aggregated macrophages that were over interpreted. Smears of the false negative ductal carcinoma was hypocellular overall, and the cells showed minimal nuclear pleomorphism. Overcrowded clusters and hypercellular smears should be carefully assessed for uniformity of cells and detailed nuclear and cytomorphological features. If the full-blown malignant cytomorphological changes are not visible, a diagnosis of suspicious or inconclusive should be made and frozen section recommended before surgery. Hypocellularity and relatively nuclear monomorphism are the reasons for failure to diagnose malignant breast lesions. Careful attention should be paid to extreme nuclear monomorphism and absence of naked bipolar cells. A cytologically atypical or suspicious diagnosis together with positive radiological and clinical findings should suggest a diagnosis of malignancy. (author)

[Expression and clinical significance of CD147 in parathyroid carcinoma].

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Du, X M; Wang, L L; Chang, H; Meng, W; Zhang, J Y; Shen, B

2016-06-08

To study the expression and clinical significance of CD147 in the patients of parathyroid carcinoma. Fourteen cases of parathyroid carcinoma encountered during the period from 2012 to 2015 were enrolled. Thirty three cases of parathyroid adenoma encountered during the same period were enrolled. The expression of CD147 in parathyroid carcinoma and parathyroid adenoma was studied by means of immunohistochemistry (EnVision method). CD147 positive color was brown and yellow, and positive position was located mainly in the cytomembrane, and a small amount of cytoplasm was appeared. Among 14 cases of parathyroid carcinoma, 11 cases of CD147 positive score was 3+ , 3 cases of CD147 positive score was 2+ ; Among 33 cases of parathyroid adenoma , 8 cases of CD147 positive score was 2+ , 15 cases of it was 1+ , 10 cases of it was negative. CD147 was highly expressed in parathyroid carcinoma tissues, and the expression of CD147 was significantly different from the expression of parathyroid adenoma(PCD147 immunohistochemical staining can help to diagnose parathyroid carcinoma.

Examining the sensitivity of ultrasound-guided large core biopsy for invasive breast carcinoma in a population screening programme

International Nuclear Information System (INIS)

Rouse, Hannah C.; Ussher, Simon; Cawson, Jennifer N.; Kavanagh, Anne M.

2013-01-01

To evaluate the sensitivity of ultrasound-guided core-needle biopsy (UCB) in invasive breast carcinoma and to establish causes of false-negative biopsy in a population screening programme. We identified 571 consecutive women diagnosed with surgically proven invasive breast cancer. Histology from 14-gauge UCB was compared with surgical histology to identify true-positive and false-negative ultrasound core biopsies. True-positive and false-negative groups were compared for tumour size and histology. On blinded review of UCB images and pathology reports from false negative (n=20) and a random sample of true-positive cases (n=80), we compared core sample number and needle visualisation in the lesion. Of 571 carcinomas sampled with UCB, 551 (96.5%) were true positive and 20 (3.5%) were false negative. The mean core number was 2.0 (range 1–3) for false negatives and 2.25 (range 1–4) for true positives (P=0.27). Mean tumour sizes were 13.3 and 16.2mm for the false-negative and true-positive groups, respectively (P=0.25). Tubular carcinomas represented 30% (6/20) of false-negative cases compared with 5.1% (28/551) of the true-positive cases (P<0.001). On blinded review, needle visualisation within the lesion was demonstrated in 47.4% (9/19) of false-negative cases and 76.3% (61/80) of true-positive cases (P=0.02).We demonstrated a sensitivity of 96.5% with a mean of 2.21 cores. False-negative results were more likely in the absence of post-fire needle position verification and with tubular carcinomas. Neither tumour size nor core number predicted diagnostic accuracy.

Collagenolytic Matrix Metalloproteinase Activities toward Peptomeric Triple-Helical Substrates.

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Stawikowski, Maciej J; Stawikowska, Roma; Fields, Gregg B

2015-05-19

Although collagenolytic matrix metalloproteinases (MMPs) possess common domain organizations, there are subtle differences in their processing of collagenous triple-helical substrates. In this study, we have incorporated peptoid residues into collagen model triple-helical peptides and examined MMP activities toward these peptomeric chimeras. Several different peptoid residues were incorporated into triple-helical substrates at subsites P3, P1, P1', and P10' individually or in combination, and the effects of the peptoid residues were evaluated on the activities of full-length MMP-1, MMP-8, MMP-13, and MMP-14/MT1-MMP. Most peptomers showed little discrimination between MMPs. However, a peptomer containing N-methyl Gly (sarcosine) in the P1' subsite and N-isobutyl Gly (NLeu) in the P10' subsite was hydrolyzed efficiently only by MMP-13 [nomenclature relative to the α1(I)772-786 sequence]. Cleavage site analysis showed hydrolysis at the Gly-Gln bond, indicating a shifted binding of the triple helix compared to the parent sequence. Favorable hydrolysis by MMP-13 was not due to sequence specificity or instability of the substrate triple helix but rather was based on the specific interactions of the P7' peptoid residue with the MMP-13 hemopexin-like domain. A fluorescence resonance energy transfer triple-helical peptomer was constructed and found to be readily processed by MMP-13, not cleaved by MMP-1 and MMP-8, and weakly hydrolyzed by MT1-MMP. The influence of the triple-helical structure containing peptoid residues on the interaction between MMP subsites and individual substrate residues may provide additional information about the mechanism of collagenolysis, the understanding of collagen specificity, and the design of selective MMP probes.

Clinical Significance of CK19 Negative Breast Cancer

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Fujisue, Mamiko, E-mail: nishimura.reiki@cityhosp-kumamoto.jp; Nishimura, Reiki; Okumura, Yasuhiro [Department of Breast and Endocrine Surgery, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto City, Kumamoto 862-8505 (Japan); Tashima, Rumiko [Department of Surgery, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto City, Kumamoto 862-8505 (Japan); Nishiyama, Yasuyuki; Osako, Tomofumi [Department of Breast and Endocrine Surgery, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto City, Kumamoto 862-8505 (Japan); Toyozumi, Yasuo; Arima, Nobuyuki [Department of Pathology, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto City, Kumamoto 862-8505 (Japan)

2012-12-21

Analysis of sentinel lymph nodes (SLNs) by means of One-Step Nucleic Acid Amplification (OSNA) is gaining widespread use as a quick and accurate method. This assay detects the expression level of cytokeratin 19 (CK19) which is present in some but not all breast tumors. In this study, the clinical significance of negative CK19 was investigated in 219 cases of primary breast cancer. In 179 patients with clinically negative nodes, OSNA and imprint smear cytology of SLN were performed simultaneously. The OSNA revealed a node-positive rate of 24.6%. Negative CK19 correlated significantly with negative ER/PgR and higher Ki-67 values, and marginally with higher nuclear grade and p53 overexpression. The triple negative subtype showed lower CK19 expression. OSNA revealed that one of the negative CK19 cases was actually a false negative but this was corrected with the use of the imprint smear cytology. In conclusion, CK19 negativity reflected the aggressiveness of primary breast cancer. OSNA assay used to analyze SLN was useful, but there is a possibility that it will mistakenly detect false negatives in CK19 negative tumors. Therefore, in tumors with negative CK19, the imprint smear cytology may be more useful in cases with macrometastasis.

Clinical Significance of CK19 Negative Breast Cancer

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Nobuyuki Arima

2012-12-01

Full Text Available Analysis of sentinel lymph nodes (SLNs by means of One-Step Nucleic Acid Amplification (OSNA is gaining widespread use as a quick and accurate method. This assay detects the expression level of cytokeratin 19 (CK19 which is present in some but not all breast tumors. In this study, the clinical significance of negative CK19 was investigated in 219 cases of primary breast cancer. In 179 patients with clinically negative nodes, OSNA and imprint smear cytology of SLN were performed simultaneously. The OSNA revealed a node-positive rate of 24.6%. Negative CK19 correlated significantly with negative ER/PgR and higher Ki-67 values, and marginally with higher nuclear grade and p53 overexpression. The triple negative subtype showed lower CK19 expression. OSNA revealed that one of the negative CK19 cases was actually a false negative but this was corrected with the use of the imprint smear cytology. In conclusion, CK19 negativity reflected the aggressiveness of primary breast cancer. OSNA assay used to analyze SLN was useful, but there is a possibility that it will mistakenly detect false negatives in CK19 negative tumors. Therefore, in tumors with negative CK19, the imprint smear cytology may be more useful in cases with macrometastasis.

Clinical Significance of CK19 Negative Breast Cancer

International Nuclear Information System (INIS)

Fujisue, Mamiko; Nishimura, Reiki; Okumura, Yasuhiro; Tashima, Rumiko; Nishiyama, Yasuyuki; Osako, Tomofumi; Toyozumi, Yasuo; Arima, Nobuyuki

2012-01-01

Analysis of sentinel lymph nodes (SLNs) by means of One-Step Nucleic Acid Amplification (OSNA) is gaining widespread use as a quick and accurate method. This assay detects the expression level of cytokeratin 19 (CK19) which is present in some but not all breast tumors. In this study, the clinical significance of negative CK19 was investigated in 219 cases of primary breast cancer. In 179 patients with clinically negative nodes, OSNA and imprint smear cytology of SLN were performed simultaneously. The OSNA revealed a node-positive rate of 24.6%. Negative CK19 correlated significantly with negative ER/PgR and higher Ki-67 values, and marginally with higher nuclear grade and p53 overexpression. The triple negative subtype showed lower CK19 expression. OSNA revealed that one of the negative CK19 cases was actually a false negative but this was corrected with the use of the imprint smear cytology. In conclusion, CK19 negativity reflected the aggressiveness of primary breast cancer. OSNA assay used to analyze SLN was useful, but there is a possibility that it will mistakenly detect false negatives in CK19 negative tumors. Therefore, in tumors with negative CK19, the imprint smear cytology may be more useful in cases with macrometastasis

Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma.

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Chuang, Ai-Ying; DeMarzo, Angelo M; Veltri, Robert W; Sharma, Rajni B; Bieberich, Charles J; Epstein, Jonathan I

2007-08-01

The histologic distinction between high-grade prostate cancer and infiltrating high-grade urothelial cancer may be difficult, and has significant implications because each disease may be treated very differently (ie, hormone therapy for prostate cancer and chemotherapy for urothelial cancer). Immunohistochemistry of novel and established prostatic and urothelial markers using tissue microarrays (TMAs) were studied. Prostatic markers studied included: prostate-specific antigen (PSA), prostein (P501s), prostate-specific membrane antigen (PSMA), NKX3.1 (an androgen-related tumor suppressor gene), and proPSA (pPSA) (precursor form of PSA). "Urothelial markers" included high molecular weight cytokeratin (HMWCK), p63, thrombomodulin, and S100P (placental S100). TMAs contained 38 poorly differentiated prostate cancers [Gleason score 8 (n=2), Gleason score 9 (n=18), Gleason score 10 (n=18)] and 35 high-grade invasive urothelial carcinomas from radical prostatectomy and cystectomy specimens, respectively. Each case had 2 to 8 tissue spots (0.6-mm diameter). If all spots for a case showed negative staining, the case was called negative. The sensitivities for labeling prostate cancers were PSA (97.4%), P501S (100%), PSMA (92.1%), NKX3.1 (94.7%), and pPSA (94.7%). Because of PSA's high sensitivity on the TMA, we chose 41 additional poorly differentiated primary (N=36) and metastatic (N=5) prostate carcinomas which showed variable PSA staining at the time of diagnosis and performed immunohistochemistry on routine tissue sections. Compared to PSA, which on average showed 18.8% of cells with moderate to strong positivity, cases stained for P501S, PSMA, and NKX3.1 had on average 42.5%, 53.7%, 52.9% immunoreactivity, respectively. All prostatic markers showed excellent specificity. HMWCK, p63, thrombomodulin, and S100P showed lower sensitivities in labeling high-grade invasive urothelial cancer in the TMAs with 91.4%, 82.9%, 68.6%, and 71.4% staining, respectively. These urothelial

Triple pelvic osteotomy in the treatment of hip dysplasia

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Vukašinović Zoran

2009-01-01

Full Text Available Introduction. Insufficient femoral head coverage is found in a variety of diseases, with acetabular dysplasia as the most frequent disorder and triple pelvic osteotomy as the most recently introduced surgical treatment. Objective. This study analyses pre- and postoperative pathoanatomic characteristics of triple in comparison to Salter and Chiari osteotomies, with a logistic regression analysis of outcome predictor and effect explanator factors in relation to the chosen type of operation. Methods. The study involved 136 adolescents treated with Salter and Chiari osteotomies or a triple pelvic osteotomy at the Institute of Orthopaedic Surgery 'Banjica' in Belgrade. The patients were between 10-20 years old at the time of operation. We collected and analyzed data from all the patients: illness history, operative parameters, preoperative and postoperative pathoanatomic data. The data was statistically processed using the statistical software SPSS, defining standard descriptive values, and by using the appropriate tests of analytic statistics: t-test for dependent and independent variables, χ2-test, Fisher's exact test, Wilcoxon's test, parameter correlation, one-way ANOVA, multi-factorial ANOVA and logistic regression, according to the type of the analyzed data and the conditions under which the statistical methods were applied. Results. The average CE angle after triple pelvic osteotomy was 43.5°, more improved than after the Salter osteotomy (33.0° and Chiari osteotomy (31.4° (F=16.822; p<0.01. Postoperative spherical congruence was also more frequent after the triple osteotomy than after the other two types of operations, and with a high significance. Preoperative painful discomfort was found to be a valid predictor of indications for the triple osteotomy over both Chiari and Salter osteotomies. The valid explanators of effect for the triple osteotomy are: postoperative joint congruence (compared to the Chiari osteotomy and increase in joint

Metastatic urachal carcinoma in bronchial brush cytology

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Fatima Zahra Aly

2013-01-01

Full Text Available Urachal carcinoma is rare comprising less than 1% of all bladder carcinomas. Metastases of urachal carcinoma have been reported to meninges, brain, ovary, lung, and maxilla. Cytologic features of metastatic urachal carcinoma have not been previously reported. We present a case of metastatic urachal adenocarcinoma in bronchial brushings and review the use of immunohistochemistry in its diagnosis. A 47-year-old female was seen initially in 2007 with adenocarcinoma of the bladder dome for which she underwent partial cystectomy. She presented in 2011 with a left lung mass and mediastinal adenopathy. Bronchoscopy showed an endobronchial lesion from which brushings were obtained. These showed numerous groups of columnar cells with medium sized nuclei and abundant cytoplasm. The cells were positive for CK20 and CDX2 and negative for CK7. The cytomorphological findings were similar to those in the previous resection specimen and concurrent biopsy. This is the first case report of bronchial brushings containing metastatic urachal carcinoma. No specific immunohistochemical profile is available for its diagnosis. The consideration of a second primary was a distinct possibility in this case due to the lapse of time from primary resection, absence of local disease, and lack of regional metastases.

Invasive Pleomorphic Lobular Carcinoma of the Breast: Pathologic, Clinical, and Therapeutic Considerations.

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Al-Baimani, Khalid; Bazzarelli, Amy; Clemons, Mark; Robertson, Susan J; Addison, Christina; Arnaout, Angel

2015-12-01

Pleomorphic lobular carcinoma is an uncommon form of breast cancer and a subtype of invasive lobular carcinoma. It has unique histopathologic features that translate to a more aggressive phenotype with an associated poor prognosis. Unlike classical invasive lobular carcinoma, it can lose estrogen and progesterone receptor expression and demonstrate HER-2/neu amplification. It remains to be determined, however, whether the pleomorphic histology independently predicts a worse outcome or whether other known associated negative prognostic factors such as larger tumor size, increased metastatic disease, and associated worse molecular subtypes commonly present in pleomorphic carcinoma account for the poor prognosis. Here we present an updated review of the unique pathologic and clinical features of pleomorphic lobular carcinoma needed to guide management for women with this subtype of cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

Staging primary breast cancer. Are there tumour pathological features that correlate with a false-negative axillary ultrasound?

International Nuclear Information System (INIS)

Johnson, S.; Brown, S.; Porter, G.; Steel, J.; Paisley, K.; Watkins, R.; Holgate, C.

2011-01-01

Aim: To investigate whether the histopathological characteristics of primary breast cancer tumours could predict the likelihood of false-negative axillary ultrasound. Materials and methods: Screening and symptomatic patients were identified from pathology records and imaging and pathology records reviewed. True and false-negative axillary staging ultrasound groups were compared statistically in terms of tumour size, pathological type and grade, lymphovascular invasion, and oestrogen receptor (ER) status. Results: Of 155 women with normal ultrasounds, 45 (29%) were node positive at axillary surgery. Breast tumour size was significantly different with the average size smaller in the true-negative group: 21 versus 30 mm (p < 0.02). The histological type varied significantly between the groups, with more lobular carcinomas in the false-negative group [6/110 (5%) versus 6/45 (13%), p < 0.001]. The false-negative group was also more likely to show lymphovascular invasion in the breast [6/110 (5%) versus 14/45 (31%), p < 0.001]. There was no significant difference in tumour grade or ER status. Conclusion: The present study has found significant differences in tumour characteristics between women with true-negative and false-negative axillary staging ultrasound in terms of size, primary tumour histological type and presence of lymphovascular invasion. In particular, axillary ultrasound in primary lobular carcinoma may be less accurate and a negative result is more likely to be spurious than with primary ductal carcinomas.

Measurement uncertainty in single, double and triple isotope dilution mass spectrometry.

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Vogl, Jochen

2012-02-15

Triple IDMS has been applied for the first time to the quantification of element concentrations. It has been compared with single and double IDMS obtained on the same sample set in order to evaluate the advantages and disadvantages of triple IDMS over single and double IDMS as an analytical reference procedure. The measurement results of single, double and triple IDMS are indistinguishable, considering rounding due to the individual measurement uncertainties. As expected, the relative expanded uncertainties (k = 2) achieved with double IDMS (0.08%) are dramatically smaller than those obtained with single IDMS (1.4%). Triple IDMS yields the smallest relative expanded uncertainties (k = 2, 0.077%) unfortunately at the expense of a much higher workload. Nevertheless triple IDMS has the huge advantage that the isotope ratio of the spike does not need to be determined. Elements with high memory effects, highly enriched spikes or highest metrological requirements may be typical applications for triple IDMS. Copyright © 2011 John Wiley & Sons, Ltd.

The mammographic spectrum of intraductal carcinoma

International Nuclear Information System (INIS)

Ikeda, D.M.; Andersson, I.

1988-01-01

To analyze the atypical radiographic spectrum of ductal carcinoma in situ (DCIS), the authors retrospectively reviewed the mammograms of 190 women who had biopsy-proved DCIS at Malmo General Hospital between January 1976 and March 1988. Of these, 117 (61.6%) showed clustered microcalcifications as the major abnormality, a finding often associated with DCIS. The remaining 73 women (38.4%) had either negative mammograms (30 women) or radiographic findings not usually associated with DCIS (43 women), including circumscribed masses (15 women) and focal conglomerates of prominent ducts and nodules (12 cases). Since treatment of DCIS may cure the disease, the radiologist should learn to recognize the more unusual mammographic manifestations of intraductal carcinoma

Tumor metabolism and perfusion ratio assessed by 18F-FDG PET/CT and DCE-MRI in breast cancer patients: Correlation with tumor subtype and histologic prognostic factors

Energy Technology Data Exchange (ETDEWEB)

An, Young-Sil [Department of Nuclear Medicine and Molecular Imaging, Ajou University School of Medicine (Korea, Republic of); Kang, Doo Kyoung [Department of Radiology, Ajou University School of Medicine (Korea, Republic of); Jung, Yong Sik; Han, Sehwan [Department of Surgery, Ajou University School of Medicine (Korea, Republic of); Kim, Tae Hee, E-mail: medhand@ajou.ac.kr [Department of Radiology, Ajou University School of Medicine (Korea, Republic of)

2015-07-15

Highlights: • In non-triple negative breast cancer, metabolic parameter (SUVmax) was significantly correlated with perfusion parameters (Kep and Ve). • In triple negative cancers, any perfusion parameters did not correlated with metabolic parameters. • Higher SUVmax, higher SUVmax/Ktrans, higher MTV50/Ktrans, higher TLG50/Ktrans, higher TLG50/Ve ratios were significantly correlated with TNBC. • In triple negative breast cancer, perfusion and metabolic parameters are not significantly correlated. • Triple negative breast cancer showed higher metabolic–perfusion ratios compared to non-triple negative breast cancer. - Abstract: Objective: Our purpose was to evaluate whether breast cancer with high metabolic–perfusion ratio would be associated with poor histopathologic prognostic factors and whether triple negative breast cancer (TNBC) would show high metabolic–perfusion ratio compared to non-triple negative breast cancer (non-TNBC). Methods: From March 2011 to November 2011, 67 females with invasive ductal carcinoma of breast who underwent both MRI and 18F-FDG PET/CT were included. Perfusion parameters including Ktrans, Kep and Ve were acquired from Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Metabolic parameters including the standardized uptake value (SUV) and volumetric metabolic parameters including metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were obtained from F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). Results: In non-TNBC, SUVmax was significantly correlated with Kep (ρ = 0.298, p = 0.036) and Ve (ρ = −0.286, p = 0.044). In TNBC, there was no significant correlation between all perfusion and metabolic parameters. Compared to non-TNBC, higher SUVmax (10.2 vs 5.3, p < 0.001), higher SUVmax/Ktrans (56.02 vs 20.3, p < 0.001), higher MTV50/Ktrans (7.8 vs 16.54, p < 0.001), higher TLG50/Ktrans (36.49 vs 12.3, p < 0.001), higher TLG50/Ve (91.34 vs 27.1 p = 0.022) were

Hepatocellular carcinoma: a clinico pathological study

International Nuclear Information System (INIS)

Abbasi, A.; Butt, N.; Bhutto, A.R.; Gulzar, K.; Munir, S.M.

2010-01-01

To describe the clinico-pathological and radiological profile of hepatocellular carcinoma. All consecutive patients suspected of having hepatocellular carcinoma (HCC), were admitted and included in this study. Diagnosis of HCC was established by clinical, biochemical, ultrasonographic and histopathologic findings. Patients with primary carcinoma elsewhere in the body, metastatic in the liver, fibrolamellar carcinoma and benign tumours were excluded from the study. At ultrasonography, the details of tumour size and number, portal vein thrombosis and presence of ascites were recorded. Patients were staged according to Okuda staging system. Results were described in mean and percentage values. There were 82 patients with hepatocellular carcinoma including 58 males and 24 females, with male to female ratio of 2.8:1. The mean age of patients was 56.24 +- 13.65 years. Right hypochondrial pain was the main symptom in 52 (63.4%) patients. The duration of symptoms varied from 1 month to 2 years. Tumour size was larger than 50% of liver size in 42 (51.2%) with portal vein thrombosis in 10 (12.19%). Anti HCV was positive in 44 (53.7%), HBsAg in 26 (31.7%) and both were found positive in 2 (2.44%) patients. Ten patients (12.2/%) found negative both for anti-HCV and HBsAg. According to Okuda staging system 18 patients had stage 1, 50 had stage 2 and 14 had stage 3 hepatocellular carcinoma. The mean age of presentation of hepatocellular carcinoma was younger as compared to western countries with potentially large non-resectable lesions. Chronic hepatitis C and B was found to be the major known factors. Patients with chronic hepatitis C and B should undergo vigorous HCC surveillance to detect early, potentially respectable HCC. (author)

Giant basal cell carcinoma Carcinoma basocelular gigante

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Nilton Nasser

2012-06-01

Full Text Available The basal cell carcinoma is the most common skin cancer but the giant vegetating basal cell carcinoma reaches less than 0.5 % of all basal cell carcinoma types. The Giant BCC, defined as a lesion with more than 5 cm at its largest diameter, is a rare form of BCC and commonly occurs on the trunk. This patient, male, 42 years old presents a Giant Basal Cell Carcinoma which reaches 180 cm2 on the right shoulder and was negligent in looking for treatment. Surgical treatment was performed and no signs of dissemination or local recurrence have been detected after follow up of five years.O carcinoma basocelular é o tipo mais comum de câncer de pele, mas o carcinoma basocelular gigante vegetante não atinge 0,5% de todos os tipos de carcinomas basocelulares. O Carcinoma Basocelular Gigante, definido como lesão maior que 5 cm no maior diâmetro, é uma forma rara de carcinoma basocelular e comumente ocorre no tronco. Este paciente apresenta um Carcinoma Basocelular Gigante com 180cm² no ombro direito e foi negligente em procurar tratamento. Foi realizado tratamento cirúrgico e nenhum sinal de disseminação ou recorrência local foi detectada após 5 anos.

Two-week, high-dose proton pump inhibitor, moxifloxacin triple Helicobacter pylori therapy after failure of standard triple or non-bismuth quadruple treatments.

Science.gov (United States)

Gisbert, Javier P; Romano, Marco; Molina-Infante, Javier; Lucendo, Alfredo J; Medina, Enrique; Modolell, Inés; Rodríguez-Tellez, Manuel; Gomez, Blas; Barrio, Jesús; Perona, Monica; Ortuño, Juan; Ariño, Inés; Domínguez-Muñoz, Juan Enrique; Perez-Aisa, Ángeles; Bermejo, Fernando; Domínguez, Jose Luis; Almela, Pedro; Gomez-Camarero, Judith; Millastre, Judith; Martin-Noguerol, Elisa; Gravina, Antonietta G; Martorano, Marco; Miranda, Agnese; Federico, Alessandro; Fernandez-Bermejo, Miguel; Angueira, Teresa; Ferrer-Barcelo, Luis; Fernández, Nuria; Marín, Alicia C; McNicholl, Adrián G

2015-02-01

Aim was to evaluate the efficacy and tolerability of a moxifloxacin-containing second-line triple regimen in patients whose previous Helicobacter pylori eradication treatment failed. Prospective multicentre study including patients in whom a triple therapy or a non-bismuth-quadruple-therapy failed. Moxifloxacin (400mg qd), amoxicillin (1g bid), and esomeprazole (40 mg bid) were prescribed for 14 days. Eradication was confirmed by (13)C-urea-breath-test. Compliance was determined through questioning and recovery of empty medication envelopes. 250 patients were consecutively included (mean age 48 ± 15 years, 11% with ulcer). Previous (failed) therapy included: standard triple (n = 179), sequential (n = 27), and concomitant (n = 44); 97% of patients took all medications, 4 were lost to follow-up. Intention-to-treat and per-protocol eradication rates were 82.4% (95% CI, 77-87%) and 85.7% (95% CI, 81-90%). Cure rates were similar independently of diagnosis (ulcer, 77%; dyspepsia, 82%) and previous treatment (standard triple, 83%; sequential, 89%; concomitant, 77%). At multivariate analysis, only age was associated with eradication (OR = 0.957; 95% CI, 0.933-0.981). Adverse events were reported in 25.2% of patients: diarrhoea (9.6%), abdominal pain (9.6%), and nausea (9.2%). 14-day moxifloxacin-containing triple therapy is an effective and safe second-line strategy in patients whose previous standard triple therapy or non-bismuth quadruple (sequential or concomitant) therapy has failed, providing a simple alternative to bismuth quadruple regimen. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

High infiltration of tumor-associated macrophages in triple-negative breast cancer is associated with a higher risk of distant metastasis

OpenAIRE

Yuan, Zhong-Yu; Luo, Rong-Zhen; Peng, Rou-Jun; Wang, Shu-Sen; Xue, Cong

2014-01-01

Zhong-Yu Yuan,1–3* Rong-Zhen Luo,1,2,4,* Rou-Jun Peng,1–3 Shu-Sen Wang,1–3 Cong Xue1–3 1State Key Laboratory of Oncology in South China, 2Collaborative Innovation Center for Cancer Medicine, 3Departments of Medical Oncology, Sun Yat-Sen University Cancer Center, 4Departments of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China  *These authors contributed equally to this work Background: Triple-ne...

A Tulczyjew triple for classical fields

International Nuclear Information System (INIS)

Grabowska, Katarzyna

2012-01-01

The geometrical structure known as the Tulczyjew triple has proved to be very useful in describing mechanical systems, even those with singular Lagrangians or subject to constraints. Starting from basic concepts of the variational calculus, we construct the Tulczyjew triple for first-order field theory. The important feature of our approach is that we do not postulate ad hoc the ingredients of the theory, but obtain them as unavoidable consequences of the variational calculus. This picture of field theory is covariant and complete, containing not only the Lagrangian formalism and Euler–Lagrange equations but also the phase space, the phase dynamics and the Hamiltonian formalism. Since the configuration space turns out to be an affine bundle, we have to use affine geometry, in particular the notion of the affine duality. In our formulation, the two maps α and β which constitute the Tulczyjew triple are morphisms of double structures of affine-vector bundles. We also discuss the Legendre transformation, i.e. the transition between the Lagrangian and the Hamiltonian formulation of the first-order field theory. (paper)

Myricetin-induced apoptosis of triple-negative breast cancer cells is mediated by the iron-dependent generation of reactive oxygen species from hydrogen peroxide.

Science.gov (United States)

Knickle, Allison; Fernando, Wasundara; Greenshields, Anna L; Rupasinghe, H P Vasantha; Hoskin, David W

2018-05-06

Myricetin is a dietary phytochemical with anticancer activity; however, the effect of myricetin on breast cancer cells remains unclear. Here, we show that myricetin inhibited the growth of triple-negative breast cancer (TNBC) cells but was less inhibitory for normal cells. The effect of myricetin was comparable to epigallocatechin gallate and doxorubicin, and greater than resveratrol and cisplatin. Myricetin-treated TNBC cells showed evidence of early and late apoptosis/necrosis, which was associated with intracellular reactive oxygen species (ROS) accumulation, extracellular regulated kinase 1/2 and p38 mitogen-activated protein kinase activation, mitochondrial membrane destabilization and cytochrome c release, and double-strand DNA breaks. The antioxidant N-acetyl-cysteine protected myricetin-treated TNBC cells from cytotoxicity due to DNA damage. Myricetin also induced hydrogen peroxide (H 2 O 2 ) production in cell-free culture medium, as well as in the presence of TNBC cells and normal cells. In addition, deferriprone-mediated inhibition of intracellular ROS generation via the iron-dependent Fenton reaction and inhibition of extracellular ROS accumulation with superoxide dismutase plus catalase prevented myricetin-induced cytotoxicity in TNBC cell cultures. We conclude that the cytotoxic effect of myricetin on TNBC cells was due to oxidative stress initiated by extracellular H 2 O 2 formed by autoxidation of myricetin, leading to intracellular ROS production via the Fenton reaction. Copyright © 2018. Published by Elsevier Ltd.

Inhibition of SK4 Potassium Channels Suppresses Cell Proliferation, Migration and the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer Cells.

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Panshi Zhang

Full Text Available Treatments for triple-negative breast cancer (TNBC are limited; intermediate-conductance calcium-activated potassium (SK4 channels are closely involved in tumor progression, but little is known about these channels in TNBC. We aimed to investigate whether SK4 channels affect TNBC. First, by immunohistochemistry (IHC and western blotting (WB, increased SK4 protein expression in breast tumor tissues was detected relative to that in non-tumor breast tissues, but there was no apparent expression difference between various subtypes of breast cancer (p>0.05. Next, functional SK4 channels were detected in the TNBC cell line MDA-MB-231 using WB, real-time PCR, immunofluorescence and patch-clamp recording. By employing SK4 specific siRNAs and blockers, including TRAM-34 and clotrimazole, in combination with an MTT assay, a colony-formation assay, flow cytometry and a cell motility assay, we found that the suppression of SK4 channels significantly inhibited cell proliferation and migration and promoted apoptosis in MDA-MB-231 cells (p<0.05. Further investigation revealed that treatment with epidermal growth factor (EGF/basic fibroblast growth factor (bFGF caused MDA-MB-231 cells to undergo the epithelial-mesenchymal transition (EMT and to show increased SK4 mRNA expression. In addition, the down-regulation of SK4 expression inhibited the EMT markers Vimentin and Snail1. Collectively, our findings suggest that SK4 channels are expressed in TNBC and are involved in the proliferation, apoptosis, migration and EMT processes of TNBC cells.

Silibinin and Paclitaxel Cotreatment Significantly Suppress the Activity and Lung Metastasis of Triple Negative 4T1 Mammary Tumor Cell in Mice

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Bing-Ying Ho

2012-10-01

Full Text Available The in vitro and in vivo bioactivities of silibinin (SB, paclitaxel (PTX and SB and PTX in combination (SB+PTX against murine metastatic mammary 4T1 cancer cell line were investigated. Isobologram and combination index (CI analyses showed that SB and PTX can function synergistically in the inhibition of 4T1 cell proliferation with a CI value<1. Both SB and PTX alone or SB+PTX treatment inhibited 4T1 cell migration and motility possibly through downregulation of the serpin protease nexin-1 (PN-1 and N-cadherin expression, inhibition of matrix metalloprotease (MMP-9 activity, and upregulation of E-cadherin. Flow cytometry and Western blot analyses demonstrated that both drugs deregulated cell-cycle mediators and induced apoptosis in 4T1 cells. A real-time in vivo bioluminescence imaging system to monitor the breast cancer cell metastasis in syngeneic BALB/c mice was established using a stable 4T1pGL−COX−2/Luc cell clone carrying a COX-2 promoter driven-luciferase reporter gene. In vivo study using the allograft 4T1pGL−COX−2/Luc metastatic mouse model indicated that SB co-treated with PTX can significantly suppress lung metastasis of 4T1 cells likely through inhibiting cell proliferation and angiogenesis. Together, this study demonstrates that SB could act synergistically with PTX in 4T1 cells, providing a therapeutic option for highly metastatic triple negative breast cancer.

The role of Tl-201 total body scintigraphy in follow up of thyroid carcinoma

International Nuclear Information System (INIS)

Hoefnagel, C.A.; Delprat, C.C.; Marcuse, H.R.

1985-01-01

To evaluate the reliability of the procedure T1-201 total body scintigraphy was performed in 294 patients (449 studies) after total thyroidectomy for thyroid carcinoma. Results were correlated with I-131-scintigraphy and tumor-marker levels (Tgb or Calcitonin/CEA). T1-201 total body scintigraphy was negative in 196 patients with no evidence of disease. T1-201-scintigraphy correctly detected tumor localizations in 24 of 30 patients with I-131-positive metastases. In 28 patients T2-201 total body scintigraphy revealed metastases which did not concentrate I-131. Histology/cytology confirmed thyroid carcinoma metastases in 16 patients and other pathology in 5 cases. 9 of 18 patients with medullary thyroid carcinoma (I-131-negative) had elevated Calcitonin/CEA-levels. The T1-201 scintigram was positive in 8 of these patients. Comparison of T1-201, I-131 and tumor markers showed that only combined use of these parameters provide complete reliability. The authors conclude that T1-201 total body scintigraphy is useful in follow up of thyroid carcinoma, especially when a discrepancy of the other parameters exists and particularly in medullary carcinoma. In long term follow up of patients who are unsuspected of disease after successful therapy for thyroid carcinoma one can rely on T1-201 total body scintigraphy in combination with tumor marker assays

Topological regularizations of the triple collision singularity in the 3-vortex problem

International Nuclear Information System (INIS)

Hiraoka, Yasuaki

2008-01-01

The triple collision singularity in the 3-vortex problem is studied in this paper. Under the necessary condition k 1 -1 +k 2 -1 +k 3 -1 =0 for vorticities to have the triple collision, the main results are summarized as follows: (i) For k 1 = k 2 , the triple collision singularity is topologically regularizable. (ii) For 0 1 − k 2 | < ε with a sufficiently small ε, the triple collision singularity is not topologically regularizable. First of all, in order to prove these statements, all singularities in the 3-vortex problem are classified. Then, we introduce a dynamical system by blowing up the triple collision singularity with an appropriate time scaling. Roughly speaking, it corresponds to pasting an invariant manifold at the triple collision singularity on the original phase space. This technique is well known as McGehee's collision manifold (1974 Inventions Math. 27 191–227) in the N-body problem of celestial mechanics. Finally, by adopting the viewpoint of Easton (1971 J. Diff. Eqns 10 92–9), topological regularizations of the triple collision singularity are studied in detail

Reliability of twin-dependent triple junction distributions measured from a section plane

International Nuclear Information System (INIS)

Hardy, Graden B.; Field, David P.

2016-01-01

Numerous studies indicate polycrystalline triple junctions are independent microstructural features with distinct properties from their constituent grain boundaries. Despite the influence of triple junctions on material properties, it is impractical to characterize triple junctions on a large scale using current three-dimensional methods. This work demonstrates the ability to characterize twin-dependent triple junction distributions from a section plane by adopting a grain boundary plane stereology. The technique is validated through simulated distributions and simulated electron back-scatter diffraction (EBSD) data. Measures of validation and convergence are adopted to demonstrate the quantitative reliability of the technique as well as the convergence behavior of twin-dependent triple junction distributions. This technique expands the characterization power of EBSD and prepares the way for characterizing general triple junction distributions from a section plane. - Graphical abstract: The distribution of planes forming a triple junction with a given twin boundary is shown partially in the stereographic projections below from a given projection. The plot on the left shows the ideal/measured distribution and the plot on the right shows the distribution obtained from the stereological method presented here.

Sound transmission through triple-panel structures lined with poroelastic materials

Science.gov (United States)

Liu, Yu

2015-03-01

In this paper, previous theories on the prediction of sound transmission loss for a double-panel structure lined with poroelastic materials are extended to address the problem of a triple-panel structure. Six typical configurations are considered for a triple-panel structure based on the method of coupling the porous layers to the facing panels which determines critically the sound insulation performance of the system. The transfer matrix method is employed to solve the system by applying appropriate types of boundary conditions for these configurations. The transmission loss of the triple-panel structures in a diffuse sound field is calculated as a function of frequency and compared with that of corresponding double-panel structures. Generally, the triple-panel structure with poroelastic linings has superior acoustic performance to the double-panel counterpart, remarkably in the mid-high frequency range and possibly at low frequencies, by selecting appropriate configurations in which those with two air gaps in the structure exhibit the best overall performance over the entire frequency range. The poroelastic lining significantly lowers the cut-on frequency above which the triple-panel structure exhibits noticeably higher transmission loss. Compared with a double-panel structure, the wider range of system parameters for a triple-panel structure due to the additional partition provides more design space for tuning the sound insulation performance. Despite the increased structural complexity, the triple-panel structure lined with poroelastic materials has the obvious advantages in sound transmission loss while without the penalties in weight and volume, and is hence a promising replacement for the widely used double-panel sandwich structure.

Basal cell carcinoma of the skin with areas of squamous cell carcinoma: a basosquamous cell carcinoma?

OpenAIRE

de Faria, J

1985-01-01

The diagnosis of basosquamous cell carcinoma is controversial. A review of cases of basal cell carcinoma showed 23 cases that had conspicuous areas of squamous cell carcinoma. This was distinguished from squamous differentiation and keratotic basal cell carcinoma by a comparative study of 40 cases of compact lobular and 40 cases of keratotic basal cell carcinoma. Areas of intermediate tumour differentiation between basal cell and squamous cell carcinoma were found. Basal cell carcinomas with ...

Excited negative parity bands in 160Yb

Science.gov (United States)

Saha, A.; Bhattacharjee, T.; Curien, D.; Dedes, I.; Mazurek, K.; Banerjee, S. R.; Rajbanshi, S.; Bisoi, A.; de Angelis, G.; Bhattacharya, Soumik; Bhattacharyya, S.; Biswas, S.; Chakraborty, A.; Das Gupta, S.; Dey, B.; Goswami, A.; Mondal, D.; Pandit, D.; Palit, R.; Roy, T.; Singh, R. P.; Saha Sarkar, M.; Saha, S.; Sethi, J.

2018-03-01

Negative parity rotational bands in {} 70160Yb{}90 nucleus have been studied. They were populated in the 148Sm(16O, 4n)160Yb reaction at 90 MeV. The gamma-coincidence data have been collected using Indian National Gamma Array composed of twenty Compton suppressed clover germanium (Ge) detectors. Double gating on triple gamma coincidence data were selectively used to develop the decay scheme for these negative parity bands by identifying and taking care of the multiplet transitions. The even- and odd-spin negative parity bands in 160Yb have been studied by comparing the reduced transition probability ratios with the similar bands in neighbouring even-even rare earth nuclei. It is concluded that the concerned odd-spin and even-spin bands are not signature partners and that their structures are compatible with those of the ‘pear-shape’ and ‘pyramid-shape’ oscillations, respectively, the octupole shapes superposed with the quadrupole shape of the ground-state.

The incidence and prognosis of true duodenal carcinomas

DEFF Research Database (Denmark)

Buchbjerg, Thomas; Fristrup, C.; Mortensen, M. B.

2015-01-01

the criteria for true PDC. The incidence was 5.4 per 1,000,000, and the pathological classification was: Adenocarcinoma 87%, mucinous adenocarcinoma 7%, carcinoma 4% and signet ring cell carcinoma 1%. Intended curative resection was performed in 28 patients (39%) (22 Whipple procedures and 6 local resections......), and all but one patient had negative resection margins. Thirteen patients (46%) had lymph node metastasis. Twenty-nine (67%) of the palliative treated patients had a single (n = 24) or double by-pass procedure (n = 5). The median and 5-year survival for the resected patients were 23 months (CI 7...

A rare case of metastatic squamous urachal carcinoma.

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Andrei, S; Andrei, A; Rusu Muntean, G; Ungureanu, M; Herlea, V; Becheanu, G; Popescu, I

2013-01-01

Squamous cell carcinoma is a very rare type of urachal malignancy, only a few cases being reported in the medical literature. We present the case of a 49-year-old male patient diagnosed with infected squamous cell urachal carcinoma with multiple pulmonary metastases, after complaints of lower abdominal pain, abdominal mass and fever, without respiratory symptoms. The abdominal ultrasonography and the CT scan revealed a tumoral mass in the lower abdomen in contact with the abdominal wall and the urinary bladder dome, displacing the small bowel. Pulmonary nodular lesions were described in the left lobe pyramid. The intraoperative diagnosis was necrotic urachal tumor with urinary bladder dome invasion and suspected pulmonary metastases, and tumor ablation with bladder dome resection and suture of the bladder were performed. The histopathological result was poorly differentiated squamous cell carcinoma (G3), with negative resection margins. The patient recovered well after surgery, but the prognosis is very poor due to the metastatic stage in which the tumor was diagnosed, no standard chemotherapy regimen for the treatment of metastatic urachal carcinoma being known as effective until now. Celsius.

Comparative transcriptional profiling of human Merkel cells and Merkel cell carcinoma.

Science.gov (United States)

Mouchet, Nicolas; Coquart, Nolwenn; Lebonvallet, Nicolas; Le Gall-Ianotto, Christelle; Mogha, Ariane; Fautrel, Alain; Boulais, Nicholas; Dréno, Brigitte; Martin, Ludovic; Hu, Weiguo; Galibert, Marie-Dominique; Misery, Laurent

2014-12-01

Merkel cell carcinoma is believed to be derived from Merkel cells after infection by Merkel cell polyomavirus (MCPyV) and other poorly understood events. Transcriptional profiling using cDNA microarrays was performed on cells from MCPy-negative and MCPy-positive Merkel cell carcinomas and isolated normal Merkel cells. This microarray revealed numerous significantly upregulated genes and some downregulated genes. The extensive list of genes that were identified in these experiments provides a large body of potentially valuable information of Merkel cell carcinoma carcinogenesis and could represent a source of potential targets for cancer therapy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mometasone-based triple combination therapy in melasma: Is it really safe?

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Majid Imran

2010-01-01

Full Text Available Background: Kligman′s triple combination formula has been one of the most popular treatment options in melasma over the last three decades. The original Kligman′s formula has been modified in many ways over the years and the most recent modification that has been introduced is a triple combination of 2% hydroquinone, 0.025% tretinoin, and 1% mometasone. The use of this triple combination in patients with melasma has seen a sharp rise over the last few years and with this rampant use the side-effect profile of this triple combination has also come to the fore. Aim : The aim of the present study was to assess the overall safety of the mometasone-based triple combination treatment in the management of melasma. Materials and Methods: This retrospective study was performed on 60 patients of melasma who had used a mometasone-based triple combination treatment for at least 3 weeks anytime in the previous 1 year. The patients were given a preformed questionnaire wherein they assessed the overall effect of the triple combination treatment on their melasma during its use as well as after its withdrawal. The patients were specifically asked about the status of their disease as well as the sun sensitivity of their skin before and after the use of triple combination treatment. In addition, the patients were assessed by a single trained dermatologist for the presence of any adverse effects arising out of the triple combination treatment in the form of telangiectasia, hypertrichosis, acne, skin atrophy, etc. Results: Majority of patients (51.7% had used the combination treatment well beyond the recommended duration. About one-third (36.7% of the patients rated their melasma as worse at the time of filling the questionnaire as compared with their disease before the use of triple combination treatment. On clinical examination, the evidence of steroid side effects was seen in 26 patients (43.3%. Steroid-induced telangiectasia was the commonest finding, seen

About the Triple A. Argentina 1973 - 1976

OpenAIRE

Rostica, Julieta

2011-01-01

On May 25, 1973, Peronism returned to govern Argentina after about two decades of prohibition and political persecution. After its establishment, certain crimes began to be signed with “AAA”. The Triple A adopted the particularity of disappearing with the coup on March 24 1976. Why could this organization only exist in a democracy erected in the middle of two military dictatorships? Why did it exist during the very wished Peronist government? The article offers an approach to the Triple A, th...

Triple valve endocarditis by mycobacterium tuberculosis. A case report

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Shaikh Quratulain

2012-09-01

Full Text Available Abstract Background Granulomas caused by Mycobacterium Tuberculosis have been observed at autopsy in the heart, pre-dominantly in the myocardium and endocardium, but rarely involving the coronary vessels and valvular structures. Mycobacterium tuberculosis valvular endocarditis is extremely rare, with most reports coming from autopsy series. Case presentation We report the case of a 17 year old immunocompetent girl who presented with history of fever, malaise, foot gangrene and a left sided hemiparesis. On investigation she was found to have infective endocarditis involving the aortic, mitral and tricuspid valves. She had developed a right middle cerebral artery stroke. She underwent dual valve replacement and tricuspid repair. The vegetations showed granulomatous inflammation but blood cultures and other biological specimen cultures were negative for any organisms. She was started on antituberculous treatment and anticoagulation. Conclusion This is the first reported case of triple valve endocarditis by Mycobacterium Tuberculosis in an immunocompetent host. Especially important is the fact that the right heart is involved which has been historically described in the setting of intravenous drug abuse. This implies that Tuberculosis should be considered in cases of culture negative endocarditis in endemic areas like Pakistan even in immunocompetent hosts.

Invasive lobular carcinoma with extracellular mucin production-a novel pattern of lobular carcinomas of the breast. Clinico-pathological description of eight cases.

Science.gov (United States)

Cserni, Gábor; Floris, Giuseppe; Koufopoulos, Nektarios; Kovács, Anikó; Nonni, Afroditi; Regitnig, Peter; Stahls, Anders; Varga, Zsuzsanna

2017-07-01

Invasive lobular carcinoma of the breast is known to produce intracellular mucin and has been recognized in single-case reports to show extracellular mucin production, as well. This latter morphology is not only rare but must also be under- or misdiagnosed. The aim was to better characterize this entity. Cases of lobular cancers demonstrating extracellular mucin formation were identified in a multi-institutional effort and their clinical and morphologic features were assessed. Immunohistochemistry was used to characterize the E-cadherin-membrane complex, neuroendocrine differentiation, and to some extent, mucin formation. All but one of the eight cases occurred in postmenopausal patients. Extracellular mucin production was present in 5 to 50% of the tumour samples and rarely also appeared in nodal and distant metastases. The tumours were completely E-cadherin negative and showed cytoplasmic p120 positivity. The majority (n = 6/8) was also completely negative for β-catenin, but two tumours displayed focal β-catenin positivity in the mucinous area. MUC1 and MUC2 expression was observed in all and 7/8 tumours, respectively; neuroendocrine differentiation was present in only one. Invasive lobular carcinoma with extracellular mucin formation is a rare morphologic variant of lobular carcinoma prone to be misdiagnosed and warranting further studies.

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

Science.gov (United States)

Keizman, Daniel; Gottfried, Maya; Ish-Shalom, Maya; Maimon, Natalie; Peer, Avivit; Neumann, Avivit; Hammers, Hans; Eisenberger, Mario A; Sinibaldi, Victoria; Pili, Roberto; Hayat, Henry; Kovel, Svetlana; Sella, Avishay; Boursi, Ben; Weitzen, Rony; Mermershtain, Wilmosh; Rouvinov, Keren; Berger, Raanan; Carducci, Michael A

2014-01-01

Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p 3 (HR: 2.95, p smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Antimetastatic Therapies of the Polysulfide Diallyl Trisulfide against Triple-Negative Breast Cancer (TNBC via Suppressing MMP2/9 by Blocking NF-κB and ERK/MAPK Signaling Pathways.