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  1. Clinicopathological and Prognostic Value of Ki-67 Expression in Bladder Cancer: A Systematic Review and Meta-Analysis.

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    Yuejun Tian

    Full Text Available Ki-67 is an established marker of cell proliferation, and the Ki-67 index correlates with the clinical course of several cancer types, including bladder cancer (BC. However, the clinicopathological and prognostic significance of Ki-67 in bladder cancer remains unclear. Therefore, we performed a systematic review and meta-analysis to clarify this relationship.A comprehensive literature search for relevant studies published up to February 1, 2016, was performed using PubMed, Cochrane Library, Embase and ISI Web of Knowledge. The effects of Ki-67 expression on survival outcome in patients with BC and BC subtypes were evaluated. Furthermore, the relationship between Ki-67 expression and the clinicopathological features of BC were assessed.Thirty-one studies with 5147 bladder cancer patients were selected for evaluation. Ki-67 expression was significantly associated with shorter recurrence-free (HR 1.69, 95% CI: 1.33-2.14, progression-free (HR 1.89, 95% CI: 1.43-2.51, overall (HR 2.03, 95% CI: 1.31-3.16, and cancer-specific (HR 1.69, 95% CI: 1.47-1.95 survival. Moreover, whereas high expression was more common in high tumor stage, recurrence status, tumor size, there was no correlation between high Ki-67 expression and age, gender, smoking habits, and tumor number. Importantly, analysis of the different subgroups of BC suggested that significant correlations between high Ki-67 expression and survival outcome (recurrence-free/progression-free/overall/cancer-specific survival are present only in European-American patients.The present results indicate that over-expression of Ki-67 is distinctly correlated with poor patient survival. Ki-67 may serve as a valuable biomarker for prognosis in BC patients, particularly in non-Asian BC patients. The results suggest no significant association between Ki-67 expression and BC prognosis in Asian patients. Further efforts are needed to fully clarify this relationship.

  2. An International Ki67 Reproducibility Study

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    2013-01-01

    Background In breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67’s value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study. Methods Eight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays—one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. Results Intralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation. Conclusions Substantial variability in Ki67 scoring was observed among some of the world’s most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without

  3. Strategies for developing Ki67 as a useful biomarker in breast cancer.

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    Denkert, Carsten; Budczies, Jan; von Minckwitz, Gunter; Wienert, Stephan; Loibl, Sibylle; Klauschen, Frederick

    2015-11-01

    Increased proliferation is a hallmark of malignant tumors. The proliferation marker Ki67 has been investigated as a breast cancer biomarker, but despite 32 years of research the best cutpoints and the best methods for determination are still under debate. This review is based on an overview on the efforts to standardize Ki67 and to optimize its performance that was presented at the St. Gallen oncology conference 2015. The clinical validity of Ki67 as a prognostic marker as well as a predictive marker (in the neoadjuvant setting) has been shown in several meta-analyses. Depending on cohort characteristics, molecular subtype and clinical setting, Ki67 is a prognostic marker, a predictive marker, or both. Many different cutpoints for Ki67 have been reported, but it is has not been possible to determine an evidence-based "optimal" cutpoint. This supports the view that Ki67 is continuous marker, reflecting the continuous variation of the proliferation rate in different tumors. We should probably stop looking for an "optimal" cutpoint for Ki67 because it simply does not exist. It is evident from the results of several ring trials that intermediate levels of Ki67 are particularly difficult for standardization. Due to the low analytical validity in the intermediate range as well as intratumoral heterogeneity, the clinical utility of intermediate Ki67 levels is limited. Clinical decisions should not be based on small differences in the intermediate range and additional molecular tests might be necessary for tumors with intermediate Ki67 levels. For the two groups of tumors with a very low or a very high Ki67 a clinical interpretation could be straightforward. Despite these limitations, the assessment of proliferation is a central parameter for tumor characterization and an important element of the pathological assessment. Copyright © 2015. Published by Elsevier Ltd.

  4. Interlaboratory variability of Ki67 staining in breast cancer.

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    Focke, Cornelia M; Bürger, Horst; van Diest, Paul J; Finsterbusch, Kai; Gläser, Doreen; Korsching, Eberhard; Decker, Thomas

    2017-10-01

    Postanalytic issues of Ki67 assessment in breast cancers like counting method standardisation and interrater bias have been subject of various studies, but little is known about analytic variability of Ki67 staining between pathology labs. Our aim was to study interlaboratory variability of Ki67 staining in breast cancer using tissue microarrays (TMAs) and central assessment to minimise preanalytic and postanalytic influences. Thirty European pathology labs stained serial slides of a TMA set of breast cancer tissues with Ki67 according to their routine in-house protocol. The Ki67-labelling index (Ki67-LI) of 70 matched samples was centrally assessed by one observer who counted all cancer cells per sample. We then tested for differences between the labs in Ki67-LI medians by analysing variance on ranks and in proportions of tumours classified as luminal A after dichotomising oestrogen receptor-positive cancers into cancers showing low (Ki67-LI using Cochran's Q. Substantial differences between the 30 labs were indicated for median Ki67-LI (0.65%-33.0%, p cancers classified as luminal A (17%-57%, p Ki67 staining of breast cancer tissue was found between 30 routine pathology labs. Clinical use of the Ki67-LI for therapeutic decisions should be considered only fully aware of lab-specific reference values. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials.

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    Regan, Meredith M; Pagani, Olivia; Francis, Prudence A; Fleming, Gini F; Walley, Barbara A; Kammler, Roswitha; Dell'Orto, Patrizia; Russo, Leila; Szőke, János; Doimi, Franco; Villani, Laura; Pizzolitto, Stefano; Öhlschlegel, Christian; Sessa, Fausto; Peg Cámara, Vicente; Rodríguez Peralto, José Luis; MacGrogan, Gaëtan; Colleoni, Marco; Goldhirsch, Aron; Price, Karen N; Coates, Alan S; Gelber, Richard D; Viale, Giuseppe

    2015-11-01

    The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.

  6. Ki67 measured after neoadjuvant chemotherapy for primary breast cancer.

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    von Minckwitz, Gunter; Schmitt, Wolfgang D; Loibl, Sibylle; Müller, Berit M; Blohmer, Jens U; Sinn, Bruno V; Eidtmann, Holger; Eiermann, Wolfgang; Gerber, Bernd; Tesch, Hans; Hilfrich, Jörn; Huober, Jens; Fehm, Tanja; Barinoff, Jana; Rüdiger, Thomas; Erbstoesser, Erhard; Fasching, Peter A; Karn, Thomas; Müller, Volkmar; Jackisch, Christian; Denkert, Carsten

    2013-08-15

    The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described. Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0-15%), intermediate (15.1-35%), or high (35.1-100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively. Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone-receptor-positive disease [hazard ratios (HR), 1.82-5.88] but not in hormone-receptor-negative disease (HR: 0.61-1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965). Posttreatment Ki67 levels provide prognostic information for patients with hormone-receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments. ©2013 AACR.

  7. Ki-67 protein: a proliferation index in breast cancer

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    Shervin Kheirandish

    2015-09-01

    Full Text Available Various clinicopathological factors are evaluated in different studies on carcinomas to demonstrate their prognostic and predictive significance during the diagnosis and therapeutic procedures of the malignancy. Ki-67 is a biomarker that was proposed as a cell proliferation related nuclear antigen, and it only expresses in growing and proliferating cells. This unique feature of Ki-67 makes it a subject of interest in different investigations. Evaluating the Ki-67 expression has been demonstrated to be beneficial in determining the tumor behavior including tumor size, stage, grading and patient survival. Moreover, it might be helpful in selecting the preferred subsequent treatment strategy. Due to the importance of Ki-67 index, we aim to briefly review its properties and the importance of its expression during various types of malignancies. At last, the prognostic and predictive value of Ki-67 would be overviewed regarding the efficacy of neoadjuvant and adjuvant therapies in breast cancer patients.

  8. Interobserver Variability of Ki-67 Measurement in Breast Cancer

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    Yul Ri Chung

    2016-03-01

    Full Text Available Background: As measurement of Ki-67 proliferation index is an important part of breast cancer diagnostics, we conducted a multicenter study to examine the degree of concordance in Ki-67 counting and to find factors that lead to its variability. Methods: Thirty observers from thirty different institutions reviewed Ki-67–stained slides of 20 different breast cancers on whole sections and tissue microarray (TMA by online system. Ten of the 20 breast cancers had hot spots of Ki-67 expression. Each observer scored Ki-67 in two different ways: direct counting (average vs. hot spot method and categorical estimation. Intraclass correlation coefficient (ICC of Ki-67 index was calculated for comparative analysis. Results: For direct counting, ICC of TMA was slightly higher than that of whole sections using average method (0.895 vs 0.858. The ICC of tumors with hot spots was lower than that of tumors without (0.736 vs 0.874. In tumors with hot spots, observers took an additional counting from the hot spot; the ICC of whole sections using hot spot method was still lower than that of TMA (0.737 vs 0.895. In categorical estimation, Ki-67 index showed a wide distribution in some cases. Nevertheless, in tumors with hot spots, the range of distribution in Ki-67 categories was decreased with hot spot method and in TMA platform. Conclusions: Interobserver variability of Ki-67 index for direct counting and categorical estimation was relatively high. Tumors with hot spots showed greater interobserver variability as opposed to those without, and restricting the measurement area yielded lower interobserver variability.

  9. Clinical impact of ki-67 labeling index in non-small cell lung cancer

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    Jakobsen, Jan Nyrop; Sørensen, Jens Benn

    2013-01-01

    The ki-67 index is a marker of proliferation in malignant tumors. Studies from the period 2000 to 2012 on the prognostic and predictive value of ki-67 labeling index (LI) in non-small cell cancer (NSCLC) are reviewed. Twenty-eight studies reported on the prognostic value of ki-67 index with various...

  10. Ki67 expression in breast cancer

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    Elkablawy, Mohamed A.; Albasri, Abdulkader M.; Mohammed, Rabab A.; Hussainy, Akbar S.; Nouh, Magdy M.; Alhujaily, Ahmed S.

    2016-01-01

    Objectives: To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC) patients and investigate any possible predictive or prognostic value for Ki67. Methods: This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI) in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) with their clinicopathological parameters. Results: Ki67 immunoreactivity was highly expressed (>25% of the tumor cells were positive) in 85 (73.9%) patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (pKi67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2) subtypes compared with the Her2/neu negative (luminal A) subtype (pKi67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients. PMID:26837394

  11. Ki67 assessment in breast cancer: an update.

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    Penault-Llorca, Frederique; Radosevic-Robin, Nina

    2017-02-01

    Although immunohistochemical detection of the Ki67 antigen has been used for many years to assess cancer proliferation, this marker is still not recommended for routine use in clinical management of breast cancer. The major reason for this situation is a lack of a standardised procedure for Ki67 assessment as well as persistence of several issues of debate with regards to the Ki67 assay interpretation and the marker's clinical utility. Nowadays Ki67 assessment is principally used for estimation of prognosis and guiding the decision on adjuvant treatment choice, as well as for prediction of response to neoadjuvant treatment in ER+/HER2- breast cancer. In ER-/HER2+ and ER-/HER2- tumours, high post-neoadjuvant Ki67 index is associated with unfavourable prognosis. We review here the elements impacting analytical validity of the Ki67 immunohistochemical assay, the evidence of its clinical utility and the current recommendations for its use in breast cancer management. Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

  12. An international study to increase concordance in Ki67 scoring

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    Polley, Mei-Yin C; Leung, Samuel C Y; Gao, Dongxia

    2015-01-01

    Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from...

  13. Is Ki-67 of Diagnostic Value in Distinguishing Between Partial and Complete Hydatidiform Moles? A Systematic Review and Meta-analysis.

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    Zhao, Yue; Xiong, Guang-Wu; Zhang, Xiao-Wei; Hang, B O

    2018-02-01

    To demonstrate the value of Ki-67 in distinguishing between partial and complete hydatidiform moles. We searched electronic databases included Medline, WOK, Cochrane Library and CNKI, through January 24, 2015. Experts were consulted, and references from related articles were examined. The meta-analysis was conducted with RevMan5.3, according to the PRISMA guidelines. Mantel-Haenszel estimates were calculated and pooled under a random effect model, with data expressed as odds ratio (OR) and 95% confidence interval (CI). We analyzed eight trials with a total of 337 participants who underwent uterine curettage and met the inclusion criteria. A significantly higher expression of Ki-67 was observed in complete than in partial hydatidiform moles (OR=3.28; 95%CI=1.80-5.96; pvalue in distinguishing between partial and complete hydatidiform moles. However, the present study had only a limited number of samples, so investigation of a greater number of cases is needed to confirm this conclusion. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  14. The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence

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    Ignatiadis, Michail; Azim, Hatem A; Desmedt, Christine

    2016-01-01

    (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value. Interventions: Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67. Main Outcomes and Measures: Distant recurrence...... to the clinicopathological prognostic factors. In patients with early node-negative breast cancer who were endocrine-only treated, 38% were GG1 with a 10-year DRFI of 99% (95% CI, 97%-100%), and 18% were histological grade 1 with a 10-year DRFI of 100% (95% CI, 100%-100%). For GG equivocal patients, the 10-year DRFI was 94......% (95% CI, 90%-98%), and for GG3 patients, the 10-year DRFI was 87% (95% CI, 80%-94%). Conclusions and Relevance: Either the GG assay or centrally reviewed Ki67 significantly improves clinicopathological models to determine distant recurrence of breast cancer. Compared with the histological grade...

  15. Neoplasias astrocitárias e correlação com as proteínas p53 mutada e Ki-67 Astrocytic neoplasms and correlation with mutate p53 and Ki-67 proteins

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    Gustavo Rassier Isolan

    2005-12-01

    Full Text Available As neoplasias astrocitárias correspondem a 60% dos tumores do sistema nervoso central, sendo o estudo da biologia molecular um importante passo para a compreensão da gênese e comportamento biológico destas doenças. As proteínas Ki-67, que é um marcador de proliferação celular, e p53, que é o produto do gene supressor de tumor de mesmo nome, são importantes marcadores tumorais. O objetivo deste estudo foi identificar e quantificar as proteínas Ki-67 e produto do gene supressor de tumor TP53 em diferentes graus de malignidade das neoplasias astrocitárias, bem como analisar suas relações com idade e sexo. Foram estudadas por imuno-histoquímica as proteínas Ki-67 e p53 em 47 pacientes com neoplasias astrocitárias ressecadas cirurgicamente, classificadas previamente e revisadas quanto ao grau de malignidade, de acordo com o proposto pela Organização Mundial da Saúde. Os núcleos celulares imunomarcados foram quantificados no programa Imagelab-softium pela razão paramétrica absoluta entre os núcleos de células positivas e o número total de células tumorais, sendo contadas 1000 células. O delineamento utilizado foi transversal não controlado. Para análise estatística as variáveis foram divididas em grupos, que para a Ki-67 foram ausente, 5% e para a p53 foram ausente (0, The astrocytic neoplasms respond by 60% of the central nervous system tumors, being the study of the molecular biology an important step for the understanding of the genesis and biological behavior of these diseases. The Ki-67 proteins, which are markers of the cellular proliferation, and p53, which is the product of the tumor suppressor gene TP53, are both important tumoral markers. This study intends to identify and quantify the Ki-67 and p53 proteins in astrocytic tumors of different grades of malignancy, as well as to analyze their relations with age and gender. Ki-67 and p53 proteins in 47 patients with surgically resected astrocytic neoplasms were

  16. High Ki67/BCL2 index is associated with worse outcome in early stage breast cancer.

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    Min, Kyueng-Whan; Kim, Dong-Hoon; Do, Sung-Im; Pyo, Jung-Soo; Chae, Seoung Wan; Sohn, Jin Hee; Kim, Kyungeun; Lee, Hyun Joo; Kim, Dong Hyun; Oh, Sukjoong; Choi, Seon Hyeong; Park, Yong Lai; Park, Chan Heun; Kwon, Mi Jung; Moon, Kyoung Min

    2016-12-01

    Breast cancers are heterogeneous, making it essential to recognise several biomarkers for cancer outcome predictions. Ki67 proliferation index and B cell lymphoma 2 (BCL2) proteins are widely used as prognostic indicators in many types of malignancies. While Ki67 is a marker of normal or tumour cell proliferation, BCL2 plays a central role in antiproliferative activities. A combination of these two biomarkers with contrary purposes can provide enhanced prognostic accuracy than an analysis using a single biomarker. We evaluated Ki67 and BCL2 expression with 203 cases of breast cancer. The relative expression of each biomarker named as Ki67/BCL2 index was divided into two groups (low vs high) with the use of area under receiver operating characteristic curves. There were significant correlations between Ki67/BCL2 index and clinicopathological findings such as age, tumour stage, size and necrosis, histological grade, extensive intraductal component, lymphatic and vascular invasion, oestrogen receptor, progesterone receptor, human epithelial growth factor receptor 2 and p53 expression (all pKi67/BCL2 index correlated with shorter disease-free survival and overall survival in patients with early stage invasive ductal carcinoma (all pKi67/BCL2 index should be considered as a prognostic predictor in patients with early stage invasive ductal carcinoma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  17. Prognostic Value of Ki-67 Labeling Index and Postoperative Radiotherapy in WHO Grade II Meningioma.

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    Choi, Yunseon; Lim, Do Hoon; Yu, Jeong Il; Jo, Kyungil; Nam, Do-Hyun; Seol, Ho Jun; Lee, Jung-Il; Kong, Doo-Sik; Suh, Yeon-Lim; Nam, Heerim

    2018-01-01

    This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P13%, PORT should be recommended to improve LC.

  18. A novel model for Ki67 assessment in breast cancer.

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    Romero, Quinci; Bendahl, Pär-Ola; Fernö, Mårten; Grabau, Dorthe; Borgquist, Signe

    2014-06-16

    Ki67 is currently the proliferation biomarker of choice, with both prognostic and predictive value in breast cancer. A lack of consensus regarding Ki67 use in pre-analytical, analytical and post-analytical practice may hinder its formal acceptance in the clinical setting. One hundred breast cancer samples were stained for Ki67. A standard estimation of Ki67 using fixed denominators of 200, 400 and 1 000 counted tumor cells was performed, and a cut-off at 20% was applied, Ki67static. A novel stepwise counting strategy for Ki67 estimation, Ki67scs, was developed based on rejection regions derived from exact two-sided binomial confidence intervals for proportions. Ki67scs was defined by the following parameters: the cut-off (20%), minimum (50) and maximum (400) number of tumor cells to count, increment (10) and overall significance level of the test procedure (0.05). Results from Ki67scs were compared to results from the Ki67static estimation with fixed denominators. For Ki67scs, the median number of tumor cells needed to determine Ki67 status was 100; the average, 175. Among 38 highly proliferative samples, the average Ki67scs fraction was 45%. For these samples, the fraction decreased from 39% to 37% to 35% with static counting of 200, 400 and 1 000 cells, respectively. The largest absolute difference between the estimation methods was 23% (42% (Ki67scs) vs. 19% (Ki67static)) and resulted in an altered sample classification. Among the 82 unequivocal samples, 74 samples received the same classification using both Ki67scs and Ki67static. Of the eight disparate samples, seven were classified highly proliferative by Ki67static when 200 cells were counted; whereas all eight cases were classified as low proliferative when 1 000 cells were counted. Ki67 estimation using fixed denominators may be inadequate, particularly for tumors demonstrating extensive heterogeneity. We propose a time saving stepwise counting strategy, which acknowledges small highly proliferative hot

  19. [Expression of Ki67 and clinicopathological features in breast cancer].

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    Wang, Baona; Wang, Xiang; Wang, Jing; Xuan, Lixue; Wang, Zhongzhao; Wang, Xin; Gao, Jidong; Zhang, Haizeng

    2014-04-01

    To analyze the relationship between the expression level of Ki67 and clinicopathological features in breast cancer. Data of 918 female patients with invasive ductal breast carcinoma treated in the Cancer Hospital, Chinese Academy of Medical Sciences from Jan. to Dec. 2010 were analyzed retrospectively. The correlation of Ki67 expression and other clinicopathological features in the breast cancer was analyzed. Among the 918 cases, the Ki67 index was 0.9% to 95% (mean value 27.8%). Taking the Ki67 index 14% as the boundary to divide the patients into two subgroups, 263 cases (28.6%) were ≤ 14%, and 655 cases (71.4%) were >14%. There were significant differences between the Ki67 expression and age, tumor size, axillary lymph nodes status, histological grade and the expressions of C-erbB-2, estrogen receptor (ER) and progesterone receptor (PR) (P Ki67 indexes of Ki67 expression in luminal B (30.44%), HER-2 overexpression (36.77%) and triple negative (47.40%) subtypes were significantly higher than that in the luminal A subtype (21.36%)(P Ki67 in triple-negative subtype (47.40%) was significantly higher than that in the non-triple-negative subtype (24.79%)(P Ki67 index is significantly correlated with the age, tumor TNM stage, axillary lymph node status, histological grading, ER status, PR status and HER-2 status. A high expression level of Ki67 is a poor prognostic factor for breast cancer. The expression level of Ki67 should be detected routinely and it may become a useful prognostic marker in the treatment of breast cancer.

  20. The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence.

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    Ignatiadis, Michail; Azim, Hatem A; Desmedt, Christine; Veys, Isabelle; Larsimont, Denis; Salgado, Roberto; Lyng, Maria B; Viale, Giuseppe; Leyland-Jones, Brian; Giobbie-Hurder, Anita; Kammler, Rosita; Dell'Orto, Patrizia; Rothé, Françoise; Laïos, Ioanna; Ditzel, Henrik J; Regan, Meredith M; Piccart, Martine; Michiels, Stefan; Sotiriou, Christos

    2016-02-01

    The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required. To evaluate the prognostic ability of the GG assay to detect breast cancer recurrence compared with centrally reviewed immunohistochemical testing of Ki67 antigen proliferation. This is an internationally collaborative substudy of a large phase 3 4-arm adjuvant trial. Patients had endocrine receptor-positive, node-positive, or node-negative nonmetastatic primary breast cancer. Patients included in this study had available formalin-fixed, paraffin-embedded samples of their primary tumors and were randomized to either a 5-year tamoxifen monotherapy arm or a 5-year letrozole monotherapy arm. Associations between either GG assay results or log2-transformed Ki67 data and survival end points were evaluated using Cox regression models stratified for chemotherapy use; the 2 vs 4 arm randomization option; and endocrine therapy assignment with and without adjustment for clinicopathological parameters, including centrally reviewed histological grade, hormone receptors, and ERBB2 (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value. Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67. Distant recurrence-free interval (DRFI). Genomic Grade assay data were obtained in 883 breast cancer samples (62%). At a median follow-up of 8.1 years, 84 (10%) had distant recurrences. Increasing GG or Ki67 were both significantly associated with lower DRFI and added independent prognostic

  1. Interlaboratory variability of Ki67 staining in breast cancer

    NARCIS (Netherlands)

    Focke, Cornelia M.; Bürger, Horst; van Diest, Paul J.; Finsterbusch, Kai; Gläser, Doreen; Korsching, Eberhard; Decker, Thomas; Anders, M.; Bollmann, R.; Eiting, Fr; Friedrich, K.; Habeck, J. O.; Haroske, G.; Hinrichs, B.; Behrens, A.; Krause, Lars Udo; Braun-Lang, U.; Lorenzen, J.; Minew, N.; Mlynek-Kersjes, M.; Nenning, H.; Packeisen, J.; Poche-de Vos, F.; Reyher-Klein, S.; Rothacker, D.; Schultz, M.; Sturm, U.; Tawfik, M.; Berghäuser, K. H.; Böcker, W; Cserni, G.; Habedank, S.; Lax, S.; Moinfar, F.; Regitnig, P.; Reiner-Concin, A.; Rüschoff, J.; Varga, Z.; Woziwodski, J.

    2017-01-01

    Background Postanalytic issues of Ki67 assessment in breast cancers like counting method standardisation and interrater bias have been subject of various studies, but little is known about analytic variability of Ki67 staining between pathology labs. Our aim was to study interlaboratory variability

  2. The Value of Ki67 in Very Young Women with Hormone Receptor-Positive Breast Cancer: Retrospective Analysis of 9,321 Korean Women.

    Science.gov (United States)

    Kim, Jisun; Han, Wonshik; Jung, So-Youn; Park, Yeon Hee; Moon, Hyeong-Gon; Ahn, Soo Kyung; Lee, Jun Woo; Kim, Min Kyoon; Kim, Jong Jin; Lee, Eun Shin; You, Tae Kyung; Kang, Han-Sung; Lee, Eun Sook; Ro, Jungsil; Lee, Jeong Eon; Nam, Seok Jin; Yim, Young-Hyuck; Park, In Ae; Noh, Dong-Young

    2015-10-01

    Young breast cancer patients have a poorer prognosis, especially when their tumors are hormone receptor positive. We analyzed the association between Ki67 and age and the impact of these factors on outcomes in hormone receptor-positive breast cancer. The records of 9,321 hormone receptor-positive invasive breast cancer patients from three large centers were retrospectively reviewed. Each institution separately assayed Ki67 level immunohistochemically. Univariate and multivariate analysis for recurrence-free survival (RFS) was performed on 4,738 patients from a single center. Ki67 level was inversely proportional to age in all three data sets and was significantly higher for younger patients (p Ki67 level (≥10 %) were independent prognostic factors. Although young age was a worse prognostic indicator regardless of HER2 status, Ki67 index was associated with worse prognosis only in HER2-negative patients. When patients were stratified into those with low and high Ki67, young age remained a significant factor for RFS, with hazard ratios in these two Ki67 groups of 2.15 and 2.57, respectively (p Ki67 group had significantly poorer RFS than the older age/high Ki67 group (p Ki67 level was higher in younger patients. However, very young patients had a poorer prognosis regardless of Ki67 level. Unknown biologic factors other than high cell proliferation might play a role in the aggressiveness of hormone receptor-positive breast cancer in very young patients.

  3. Expression of Progestrone Receptor and Proliferative Marker ki 67, in Various Grades of Meningioma

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    Nasrin Shayanfar

    2010-05-01

    Full Text Available Meningiomas are slow-growing neoplasms which recur locally, their morphologic grading is simple but do not always correlate with patient outcome. The aim of present study is to evaluate the status of progesterone receptor (PR and proliferation marker Ki67 in various grades of meningioma in a group of Iranian patients. 78 cases of meningioma were selected from the file of a hospital university. All archival H&E stained sections were reviewed and regraded according to WHO criteria. Immunohistochemical analysis for PR and Ki67 was performed on formalin- fixed, paraffin- embedded samples. PR status considered positive if > 10% of tumor cell's nuclei were strongly immunoreactive, or if > 50% of nuclei were stained with medium intensity. The Ki67 labeling index (LI is defined as the percentage area with strongest immunostaining. PR were positive in 61/63(96.8% of grade I tumors,2/10(20% of grade II,and 0/5(0% of grade III tumors.Ki67 LI was %2.98±2.27 in grade I tumors, %9.30±5.79 in grade II tumors and %34.00±5.47 in grade III tumors. For both markers, differences between grade I,II and III tumors were significant(P<0.001.There was a reverse relationship between mean of Ki67 LI and PR status,with increasing grade of tumor. Evaluation of PR status and Ki67 LI together with conventional histologic evaluation can help in providing more information about the biologic behaviour of meningiomas,especially for those that histological grading is not straightforward.

  4. Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups.

    Science.gov (United States)

    Abubakar, Mustapha; Orr, Nick; Daley, Frances; Coulson, Penny; Ali, H Raza; Blows, Fiona; Benitez, Javier; Milne, Roger; Brenner, Herman; Stegmaier, Christa; Mannermaa, Arto; Chang-Claude, Jenny; Rudolph, Anja; Sinn, Peter; Couch, Fergus J; Devilee, Peter; Tollenaar, Rob A E M; Seynaeve, Caroline; Figueroa, Jonine; Sherman, Mark E; Lissowska, Jolanta; Hewitt, Stephen; Eccles, Diana; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; Investigators, kConFab; Bolla, Manjeet K; Wang, Qin; Jones, Michael; Schoemaker, Minouk; Wesseling, Jelle; van Leeuwen, Flora E; Van 't Veer, Laura; Easton, Douglas; Swerdlow, Anthony J; Dowsett, Mitch; Pharoah, Paul D; Schmidt, Marjanka K; Garcia-Closas, Montserrat

    2016-10-18

    automated measures of KI67 in a subset of 2440 patients with information from both sources. Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment.

  5. Prothymosin-alpha and Ki-67 expression in pituitary adenomas

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    Iga Wierzbicka-Tutka

    2016-11-01

    Full Text Available Introduction: Prothymosin alpha (PTMA, a nuclear oncoprotein involved in cell cycle regulation, is used as a prognostic marker in many cancers. The histopathology of pituitary carcinomas and locally invasive adenomas is indistinguishable from that of benign tumors. A new marker is needed to differentiate these lesions. We evaluated PTMA in pituitary adenomas to determine its usefulness as a prognostic factor of tumor proliferation.Material/Methods: We conducted a retrospective analysis of a group of 27 patients, including 15 females (56% and 12 males (44% with a mean age of 58.6±12 years, who underwent pituitary tumor surgery between 2003 and 2012. The Ki-67 and PTMA-nuclear (PTMA-n and PTMA-cytoplasmic (PTMA-c indices were determined by immunohistochemical staining. We studied histopathological features, clinical symptoms, and magnetic resonance imaging or computed tomography performed before surgery and one year following surgery to evaluate tumor size and progression.Results: The expression of Ki-67 was revealed in 77.8% of adenomas, PTMA-n in 81.5% and PTMA-c in 92.6%. The mean value of the Ki-67 index was 1.8%, PTMA-n was 1.84%, and PTMA-c was 35.6%. There was a significant positive correlation between Ki-67 and PTMA-n (p=0.009. We did not find any correlation between Ki-67, PTMA-c, and tumor progression. PTMA-n was found to be correlated with tumor size (p=0.045 and was higher in the case of gonadotropinomas (p=0.026.Conclusions: The positive nuclear expression of Ki-67 and PTMA was observed in the majority of pituitary adenomas. Neither the expression of Ki-67 nor that of PTMA-c was related to tumor recurrence or local invasion.

  6. Interobserver concordance of Ki67 labeling index in breast cancer: Japan Breast Cancer Research Group Ki67 ring study.

    Science.gov (United States)

    Mikami, Yoshiki; Ueno, Takayuki; Yoshimura, Kenichi; Tsuda, Hitoshi; Kurosumi, Masafumi; Masuda, Shinobu; Horii, Rie; Toi, Masakazu; Sasano, Hironobu

    2013-11-01

    The standardized assessment of Ki67 labeling index (LI) is of clinical importance to identify patients with primary breast cancer who could benefit from chemotherapy. In this study, we evaluated the interobserver concordance of Ki67 LI assessment. Six surgical pathologists participated and all the slides were prepared from archival breast cancer tissues fixed in 10% buffered formalin for 24 h and stained with MIB-1. Three independent studies were conducted. In the first study, 30 stained slides were assessed using two different methods: the scoring system, with a positive rate scored from 1 (0-9%) to 10 (90-100%) by visual estimate; and the counting method, with approximately 1000 cells counted in hot spots. In the second study, 20 tumors with Ki67 LI 5-25% were assessed, and in the third study, 15 printed photographs of stained slides were assessed to avoid variations by selecting different fields. In study 1, the counting system (intraclass correlation coefficient [ICC], 0.66 [95% confidence interval 0.52-0.78]) demonstrated a better correlation than the scoring system (ICC, 0.57 [0.42-0.72]). In study 2, the assessment for Ki67 LI of 5-25% demonstrated a correlation (ICC, 0.68 [0.50-0.81]) similar to that of study 1 (unrestricted range of Ki67 LI). In study 3, the assessment of Ki67 LI by counting yielded a good concordance (ICC, 0.94 [0.88-0.97]). In conclusion, there was better concordance with the counting system, and concordance was high when the assessed field was predetermined, indicating that the selection of the evaluation area is critical for obtaining reproducible Ki67 LI in breast cancer. © 2013 Japanese Cancer Association.

  7. Quality assurance trials for Ki67 assessment in pathology.

    Science.gov (United States)

    Raap, M; Ließem, S; Rüschoff, J; Fisseler-Eckhoff, A; Reiner, A; Dirnhofer, S; von Wasielewski, R; Kreipe, H

    2017-10-01

    Ki67 is a broadly used proliferation marker in surgical pathology with an obvious need for standardization to improve reproducibility of assessment. Here, we present results of the so far only existing round robin tests on Ki67, organized annually in Germany, Austria, and Switzerland from 2010 to 2015 with up to 160 participating laboratories (QuIP). In each quality assessment trial, eight probes from each breast cancer, neuroendocrine tumor, and malignant lymphoma were compiled on a tissue microarray (TMA). TMAs were stained in the participants' laboratories with antibodies and procedures also applied in their daily routine. Participating pathologists were expected to assign Ki67 values to one of four different categories for each tumor type. All local stainings and evaluations were reassessed by the organizing panel and compared to a preset standard. On average, 95% of participants reached the benchmark of over 80% concordance rates with the Ki67 category pre-established by the panel. Automatization and type of antibody did not affect the success rate. Concordance rates differed between tumor entities being highest in each tumor type with either very high or very low labeling indices. Lower rates were seen for intermediate Ki67 levels. Staining quality improved during the observation period as did inter-observer concordance with 85% of participants achieving excellent agreement (kappa > 0.8) in the first year and over 95% in 2015. In conclusion, regular external quality assurance trials have been established as a tool to improve the reproducibility and reliability of the prognostic and predictive proliferation marker Ki67.

  8. Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group

    Science.gov (United States)

    Nielsen, Torsten O.; A’Hern, Roger; Bartlett, John; Coombes, R. Charles; Cuzick, Jack; Ellis, Matthew; Henry, N. Lynn; Hugh, Judith C.; Lively, Tracy; McShane, Lisa; Paik, Soon; Penault-Llorca, Frederique; Prudkin, Ljudmila; Regan, Meredith; Salter, Janine; Sotiriou, Christos; Smith, Ian E.; Viale, Giuseppe; Zujewski, Jo Anne; Hayes, Daniel F.

    2011-01-01

    Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice. PMID:21960707

  9. Ki-67 immunoreactivity in meningiomas--determination of the proliferative potential of meningiomas using the monoclonal antibody Ki-67

    DEFF Research Database (Denmark)

    Madsen, C; Schrøder, H D

    1997-01-01

    The proliferative potential of 66 human intracranial meningiomas (15 benign, 15 atypical, 15 recurrent, 13 bone-invasive, and 8 brain-invasive) was investigated by means of immunohisto-chemistry using the monoclonal antibody Ki-67. This antibody recognizes a nuclear antigen present in human cells...... during all active phases of the cell cycle, but absent in the resting phase. The purpose of this retrospective study was to estimate the Ki-67-labelling index (L.I.) and see if this index could help discriminate between the different groups of meningiomas. Our results demonstrated that L.I. could...

  10. Quantum dots-based quantitative and in situ multiple imaging on ki67 and cytokeratin to improve ki67 assessment in breast cancer.

    Science.gov (United States)

    Yuan, Jing Ping; Wang, Lin Wei; Qu, Ai Ping; Chen, Jia Mei; Xiang, Qing Ming; Chen, Chuang; Sun, Sheng-Rong; Pang, Dai-Wen; Liu, Juan; Li, Yan

    2015-01-01

    As a marker for tumor cell proliferation, Ki67 has important impacts on breast cancer (BC) prognosis. Although immunohistochemical staining is the current standard method, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study was to develop a fluorescent spectrum-based quantitative analysis of Ki67 expression by quantum-dots (QDs) multiple imaging technique. A QDs-based in situ multiple fluorescent imaging method was developed, which stained nuclear Ki67 as red signal and cytoplasmic cytokeratin (CK) as green signal. Both Ki67 and CK signals were automatically separated and quantified by professional spectrum analysis software. This technique was applied to tissue microarrays from 240 BC patients. Both Ki67 and CK values, and Ki67/CK ratio were obtained for each patient, and their prognostic value on 5-year disease free survival was assessed. This method simultaneously stains nuclear Ki67 and cytoplasmic CK with clear signal contrast, making it easy for signal separation and quantification. The total fluorescent signal intensities of both Ki67 sum and CK sum were obtained, and Ki67/CK ratio calculated. Ki67 sum and Ki67/CK ratio were each attributed into two grades by X-tile software based on the best P value principle. Multivariate analysis showed Ki67 grade (P = 0.047) and Ki67/CK grade (P = 0.004) were independent prognostic factors. Furthermore, area under curve (AUC) of ROC analysis for Ki67/CK grade (AUC: 0.683, 95%CI: 0.613-0.752) was higher than Ki67 grade (AUC: 0.665, 95%CI: 0.596-0.734) and HER-2 gene (AUC: 0.586, 95%CI: 0.510-0.661), but lower than N stage (AUC: 0.760, 95%CI: 0.696-0.823) and histological grade (AUC: 0.756, 95%CI: 0.692-0.820) on predicting the risk for recurrence. A QDs-based quantitative and in situ multiple imaging on Ki67 and CK was developed to improve Ki67 assessment in BC, and Ki67/CK grade had better performance than Ki67 grade in predicting prognosis.

  11. Quantum dots-based quantitative and in situ multiple imaging on ki67 and cytokeratin to improve ki67 assessment in breast cancer.

    Directory of Open Access Journals (Sweden)

    Jing Ping Yuan

    Full Text Available As a marker for tumor cell proliferation, Ki67 has important impacts on breast cancer (BC prognosis. Although immunohistochemical staining is the current standard method, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study was to develop a fluorescent spectrum-based quantitative analysis of Ki67 expression by quantum-dots (QDs multiple imaging technique.A QDs-based in situ multiple fluorescent imaging method was developed, which stained nuclear Ki67 as red signal and cytoplasmic cytokeratin (CK as green signal. Both Ki67 and CK signals were automatically separated and quantified by professional spectrum analysis software. This technique was applied to tissue microarrays from 240 BC patients. Both Ki67 and CK values, and Ki67/CK ratio were obtained for each patient, and their prognostic value on 5-year disease free survival was assessed.This method simultaneously stains nuclear Ki67 and cytoplasmic CK with clear signal contrast, making it easy for signal separation and quantification. The total fluorescent signal intensities of both Ki67 sum and CK sum were obtained, and Ki67/CK ratio calculated. Ki67 sum and Ki67/CK ratio were each attributed into two grades by X-tile software based on the best P value principle. Multivariate analysis showed Ki67 grade (P = 0.047 and Ki67/CK grade (P = 0.004 were independent prognostic factors. Furthermore, area under curve (AUC of ROC analysis for Ki67/CK grade (AUC: 0.683, 95%CI: 0.613-0.752 was higher than Ki67 grade (AUC: 0.665, 95%CI: 0.596-0.734 and HER-2 gene (AUC: 0.586, 95%CI: 0.510-0.661, but lower than N stage (AUC: 0.760, 95%CI: 0.696-0.823 and histological grade (AUC: 0.756, 95%CI: 0.692-0.820 on predicting the risk for recurrence.A QDs-based quantitative and in situ multiple imaging on Ki67 and CK was developed to improve Ki67 assessment in BC, and Ki67/CK grade had better performance than Ki67 grade in predicting prognosis.

  12. Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration

    Science.gov (United States)

    Leung, Samuel C Y; Nielsen, Torsten O; Zabaglo, Lila; Arun, Indu; Badve, Sunil S; Bane, Anita L; Bartlett, John M S; Borgquist, Signe; Chang, Martin C; Dodson, Andrew; Enos, Rebecca A; Fineberg, Susan; Focke, Cornelia M; Gao, Dongxia; Gown, Allen M; Grabau, Dorthe; Gutierrez, Carolina; Hugh, Judith C; Kos, Zuzana; Lænkholm, Anne-Vibeke; Lin, Ming-Gang; Mastropasqua, Mauro G; Moriya, Takuya; Nofech-Mozes, Sharon; Osborne, C Kent; Penault-Llorca, Frédérique M; Piper, Tammy; Sakatani, Takashi; Salgado, Roberto; Starczynski, Jane; Viale, Giuseppe; Hayes, Daniel F; McShane, Lisa M; Dowsett, Mitch

    2016-01-01

    Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81–0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999–0.93) and hot-spot methods (0.84; 95% CI: 0.77–0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples. PMID:28721378

  13. Prognostic value of Ki-67 in breast cancer patients with positive axillary lymph nodes: a retrospective cohort study.

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    Feng-yan Li

    Full Text Available INTRODUCTION: Ki-67 expression is a biomarker for proliferation. Its prognostic value is recognized in breast cancer (BC patients with negative axillary nodes, but is less clear in BC patients with positive axillary lymph nodes. METHODS: We retrospectively reviewed the medical records of 1131 Chinese BC patients treated from January 2002 to June 2007 and 450 patients met the inclusion criteria: positive nodes, adjuvant therapy, and complete biomarker profile (estrogen receptor (ER, progesterone receptor (PR, HER2, p53, Ki-67. Univariate and multivariate regression analysis were used to correlate biomarkers and tumor characteristics with metastasis free survival (MFS and overall survival (OS. RESULTS: Median follow-up time was 46 months (range 5-76 months. The Ki-67 expression was associated significantly with histological grade, ER, PR, HER2, and P53 status (P<0.05. Tumor stage, nodal stage, and ER status were independent prognostic factors for MFS. Ki-67 status was associated significantly with OS but not MFS. To determine whether the extent of LN involvement in the BC patients influenced the role of Ki-67 in survival rates, we compared these variables in patients with 1-3 positive lymph nodes (N1 to those of patients with ≥ 4 positive lymph nodes. Ki-67 status was an independent prognostic factor for MFS (Hazard Ratio, 3.27, P = 0.026 and overall survival (HR, 10.64, P = 0.007 in patients with 1-3 positive nodes (N1. CONCLUSIONS: The possibility that Ki-67 expression together with clinical factors can improve prediction of the prognosis of BC patients with 1 ∼ 3 positive axillary lymph nodes warrants further studies.

  14. Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer.

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    Juríková, Miroslava; Danihel, Ľudovít; Polák, Štefan; Varga, Ivan

    2016-06-01

    The proliferative activity of tumour cells represents an important prognostic marker in the diagnosis of cancer. One of the methods for assessing the proliferative activity of cells is the immunohistochemical detection of cell cycle-specific antigens. For example, Ki67, proliferating cell nuclear antigen (PCNA), and minichromosome maintenance (MCM) proteins are standard markers of proliferation that are commonly used to assess the growth fraction of a cell population. The function of Ki67, the widely used marker of proliferation, still remains unclear. In contrast, PCNA and MCM proteins have been identified as important participants of DNA replication. All three proteins only manifest their expression during the cell division of normal and neoplastic cells. Since the expression of these proliferative markers was confirmed in several malignant tumours, their prognostic and predictive values have been evaluated to determine their significance in the diagnosis of cancer. This review offers insight into the discovery of the abovementioned proteins, as well as their current molecular and biological importance. In addition, the functions and properties of all three proteins and their use as markers of proliferation in the diagnosis of breast cancer are described. This work also reveals new findings about the role of Ki67 during the mitotic phase of the cell cycle. Finally, information is provided about the advantages and disadvantages of using all three antigens in the diagnosis of cancer. Copyright © 2016 Elsevier GmbH. All rights reserved.

  15. Ki-67 as a prognostic marker according to breast cancer molecular subtype

    OpenAIRE

    Soliman, Nahed A.; Yussif, Shaimaa M.

    2016-01-01

    Objective: Ki-67 plays an important function in cell division, but its exact role is still unknown. Moreover, few works regarding its overall function were published. The present study evaluated the clinical significance of Ki-67 index as a prognostic marker and predictor of recurrence in different molecular subtypes of breast cancer. The relationship of Ki-67 index with different clinicopathological factors was also analyzed. Methods: Ki-67 index was measured in 107 cases of primary breast c...

  16. Ki67 and p53 in gastrointestinal stromal tumors - GIST Ki67 and p53 em tumores estromais gastrointestinais - GIST

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    Lúcio Roberto de Oliveira das Neves

    2009-06-01

    Full Text Available CONTEXT: Gastrointestinal stromal tumor (GIST is the most common mesenchymal tumor. Cellular proliferation and apoptosis is gaining importance for predicting prognosis in several cancers. OBJECTIVE: To investigate the Ki67 and p53 immunostaining in GISTs. METHODS: Specimens from 40 patients with GIST were assessed for immunohistochemical expression of Ki67 and p53. The tumors were divided according the risk of recurrence in two groups: I with high or intermediate risk and; II with low or very low risk. RESULTS: Among the 40 patients, 21 were men, the mean age was 56 years, 16 occurred in the small intestine and 13 in the stomach, 5 in the retroperitonium, 4 in the colon or rectum and 2 in the mesenterium. Thirty two tumors were from group I and 8 from group II. Half of the patients developed recurrence, being 90% of the group I (P = 0.114. The tumor Ki67 labelling index ranged from 0.02 to 0.35 (mean level 0.12. This index was marginally higher in the group I patients with recurrence (P = 0.09 compared to the patients of the same group without recurrence. p53 staining was expressed in 65% of the GISTs. A higher frequency of p53 and Ki67 had been found in the group I tumors when compared to the other group (P = 0.022; OR = 8.00 - IC 95%: 1.32-48.65. CONCLUSION: The most common site was the small intestine and 80% had a malignant potential justifying the high recurrence observed. No significant correlation was found between p53 and overall outcome of the patients. In group I patients, the evaluation Ki67LI may be a marker of prognosis. The positivity of both markers is higher among the patients with worst prognosis than in the others.CONTEXTO: Os tumores estromais gastrointestinais (GIST são os tumores mesenquimais mais frequentes. A proliferação intestinal e a apoptose são cada vez mais importantes na avaliação do prognóstico de diversos cânceres. OBJETIVO: Avaliar a imunoexpressão de Ki67 e p53 em GIST. MÉTODOS: Foram estudados a

  17. Differences in Expression of EGFR, Ki67 and p-EPK in Oral Cavity ...

    African Journals Online (AJOL)

    Overexpression of EGFR and Ki67 and loss of p-EPK were observed more frequently in HPV negative tumors. Multivariate Cox regression analysis showed that Ki67 expression had a significantly unfavorable impact on relapse free survival in oropharyngeal cancer. Conclusion: The expression levels of EGFR, Ki67, and ...

  18. Associations and indications of Ki67 expression with clinicopathological parameters and molecular subtypes in invasive breast cancer: A population-based study.

    Science.gov (United States)

    Sun, Jinzhong; Chen, Chuang; Wei, Wen; Zheng, Hongmei; Yuan, Jingping; Tu, Y I; Yao, Feng; Wang, Lijun; Yao, Xiaoli; Li, Juanjuan; Li, Yan; Sun, Shengrong

    2015-09-01

    Ki67 has potential prognostic and predictive values for breast cancer patients, and has become an important biomarker in routine clinical practice. The aims of the present study were to investigate the distribution of Ki67 expression and its correlation with other clinicopathological parameters in central China. In total, 1,259 patients with newly-diagnosed invasive breast cancer were included in the present study. The clinical information was obtained from the electronic medical records. The expression levels of Ki67, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) were detected by immunohistochemical analysis. The associations between Ki67 scores and other prognostic factors were evaluated as continuous and categorical variables. The mean value of the Ki67 scores of all patients was 31%. In total, ~36% (456/1,259) of the patients demonstrated a low expression of Ki67. A statistically significant correlation was identified between the mean Ki67 scores and the lymph node status, tumor grade, ER, PR and HER2 status, and clinical stage or molecular subtypes (all PKi67 was categorized into high (>14%) and low (≤14%) level groups, the χ 2 test was used to verify these results. The Ki67 scores demonstrated no statistically significant differences between the HER2-positive (non-luminal) and three negative subtypes, with the exception of patients with a tumor size of >2 cm (P=0.02). In conclusion, the results revealed the presence of significant correlations between Ki67 and other clinicopathological parameters.

  19. The prognostic value of Ki67 in systemically untreated patients with node-negative breast cancer.

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    Pathmanathan, Nirmala; Balleine, Rosemary L; Jayasinghe, Upali W; Bilinski, Kellie L; Provan, Pamela J; Byth, Karen; Bilous, A Michael; Salisbury, Elizabeth L; Boyages, John

    2014-03-01

    To evaluate the utility of Ki67 as a prognostic marker in a series of patients with node-negative breast cancer untreated with adjuvant systemic therapy. The cohort consisted of 203 cases treated with breast conserving surgery and radiation only; median follow-up was 183 months (range 156-277 months). An immunohistochemical panel of oestrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK)5/6 and Ki67 and human epidermal growth factor 2 in situ hybridization (HER2-ISH) was performed on the tumour samples. Ki67 scores were evaluable in 193/203 patients (95.1%). The primary outcome was breast cancer specific survival (BCSS). Of the cohort, 29 (14.2%) died of breast cancer. A cut off of 10% separated tumours into a 'Ki67-low' (n=70) or 'Ki67-high' group (n=123). The breast cancer specific survival was 97.1% and 77.6% for Ki67-low and Ki67-high groups, respectively. Univariate analysis showed that in this lymph node-negative cohort, the predictors for BCSS were tumour size, Ki67, LVI, age and histological grade 3. Multivariable analysis showed that Ki67 index and lymphovascular space invasion were independent predictors of breast cancer death. To examine the utility of Ki67 in assignment of immunohistochemically molecular subtypes, cases were assigned into Luminal A (ER-positive, HER2-negative, Ki67 ≤14%), Luminal B (ER-positive, HER2-negative, Ki67 >14%) and triple negative (ER/PR-negative and HER2-negative, any Ki67). The 15-year breast cancer specific survival was 91.7%, 79.4% and 75.8%, respectively. A statistically significant difference in breast cancer specific survival is seen in groups defined using Ki67 and receptor status, whereas histological grading was not a significant predictor of survival. Ki67 immunostaining provides prognostic information beyond traditionally assessed clinicopathological variables.

  20. Correlating Ki67 and other prognostic markers with Oncotype DX recurrence score in early estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Tan, Aaron C; Li, Bob T; Nahar, Kazi; Danieletto, Suzanne; Fong, Eva S; Currer, Trevor; Parasyn, Andrew; Middleton, Philip; Wong, Heidi; Smart, Denis; Rutovitz, Josie J; McCloud, Philip; Hughes, T Michael; Marx, Gavin M

    2017-09-29

    Decisions regarding adjuvant chemotherapy for early breast cancer are complex. Ki67 is increasingly used, in conjunction with conventional prognostic markers, to help decide the use of adjuvant chemotherapy for early breast cancer. Ki67 has been proposed as an economical alternative to Oncotype DX recurrence score (RS), which is a validated prognostic marker for disease recurrence and predictive marker for benefit from chemotherapy. This study aimed to determine in patients where conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy, whether Ki67 could be a substitute for RS. We reviewed all cases of luminal-type node-negative early breast cancer (T1-2, N0-1mi, M0, estrogen receptor positive, HER2 negative) referred for Oncotype DX testing by the multidisciplinary team at an Australian tertiary private hospital from 14th December 2006 to 31st December 2013, when conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy. RS was correlated with Ki67, along with other conventional prognostic markers including tumor size, grade, mitotic rate and lymphovascular invasion. Spearman's rank order correlation coefficient and Pearson product-moment correlation coefficient (r) were used for ordinal and continuous variables, respectively. A total of 58 patients were analyzed, median Ki67 was 15% (range 2-50%) and the median RS was 16 (range 3-65). There was no positive correlation between Ki67 and RS (r = 0.01, P = 0.93). No single conventional prognostic marker was shown to significantly correlate with RS, including tumor size (r = -0.02, P = 0.88), grade (r = 0.10, P = 0.44), mitotic rate (r = -0.07, P = 0.69) and lymphovascular invasion (r = -0.12, P = 0.39). Ki67 and conventional prognostic markers do not correlate with Oncotype DX RS. In the setting where conventional prognostic markers do not show a clear indication for or against adjuvant chemotherapy as determined by

  1. [Neuroendocrine tumors of digestive system: morphologic spectrum and cell proliferation (Ki67 index)].

    Science.gov (United States)

    Delektorskaia, V V; Kushliskiĭ, N E

    2013-01-01

    This review deals with the analysis of up-to-date concepts ofdiferent types of human neuroendocrine tumors of the digestive system. It summarizes the information on the specifics of recent histological classifications and criteria of morphological diagnosis accounting histological, ultrastructural and immunohistochemical parameters. Current issues of the nomenclature as well as various systems of grading and staging are discussed. In the light of these criteria the results of the own research clinical value of the determination of cell proliferation in primary and metastatic gastroenteropancreatic neuroendocrine neoplasms on the basis of evaluation of the Ki67 antigen expression are also presented.

  2. Standardization for Ki-67 assessment in moderately differentiated breast cancer. A retrospective analysis of the SAKK 28/12 study.

    Directory of Open Access Journals (Sweden)

    Zsuzsanna Varga

    Full Text Available Proliferative activity (Ki-67 Labelling Index in breast cancer increasingly serves as an additional tool in the decision for or against adjuvant chemotherapy in midrange hormone receptor positive breast cancer. Ki-67 Index has been previously shown to suffer from high inter-observer variability especially in midrange (G2 breast carcinomas. In this study we conducted a systematic approach using different Ki-67 assessments on large tissue sections in order to identify the method with the highest reliability and the lowest variability.Five breast pathologists retrospectively analyzed proliferative activity of 50 G2 invasive breast carcinomas using large tissue sections by assessing Ki-67 immunohistochemistry. Ki-67-assessments were done on light microscopy and on digital images following these methods: 1 assessing five regions, 2 assessing only darkly stained nuclei and 3 considering only condensed proliferative areas ('hotspots'. An individual review (the first described assessment from 2008 was also performed. The assessments on light microscopy were done by estimating. All measurements were performed three times. Inter-observer and intra-observer reliabilities were calculated using the approach proposed by Eliasziw et al. Clinical cutoffs (14% and 20% were tested using Fleiss' Kappa.There was a good intra-observer reliability in 5 of 7 methods (ICC: 0.76-0.89. The two highest inter-observer reliability was fair to moderate (ICC: 0.71 and 0.74 in 2 methods (region-analysis and individual-review on light microscopy. Fleiss'-kappa-values (14% cut-off were the highest (moderate using the original recommendation on light-microscope (Kappa 0.58. Fleiss' kappa values (20% cut-off were the highest (Kappa 0.48 each in analyzing hotspots on light-microscopy and digital-analysis. No methodologies using digital-analysis were superior to the methods on light microscope.Our results show that all methods on light-microscopy for Ki-67 assessment in large tissue

  3. Can Ki-67 Play a Role in Prediction of Breast Cancer Patients' Response to Neoadjuvant Chemotherapy?

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    Juhasz-Böss Ingolf

    2014-01-01

    Full Text Available Background. Currently the choice of breast cancer therapy is based on prognostic factors. The proliferation marker Ki-67 is used increasingly to determine the method of therapy. The current study analyses the predictive value of Ki-67 in foreseeing breast cancer patients’ responses to neoadjuvant chemotherapy. Methods. This study includes patients with invasive breast cancer treated between 2008 and 2013. The clinical response was assessed by correlating Ki-67 to histological examination, mammography, and ultrasonography findings. Results. The average Ki-67 value in our patients collectively (n=77 is 34.9 ± 24.6%. The average Ki-67 value is the highest with 37.4 ± 24.0% in patients with a pCR. The Ki-67 values do not differ significantly among the 3 groups: pCR versus partial pathological response versus stable disease/progress (P=0.896. However, Ki-67 values of patients with luminal, Her2 enriched, and basal-like cancers differed significantly from each other. Furthermore, within the group of luminal tumors Ki-67 values of patients with versus without pCR also differed significantly. Conclusion. Our data shows that the Ki-67 value predicts the response to neoadjuvant chemotherapy as a function of the molecular subtype, reflecting the daily routine concerning Ki-67 and its impressing potential and limitation as a predictive marker for neoadjuvant chemotherapy response.

  4. Menstrual cycle could affect Ki67 expression in estrogen receptor-positive breast cancer patients.

    Science.gov (United States)

    Horimoto, Yoshiya; Arakawa, Atsushi; Tanabe, Masahiko; Kuroda, Keiji; Matsuoka, Joe; Igari, Fumie; Himuro, Takanori; Yoshida, Yuko; Tokuda, Emi; Shimizu, Hideo; Hino, Okio; Saito, Mitsue

    2015-10-01

    Ki67 is a potent prognostic marker for determining systemic treatment of patients with hormone receptor-positive breast cancer. However, evaluation of Ki67 expression can be difficult, due mostly to its heterogeneity. The Ki67 expression level, which indicates that a cell is undergoing division (cell cycle), rises when proliferation activity increases. Thus, Ki67 expression might be affected by hormonal stimuli. We hypothesised that Ki67 expression level might change during the menstrual cycle. We examined pairs of biopsy and surgical specimens from individual patients to evaluate this hypothesis. First, the effects of estradiol on Ki67 expression in breast cancer cell lines were examined employing immunocytochemistry and Western blotting. Next, differences in Ki67 expression between biopsy and surgical specimens from 131 patients with estrogen receptor-positive tumours were retrospectively examined. In vitro experiments showed Ki67 expression in estrogen receptor-positive cancer cells to be dependent on estradiol stimulation. Ki67 expression was higher in biopsy samples collected in the luteal phase than in those from other phases. When biopsy and surgical samples were obtained at different times during the menstrual cycle in the same individual, there were differences in Ki67 expression between these samples. Those collected in the luteal phase showed higher Ki67 expression than samples obtained during other phases (pKi67 expression varied in the same patients according to menstrual cycle phase. Our results suggest that Ki67 expression in estrogen receptor-positive breast cancer should be carefully assessed bearing in mind the patient's menstrual cycle, since the interpretation of expression could affect treatment decisions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  5. Digital image analysis of Ki67 in hot spots is superior to both manual Ki67 and mitotic counts in breast cancer.

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    Stålhammar, Gustav; Robertson, Stephanie; Wedlund, Lena; Lippert, Michael; Rantalainen, Mattias; Bergh, Jonas; Hartman, Johan

    2017-12-08

    During pathological examination of breast tumours, proliferative activity is routinely evaluated by a count of mitoses. Adding immunohistochemical stains of Ki67 provides extra prognostic and predictive information. However, the currently used methods for these evaluations suffer from imperfect reproducibility. It is still unclear whether analysis of Ki67 should be performed in hot spots, in the tumour periphery, or as an average of the whole tumour section. The aim of this study was to compare the clinical relevance of mitoses, Ki67 and phosphohistone H3 in two cohorts of primary breast cancer specimens (total n = 294). Both manual and digital image analysis scores were evaluated for sensitivity and specificity for luminal B versus A subtype as defined by PAM50 gene expression assays, for high versus low transcriptomic grade, for axillary lymph node status, and for prognostic value in terms of prediction of overall and relapse-free survival. Digital image analysis of Ki67 outperformed the other markers, especially in hot spots. Tumours with high Ki67 expression and high numbers of phosphohistone H3-positive cells had significantly increased hazard ratios for all-cause mortality within 10 years from diagnosis. Replacing manual mitotic counts with digital image analysis of Ki67 in hot spots increased the differences in overall survival between the highest and lowest histological grades, and added significant prognostic information. Digital image analysis of Ki67 in hot spots is the marker of choice for routine analysis of proliferation in breast cancer. © 2017 John Wiley & Sons Ltd.

  6. Immunohistochemical expression of Bcl-2 and Ki-67 in oral lichen planus and leukoplakia with different degrees of dysplasia.

    Science.gov (United States)

    Pigatti, Fernanda Mombrini; Taveira, Luís Antônio de Assis; Soares, Cléverson Teixeira

    2015-02-01

    Oral lichen planus (OLP) is a chronic inflammatory disease of unknown cause. Malignant transformation in OLP lesions may be favored by changes in the expression of proteins that regulate cell proliferation and apoptosis. This study aimed to investigate these issues by immunohistochemical staining for Bcl-2 and Ki-67 and by correlating histopathological findings in samples from lesions of OLP and leukoplakia with epithelial dysplasia. Data for patients with OLP or leukoplakia with moderate or severe epithelial dysplasia recorded during 2006-2011 were retrospectively reviewed. The study samples represented 37 subjects with OLP (n = 14), leukoplakia with moderate (n = 8) or severe (n = 6) epithelial dysplasia, and normal buccal mucosa (controls, n = 9). New sections were subjected to histological examination and immunohistochemistry for Bcl-2 and Ki-67 in the basal layer, suprabasal layer, and inflammatory infiltrate, respectively. All basal layer sections stained either negative or positive in leukoplakia, 85.7% of sections indicated positivity in leukoplakia (64.3%) sections stained positive for Ki-67 in >50% of cells. All suprabasal sections stained either negative or positive in leukoplakia (42.9% and 57.1%, respectively), and control (88.9% and 11.1%, respectively) samples. Suprabasal staining for Ki-67 was negative or positive in leukoplakia (7.1% and 92.9%, respectively), and controls (88.9% and 11.1%, respectively). Staining for Bcl-2 in inflammatory infiltrate in OLP was positive in 92.9% of sections. Expression of Bcl-2 may play a dual role in tumor development and progression. Increased cell proliferation in the epithelium may present a predisposition to cancer in OLP. The expression of Ki-67 can be considered as an adjunct marker for proliferative activity in lesions with malignant potential. The prognostic value of these immunomarkers in the evaluation of precancerous oral lesions requires further investigation. © 2014 The International Society

  7. Can Histological Grade and Mitotic Index Replace Ki67 to Determine Luminal Breast Cancer Subtypes?

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    Oddó, David; Pulgar, Dahiana; Elgueta, Nicole; Acevedo, Francisco; Razmiliz, Dravna; Navarro, María Elena; Camus, Mauricio; Merino, Tomás; Retamal, Ignacio; Pérez-Sepúlveda, Alejandra; Villarroel, Alejandra; Galindo, Héctor; Peña, José; Sánchez, César

    2018-01-27

    Introduction: Breast cancer can be classified into subtypes based on immunohistochemical markers, with Ki67 expression levels being used to divide luminal BC tumors in luminal A and B subtypes; however, Ki67 is not routinely determined due to a lack of standardization. Objective: To evaluate histological grade and Eliminate: the mitotic index to determine if they can be used as an alternative method to Ki67 staining for luminal subtype definition. Methods: We evaluated estrogen receptor positive breast cancer tissue samples. Pathological analysis included determination of Ki67. A low level of Ki67 was defined as breast cancer samples; 24 (15,9%) were classified as I; 74 as HG II (49%), and 53 (35,1%) as HG III. The median value for Ki67 was 13% (range: Ki67 values significantly lower than HG II and III tumors (Anova, Tamhane test p=0,001). A higher Ki67 value was related to a higher MI (Rho Sperman p=0,336; R2= 0,0273). ROC curve analysis determined that a MI ≥ 3 had a sensibility of 61.9% and specificity of 66.7% in predicting a high Ki67 value (≥14%) (area under the curve: 0,691; p =0,0001). A HG I tumor or HG II-III with MI ≤2, had a high probability of corresponding to a LA tumor (76,3%), as defined using Ki67 expression, while the probability of a LB subtype was higher with HG II-III and a MI ≥3 (57.4%). Global discrimination was 68.1%. Conclusions: For the LA subtype, our predictive model showed a good correlation of HG and MI with the classification based on Ki67Ki67 determination seems to be needed for this group of patients. Creative Commons Attribution License

  8. New insight into Ki67 expression at the invasive front in breast cancer.

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    Peng Gong

    Full Text Available PURPOSE: To investigate the distribution of Ki67+ cells in breast cancer in relation to clinical-pathological parameters and prognosis. MATERIALS AND METHODS: Ki67 expression status was detected in 1,086 breast cancer specimens using immunohistochemistry staining and examining the relationship between the Ki67+ cells' location. Subsequently, clinical-pathological parameters and prognosis were determined. RESULTS: In total, Ki67 protein expression was found in 781 (71.92% of the 1,086 breast cancer specimens. Among the 781 Ki67+ cases, 461 were defined as diffuse type and 320 were defined as borderline type. After universal correlation analysis, significant differences were observed in age, histological grade, metastatic nodes, postoperative distant metastasis, and molecular subtype between Ki67+ and Ki67- cases (P = 0.01, 0.001, 0.001, 0.001, and 0.001, respectively. After subgroup analysis, the borderline cases were found to be characterized by a high distant metastasis rate compared to the diffuse cases as well as the Ki67- cases (P = 0.001. No differences were observed between diffuse type or Ki67- cases (P = 0.105. Multivariate analysis showed that age, tumor size, histological grade, lymph node metastasis, molecular subtype, and the Ki67 distribution pattern were observed to be related to postoperative distant metastasis (all P<0.05. Furthermore, borderline type was shown to attain a significantly more distant bone and liver metastasis and worse disease-specific survival than the other types (P = 0.001. In the Cox regression test, the Ki67 distribution pattern was detected as an independent prognostic factor (P = 0.001. CONCLUSION: The distribution pattern of Ki67 may be a new independent prognostic factor for breast cancer.

  9. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours.

    Science.gov (United States)

    Focke, Cornelia M; Decker, Thomas; van Diest, Paul J

    2016-11-01

    Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the extent of intratumoral heterogeneity of Ki67 expression. Our aim was to study the intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with clinicopathological features, such as oestrogen receptor (ER) status, grade and histological subtype. The Ki67-labelling index (Ki67-LI) was assessed in hot, cold and intermediate spots of 233 invasive breast cancers by counting a total of 1020 cells, according to a protocol of the International Ki67 in Breast Cancer Working Group. Differences between the spots per tumour were analysed further for clinicopathological subgroups defined by ER status, grade and histological subtype. All clinicopathological subgroups showed significant differences in Ki67-LI between hot, intermediate and cold spots (P cancers (72.6 versus 49.2%, P cancers. Nested analysis of variance indicated that in both ER-positive and ER-negative cancers, variance in Ki67-LI within tumours contributed more to the total variance (56% for ER-positive, 60% for ER-negative cancers) than the variance between tumours. Intratumoral heterogeneity in Ki67-LI is a ubiquitous phenomenon across various pathological subgroups of breast cancer that may impact assessment of Ki67 levels for clinical decision-making, and sheds new light on recommended cut-offs. © 2016 John Wiley & Sons Ltd.

  10. An interobserver reproducibility analysis of Ki67 visual assessment in breast cancer.

    Science.gov (United States)

    Shui, Ruohong; Yu, Baohua; Bi, Rui; Yang, Fei; Yang, Wentao

    2015-01-01

    Ki67 labeling index (LI) is used as a predictive marker and is associated with prognosis in breast cancer. However, standardised methodologies for measurement are lacking which has limited its application in clinical practice. In this study, we evaluated the interobserver concordance of visual assessment of Ki67 LI in breast cancer. Ki67-immunostained slides of 160 cases of primary invasive breast cancer were visual assessed by five breast pathologists with two different methods to choose the scoring fields: (1) hot-spot score, (2) average score. Proportions of positive invasive tumor cells at 10 % intervals were scored. The intra-class correlation coefficient (ICC) was used to assess the interobserver reproducibility. (1) A perfect concordance of Ki67 LI was demonstrated according to both score methods (P30% Ki-67 LI). The concordance was relatively low in intermediate Ki67 LI group compared with low and high Ki67 LI groups. (3) All cases were classified into three groups by paired-difference (d) between means of hot-spot score and average score (dKi67 LI at 10 % intervals is a candidate for a standard method in breast cancer clinical practice. Average score and hot-spot score of visual assessment both demonstrated a perfect concordance, and an overall average assessment across the whole section including hot spots may be a better method. Interobserver concordance of intermediate Ki67 LI in which most cutoffs are located for making clinical decisions was relatively low.

  11. St Gallen 2015 subtyping of luminal breast cancers : impact of different Ki67-based proliferation assessment methods

    NARCIS (Netherlands)

    Focke, Cornelia M.|info:eu-repo/dai/nl/413647927; van Diest, Paul J.|info:eu-repo/dai/nl/075281775; Decker, Thomas

    2016-01-01

    Ki67 has been proposed as prognostic proliferation marker in luminal breast cancer (BC), but little is known on the influence of Ki67 assessment methods on subtyping into luminal A- and B-like tumors. Our aim was to study the influence of different Ki67-labeling index (Ki67-LI) assessment methods on

  12. Prognostic significance of the Ki67 scoring categories in breast cancer subgroups.

    Science.gov (United States)

    Niikura, Naoki; Masuda, Shinobu; Kumaki, Nobue; Xiaoyan, Tang; Terada, Mizuho; Terao, Mayako; Iwamoto, Takayuki; Oshitanai, Risa; Morioka, Toru; Tuda, Banri; Okamura, Takuho; Saito, Yuki; Suzuki, Yasuhiro; Tokuda, Yutaka

    2014-10-01

    Immunohistochemical (IHC) expression of Ki67 has a prognostic and predictive value for breast cancer, and the IHC Ki67 labeling index is estimated by counting the number of positive and negative cells. It has not been clarified whether IHC Ki67 estimated using a semiquantitative scoring system has a prognostic value. We aimed to estimate the usefulness of scoring categories of IHC Ki67 as a prognostic factor for breast cancer subgroups. We retrospectively identified patients in the Tokai University breast cancer database for whom IHC Ki67 data were available between January 1, 2000 and December 31, 2010. Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test. Of the 1331 primary breast cancer patients included in the study, In patients with estrogen receptor (ER)-positive and HER2-negative tumors (n = 971), high and intermediate Ki67 scores were associated with poorer relapse-free survival than low Ki67 scores (P Ki67 scores than in patients with high Ki67 scores (hazard ratio, 0.387; 95% confidence interval, 0.233-0.643; P Ki67 score was not significantly associated with PFS in the ER-positive and HER2-positive, ER-negative and HER2-positive, or ER-negative and HER2-negative subgroups. Our data demonstrated that low, intermediate, and high Ki67 scores have a prognostic value in breast cancer patients with ER-positive and HER2-negative tumors. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. New insight into Ki67 expression at the invasive front in breast cancer.

    Science.gov (United States)

    Gong, Peng; Wang, Yingxin; Liu, Gavin; Zhang, Jing; Wang, Zhongyu

    2013-01-01

    To investigate the distribution of Ki67+ cells in breast cancer in relation to clinical-pathological parameters and prognosis. Ki67 expression status was detected in 1,086 breast cancer specimens using immunohistochemistry staining and examining the relationship between the Ki67+ cells' location. Subsequently, clinical-pathological parameters and prognosis were determined. In total, Ki67 protein expression was found in 781 (71.92%) of the 1,086 breast cancer specimens. Among the 781 Ki67+ cases, 461 were defined as diffuse type and 320 were defined as borderline type. After universal correlation analysis, significant differences were observed in age, histological grade, metastatic nodes, postoperative distant metastasis, and molecular subtype between Ki67+ and Ki67- cases (P = 0.01, 0.001, 0.001, 0.001, and 0.001, respectively). After subgroup analysis, the borderline cases were found to be characterized by a high distant metastasis rate compared to the diffuse cases as well as the Ki67- cases (P = 0.001). No differences were observed between diffuse type or Ki67- cases (P = 0.105). Multivariate analysis showed that age, tumor size, histological grade, lymph node metastasis, molecular subtype, and the Ki67 distribution pattern were observed to be related to postoperative distant metastasis (all PKi67 distribution pattern was detected as an independent prognostic factor (P = 0.001). The distribution pattern of Ki67 may be a new independent prognostic factor for breast cancer.

  14. Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer.

    Science.gov (United States)

    Aleskandarany, M A; Green, A R; Ashankyty, I; Elmouna, A; Diez-Rodriguez, M; Nolan, C C; Ellis, I O; Rakha, E A

    2016-07-01

    In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.

  15. Ki-67 marker useful for classification of malignant invasive ductal breast cancer

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    Irmawati Hassan

    2013-12-01

    Full Text Available BACKGROUND Breast cancer is an important health problem in the world. Uncontrolled cell proliferation represents a malignant characteristic of neoplasia such as breast cancer, and can be examined immunohistochemically by measuring the Ki-67 proliferative marker. The objective of this study was to determine the role of Ki-67 for classification of the degree of malignancy in women with invasive ductal breast cancer. METHODS A cross-sectional study was conducted on 20 women with invasive ductal breast cancer. The samples were immuno-histochemically tested for Ki-67 using anti-Ki-67 primary antibody. The Ki-67 proliferative index was determined by enumerating the proportion of Ki-67 positive nuclei among the total number of cells in ten areas observed at 400x magnification, using a 20% cut-off value to distinguish between low and high proliferative indices. Statistical analysis was by means of the chi-square test. RESULTS Seventy five persent of the high grade malignancies had a high Ki-67 proliferative index (>20%, while only 12.5% of the low grade malignancies had a high Ki-67 index (>20%. The difference in grade malignancy was statistically significant (p=0.022, whereas tumor size was not associated with a statistically significant difference in Ki-67 index (p=0.648. CONCLUSION The study showed that invasive ductal breast cancer with high Ki-67 index was significantly associated with high grade of malignacy. The high Ki-67 marker index can be used for classification of the grade of malignancy of invasive ductal breast cancer.

  16. Distinguishing Low-Risk Luminal A Breast Cancer Subtypes with Ki-67 and p53 Is More Predictive of Long-Term Survival.

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    Se Kyung Lee

    Full Text Available Overexpression of p53 is the most frequent genetic alteration in breast cancer. Recently, many studies have shown that the expression of mutant p53 differs for each subtype of breast cancer and is associated with different prognoses. In this study, we aimed to determine the suitable cut-off value to predict the clinical outcome of p53 overexpression and its usefulness as a prognostic factor in each subtype of breast cancer, especially in luminal A breast cancer. Approval was granted by the Institutional Review Board of Samsung Medical Center. We analyzed a total of 7,739 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between Dec 1995 and Apr 2013. Luminal A subtype was defined as ER&PR + and HER2- and was further subclassified according to Ki-67 and p53 expression as follows: luminal A (Ki-67-,p53-, luminal A (Ki-67+, p53-, luminal A (Ki-67 -, p53+ and luminal A (Ki-67+, p53+. Low-risk luminal A subtype was defined as negative for both Ki-67 and p53 (luminal A [ki-67-, p53-], and others subtypes were considered to be high-risk luminal A breast cancer. A cut-off value of 10% for p53 was a good predictor of clinical outcome in all patients and luminal A breast cancer patients. The prognostic role of p53 overexpression for OS and DFS was only significant in luminal A subtype. The combination of p53 and Ki-67 has been shown to have the best predictive power as calculated by the area under curve (AUC, especially for long-term overall survival. In this study, we have shown that overexpression of p53 and Ki-67 could be used to discriminate low-risk luminal A subtype in breast cancer. Therefore, using the combination of p53 and Ki-67 expression in discriminating low-risk luminal A breast cancer may improve the prognostic power and provide the greatest clinical utility.

  17. Higher Ki67 expression is associates with unfavorable prognostic factors and shorter survival in breast cancer.

    Science.gov (United States)

    Kilickap, Saadettin; Kaya, Yalcin; Yucel, Birsen; Tuncer, Ersin; Babacan, Nalan Akgul; Elagoz, Sahande

    2014-01-01

    The prognostic value of the Ki67 expression level is yet unclear in breast cancer. The aim of this study was to investigate the association between Ki67 expression levels and prognostic factors such as grade, Her2 and hormone receptor expression status in breast cancers. Clinical and pathological features of the patients with breast cancer were retreived from the hospital records. In this study, 163 patients with breast cancer were analyzed, with a mean age of 53.4±12.2 years. Median Ki67 positivity was 20% and Ki67-high tumors were significantly associated with high grade (pKi67 levels were significantly associated with longer median relapse-free and overall survival compared to those of higher Ki67 levels. High Ki67 expression is associated with ER negativity, Her2 positivity, higher grade and axillary lymph node involvement in breast cancers. The level of Ki67 expression is a prognostic factor predicting relapse-free and overall survival in breast cancer patients.

  18. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours

    NARCIS (Netherlands)

    Focke, Cornelia M.; Decker, Thomas; van Diest, Paul J.

    2016-01-01

    Aims: Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the extent of intratumoral heterogeneity of Ki67 expression. Our aim was to study the intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with

  19. Standardizing evaluation of sarcoma proliferation- higher Ki-67 expression in the tumor periphery than the center

    DEFF Research Database (Denmark)

    Fernebro, J; Engellau, J; Persson, A

    2007-01-01

    Soft tissue sarcomas often present as large and histopathologically heterogenous tumors. Proliferation has repeatedly been identified as a prognostic factor and immunostaining for Ki-67 represents the most commonly used proliferation marker. There is, however, a lack of consensus on how to evaluate...... of proliferation in soft tissue sarcomas should be standardized for clinical application of Ki-67 as a prognostic marker....

  20. An inter-observer Ki67 reproducibility study applying two different assessment methods

    DEFF Research Database (Denmark)

    Laenkholm, Anne-Vibeke; Grabau, Dorthe; Møller Talman, Maj-Lis

    2018-01-01

    INTRODUCTION: In 2011, the St. Gallen Consensus Conference introduced the use of pathology to define the intrinsic breast cancer subtypes by application of immunohistochemical (IHC) surrogate markers ER, PR, HER2 and Ki67 with a specified Ki67 cutoff (>14%) for luminal B-like definition. Reports...... concerning impaired reproducibility of Ki67 estimation and threshold inconsistency led to the initiation of this quality assurance study (2013-2015). The aim of the study was to investigate inter-observer variation for Ki67 estimation in malignant breast tumors by two different quantification methods....... 0.84 (95% CI: 0.80-0.87) by the count method. CONCLUSION: Although the study in general showed a moderate to good inter-observer agreement according to both ICC and Lights Kappa, still major discrepancies were identified in especially the mid-range of observations. Consequently, for now Ki67...

  1. Ki67 expression in breast cancer. Correlation with prognostic markers and clinicopathological parameters in Saudi patients.

    Science.gov (United States)

    Elkablawy, Mohamed A; Albasri, Abdulkader M; Mohammed, Rabab A; Hussainy, Akbar S; Nouh, Magdy M; Alhujaily, Ahmed S

    2016-02-01

    To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC) patients and investigate any possible predictive or prognostic value for Ki67. This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI) in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) with their clinicopathological parameters.   Ki67 immunoreactivity was highly expressed (greater than 25% of the tumor cells were positive) in 85 (73.9%) patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (p less than 0.02), high tumor grade (p less than 0.01), lymph node metastasis (p less than 0.001), and Her-2/neu positivity (p less than 0.009). However, the association with ER positivity, PR positivity, tumor size, and lymphovascular invasion were not statistically significant. The Ki67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2) subtypes compared with the Her2/neu negative (luminal A) subtype (p less than 0.04). The Ki67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients.

  2. Role of Ki67 in predicting resistance to adjuvant tamoxifen in postmenopausal breast cancer patients.

    Science.gov (United States)

    Elzawahry, Heba M; Saber, Magdy M; Mokhtar, Nadia M; Zeeneldin, Ahmed A; Ismail, Yahia M; Alieldin, Nelly H

    2013-12-01

    Breast cancer (BC) is a major health problem in Egypt and worldwide. Its prognosis depends not only on tumor stage but also on tumor biology. To correlate the expression of Ki67 with the clinical outcomes of early hormone-receptor positive postmenopausal BC patients who are receiving tamoxifen. This cohort study included 70 patients. They were followed up for a minimum of 2 years. Ki67 was assessed on paraffin-embedded blocks using immunohistochemistry methods. The median Ki67 value was 22.5% (IQR, 10%-50%). Ki67 was significantly higher in patients with HER2 positive tumors compared to HER2 negative tumors. After a median follow up period of 53 months, 22 patients (31%) developed disease recurrence either loco-regional or distant in 5.7% and 30%, respectively. Recurrent patients had significantly higher tumor stage, nodal stage and Ki67 values compared to non-recurrent cases. The 2-, 3- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 100% & 91%, 98% & 84% and 77% & 59%, respectively. DFS was significantly worse with higher TNM stage, lower ER expression and higher Ki67 values. OS was significantly worse in patients with Ki67 values ≥ 30%. Ki67 ≥ 30% was an independent predictor of recurrence, poor DFS and OS. High Ki67 expression is predictive of poor prognosis and of resistance to adjuvant tamoxifen therapy in postmenopausal BC. We recommend considering Ki67 as one of the risk factors that guide adjuvant treatment decisions. Copyright © 2013. Production and hosting by Elsevier B.V.

  3. Correlation between Ki67 and histological grade in breast cancer patients treated with preoperative chemotherapy.

    Science.gov (United States)

    Petric, Militza; Martinez, Santiago; Acevedo, Francisco; Oddo, David; Artigas, Rocio; Camus, Mauricio; Sanchez, Cesar

    2014-01-01

    Breast cancer (BC) is a heterogeneous disease and cell proliferation markers may help to identify subtypes of clinical interest. We here analyzed the correlation between cell proliferation determined by Ki67 and HG in BC patients undergoing preoperative chemotherapy (PCT). We obtained clinical/pathological data from patients with invasive BC treated at our institution from 1999 until 2012. Expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor type 2 (HER2) and Ki67 were determined by immuno-histochemistry (IHC). Clinicopathological subtypes were defined as: Luminal A, ER and/or PR positive, HER2 negative, HG 1 or 2; Luminal B, ER and/or PR positive, HER2 negative or positive and/or HG 3; triple negative (TN), ER, PR and HER2 negative independent of HG; HER2 positive, ER, PR negative and HER2 positive, independent of HG. By using Ki67, a value of 14% separated Luminal A and B tumors, independently of the histological grade. We analyzed correlations between Ki67 and HG, to define BC subtypes and their predictive value for response to PCT. 1,560 BC patients were treated in the period, 147 receiving PCT (9.5%). Some 57 had sufficient clinicopathological information to be included in the study. Median age was 52 years (26-72), with 87.7% invasive ductal carcinomas (n=50). We performed IHC for Ki67 in 40 core biopsies and 50 surgical biopsies, 37 paired samples with Ki67 before and after chemotherapy being available. There was no significant correlation between Ki67 and HG (p=0.237), both categorizing patients into different subtypes. In most cases Ki67 decreased after PCT (65.8%). Only 3 patients had pathologic complete response (cPR). In our experience we did not find associations between Ki67 and HG. Determination of clinicopathological luminal subtypes differs by using Ki67 or HG.

  4. Ki67 expression in breast cancer. Correlation with prognostic markers and clinicopathological parameters in Saudi patients

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    Mohamed A. Elkablawy

    2016-02-01

    Full Text Available Objectives: To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC patients and investigate any possible predictive or prognostic value for Ki67. Methods: This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor 2 (HER2/neu with their clinicopathological parameters. Results: Ki67 immunoreactivity was highly expressed (greater than 25% of the tumor cells were positive in 85 (73.9% patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (p less than 0.02, high tumor grade (p less than 0.01, lymph node metastasis (p less than 0.001, and Her-2/neu positivity (p less than 0.009. However, the association with ER positivity, PR positivity, tumor size, and lymphovascular invasion were not statistically significant. The Ki67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2 subtypes compared with the Her2/neu negative (luminal A subtype (p less than 0.04. Conclusion: The Ki67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients.

  5. Immunohistochemical Ki-67/KL1 double stains increase accuracy of Ki-67 indices in breast cancer and simplify automated image analysis

    DEFF Research Database (Denmark)

    Nielsen, Patricia S; Bentzer, Nina K; Jensen, Vibeke

    2014-01-01

    observers and automated image analysis. RESULTS: Indices were predominantly higher for single stains than double stains (P≤0.002), yet the difference between observers was statistically significant (Pmanual and automated indices ranged from 0...... by digital image analysis. This study aims to detect the difference in accuracy and precision between manual indices of single and double stains, to develop an automated quantification of double stains, and to explore the relation between automated indices and tumor characteristics when quantified...... in different regions: hot spots, global tumor areas, and invasive fronts. MATERIALS AND METHODS: Paraffin-embedded, formalin-fixed tissue from 100 consecutive patients with invasive breast cancer was immunohistochemically stained for Ki-67 and Ki-67/KL1. Ki-67 was manually scored in different regions by 2...

  6. Phosphohistone H3 outperforms Ki67 as a marker of outcome for breast cancer patients.

    Science.gov (United States)

    Gerring, Zac; Pearson, John F; Morrin, Helen R; Robinson, Bridget A; Harris, Gavin C; Walker, Logan C

    2015-10-01

    The proliferation marker Ki67 has been extensively investigated as a prognostic factor in breast cancer, but has not gained widespread clinical acceptance. Phosphohistone H3 is a new immunohistochemical marker for quantifying mitoses; however, there is limited information on its prognostic value in breast cancer. In this study, we performed a head-to-head comparison of Ki67 and phosphohistone H3 to establish the marker with the greatest prognostic value. Tissue microarrays from 108 breast cancer patients were immunohistochemically stained for Ki67 and phosphohistone H3. Our results showed that phosphohistone H3 had a greater prognostic value than Ki67 in a multivariable model that adjusted for traditional prognostic variables in breast cancer. Phosphohistone H3 staining was a stronger predictor of survival at 5 years after diagnosis [hazard ratio (HR) 4.35, P Ki67 (HR 2.44, P = 0.004), and better separated the risk of death in patients aged >45 years. Importantly, phosphohistone H3 consistently showed strong unequivocal staining, in contrast to the variable staining intensities associated with Ki67. Our study suggests that phosphohistone H3 staining is a stronger and more robust prognostic indicator than Ki67 staining in breast cancer patients, and has the potential for use in routine diagnostic laboratories. © 2015 John Wiley & Sons Ltd.

  7. Radiomic features predict Ki-67 expression level and survival in lower grade gliomas.

    Science.gov (United States)

    Li, Yiming; Qian, Zenghui; Xu, Kaibin; Wang, Kai; Fan, Xing; Li, Shaowu; Liu, Xing; Wang, Yinyan; Jiang, Tao

    2017-11-01

    To investigate the radiomic features associated with Ki-67 expression in lower grade gliomas and assess the prognostic values of these features. Patients with lower grade gliomas (n = 117) were randomly assigned into the training (n = 78) and validation (n = 39) sets. A total of 431 radiological features were extracted from each patient. Differential radiological features between the low and high Ki-67 expression groups were screened by significance analysis of microarrays. Then, generalized linear analysis was performed to select features that could predict the Ki-67 expression level. Predictive efficiencies were further evaluated in the validation set. Cox regression analysis was performed to investigate the prognostic values of Ki-67 expression level and Ki-67-related radiological features. A group of nine radiological features were screened for prediction of Ki-67 expression status; these achieved accuracies of 83.3% and 88.6% (areas under the curves, 0.91 and 0.93) in the training and validation sets, respectively. Of these features, only spherical disproportion (SD) was found to be a prognostic factor. Patients in the high SD group exhibited worse outcomes in the whole cohort (overall survival, p level and SD were independent prognostic factors in the multivariate Cox regression analysis. This study identified a radiomic signature for prediction of Ki-67 expression level as well as a prognostic radiological feature in patients with lower grade gliomas.

  8. A study of Ki-67 expression and its clinicopathological determinants in nondysplastic oral leukoplakia

    Directory of Open Access Journals (Sweden)

    Krishnendu Mondal

    2016-01-01

    Full Text Available Context: Oral cancer is the third most prevalent malignancy in India. Leukoplakia is its most common precursor lesion. Aims: This study aimed at evaluation of the Ki-67 expression and thereby detection of the dysplastic potential in histopathologically nondysplastic oral leukoplakia (OL. Secondarily, another purpose was to correlate various clinicopathological factors with the labeling indices (LIs of Ki-67 in those cases as well. Settings and Design: In total, 97 OL cases were examined. Relevant clinical and demographic information was retrieved from the pro forma, prefilled by the patients themselves during their first visit. Subjects and Methods: Ki-67 immunohistochemical staining was performed on paraffin-embedded tissue samples. Its LIs were calculated and correlated with different clinicopathological parameters using statistical software SPSS version 16.0. Results: 58.8% (57 cases lesions exhibited a Ki-67 positivity of ≤5%, and 25.8% (25 cases lesions exhibited it in the range of 6%–25%. Only 15 (15.4% patches were stained positively between 26% and 60%. Patients' age beyond 50 years, nonhomogeneous leukoplakia, and tobacco addiction were the significant risk factors for high Ki-67 scores (P < 0.05. Conclusions: Ki-67 is an essential immunohistochemical marker for epithelial dysplasia in OL, especially when the conventional histopathology fails to appreciate the same. In this purpose, Ki-67 labeling on a routine basis delivers the most convenient results for patients aged above 50 years, and/or addicted to tobacco products, and/or suffering from nonhomogeneous patches.

  9. Application of DWIBS in malignant lymphoma: correlation between ADC values and Ki-67 index.

    Science.gov (United States)

    Sun, Mengtian; Cheng, Jingliang; Zhang, Yong; Bai, Jie; Wang, Feifei; Meng, Yun; Li, Zhenqian

    2018-04-01

    We investigated the correlation between the apparent diffusion coefficient (ADC) and Ki-67 index using diffusion-weighted whole-body imaging with background body signal suppression (DWIBS), and their utility in evaluating malignant lymphoma cell proliferation. Seventy-four patients with malignant lymphoma underwent DWIBS within 1 week before pathological confirmation. The ADC value was measured at the site of the pathological examination, and specimens were also stained with Ki-67. The ADC values and Ki-67 indices in aggressive non-Hodgkin's lymphoma (NHL), indolent NHL, and Hodgkin's lymphoma (HL) were compared using Spearman's rank correlation coefficient and the Kruskal-Wallis test. The Ki-67 indices and ADC values were inversely correlated (r = -0.289, p = 0.0125); the differences in the Ki-67 index between aggressive NHL, indolent NHL, and HL were significant (p values were significantly different between the types of lymphoma (p = 0.013); the Nemenyi test showed a significant difference only between aggressive NHL and HL. The Ki-67 indices and ADC values are inversely correlated in patients with lymphoma, combining DWIBS and ADC values can evaluate the proliferation level of malignant lymphoma cells noninvasively. • By using DWIBS, malignant lymphoma cell proliferation can be assessed noninvasively. • The ADC value and Ki-67 index are significantly and inversely correlated. • The ADC values were lower in aggressive NHL than in HL. • The ADC values of aggressive and indolent NHL were not significantly different.

  10. An interobserver reproducibility analysis of Ki67 visual assessment in breast cancer.

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    Ruohong Shui

    Full Text Available Ki67 labeling index (LI is used as a predictive marker and is associated with prognosis in breast cancer. However, standardised methodologies for measurement are lacking which has limited its application in clinical practice. In this study, we evaluated the interobserver concordance of visual assessment of Ki67 LI in breast cancer.Ki67-immunostained slides of 160 cases of primary invasive breast cancer were visual assessed by five breast pathologists with two different methods to choose the scoring fields: (1 hot-spot score, (2 average score. Proportions of positive invasive tumor cells at 10 % intervals were scored. The intra-class correlation coefficient (ICC was used to assess the interobserver reproducibility.(1 A perfect concordance of Ki67 LI was demonstrated according to both score methods (P30% Ki-67 LI. The concordance was relatively low in intermediate Ki67 LI group compared with low and high Ki67 LI groups. (3 All cases were classified into three groups by paired-difference (d between means of hot-spot score and average score (d<5, 5≤d<10, d≥10. The consistency was observed to decrease with increasing paired-difference according to both methods.Visual assessment of Ki67 LI at 10 % intervals is a candidate for a standard method in breast cancer clinical practice. Average score and hot-spot score of visual assessment both demonstrated a perfect concordance, and an overall average assessment across the whole section including hot spots may be a better method. Interobserver concordance of intermediate Ki67 LI in which most cutoffs are located for making clinical decisions was relatively low.

  11. Identifying tumor in pancreatic neuroendocrine neoplasms from Ki67 images using transfer learning.

    Science.gov (United States)

    Niazi, Muhammad Khalid Khan; Tavolara, Thomas Erol; Arole, Vidya; Hartman, Douglas J; Pantanowitz, Liron; Gurcan, Metin N

    2018-01-01

    The World Health Organization (WHO) has clear guidelines regarding the use of Ki67 index in defining the proliferative rate and assigning grade for pancreatic neuroendocrine tumor (NET). WHO mandates the quantification of Ki67 index by counting at least 500 positive tumor cells in a hotspot. Unfortunately, Ki67 antibody may stain both tumor and non-tumor cells as positive depending on the phase of the cell cycle. Likewise, the counter stain labels both tumor and non-tumor as negative. This non-specific nature of Ki67 stain and counter stain therefore hinders the exact quantification of Ki67 index. To address this problem, we present a deep learning method to automatically differentiate between NET and non-tumor regions based on images of Ki67 stained biopsies. Transfer learning was employed to recognize and apply relevant knowledge from previous learning experiences to differentiate between tumor and non-tumor regions. Transfer learning exploits a rich set of features previously used to successfully categorize non-pathology data into 1,000 classes. The method was trained and validated on a set of whole-slide images including 33 NETs subject to Ki67 immunohistochemical staining using a leave-one-out cross-validation. When applied to 30 high power fields (HPF) and assessed against a gold standard (evaluation by two expert pathologists), the method resulted in a high sensitivity of 97.8% and specificity of 88.8%. The deep learning method developed has the potential to reduce pathologists' workload by directly identifying tumor boundaries on images of Ki67 stained slides. Moreover, it has the potential to replace sophisticated and expensive imaging methods which are recently developed for identification of tumor boundaries in images of Ki67-stained NETs.

  12. Visual assessment of Ki67 using a 5-grade scale (Eye-5) is easy and practical to classify breast cancer subtypes with high reproducibility.

    Science.gov (United States)

    Hida, Akira I; Bando, Kenji; Sugita, Atsuro; Maeda, Toshiharu; Ueda, Norifumi; Matsukage, Shoichi; Nakanishi, Mamoru; Kito, Katsumi; Miyazaki, Tatsuhiko; Ohtsuki, Yuji; Oshiro, Yumi; Inoue, Hiromichi; Kawaguchi, Hidetoshi; Yamashita, Natsumi; Aogi, Kenjiro; Moriya, Takuya

    2015-05-01

    Personalised breast cancer therapy requires pathological characterisation of tumours. The proliferative index, based on Ki67, is pivotal, but a standard method has not been established. Here we look for an easy and practical way to evaluate Ki67. Immunohistochemical staining of estrogen receptors, progesterone receptors, HER2 and Ki67 (MIB-1) was performed on resected specimens from 406 primary invasive ductal carcinomas. Ki67 labelling index (LI) from manual counting was compared with visual assessment using a 5-grade scale (Eye-5). Next, 10 pathologists evaluated 100 samples with marked hot spots by using Eye-5. Another 100 samples without marking were also assessed by eight pathologists. One year later, two pathologists reviewed 222 cases with Eye-5. Prognosis was analysed among estrogen receptor-positive cases with postoperative endocrine therapy. Eye-5 showed good correlation to LI. All 136 cases of score 4-5 had LI >20% and all 56 cases of score 1 had LIKi67 by a 5-grade scale (Eye-5) is fast, easy, and reliable with acceptably low interobserver and intraobserver variability. Eye-5 can replace LI in many luminal tumours, and is a strong candidate as a standard method of evaluating Ki67. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. Expression of Oestrogen and progesterone receptors, Ki-67,p53 and ...

    African Journals Online (AJOL)

    Expression of Oestrogen and progesterone receptors, Ki-67,p53 and bcl-2 proteins, cathepsin D, urokinase plasminogen activator and urokinase plasminogen activator-receptors in carcinomas of the female breast in an African population.

  14. Risk Factors Associated with Discordant Ki-67 Levels between Preoperative Biopsy and Postoperative Surgical Specimens in Breast Cancers

    OpenAIRE

    Kim, Hyung Sun; Park, Seho; Koo, Ja Seung; Kim, Sanghwa; Kim, Jee Ye; Nam, Sanggeun; Park, Hyung Seok; Kim, Seung Il; Park, Byeong-Woo

    2016-01-01

    Purpose The Ki-67 labelling index is significant for the management of breast cancer. However, the concordance of Ki-67 expression between preoperative biopsy and postoperative surgical specimens has not been well evaluated. This study aimed to find the correlation in Ki-67 expression between biopsy and surgical specimens and to determine the clinicopathological risk factors associated with discordant values. Patients and Methods Ki-67 levels were immunohistochemically measured using paired b...

  15. Profile of mRNA Expression of Ki-67 in Breast Cancer Patients Pre- and Post- Chemotherapy

    OpenAIRE

    Andi Asadul Islam, Andi Asadul Islam

    2017-01-01

    Abstract: Background: Proliferation is a distinct hallmarks of cancer. Ki-67 designated as a marker of proliferation in solid tumors. The proliferative activity of tumor demonstrated by expression of Ki-67 in breast cancer has been associated with a poor prognosis. Changes in the relative proportions of Ki-67 can be observed during chemotherapy and may correlated with clinical response in breast cancer. Purpose: Evaluate changes in mRNA expression of proliferation marker Ki-67 in bre...

  16. Expression and significance of VEGF, CD34, Ki-67 and p21 in pterygium

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    Li-Bo Wang

    2014-07-01

    Full Text Available AIM: To investigate the expression of VEGF, CD34, Ki-67 and p21 in pterygium as well as the correlation between their expression and clinical pathological characteristics; explore its pathogenesis. METHODS: Immunohistochemical S-P staining method was adopted in detecting the expression of VEGF, CD34, Ki-67 and p21 in 62 cases of pterygia and 20 cases of normal conjunctival tissues. Relationship between these markers and clinical pathological characteristics was analyzed. RESULTS:(1The positive expression of VEGF, CD34, Ki-67 and p21 in 62 cases of pterygia was 74.2%(46/62, 77.4%(48/62, 66.1%(41/62and 40.3%(25/62respectively. The differences were statistically significant compared with normal conjunctival tissues(PPP>0.05; the expression of Ki-67 was correlated with clinical stages(PP>0.05; the expression of p21 was correlated with clinical stages and pterygium characters(PP>0.05.(3Spearman correlation showed that there was a positive correlation between VEGF and Ki-67(r=0.279, Pr=0.299, Pr=-0.267, PP>0.05.CONCLUSION:(1Overexpression of VEGF, Ki-67, CD34 and low expression of p21 suggest that these markers are concerned with the development and progression of pterygium.(2Expression of VEGF and CD34 increases along with the increase of clinical types and stages, expression of Ki-67 increases along with the increase of clinical stages, and expression of p21 decreases along with the improvement of clinical types or stages; they suggest that these markers may play important roles in the development and recurrence of pterygium.(3There is positive correlation between VEGF and Ki-67, VEGF and CD34 as well as negative correlation between VEGF and p21. They suggest that there may be synergistic action between two factors during the development and progression of pterygium.

  17. Reliability of the Ki67-Labelling Index in Core Needle Biopsies of Luminal Breast Cancers is Unaffected by Biopsy Volume

    NARCIS (Netherlands)

    Focke, C. M.|info:eu-repo/dai/nl/413647927; Decker, T.; van Diest, P. J.|info:eu-repo/dai/nl/075281775

    Background: Assessing prognostic and predictive factors like the Ki67 labelling index (Ki67-LI) in breast cancer core needle biopsies (CNB) may be hampered by undersampling. Our aim was to arrive at a representative assessment of Ki67-LI in CNB of luminal breast cancers by defining optimal cutoffs

  18. Prognostic value of automated KI67 scoring in breast cancer: A centralised evaluation of 8088 patients from 10 study groups

    NARCIS (Netherlands)

    Abubakar, M. (Mustapha); N. Orr (Nick); F. Daley (Frances); P. Coulson (Penny); H.R. Ali (Hamid Raza); Blows, F. (Fiona); J. Benítez (Javier); R.L. Milne (Roger); H. Brenner (Hermann); C. Stegmaier (Christa); A. Mannermaa (Arto); J. Chang-Claude (Jenny); Rudolph, A. (Anja); P. Sinn (Peter); F.J. Couch (Fergus); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); J.D. Figueroa (Jonine); M.E. Sherman (Mark); J. Lissowska (Jolanta); S.M. Hewitt (Stephen); D. Eccles (Diana); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John); C.H.M. van Deurzen (Carolien); Investigators, C.F. (kConFab); M.K. Bolla (Manjeet K.); Wang, Q. (Qin); M. Jones (Michael); M. Schoemaker (Minouk); J. Wesseling (Jelle); F.E. van Leeuwen (F.); L.J. van 't Veer (Laura); D.F. Easton (Douglas); A.J. Swerdlow (Anthony ); M. Dowsett (Mitch); P.D.P. Pharoah (Paul); M.K. Schmidt (Marjanka); M. García-Closas (Montserrat)

    2016-01-01

    textabstractBackground: The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large,

  19. Ki67--no evidence for its use in node-positive breast cancer.

    Science.gov (United States)

    Andre, Fabrice; Arnedos, Monica; Goubar, Aicha; Ghouadni, Amal; Delaloge, Suzette

    2015-05-01

    The expression of Ki67 in breast cancer has been associated with the luminal B phenotype, a high risk of relapse, and likelihood of good response to neoadjuvant chemotherapy. Several guidelines propose assays to determine Ki67 expression levels to select which patients with early stage breast cancer and 1-3 positive axillary nodes should not receive adjuvant chemotherapy. We discuss why oncologists should not rely on the use of this biomarker for patients with early stage breast cancer and only 1-3 positive axillary nodes. First, Ki67 staining lacks analytical validity. Second, the performance of the biomarker for prognostic purposes is poor, with no compelling evidence to indicate that patients with oestrogen receptor (ER)-positive disease, low Ki67 expression and 1-3 positive axillary nodes have a very low risk of disease relapse. Finally, no robust evidence indicates that Ki67 staining predicts the efficacy of adjuvant chemotherapy. Overall, evidence does not support withholding adjuvant chemotherapy in patients with ER-positive, Ki67-low breast cancer and 1-3 positive nodes without risk in daily practice.

  20. Cyclooxygenase-2 and Ki67 Expression in Oral Leukoplakia: a Clinicopathological Study

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    Alper Sinanoglu

    2015-06-01

    Full Text Available Objectives: Oral leukoplakia is a precancerous lesion of the oral mucosa. The upregulation of Ki67 and cyclooxygenase-2 has been reported in both dysplastic and non-dysplastic tissues. The aim of this clinicopathological study was to investigate the prognostic value of Ki67 and cyclooxygenase-2 expression for oral leukoplakia. Material and Methods: A total of 50 samples were investigated and the study group consisted of 30 oral leukoplakia samples. Samples of 10 intact oral mucosa and 10 squamous cell carcinoma were included as negative and positive control groups, respectively. Epithelial dysplasia was defined as oral intraepithelial neoplasia (OIN and classified into subgroups 1 - 3. Tissue samples were assessed immunohistochemically for Ki67 and cyclooxygenase-2 expression. Clinicopathological correlations of oral leukoplakia patients were also investigated. Results: All OIN 3 patients were non-smokers (P < 0.05, and homogeneous oral leukoplakia lesions also presented OIN. Both cyclooxygenase-2 and Ki67 expression increased with the severity of lesions, which defined different subgroups (P < 0.05, except there was no significant difference between the hyperkeratosis and OIN groups for Ki67 expression. Conclusions: Cyclooxygenase-2 and Ki67 expression may have a prognostic value for the malignant transformation of oral leukoplakia.

  1. Correlation analysis between expression of PCNA, Ki-67 and COX-2 and X-ray features in mammography in breast cancer.

    Science.gov (United States)

    Qiu, Xiaoming; Mei, Jixin; Yin, Jianjun; Wang, Hong; Wang, Jinqi; Xie, Ming

    2017-09-01

    This study investigated expression of proliferating cell nuclear antigen (PCNA), proliferation-associated nuclear antigen (Ki-67) and cyclooxygenase-2 (COX-2) in tissues of breast invasive ductal carcinoma, and analyzed the correlations between these indexes and X-ray features in mammography. A total of 90 patients who were admitted to Huangshi Central Hospital and diagnosed as breast invasive ductal carcinoma from January 2014 to January 2016 were selected. The expression of PCNA, Ki-67 and COX-2 in cancer tissues and cancer-adjacent normal tissues of patients were detected by immunohistochemical staining, and X-ray features in mammography of patients were observed. By using Spearman correlation analysis, the correlations between expression of PCNA, Ki-67 and COX-2 and X-ray features in mammography in breast cancer were investigated. As a result, the positive expression rates of PCNA, Ki-67 and COX-2 in cancer tissues of the patient groups were respectively 42.2, 45.6 and 51.1%, which were significantly higher than those in cancer-adjacent normal tissues of the control group (pCOX-2 expression in cancer tissues of the patient group was associated with clinical staging and lymphatic metastasis (p0.05). PCNA, Ki-67 and COX-2 expression in cancer tissues of the patient group had no correlation with the existence of lumps and localized density-increased shadows (p>0.05), but were associated with manifestations of architectural distortion, calcification as well as skin and nipple depression (pCOX-2 in cancer tissues of the patient group (r=0.676, pCOX-2 (r=0.724, p0.05). In conclusion, PCNA, Ki-67 and COX-2 expression is of great significance in the occurrence, invasion and metastasis of breast invasive ductal carcinoma. There is a strong correlation between PCNA, Ki-67 and COX-2 expression levels and X-ray features in mammography in breast invasive ductal carcinoma. The application of X-ray features in mammography can evaluate the expression levels of PCNA, Ki-67 and

  2. Ki67 Changes Identify Worse Outcomes in Residual Breast Cancer Tumors After Neoadjuvant Chemotherapy.

    Science.gov (United States)

    Cabrera-Galeana, Paula; Muñoz-Montaño, Wendy; Lara-Medina, Fernando; Alvarado-Miranda, Alberto; Pérez-Sánchez, Victor; Villarreal-Garza, Cynthia; Quintero, R Marisol; Porras-Reyes, Fany; Bargallo-Rocha, Enrique; Del Carmen, Ignacio; Mohar, Alejandro; Arrieta, Oscar

    2018-02-28

    Several breast cancer (BC) trials have adopted pathological complete response (pCR) as a surrogate marker of long-term treatment efficacy. In patients with luminal subtype, pCR seems less important for outcome prediction. BC is a heterogeneous disease, which is evident in residual tumors after neoadjuvant-chemotherapy (NAC). This study evaluates changes in Ki67 in relation to disease-free survival (DFS) and overall survival (OS) in patients without pCR. Four hundred thirty-five patients with stage IIA-IIIC BC without pCR after standard NAC with anthracycline and paclitaxel were analyzed. We analyzed the decrease or lack of decrease in the percentage of Ki67-positive cells between core biopsy samples and surgical specimens and correlated this value with outcome. Twenty-five percent of patients presented with luminal A-like tumors, 45% had luminal B-like tumors, 14% had triple-negative BC, 5% had HER2-positive BC, and 11% had triple-positive BC. Patients were predominantly diagnosed with stage III disease (52%) and high-grade tumors (46%). Median Ki67 level was 20% before NAC, which decreased to a median of 10% after NAC. Fifty-seven percent of patients had a decrease in Ki67 percentage. Ki67 decrease significantly correlated with better DFS and OS compared with no decrease, particularly in the luminal B subgroup. Multivariate analysis showed that nonreduction of Ki67 significantly increased the hazard ratio of recurrence and death by 3.39 (95% confidence interval [CI] 1.8-6.37) and 7.03 (95% CI 2.6-18.7), respectively. Patients without a decrease in Ki67 in residual tumors after NAC have poor prognosis. This warrants the introduction of new therapeutic strategies in this setting. This study evaluates the change in Ki67 percentage before and after neoadjuvant chemotherapy (NAC) and its relationship with survival outcomes in patients with breast cancer who did not achieve complete pathological response (pCR). These patients, a heterogeneous group with diverse

  3. Prognostic significance of pathologic complete response and Ki67 expression after neoadjuvant chemotherapy in breast cancer.

    Science.gov (United States)

    Yoshioka, Tatsuya; Hosoda, Mitsuchika; Yamamoto, Mitsugu; Taguchi, Kazunori; Hatanaka, Kanako C; Takakuwa, Emi; Hatanaka, Yutaka; Matsuno, Yoshihiro; Yamashita, Hiroko

    2015-03-01

    Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype. Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) Ki67 LI ≥ 14 %) subtypes, 11 (17 %) were ER+ HER2-positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype. It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy.

  4. Screening for precancerous anal lesions with P16/Ki67 immunostaining in HIV-infected MSM.

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    Sergio Serrano-Villar

    Full Text Available Screening of anal cancer in HIV-infected MSM with anal cytology results in high rates of false positive results and elevated burden of high-resolution anoscopies. High-risk HPV up-regulates p16 and Ki67 expression in epithelial cells. We assessed the usefulness of P16/Ki-67 immunostaining cytology for the diagnosis of precancerous anal lesions.Cross-sectional multicenter study. Concomitant anal liquid cytology with p16/Ki-67 immunostaining and HRA with biopsy of acetowhite lugol-negative lesions was performed in HIV-infected MSM. We compared the diagnostic performance of an abnormal anal cytology and p16/Ki-67 immunostaining relative to HRA-guided biopsy by logistic regression and comparison of ROC areas.We included 328 HIV-infected MSM. HSIL was histologically diagnosed in 72 subjects (25.1%, and 2 (0.6% were diagnosed with anal cancer. An abnormal cytology showed a sensitivity of 95.6% and a specificity of 58.8% for the diagnosis of biopsy-proven HSIL. P16/Ki67 positivity was associated with the presence of biopsy-proven HSIL (P trend = 0.004 but with low sensitivity (41.2% and specificity (71%. The combination of standard cytology with P16/Ki67 immunostaining did not increment the predictive value of standard cytology alone (AUC 0.685 vs. 0.673, respectively, P = 0.688.In HIV-infected MSM P16/Ki67 immunostaining does not improve the diagnostic accuracy of anal cytology, which shows a high sensitivity yet poor specificity. Other approaches aimed at improving the diagnostic accuracy of current techniques for the diagnostic of precancerous HSIL are warranted.

  5. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.

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    Beuschlein, Felix; Weigel, Jens; Saeger, Wolfgang; Kroiss, Matthias; Wild, Vanessa; Daffara, Fulvia; Libé, Rosella; Ardito, Arianna; Al Ghuzlan, Abir; Quinkler, Marcus; Oßwald, Andrea; Ronchi, Cristina L; de Krijger, Ronald; Feelders, Richard A; Waldmann, Jens; Willenberg, Holger S; Deutschbein, Timo; Stell, Anthony; Reincke, Martin; Papotti, Mauro; Baudin, Eric; Tissier, Frédérique; Haak, Harm R; Loli, Paola; Terzolo, Massimo; Allolio, Bruno; Müller, Hans-Helge; Fassnacht, Martin

    2015-03-01

    Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. The aim of this study was to identify markers with prognostic value for patients in this clinical setting. From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

  6. The expression and significance of p53 protein and Ki-67 protein in pterygium

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    Ljubojević Vesna

    2016-01-01

    Full Text Available Background/Aim. Pterygium is considered to be a degenerative disease of the conjunctiva, however, the presence of tumor markers in pterygium reinforces the hypothesis that this lesion is similar to tumor. Inactivation of p53 function removes an obstacle to increased proliferation. Factors affecting the prevalence of p53 expression in pterygium deserve investigation. The aim of the study was to investigate the expression of p53 and Ki-67 proteins in pterygium and normal conjunctiva, the effects of gender and age on p53 expression, and the relationship between the expression of p53 and Ki-67 proteins. Methods. A total of 34 samples of pterygium and 34 samples of the normal conjunctiva were analyzed. The samples were studied by immunohistochemistry using antibodies against p53 and Ki-67. Results. Totally 15 (44% samples of pterygia were p53 positive. Correlations between the expression of p53 protein and sex, and age were not established. The number of Ki-67 positive cells in pterygium (9.74% was significantly higher than the number of Ki-67 positive cells in the normal conjunctiva (1.74%, (p = 0.001. Between the expression of p53 protein and Ki-67 protein in pterygium there was a significant positive correlation (p = 0.000. Conclusion. The prevalence of p53 positive samples of pterygium was 44%. The influence of sex and age on p53 protein expression in pterygium was not found. The increased proliferative acivity was present in the epithelium of pterygium. The expression of Ki-67 protein is associated with the expression of p53 protein in pterygium. The findings of our study support the thesis of pterygium as tissue growth disorder.

  7. The region-of-interest size impacts on Ki67 quantification by computer-assisted image analysis in breast cancer.

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    Christgen, Matthias; von Ahsen, Sabrina; Christgen, Henriette; Länger, Florian; Kreipe, Hans

    2015-09-01

    Therapeutic decision-making in breast cancer depends on histopathologic biomarkers and is influenced by the Ki67 proliferation index. Computer-assisted image analysis (CAIA) promises to improve Ki67 quantification. Several commercial applications have been developed for semiautomated CAIA-based Ki67 quantification, many of which rely on measurements in user-defined regions of interest (ROIs). Because of intratumoral proliferative heterogeneity, definition of the ROI is an important step in the analytical procedure. This study explores the ROI size impacts on Ki67 quantification. Whole-slide sections of 100 breast cancers were immunostained with the anti-Ki67 antibody 30-9 and were analyzed on the iScan Coreo digital pathology platform using a Food and Drug Administration-cleared Ki67 quantification software version v5.3 (Virtuoso; Ventana, Tucson, TX). For each case, the Ki67 labeling index (LI) was determined in multiple ROIs of gradually increasing size centered around a high-proliferation area. The spatial Ki67 decline was modeled with nonlinear regression. Depending on the ROI size, the median Ki67 LI varied between 55% and 15%. The proportion of tumors classified as Ki67 low according to the St Gallen 2013/2015 cutoff increased from 2% to 56%, as the ROI size increased from 50 to 10,000 cells captured. The interrater reliability of conventional Ki67 assessment versus CAIA-based Ki67 quantification was also dependent on the ROI size and varied between slight and almost perfect agreement (Cohen κ = 0.06-0.85). In conclusion, the ROI size is a critically important parameter for semiautomated Ki67 quantification by CAIA. Ki67 LIs determined on platforms like iScan Coreo/Virtuoso require an ROI size adjustment, for which we offer a downloadable data transformation tool. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment

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    Fasching Peter A

    2011-11-01

    Full Text Available Abstract Background The pathological complete response (pCR after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer. Methods Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible. Results Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1 and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4 and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9. The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells. Conclusions Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.

  9. Ki-67 labeling index as an adjunct in the diagnosis of serous tubal intraepithelial carcinoma.

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    Kuhn, Elisabetta; Kurman, Robert J; Sehdev, Ann Smith; Shih, Ie-Ming

    2012-09-01

    There is mounting evidence that serous tubal intraepithelial carcinoma (STIC) may be the immediate precursor of ovarian high-grade serous carcinoma (HGSC) but the criteria for its diagnosis are not well established as highlighted in a recent study showing that interobserver reproducibility, even among expert gynecologic pathologists, was moderate at best. Given the clinical significance of a diagnosis of STIC in a patient who has no other evidence of ovarian carcinoma, this is a serious issue that we felt needed to be addressed. Although it is not clear, at this time, whether such a patient should or should not be treated, the importance of an accurate and reproducible diagnosis of precursors of ovarian carcinoma cannot be underestimated. We hypothesized that an elevated Ki-67 labeling index may aid the diagnosis of STIC. Accordingly, we compared the Ki-67 index of STIC and HGSC to normal fallopian tube epithelium (FTE) in the same patients and to a control group of patients without carcinoma, matched for age. A total of 41 STICs were analyzed, of which 35 were associated with a concurrent HGSC. In FTE, immunoreactivity for Ki-67 was restricted to a few scattered cells (mean 2.0%). No statistically significant difference was found between patients with and without HGSC (P>0.05). However, both STICs and HGSC had significantly higher Ki-67 indices than normal FTE (PSTICs uniformly had an elevated Ki-67 labeling index that ranged from 11.7% to 71.1% (average 35.6%). There was no correlation of the Ki-67 labeling index in the STICs and the associated HGSC, as the labeling index was lower in STIC in 18/35 (51.4%) whereas it was higher in 17/35 (48.6%) (P=0.86). In conclusion, the findings in this study indicate that compared with FTE, STICs have a significantly higher Ki-67 index similar to HGSC. Accordingly, the Ki-67 index can aid the diagnosis of intraepithelial tubal proliferations suspicious for STIC. Therefore, we propose that a Ki-67 index of 10% is a useful

  10. Analysis of clinically relevant values of Ki-67 labeling index in Japanese breast cancer patients.

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    Tamaki, Kentaro; Ishida, Takanori; Tamaki, Nobumitsu; Kamada, Yoshihiko; Uehara, Kanou; Miyashita, Minoru; Amari, Masakazu; Tadano-Sato, Akiko; Takahashi, Yayoi; Watanabe, Mika; McNamara, Keely; Ohuchi, Noriaki; Sasano, Hironobu

    2014-05-01

    It has become important to standardize the methods of Ki-67 evaluation in breast cancer patients, especially those used in the interpretation and scoring of immunoreactivity. Therefore, in this study, we examined the Ki-67 immunoreactivity of breast cancer surgical specimens processed and stained in the same manner in one single Japanese institution by counting nuclear immunoreactivity in the same fashion. We examined 408 Japanese breast cancers with invasive ductal carcinoma and studied the correlation between Ki-67 labeling index and ER/HER2 status and histological grade of breast cancer. We also analyzed overall survival (OS) and disease-free survival (DFS) of these patients according to individual Ki-67 labeling index. There were statistically significant differences of Ki-67 labeling index between ER positive/HER2 negative and ER positive/HER2 positive, ER negative/HER2 positive or ER negative/HER2 negative, and ER positive/HER2 positive and ER negative/HER2 negative groups (all P < 0.001). There were also statistically significant differences of Ki-67 labeling index among each histological grade (P < 0.001, respectively). As for multivariate analyses, Ki-67 labeling index was strongly associated with OS (HR 39.12, P = 0.031) and DFS (HR 10.85, P = 0.011) in ER positive and HER2 negative breast cancer patients. In addition, a statistically significant difference was noted between classical luminal A group and "20 % luminal A" in DFS (P = 0.039) but not between classical luminal A group and "25 % luminal A" (P = 0.105). A significant positive correlation was detected between Ki-67 labeling index and ER/HER2 status and histological grades of the cases examined in our study. The suggested optimal cutoff point of Ki-67 labeling index is between 20 and 25 % in ER positive and HER2 negative breast cancer patients.

  11. Ki67/KIT double immunohistochemical staining in cutaneous mast cell tumors from Boxer dogs.

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    Fonseca-Alves, Carlos Eduardo; Bento, Daniel Diola; Torres-Neto, Rafael; Werner, Juliana; Kitchell, Barbara; Laufer-Amorim, Renée

    2015-10-01

    Cutaneous mast cell tumors (MCTs) are among the most frequent malignant tumors in dogs and Boxer breed dogs have a higher incidence of this disease. Ki67 staining and KIT staining are widely used to predict natural behavior in canine MCT but no previous study has evaluated double staining of these proteins as a prognostic factor. Based on biological behavior predictors in canine MCT, the purpose of this study was to determine the Ki67 proliferative index in KIT positive cells using double stain immunohistochemistry technique. Sixty-nine MCTs from Boxer dogs were selected and a tissue microarray was constructed for the double stained immunohistochemistry. Double positivity (Ki67(+)/KIT(+)) was observed in 20/69 (29%) MCT, with a mean of 9.06 double positive cells per tissue core (range 0.48%-43.97%) and Ki67(-)/KIT(+) animals had a longer survival time than Ki67(+)/KIT(+) animals (p=0.03). Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Automatic Ki-67 counting using robust cell detection and online dictionary learning.

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    Xing, Fuyong; Su, Hai; Neltner, Janna; Yang, Lin

    2014-03-01

    Ki-67 proliferation index is a valid and important biomarker to gauge neuroendocrine tumor (NET) cell progression within the gastrointestinal tract and pancreas. Automatic Ki-67 assessment is very challenging due to complex variations of cell characteristics. In this paper, we propose an integrated learning-based framework for accurate automatic Ki-67 counting for NET. The main contributions of our method are: 1) A robust cell counting and boundary delineation algorithm that is designed to localize both tumor and nontumor cells. 2) A novel online sparse dictionary learning method to select a set of representative training samples. 3) An automated framework that is used to differentiate tumor from nontumor cells (such as lymphocytes) and immunopositive from immunonegative tumor cells for the assessment of Ki-67 proliferation index. The proposed method has been extensively tested using 46 NET cases. The performance is compared with pathologists' manual annotations. The automatic Ki-67 counting is quite accurate compared with pathologists' manual annotations. This is much more accurate than existing methods.

  13. P53, MAPK, topoisomerase II alpha and Ki67 immunohistochemical expression and KRAS/BRAF mutation in ovarian serous carcinomas.

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    Sundov, Dinka; Caric, Ana; Mrklic, Ivana; Gugic, Dijana; Capkun, Vesna; Hofman, Irena Drmic; Mise, Branka Petric; Tomic, Snjezana

    2013-02-06

    We investigated the immunohistochemical expression of p53, MAPK, topoisomerase II alpha (topoII alpha) and Ki67 in ovarian serous carcinomas (OSCs) along with mutational analysis for KRAS and BRAF. Eighty one cases of OSCs were reviewed and examined immunohistochemically using antibodies against p53, MAPK, topoII alpha and Ki67. Staining was evaluated as a percentage of immunopositive cells with cut-off levels at 10% for p53 and topoII alpha, and 5% for MAPK. The Ki67 immunoexpression was assessed by means of Olympus Image Analysis System as a percentage of immunopositive cells in 1000 tumor cells. KRAS and BRAF mutational analysis was performed on 73 available microdissected samples. Of 81 cases of OSCs 13.6% were of low-grade and 86.4% were of high-grade morphology. In the high-grade group there was a significantly higher immunoexpression of p53 (P p53 immunopositivity. Although this study is limited by its humble number of low-grade samples, our data fit the proposed dualistic pathway of ovarian carcinogenesis. Mutational analysis for KRAS and BRAF discloses some possible interactions between different tumorigenic pathways of low- and high-grade carcinomas. Immunohistochemical staining for MAPK was not sufficiently sensitive, nor specific, to precisely predict the KRAS mutation. However, it appears to be quite reliable in ruling out a KRAS mutation if the staining is negative. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9283563368804632.

  14. Typical and atypical bronchopulmonary carcinoid tumors: a clinicopathologic and KI-67-labeling study.

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    Costes, V; Marty-Ané, C; Picot, M C; Serre, I; Pujol, J L; Mary, H; Baldet, P

    1995-07-01

    Expression of a proliferating antigen by KI-67 immunohistochemistry was analyzed with a SAMBA 2005 computer-assisted image processor (Traitement de l'Information for des Techniques Nouvelles, Grenoble, France) in 47 surgically resected bronchopulmonary carcinoids embedded in paraffin. The clinicopathologic characteristics and KI-67 labeling, expressed in percentage of stained nuclear surface relative to the total nuclear surface, of 31 typical carcinoids and 16 atypical carcinoids were compared and assessed with respect to patient survival. The proliferation status was significantly higher in histologically atypical than in typical carcinoids. Moreover, using a 4% cutoff, we observed a significant difference for the 4-year overall survival rate. Semiquantitative analysis of the proliferation index by KI-67 immunostaining seemed to be an effective means of identifying high risk subsets among patients with histologically atypical carcinoids and for whom adjuvant chemotherapy could be proposed.

  15. Standardized Ki67 Diagnostics Using Automated Scoring--Clinical Validation in the GeparTrio Breast Cancer Study.

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    Klauschen, Frederick; Wienert, Stephan; Schmitt, Wolfgang D; Loibl, Sibylle; Gerber, Bernd; Blohmer, Jens-Uwe; Huober, Jens; Rüdiger, Thomas; Erbstößer, Erhard; Mehta, Keyur; Lederer, Bianca; Dietel, Manfred; Denkert, Carsten; von Minckwitz, Gunter

    2015-08-15

    Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of "visual" Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies. We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring. The three groups of autoKi67 as defined by low (≤ 15%), medium (15.1%-35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values P(OS) Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with P(OS) = 0.002, P(PFS) = 0.009 (autoKi67) versus P(OS) = 0.007, PPFS = 0.004 (manual Ki67). The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics. ©2014 American Association for Cancer Research.

  16.  Immunohistochemical Expression of ki-67 and p53 in Colorectal Adenomas: A Clinicopathological Study

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    Hussam Hasson Ali

    2011-07-01

    Full Text Available  Objectives: To evaluate the significance of P53 and Ki-67 expression as immunohistochemical markers in early detection of premalignant changes in different types of colorectal adenomas. Also, to correlate immunohistochemical expression of the two markers with different clinicopathological parameters including; age, and sex of the patient, type, site, size and grade of dysplasia of colorectal adenomas.Methods: Forty-seven polypectomy specimens of colorectal adenomas were retrieved from the archival materials of the Gastrointestinal and Hepatic Diseases Teaching Hospital in Baghdad from 2009 - 2010. Four µm section specimens were stained by immunohistochemical technique with Ki-67 and P53 tumor markers. P-values <0.05 were considered statistically significant.Results: Immunohistochemical expressions of Ki-67 and P53 had a significant correlation with the size and grade of dysplasia in colorectal adenomas. However, there was no significant correlation among the immunohistochemical expression of Ki-67 and P53 with the age and gender of the patient, and the type and site of colorectal adenomas. There was no significant correlation between Ki-67 and P53 expressions in colorectal adenomas. Villous adenomas of colorectum showed a significant correlation with the grade of dysplasia, while there was no significant correlation between size and site of colorectal adenoma with the grade of dysplasia.Conclusion: High grade dysplasia with significant positive immunohistochemical markers of Ki-67 and P53 could be valuable parameters for selecting from the total colorectal adenoma population, those most deserving of close surveillance in follow-up cancer prevention programs. It is closely linked with increasing age particularly in patients with a large size adenoma of villous component in their histology.

  17. Typhonium flagelliforme decreases tyrosine kinase and Ki67 expression in mice

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    Chodidjah Chodidjah

    2015-12-01

    Full Text Available Background Worldwide, breast cancer is the most frequent cancer in women after lung cancer. Treatments include surgery, radiation, immunotherapy and chemotherapy, but are not effective. Tyrosine kinase and Ki67 protein are markers of proliferation. Typhonium flagelliforme ethanol extract (TFEE has been shown to inhibit proliferation of Michigan Cancer Foundation-7 (MCF7 cells in culture. The aim of the present study was to examine the effect of administration of TFEE on tyrosine kinase and Ki67 expression in mice. Methods This experimental study using post test randomized design with control group was conducted in 24 tumor-bearing CH3 mice. They were randomly divided into 4 groups, consisting of one control and 3 treatment groups (TI, T2, T3 treated daily for 30 days with 0.2 ml TFEE at dosages of 200, 400, and 800 mg/kgBW, respectively. On day 31 the tumor tissues were collected and their tyrosine kinase and Ki67 expression were levels assessed using ELISA and immunohistochemical staining, respectively. Tyrosine kinase and Ki67 expression levels were analyzed, respectively using Kruskal Wallis test and one-way Anova followed by Bonferroni post hoc test. Results Mean tyrosine kinase level was highest in the control group, followed by T3, T2 and T1 (p=0.019. Mean level of Ki 67 expression was highest in the control group, followed by T2, T3 and T1 (p=0.000. Conclussions Oral administration of TFEE at a dose of 200 mg/kgBW decreases tyrosine kinase levels and Ki 67 expression.

  18. Immunohistochemicai study of Ki- 67 expression in unicystic Ameloblastoma and Dentigerous cyst

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    Eslami M.

    2004-06-01

    Full Text Available Statement of Problem: Differentiation of dentigerous cyst from unicystic ameloblastoma, discovering any initial ameloblastic changes in lining epithelium of dentigerous cyst at early stage, and differentiation between hyperplastic odontogenic epithelium in fibrous capsule of dentigerous cyst from ameloblastic proliferation, need to an accurate and reliable technique."nPurpose: The aim of this study was to determine and compare Ki-67 immunoreactivity in various locations of the epithelium of Dentigerous cyst and Unicystic Ameloblastoma."nMaterials and Methods: In this historical Cohort study, 15 cases of dentigerous cyst and 9 cases of unicystic ameloblastoma were selected. Immunohistochemistry staining was performed by M1B-1 (murine monoclonal antibody against Ki-67. The stained nucleous were counted in basal and suprabasal layer of lining epithelium of both lesions in 3000 epithelial cells. Finally, the percentage of positive cells (presented as labeling index was calculated, t- student test was used to analyze the related data."nResults: Ki-67 (LI in basal layer of Dentigerous cyst (2.59±1.66 and Unicystic Ameloblastoma (3.76±79 had no significant differences, but Ki-67 (LI in suprabasal layer of unicystic ameloblastoma (2.15±0.69 was significantly higher than dentigerous cyst (0.77±0.55 P=0.003."nThe difference between the average numbers of positive cells for Ki-67 (LI in these two lesions was statistically significant (P<0.05 and it was higher in Unicystic Ameloblastoma than Dentigerous cyst."nConclusion: Based on the findings of this study, it is suggested that Ki-67 (LI in suprabasal layer or throughout the epithelium can be considered as a useful marker for differential diagnosis between dentigerous cyst and unicystic ameloblastoma.

  19. Quantum dots-based double imaging combined with organic dye imaging to establish an automatic computerized method for cancer Ki67 measurement

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    Wang, Lin-Wei; Qu, Ai-Ping; Liu, Wen-Lou; Chen, Jia-Mei; Yuan, Jing-Ping; Wu, Han; Li, Yan; Liu, Juan

    2016-02-01

    As a widely used proliferative marker, Ki67 has important impacts on cancer prognosis, especially for breast cancer (BC). However, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study is to establish quantum dots (QDs)-based double imaging of nuclear Ki67 as red signal by QDs-655, cytoplasmic cytokeratin (CK) as yellow signal by QDs-585, and organic dye imaging of cell nucleus as blue signal by 4‧,6-diamidino-2-phenylindole (DAPI), and to develop a computer-aided automatic method for Ki67 index measurement. The newly developed automatic computerized Ki67 measurement could efficiently recognize and count Ki67-positive cancer cell nuclei with red signals and cancer cell nuclei with blue signals within cancer cell cytoplasmic with yellow signals. Comparisons of computerized Ki67 index, visual Ki67 index, and marked Ki67 index for 30 patients of 90 images with Ki67 ≤ 10% (low grade), 10% Ki67Ki67 ≥ 50% (high grade) showed computerized Ki67 counting is better than visual Ki67 counting, especially for Ki67 low and moderate grades. Based on QDs-based double imaging and organic dye imaging on BC tissues, this study successfully developed an automatic computerized Ki67 counting method to measure Ki67 index.

  20. Ki67 Heterogeneity in Estrogen Receptor-Positive Breast Cancers: Which Tumor Type Has the Most Heterogeneity?

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    Himuro, Takanori; Horimoto, Yoshiya; Arakawa, Atsushi; Tanabe, Masahiko; Saito, Mitsue

    2016-04-01

    Heterogeneity of Ki67 expression, often seen in breast cancer, can make evaluation of the expression of this marker difficult and give rise to confusion when considering adjuvant treatments for patients. Herein, we investigated estrogen receptor-positive breast cancers to reveal the tumor characteristics associated with Ki67 heterogeneity. Surgical specimens from 85 invasive ductal carcinomas of no special type and 13 invasive lobular carcinomas were examined. We first calculated the differences between Ki67 expression in a hot spot and those in 4 random fields on the same slide. We then evaluated Ki67 heterogeneity within the tumor, based on these differences. Among clinicopathological factors, solid-tubular carcinoma, an architectural growth pattern subtype of invasive ductal carcinoma, correlated with high Ki67 heterogeneity (P Ki67 expression. © The Author(s) 2015.

  1. A comparison of Ki-67 counting methods in luminal Breast Cancer: The Average Method vs. the Hot Spot Method.

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    Min Hye Jang

    Full Text Available In spite of the usefulness of the Ki-67 labeling index (LI as a prognostic and predictive marker in breast cancer, its clinical application remains limited due to variability in its measurement and the absence of a standard method of interpretation. This study was designed to compare the two methods of assessing Ki-67 LI: the average method vs. the hot spot method and thus to determine which method is more appropriate in predicting prognosis of luminal/HER2-negative breast cancers. Ki-67 LIs were calculated by direct counting of three representative areas of 493 luminal/HER2-negative breast cancers using the two methods. We calculated the differences in the Ki-67 LIs (ΔKi-67 between the two methods and the ratio of the Ki-67 LIs (H/A ratio of the two methods. In addition, we compared the performance of the Ki-67 LIs obtained by the two methods as prognostic markers. ΔKi-67 ranged from 0.01% to 33.3% and the H/A ratio ranged from 1.0 to 2.6. Based on the receiver operating characteristic curve method, the predictive powers of the KI-67 LI measured by the two methods were similar (Area under curve: hot spot method, 0.711; average method, 0.700. In multivariate analysis, high Ki-67 LI based on either method was an independent poor prognostic factor, along with high T stage and node metastasis. However, in repeated counts, the hot spot method did not consistently classify tumors into high vs. low Ki-67 LI groups. In conclusion, both the average and hot spot method of evaluating Ki-67 LI have good predictive performances for tumor recurrence in luminal/HER2-negative breast cancers. However, we recommend using the average method for the present because of its greater reproducibility.

  2. Profile of mRNA Expression of Ki-67 in Breast Cancer Patients Pre- and Post- Chemotherapy

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    Prihantono, Prihantono; Hatta, Mochammad; Sampepajung, Daniel; Islam, Andi Asadul

    2017-01-01

    Journal International Prihantono Abstract: Background: Proliferation is a distinct hallmarks of cancer. Ki-67 designated as a marker of proliferation in solid tumors. The proliferative activity of tumor demonstrated by expression of Ki-67 in breast cancer has been associated with a poor prognosis. Changes in the relative proportions of Ki-67 can be observed during chemotherapy and may correlated with clinical response in breast cancer. Purpose: Evaluate changes in mRNA expression ...

  3. Clinical relevance of Ki67 gene expression analysis using formalin-fixed paraffin-embedded breast cancer specimens.

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    Yamamoto, Satoko; Ibusuki, Mutsuko; Yamamoto, Yutaka; Fu, Peifen; Fujiwara, Saori; Murakami, Keiichi; Iwase, Hirotaka

    2013-07-01

    Ki67 is a protein associated with cell cycle activity and shows a good correlation with the growth fraction, which has been proposed as a prognostic or predictive marker in breast cancer. In this study, we aimed to analyze the expression levels of Ki67 (MKI67) messenger RNA (mRNA) derived from formalin-fixed paraffin-embedded (FFPE) tissues for comparison with the immunohistochemical Ki67 labeling index, and investigate the correlation coefficients with clinical outcomes. We analyzed the data of Ki67 mRNA from FFPE and matched fresh-frozen (FF) tissues based on a real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) assay system in 203 cases of primary invasive breast cancer. The correlation between Ki67 mRNA expression of either FFPE or FF specimens and Ki67 labeling index was positive, as was the correlation between the FFPE and FF results (P Ki67 mRNA expression of FFPE specimens was significantly associated with clinicopathological characteristics: tumor size, lymph node status, nuclear grade, hormone receptors, human epidermal growth factor receptor 2 (Her2) status, and tumor subtype. In prognostic results, Ki67 gene expression in the FFPE specimens revealed almost similar patterns of significance in Kaplan-Meier curves and univariate and multivariate relapse-free survival results as the Ki67 labeling index. Gene expression analysis of Ki67 of FFPE specimens could be successfully performed using RT-qPCR, closely resembling the significant clinical characteristics of Ki67 labeling index. These results confirm that Ki67 gene expression of FFPE specimens has potential for evaluation of cell cycle activity of breast cancer specimens.

  4. Surgery time interval and molecular subtype may influence Ki67 change after core needle biopsy in breast cancer patients.

    Science.gov (United States)

    Chen, Xiaosong; Zhu, Siji; Fei, Xiaochun; Garfield, David H; Wu, Jiayi; Huang, Ou; Li, Yafen; Zhu, Li; He, Jianrong; Chen, Weiguo; Jin, Xiaolong; Shen, Kunwei

    2015-10-30

    To investigate the accuracy of core needle biopsy (CNB) in evaluating breast cancer estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 status and to identify factors which might be associated with Ki67 value change after CNB. A retrospective study was carried out on 276 patients with paired CNB and surgically removed samples (SRS). Clinico-pathological factors as well as the surgery time interval (STI) between CNB and surgery were analyzed to determine whether there were factors associated with Ki67 value change after CNB. Five tumor subtypes were classified as follows: Luminal A, Luminal B-HER2-, Luminal B-HER2+, Triple Negative (TN), and HER2+. Ki67 value change was calculated as SRS minus CNB. Mean STI after CNB was 4.5 (1-37) days. Good agreement was achieved for ER, PR, and HER2 evaluation between CNB and SRS. However, Ki67 expression level was significantly higher in SRS compared with CNB samples: 29.1 % vs. 26.2 % (P Ki67 change after CNB. Luminal A tumors experienced more Ki67 elevation than Luminal B-HER2- diseases (6.2 % vs -0.1 %, P = 0.014). Patients with longer STI after CNB had a higher Ki67 increase: -1.1 % within 1-2 days, 2.1 % with 3-4 days, and 5.6 % more than 4 days, respectively (P = 0.007). For TN and HER2+ tumors, the Ki67 change was apt to be 0 with STI ≤ 4 days, while a >7 % Ki67 increase was noticed in patients with STI ≥ 5 days. CNB was accurate in evaluating ER, PR, HER2, and molecular subtype status. Ki67 value significantly increased after CNB, which was associated with STI and molecular subtype. Further translational research needs to consider Ki67 changes following CNB among different breast cancer molecular subtypes.

  5. The satisfactory reproducibility of the Ki-67 index in breast carcinoma, and it′s correlation with the recurrence score

    OpenAIRE

    Varsha Manucha; Xinmin Zhang; Rebecca M. Thomas

    2014-01-01

    Objective: The clinical utility of Ki-67 in predicting response to neoadjuvant chemotherapy is limited by lack of an accepted validated method of assessment of Ki-67 and wide variations in the cut-offs. In this study, the interobserver variability in the estimation of Ki-67 proliferation index (PI) and its association with recurrence score (RS) was assessed. Materials and Methods: The interobserver variability was assessed between 3 pathologists in 27 invasive breast carcinomas that had also ...

  6. Reliability of the Ki67-Labelling Index in Core Needle Biopsies of Luminal Breast Cancers is Unaffected by Biopsy Volume.

    Science.gov (United States)

    Focke, C M; Decker, T; van Diest, P J

    2017-05-01

    Assessing prognostic and predictive factors like the Ki67 labelling index (Ki67-LI) in breast cancer core needle biopsies (CNB) may be hampered by undersampling. Our aim was to arrive at a representative assessment of Ki67-LI in CNB of luminal breast cancers by defining optimal cutoffs and establishing the minimum CNB volume needed for highest concordance of Ki67-LI between CNB and subsequent surgical excision biopsy (SEB). We assessed the Ki67-LI in CNB and subsequent SEB of 170 luminal breast cancers according to two counting methods recommended by the International Ki67 in Breast Cancer Working Group and applied the cutoffs to distinguish low and high proliferation given by the St Gallen 2013 and 2015 consensus, respectively. We then compared CNB volume characteristics for cases with concordant and discordant Ki67-LI between CNB versus SEB. Highest concordance (75%, κ = 0.44) between CNB and SEB was achieved using the method that assesses the average tumor Ki67-LI and a cutoff of 20%. No significant differences were found between cases with concordant and discordant Ki67-LI in CNB versus SEB for number of biopsy cores, total core length, tumor tissue length, or total CNB or tumor tissue area size in the CNB for two various cutoffs. A concordance of 75% between CNB and SEB can be achieved for the Ki67-LI using a method assessing average Ki67-LI at the threshold of 20%. Increasing CNB volume did not result in improved agreement rates, indicating that reliability of Ki67 levels in CNB of luminal breast cancers is unaffected by CNB volume.

  7. Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen

    Directory of Open Access Journals (Sweden)

    Afif Rieth Nery-Aguiar

    2016-02-01

    Full Text Available OBJECTIVES: Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Forty Wistar-Hannover adult, virgin, castrated rats were randomly divided into two groups, group I (control, n=20 and group II (tamoxifen, n=20, receiving 0.5 ml of propylene glycol and 250 µg of tamoxifen diluted in 0.5 ml of propylene glycol, respectively, daily by gavage for 30 days. On the 31st day, the rats were euthanized and their vaginas were removed and fixed in 10% buffered formalin for the immunohistochemical study of Ki-67 protein expression. Data were analyzed by the Levene and Student’s t tests (p<0.05. RESULTS: The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04±0.96 and 26.86±2.19, respectively (p<0.001. CONCLUSIONS: According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression.

  8. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology

    DEFF Research Database (Denmark)

    Ikenberg, Hans; Bergeron, Christine; Schmidt, Dietmar

    2013-01-01

    Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infectio...

  9. Vitamin D Receptor, Retinoid X Receptor, Ki-67, Survivin, and Ezrin Expression in Canine Osteosarcoma

    Directory of Open Access Journals (Sweden)

    John Davies

    2012-01-01

    Full Text Available Canine osteosarcoma (OS is an aggressive malignant bone tumor. Prognosis is primarily determined by clinical parameters. Vitamin D has been postulated as a novel therapeutic option for many malignancies. Upon activation, vitamin D receptors (VDRs combine with retinoid receptor (RXR forming a heterodimer initiating a cascade of events. Vitamin D's antineoplastic activity and its mechanism of action in OS remain to be clearly established. Expression of VDR, RXR, Ki-67, survivin, and ezrin was studied in 33 archived, canine OS specimens. VDR, RXR, survivin, and ezrin were expressed in the majority of cases. There was no statistically significant difference in VDR expression in relationship with tumor grade, type, or locations or animal breed, age, and/or sex. No significant association (p=0.316 between tumor grade and Ki-67 expression was found; in particular, no difference in Ki-67 expression between grades 2 and 3 OSs was found, while a negative correlation was noted between Ki-67 and VDR expression (ρ=−0.466, a positive correlation between survivin and RXR expression was found (p=0.374. A significant relationship exists between VDR and RXR expression in OSs and proliferative/apoptosis markers. These results establish a foundation for elucidating mechanisms by which vitamin D induces antineoplastic activity in OS.

  10. Study of Ki67 and CD10 expression as predictive factors of recurrence of ameloblastoma.

    Science.gov (United States)

    Ahlem, B; Wided, A; Amani, L; Nadia, Z; Amira, A; Faten, F

    2015-11-01

    Ameloblastoma is a rare, benign, purely epithelial odontogenic tumour, characterized by a high potential for local invasion and recurrence. To study the epidemiological and histological characteristics of ameloblastoma. To study Ki67 and CD10 immunostaining in ameloblastoma and to investigate a possible correlation between these two markers and recurrence of this tumour. An immunohistochemical study using Ki67 and CD10 monoclonal antibodies was performed on 37 paraffin blocks obtained from the Charles-Nicolle hospital pathology department in Tunis over a 9-year period (2004-2012). Statistical analysis was performed with Statistical Package for Social Sciences (SPSS) software version 15.1. This series of 37 cases comprised 21 males and 16 females (sex ratio: 1.3) with a mean age of 39 years (range: 7 to 70 years), corresponding to 36 cases of intraosseous ameloblastoma and one case of gingival ameloblastoma. Thirty-two cases were polycystic and 5 cases were unicystic. Eighteen cases of local recurrence were observed. No correlation was demonstrated between recurrence and the various clinical and histological parameters and treatment modalities. However, a significant correlation was demonstrated between recurrence and Ki67 and CD10 expression (P=0.000 and 0.002, respectively). The Ki67 proliferation index and stromal CD10 expression can be considered to be predictive factors of ameloblastoma recurrence. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  11. Analysis on the relation of pterygium with VEGF,SDF-1,Ki-67,PCNA and Survivin

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    Ying Song

    2015-12-01

    Full Text Available AIM:To analyze and study the relation of pterygium with vascular endothelial growth factor(VEGF,stroma cell-derived factor 1(SDF-1,tumor proliferating antigen(Ki-67,proliferating cell nuclear antigen(PCNAand survivin. METHODS:Seventy-nine patients(106 eyeswith pterygium from January 2013 to May 2015 in our hospital were selected as observation group. Seventy-nine persons with normal conjunctiva during the same period were selected as control group. Then the number of positive cells and staining intensity classification of the two groups for VEGF,SDF-1,Ki-67,PCNA and survivin were compared,and the detection results of patients with different gender,stages and types were compared too. Then the relation between pterygium and those indexes were analyzed by the Logistic analysis. RESULTS:The number of positive cells and staining intensity classification of observation group for VEGF,SDF-1,Ki-67,PCNA and survivin were all higher than those of control group,and the detection results of patients with different stages and types had certain differences too(all PP>0.05. All those indexes had close relation to pterygium by the Logistic analysis. CONCLUSION:The expression of VEGF,SDF-1,Ki-67,PCNA and survivin in tissue of patients with pterygium all show abnormal state,and those indexes all have close relation to pterygium.

  12. Association of tissue inhibitor of metalloproteinases-1 and Ki67 in estrogen receptor positive breast cancer

    DEFF Research Database (Denmark)

    Bjerre, Christina Annette; Knoop, Ann; Bjerre, Karsten

    2013-01-01

    The role of tissue inhibitor of metalloproteinases-1 (TIMP-1) in estrogen receptor (ER) positive breast cancer remains to be fully elucidated. We evaluated TIMP-1 as a prognostic marker in patients treated with adjuvant tamoxifen and investigated TIMP-1s association with Ki67 and ER/progesterone ....../progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) profiles....

  13. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes

    Science.gov (United States)

    Cuylen, Sara; Blaukopf, Claudia; Politi, Antonio Z.; Müller-Reichert, Thomas; Neumann, Beate; Poser, Ina; Ellenberg, Jan; Hyman, Anthony A.; Gerlich, Daniel W.

    2016-01-01

    Summary Eukaryotic genomes are partitioned into chromosomes, which during mitosis form compact and spatially well-separated mechanical bodies1–3.This enables chromosomes to move independently of each other for segregation of precisely one copy of the genome to each of the nascent daughter cells. Despite insights into the spatial organization of mitotic chromosomes4 and the discovery of proteins at the chromosome surface3,5,6, the molecular and biophysical basis of mitotic chromosome individuality have remained unclear. We report that Ki-67, a component of the mitotic chromosome periphery, prevents chromosomes from collapsing into a single chromatin mass after nuclear envelope disassembly, thus enabling independent chromosome motility and efficient interactions with the mitotic spindle. The chromosome separation function of Ki-67 is not confined within a specific protein domain but correlates with size and net charge of truncation mutants that apparently lack secondary structure. This suggests that Ki-67 forms a steric and electrical barrier, similar to surface-active agents (surfactants) that disperse particles or phase-separated liquid droplets in solvents. Fluorescence correlation spectroscopy showed a high surface density of Ki-67 and dual-color labeling of both protein termini revealed an extended molecular conformation, indicating brush-like arrangements that are characteristic for polymeric surfactants. Our study thus elucidates a biomechanical role of the mitotic chromosome periphery and suggests that natural proteins can function as surfactants in intracellular compartmentalization. PMID:27362226

  14. EGFR, CD10 and proliferation marker Ki67 expression in ameloblastoma: possible role in local recurrence

    Directory of Open Access Journals (Sweden)

    Abdel-Aziz Azza

    2012-02-01

    Full Text Available Abstract Background Ameloblastoma is an odontogenic neoplasm characterized by local invasiveness and tendency towards recurrence. Aims Studying the role played by EGFR, CD10 and Ki67 in the recurrence of ameloblastoma. Methods This study was carried out on 22 retrospective cases of mandibular ameloblastoma from the period from Jan 2002 to Jan 2008 with follow up period until Jan 2011 (3 to 8 years follow up peroid. Archival materials were obtained from pathology department, Mansoura university. Paraffin sections of tumor tissue from all cases were submitted for routine H&E stains and immunohistochemistry using EGFR, CD10 and Ki67 monoclonal antibodies. Statistical analysis using of clinical data for all patients, tumor type, EGFR, CD10 and Ki67 expression in relation to recurrence were evaluated. Results Among the 22 cases, 10 cases were males and 12 were females with sex ratio 1:1.2. Age ranged from 34 to 59 years old with a mean age 44.18 year. Five cases showed local recurrence within studied period and proved by biopsy. No statistically significant relation was found between local recurrence and patient age, tumor size, tumor type, EGFR expression. There was a significant relation between CD10 expression as well as Ki67 labelling index and recurrence (P value = 0.003, 0.000 respectively. Conclusion Evaluation of CD10 and Ki67 status together with conventional histological evaluation can help in providing more information about the biologic behavior of the tumor, while EGFR could be a target of an expanding class of anticancer therapies. Since ameloblastomas are EGFR-positive tumors, anti-EGFR agents could be considered to reduce the size of large tumors and to treat unresectable tumors that are in close proximity to vital structures. Virtual Slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1902106905645651

  15. Immunohistochemical expression of GLUT-1 and Ki-67 in chronic plaque psoriasis.

    Science.gov (United States)

    Abdou, Asmaa G; Maraee, Alaa H; Eltahmoudy, Mohamed; El-Aziz, Reem A

    2013-10-01

    Many inflammatory mediators and other biological markers are upregulated in psoriatic lesions; some of these alterations also persist in nonlesional skin. Glucose is the major source of energy for cells, and glucose transporter 1 is the most common glucose transporter in humans (GLUT-1). The present study aimed at evaluating the pattern of expression of GLUT-1 and Ki-67 in psoriatic skin (involved and uninvolved) and correlating their expression with the clinicopathological parameters in the studied patients. This study was carried out on 30 patients presented with chronic plaque psoriasis and 10 apparently healthy volunteers as a control group. GLUT-1 was not expressed in epidermis of normal skin, whereas it was expressed in 76.6% of uninvolved and 86.7% of involved skin of psoriatic patients, where both the latter differed significantly regarding the intensity (P = 0.001) and localization (P = 0.001) of GLUT-1 expression. The percentage of Ki-67 expression did not differ significantly between involved and uninvolved skin of psoriatic patients, but they were higher than that of normal skin of control group. Nucleolar pattern of Ki-67 expression was significantly associated with male sex (P = 0.05), marked parakeratosis (P = 0.01), and marked angiogenesis (P = 0.05). GLUT-1 expression was associated with degree of acanthosis and percentage of Ki-67 expression. From this study, GLUT-1 is upregulated in psoriatic epidermis and may be involved in facilitation of keratinocyte proliferation in psoriasis. Nucleolar pattern of Ki-67 is an indicator of progressive keratinocyte proliferation in psoriasis.

  16. St Gallen 2015 subtyping of luminal breast cancers: impact of different Ki67-based proliferation assessment methods.

    Science.gov (United States)

    Focke, Cornelia M; van Diest, Paul J; Decker, Thomas

    2016-09-01

    Ki67 has been proposed as prognostic proliferation marker in luminal breast cancer (BC), but little is known on the influence of Ki67 assessment methods on subtyping into luminal A- and B-like tumors. Our aim was to study the influence of different Ki67-labeling index (Ki67-LI) assessment methods on the proportion of BCs classified as luminal A-like. 280 early BCs were subtyped according to the St Gallen 2015 definitions into 71 % luminal (HER2 negative), 6 % luminal B-like (HER2 positive), 13 % triple negative, 1 % HER2 positive (nonluminal), and 9 % special type. Digitized whole slides were counted manually on the screen. We used nine defined counting methods to assess the Ki67-LI (including the International Ki67 in Breast Cancer Working Group recommendations), and compared the resulting medians and the proportions of cancers classified as luminal A-like according to the formerly used cut-off Ki67-LI medians than those measuring an average proliferation (27.45 % vs 16.96 %, p Ki67-LI were found when assessing 1020 compared to counting 100, 200, 300 cells (17.65 vs 33 %, vs 28 %, vs 24.33 %, respectively; p Ki67-LI cut-off cancers varied between 13 and 44 %. The proportion of BCs classified as luminal A-like is highly influenced by the Ki67-LI assessment method. As a consequence, the selection of a specific Ki67-LI assessment method may have a direct effect on the proportion of patients considered having low-risk disease and thus influence therapeutic decision making. This calls for a standardized assessment method.

  17. Predictive value of Ki67 for adjuvant chemotherapy in node-negative, hormone receptor-positive breast cancer.

    Science.gov (United States)

    Sutepvarnon, Apisada; Warnnissorn, Malee; Srimuninnimit, Vichien

    2013-02-01

    Ki67 labeling index (Ki67 LI) is a measure of tumor proliferation. In breast cancer, evidence supporting its prognostic value is clear and its predictive value for response to treatment finds some benefits. However studies of Ki67 LI as a predictive marker in early breast cancer are still limited worldwide and there is no data in Thailand. To assess the predictive value of Ki67 expression for adjuvant chemotherapy in patients with node-negative, hormone receptor-positive breast cancer The authors retrospectively evaluated 127 diagnosed early breast cancer with node-negative, hormone receptor-positive patients and receiving adjuvant systemic treatment at Siriraj hospital. Disease free survival (DFS) was compared with the log-rank test according to Ki67 LI and adjuvant systemic treatment (chemoendocrine therapy and endocrine therapy alone). At a median follow-up of 3.3 years. The 5-year DFS rate was 79% for patients with low Ki67 expression and 75% for patients with high Ki67 expression. Of the 127 patients, 56 (44.1%) received chemoendocrine therapy and 71 (55.9%) were treated with endocrine therapy alone. There was no different effect of DFS among those receiving adjuvant endocrine therapy alone and those receiving adjuvant chemoendocrine therapy depending on Ki67 expression. Among patients with node-negative, hormone receptor-positive breast cancer, a high Ki67 LI had worse DFS trend than a low Ki67 LI but the Ki67 LI did not predict the efficacy of adjuvant chemotherapy.

  18. Assessment of Ki67 expression for breast cancer subtype classification and prognosis in the Nurses' Health Study.

    Science.gov (United States)

    Healey, Megan A; Hirko, Kelly A; Beck, Andrew H; Collins, Laura C; Schnitt, Stuart J; Eliassen, A Heather; Holmes, Michelle D; Tamimi, Rulla M; Hazra, Aditi

    2017-11-01

    Ki67 is a proliferation marker commonly assessed by immunohistochemistry in breast cancer, and it has been proposed as a clinical marker for subtype classification, prognosis, and prediction of therapeutic response. However, the clinical utility of Ki67 is limited by the lack of consensus on the optimal cut point for each application. We assessed Ki67 by immunohistochemistry using Definiens digital image analysis (DIA) in 2653 cases of incident invasive breast cancer diagnosed in the Nurses' Health Study from 1976 to 2006. Ki67 was scored as continuous percentage of positive tumor cells, and dichotomized at various cut points. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models for distant recurrence, breast cancer-specific mortality and overall mortality in relation to luminal subtypes defined with various Ki67 cut points, adjusting for breast cancer prognostic factors, clinico-pathologic features and treatment. DIA was highly correlated with manual scoring of Ki67 (Spearman correlation ρ = 0.86). Mean Ki67 score was higher in grade-defined luminal B (12.6%), HER2-enriched (17.9%) and basal-like (20.6%) subtypes compared to luminal A (8.9%). In multivariable-adjusted models, luminal B tumors had higher breast cancer-specific mortality compared to luminal A cancer classified using various cut points for Ki67 positivity including the 14% cut point routinely reported in the literature (HR 1.38, 95% CI 1.11-1.72, p = 0.004). There was no significant difference in clinical outcomes for ER- tumors according to Ki67 positivity defined at various cut points. Assessment of Ki67 in breast tumors by DIA was a robust and quantitative method. Results from this large prospective cohort study provide support for the clinical relevance of using Ki67 at the 14% cut point for luminal subtype classification and breast cancer prognosis.

  19. High-throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium (BCAC) : Large-scale scoring of Ki67 in breast cancer TMAs

    NARCIS (Netherlands)

    M. Abubakar (Mustapha); W.J. Howat (Will); F. Daley (Frances); L. Zabaglo (Lila); L.A. McDuffus (Leigh-Anne); F. Blows (Fiona); P. Coulson (Penny); H.A. Raza (Ali); J. Benitez (Javier); R.L. Milne (Roger); H. Brenner (Hermann); C. Stegmaier (Christa); A. Mannermaa (Arto); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Sinn (Peter); F.J. Couch (Fergus); P. Devilee (Peter); J.D. Figueroa (Jonine); M.E. Sherman (Mark); J. Lissowska (Jolanta); S.M. Hewitt (Stephen); D. Eccles (Diana); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John); C.H.M. van Deurzen (Carolien); K. Investigators (Kconfab); M.K. Bolla (Manjeet); Q. Wang (Qin); M. Jones (Michael); M. Schoemaker (Minouk); A. Broeks (Annegien); F.E. van Leeuwen (Flora); L.J. van 't Veer (Laura); A.J. Swerdlow (Anthony ); N. Orr (Nick); M. Dowsett (Mitch); D.F. Easton (Douglas); M. Schmidt (Marjanka); P.D.P. Pharoah (Paul); M. García-Closas (Montserrat)

    2016-01-01

    textabstractAutomated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in

  20. Automated characterization and counting of Ki-67 protein for breast cancer prognosis: A quantitative immunohistochemistry approach.

    Science.gov (United States)

    Mungle, Tushar; Tewary, Suman; Arun, Indu; Basak, Bijan; Agarwal, Sanjit; Ahmed, Rosina; Chatterjee, Sanjoy; Maity, Asok Kumar; Chakraborty, Chandan

    2017-02-01

    Ki-67 protein expression plays an important role in predicting the proliferative status of tumour cells and deciding the future course of therapy in breast cancer. Immunohistochemical (IHC) determination of Ki-67 score or labelling index, by estimating the fraction of Ki67 positively stained tumour cells, is the most widely practiced method to assess tumour proliferation (Dowsett et al. 2011). Accurate manual counting of these cells (specifically nuclei) due to complex and dense distribution of cells, therefore, becomes critical and presents a major challenge to pathologists. In this paper, we suggest a hybrid clustering algorithm to quantify the proliferative index of breast cancer cells based on automated counting of Ki-67 nuclei. The proposed methodology initially pre-processes the IHC images of Ki-67 stained slides of breast cancer. The RGB images are converted to grey, L*a*b*, HSI, YCbCr, YIQ and XYZ colour space. All the stained cells are then characterized by two stage segmentation process. Fuzzy C-means quantifies all the stained cells as one cluster. The blue channel of the first stage output is given as input to k-means algorithm, which provides separate cluster for Ki-67 positive and negative cells. The count of positive and negative nuclei is used to calculate the F-measure for each colour space. A comparative study of our work with the expert opinion is studied to evaluate the error rate. The positive and negative nuclei detection results for all colour spaces are compared with the ground truth for validation and F-measure is calculated. The F-measure for L*a*b* colour space (0.8847) provides the best statistical result as compared to grey, HSI, YCbCr, YIQ and XYZ colour space. Further, a study is carried out to count nuclei manually and automatically from the proposed algorithm with an average error rate of 6.84% which is significant. The study provides an automated count of positive and negative nuclei using L*a*b*colour space and hybrid

  1. Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers.

    Science.gov (United States)

    Iwamoto, Takayuki; Katagiri, Toyomasa; Niikura, Naoki; Miyoshi, Yuichiro; Kochi, Mariko; Nogami, Tomohiro; Shien, Tadahiko; Motoki, Takayuki; Taira, Naruto; Omori, Masako; Tokuda, Yutaka; Fujiwara, Toshiyoshi; Doihara, Hiroyoshi; Gyorffy, Balazs; Matsuoka, Junji

    2017-04-18

    The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers. Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P Ki67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre- and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed. IHC based post-Ki67 levels may have distinct predictive power compared with the naïve IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

  2. Correlation between expression of LRP16, Ki67 and EGFR and breast cancer clinical pathologic factors and prognosis.

    Science.gov (United States)

    Yao, D-J; Qiao, S; Zhang, Y; Zhao, Y-T; Yuan, C-H

    2017-07-01

    To investigate the expression of leukemia-related protein 16 (LRP16), proliferating cell nuclear antigen K-67 (Ki67) and epidermal growth factor receptor-1 (EGFR-1) in breast cancer tissue and to explore the correlation between the expression of those proteins and breast cancer clinical pathologic factors and prognosis. The expressions of LRP16, Ki67 and EGFR in breast cancer tissues of 86 cases were detected by the immunohistochemical method and the correlations between the expression of LRP16, Ki67 and EGFR and clinical pathologic factors and prognosis were investigated. Positive expression rates of LRP16, Ki67 and EGFR in breast cancer tissue were 52.3%, 70.9% and 16.3%, respectively. There was no statistical difference in the expression of RP16, Ki67 and EGFR between different age groups (p>0.05). The expression of LRP16 was correlated with clinical stage, histological grade, tumor size and lymphatic metastasis (pKi67 was correlated with clinical stage, histological grade, tumor size and lymphatic metastasis (pKi67 positive group and negative group also showed statistically significant difference (pKi67 and EGFR in breast cancer tissue improves the understanding of biological behaviors of breast cancer, which in turn provide clinical guidance in diagnosis, treatment and prognosis assessment.

  3. Inverse relationship between Ki67 and survival in early luminal breast cancer: confirmation in a multivariate analysis.

    Science.gov (United States)

    Gallardo, Alberto; Garcia-Valdecasas, Barbara; Murata, Paola; Teran, Rolando; Lopez, Laura; Barnadas, Agusti; Lerma, Enrique

    2018-01-01

    Ki67 is a prognostic marker in early breast cancer, but its real usefulness remains controversial. The standard cut-off values for Ki67 have not been universally accepted and different values may be used depending on the type of biopsy (fine needle biopsy versus surgical specimen biopsy). The objective of this study was to evaluate the prognostic significance of Ki67 and to determine the most accurate prognostic cut-off. 495 tissue samples from patients with luminal tumours who underwent breast surgery between 2005 and 2011 were collected from the Department of Pathology at Hospital de la Santa Creu i Sant Pau, Barcelona. Patients with stage IV, HER2-positive tumours or triple-negative breast carcinoma were excluded from the study. Pathology data including tumour grading and ki67 percentage were obtained retrospectively from clinical records. In all cases, the percentage of ki67 was evaluated in fine needle biopsies. In the multivariate analysis, Ki67 as a continuous variable was associated with poor overall survival (OS) and cancer-specific survival (CSS) (OS p = 0.0001, HR 1.037, CI 1.014-1.059; CSS p = 0.0001, HR 1.063, CI 1.031-1.096) (Cox regression model). CSS was poor when associated with a KI67 cut-off point >14% (p = 0.013, HR 14.85; CI 1.074-120.53) (Cox regression model). Disease-free survival (DFS) was not associated with Ki67 CONCLUSIONS: Prognosis of luminal breast carcinoma can be predicted using Ki67 as a continuous variable and a standard cut-off value of 14%. Information about the specimen type used to determine ki67 should be recorded in the pathological report.

  4. Prognostic value of Ki67 expression in HR-negative breast cancer before and after neoadjuvant chemotherapy.

    Science.gov (United States)

    Tan, Qi-Xing; Qin, Qing-Hong; Yang, Wei-Ping; Mo, Qin-Guo; Wei, Chang-Yuan

    2014-01-01

    Immunohistochemical (IHC) expression of Ki67 has been identified as a prognostic and predictive marker in hormone receptor (HR)-positive breast cancer, however, there is little evidence of the association of Ki67 with prognosis in HR-negative patients. We aimed to assess the benefit of Ki67 assessment in HR-negative breast cancers after neoadjuvant chemotherapy (NAC). In the present study, a total of 183 HR-negative breast cancer patients with Stage II to III that treated with anthracycline and/or taxane-based neoadjuvant chemotherapy between 2004 and 2011 were retrospectively analyzed. Endocrine therapy and trastuzumab was not administered to any patients in this study. Clinical and pathological features of the patients with breast cancer were retrieved from the hospital records. Predictive factors for NAC response and survival were analyzed. Of the 183 patients, 122 (66.6%) were HR- HER2+, and 61 (33.3%) were triple-negative. The clinical response rates were similar across breast cancer subtype. Patients whose tumors contained high Ki67 expression effectively responded to NAC. Ki67 labeling index was a predictive marker for pathologic complete response (pCR). Ki67 expression showed a positive correlation with HER2 status, tumor size, lymph node status, lymphovascular invasion and tumor grade. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free survival (DFS), but no correlation of Ki-67 expression with overall survival (OS) was observed. Our results suggest that Ki67 expression in HR-negative breast cancer may improve the assessment of pathological response after NAC, and Ki67 score in residual tumor was an independent prognosticator for DFS in the HR-negative breast cancer patients.

  5. Prognostic value of programmed death ligand 1, p53, and Ki-67 in patients with advanced-stage colorectal cancer.

    Science.gov (United States)

    Wang, Lisha; Liu, Zebing; Fisher, Kurt W; Ren, Fei; Lv, Jiaojie; Davidson, Darrell D; Baldridge, Lee A; Du, Xiang; Cheng, Liang

    2018-01-01

    Current prognostic indicators are ineffective for identifying advanced-stage colorectal cancer (CRC) patients with high risk of recurrence after surgical resection. We investigated the prognostic value of p53, Ki-67, and programmed death ligand 1 (PD-L1) in 254 patients with stage II and III CRC. The expression of p53 was positive in 63% of cases. Up-regulation of p53 was associated with smaller tumor size (P=.001) and higher Ki-67 labeling index (LI) (P=.031). The tumor Ki-67 LI was high (≥20%) in 197 (78%) of the patients. High Ki-67 LI was associated with higher TNM stage (P=.031), positive p53 expression (P=.031), and negative PD-L1 expression (P=.003). The 5-year relapse-free survivals (RFS) were 53% and 89%, respectively, for the p53-positive and Ki-67 LI-high patients and the p53-negative and Ki-67 LI-low patients (P<.001). In univariate analysis, negative p53 (P=.001), low Ki-67 LI (P=.006), low PD-L1 expression (P=.044), low TNM stage (P<.001), rectosigmoid location (P=.026), and small size (P=.013) were significantly related to RFS. In multivariate Cox regression analysis, positive p53 expression (hazard ratio [HR]: 2.48; 95% confidence interval: 1.34-4.59, P=.004), high Ki-67 LI (HR, 2.62; 95% CI, 1.12-6.14, P=.027) and high TNM stage (HR, 2.598; 95% CI, 1.55-4.37, P<.001,) were independent predictors of unfavorable prognosis. In summary, PD-L1, Ki-67, and p53 staining individually had significant prognostic value for patients with stage II and III CRC. Moreover, combining p53 H-score ≥35 and Ki-67 LI ≥20% identifies patients with poor clinical outcome. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Expression of Ki-67 (MIB-1) and GLUT-1 proteins in non-advanced prostatic cancer.

    Science.gov (United States)

    Luczynska, Elzbieta; Gasinska, Anna; Wilk, Waclaw

    2012-12-01

    The expression of Ki-67 (MIB-1) and glucose transporter-1 (GLUT-1) were evaluated in patients with clinically localized prostate cancer (PC) who had undergone radical prostatectomy with curative intent. 140 low advanced PC specimens were studied. Protein expression was assessed immunohistochemically on tumour sections and expressed as a labelling index, i.e. the percentage of positively stained cells. In the case of Ki-67 nuclear staining and in the case of GLUT-1 membrane and cytoplasmic staining was considered as positive. The patients' mean age was 62.9 ±6.2 years. There were 13 (9.3%) at pTNM stage 1, 78 (55.7%) at stage 2, 40 (28.6%) at stage 3 and 9 (6.4%) at stage 4, respectively. 75 (53.6%) tumours were well differentiated (Gleason score ≤6), 52 (37.1%) moderately differentiated (Gleason score of 7) and 13 (9.3%) poorly differentiated (Gleason score 8-10). The mean pre-operative serum PSA was 9.9 ± SE 0.5 ng/ml, and the mean LI was equal to 8.1 ±0.6% and 29.7 ±2.0%, for MIB-1 and GLUT-1, respectively. Increase of pathological tumor volume and tumor grade was associated with statistically significant growth of PSA (p GLUT-1 LI the relation was not significant. Ki-67 expression was correlated with PSA levels (p = 0.013) and GLUT-1 scores (p = 0.04). In PC, an increase in the proliferation rate (higher MIB-1LI) in higher pTNM stages and tumour grades may point to Ki-67 as a good marker of biological aggressiveness useful in selecting patients for more aggressive treatment. A correlation between proliferation and GLUT-1 score may be the evidence of active glycolytic metabolism in hypoxic regions.

  7. STEREOLOGIC ESTIMATION OF KI-67, CASPASE 3 AND GSTP1 POSITIVE CELLS IN PROSTATE LESIONS

    Directory of Open Access Journals (Sweden)

    Luis Santamaría

    2011-05-01

    Full Text Available Cell proliferation, caspase 3 and pi-form of glutathione S transferase (GSTP1 were evaluated in prostate carcinoma (PCA, proliferative inflammatory atrophy (PIA and prostate intraepithelial neoplasia (PIN. Forty biopsies were classified as: without morphological lesions (controls: CTR, PIA, PIN and PCA. Ki67, caspase3 and GSTP1 were immunostained. The following estimates were performed: Numerical densities of Ki67+ cells (NVEPKi67, of all epithelial cells (NVEPtotal and of GSTP1+ cells (NVEPGSTP1; labelling index for Ki67 (LIKi67; volume fraction to caspase 3 positive tissue (VVcaspase 3 and of GSTP1 positive tissue (VVGSTP1. ANOVA was performed to compare the groups. NVEPtotal and NVEPKi67 were increased in PIA. LIKi67 was only increased in PCA. VVcaspase 3 was decreased in PIN and PCA. VVEGSTP1 was decreased in PCA. In our results PIA lacks the characteristics of a premalignant lesion. The result may be explained by the use of unbiased quantitative methods, the inadequate definition of PIA and the scarce inflammation observed in the samples with PIA included in this study.

  8. P53, MAPK, topoisomerase II alpha and Ki67 immunohistochemical expression and KRAS/BRAF mutation in ovarian serous carcinomas

    Directory of Open Access Journals (Sweden)

    Sundov Dinka

    2013-02-01

    Full Text Available Abstract Background We investigated the immunohistochemical expression of p53, MAPK, topoisomerase II alpha (topoII alpha and Ki67 in ovarian serous carcinomas (OSCs along with mutational analysis for KRAS and BRAF. Methods Eighty one cases of OSCs were reviewed and examined immunohistochemically using antibodies against p53, MAPK, topoII alpha and Ki67. Staining was evaluated as a percentage of immunopositive cells with cut-off levels at 10% for p53 and topoII alpha, and 5% for MAPK. The Ki67 immunoexpression was assessed by means of Olympus Image Analysis System as a percentage of immunopositive cells in 1000 tumor cells. KRAS and BRAF mutational analysis was performed on 73 available microdissected samples. Results Of 81 cases of OSCs 13.6% were of low-grade and 86.4% were of high-grade morphology. In the high-grade group there was a significantly higher immunoexpression of p53 (P P = 0.001, with Ki67 median 56.5 vs. 19 in low-grade group (P P = 0.003. MAPK positive immunostaining was detected in 63.6% of low-grade vs. 17.1% of high-grade OSCs. The frequency of KRAS mutation was significantly higher in low-grade as compared to high-grade group (P = 0.006. None of the samples had BRAF mutation. In addition, we detected positive MAPK immunoexpression in 13/59 samples with wild-type KRAS, suggesting that activation of MAPK pathway is not ultimately related either to KRAS or BRAF mutation. Seven morphologically high-grade samples (11.7% showed both KRAS mutation and p53 immunopositivity. Conclusions Although this study is limited by its humble number of low-grade samples, our data fit the proposed dualistic pathway of ovarian carcinogenesis. Mutational analysis for KRAS and BRAF discloses some possible interactions between different tumorigenic pathways of low- and high-grade carcinomas. Immunohistochemical staining for MAPK was not sufficiently sensitive, nor specific, to precisely predict the KRAS mutation. However, it appears

  9. A Comparison of Visual Assessment and Automated Digital Image Analysis of Ki67 Labeling Index in Breast Cancer.

    Science.gov (United States)

    Zhong, Fangfang; Bi, Rui; Yu, Baohua; Yang, Fei; Yang, Wentao; Shui, Ruohong

    2016-01-01

    Ki67 labeling index (LI) is critical for treatment options and prognosis evaluation in breast cancer. Visual assessment (VA) is widely used to assess Ki67 LI, but has some limitations. In this study, we compared the consistency between VA and automated digital image analysis (DIA) of Ki67 LI in breast cancer, and to evaluate the application value of DIA in Ki67 LI assessment. Ki67 immunostained slides of 155 cases of primary invasive breast cancer were eyeballing assessed by five breast pathologists and automated digital image analyzed by one breast pathologist respectively. Two score methods, hot-spot score and average score, were used to choose score areas. The intra-class correlation coefficient (ICC) was used to analyze the consistency between VA and DIA, and Wilcoxon signed-rank test was used to compare the median of paired-difference between VA and DIA values. (1) A perfect agreement was demonstrated between VA and DIA of Ki67 LI by ICC analysis (PKi67 LI was also showed in G2-G3, ER positive/HER2 negative cases. Average score and hot-spot score methods both demonstrated a perfect concordance between VA and DIA of Ki67 LI. (2) All cases were classified into three groups by VA values (≤10%, 11%-30% and >30% Ki67 LI). The concordance was relatively lower in intermediate Ki67 LI group (11%-30%) compared with high (>30%) Ki67 LI groups according to both methods. (3) All cases were classified into three groups by paired-difference (d) between VA values of hot-spot score and average score (dKi67 staining distribution (heterogeneous or homogenous) and reproducibility of assessment. A perfect agreement was all demonstrated in three groups, and a slightly better Ki67 LI agreement between VA and DIA was indicated in homogenous staining slides than in heterogeneous staining ones. (4) VA values were relatively smaller than DIA values (average score: median of paired-difference -3.72; hot-spot score: median of paired-difference -9.12). An excellent agreement between VA

  10. Prognostic significance of Ki67 in Chinese women diagnosed with ER+/HER2-breast cancers by the 2015 St. Gallen consensus classification.

    Science.gov (United States)

    Hu, Yue; Gu, Ran; Zhao, Jinghua; Yang, Yaping; Liu, Fengtao; Jin, Liang; Chen, Kai; Jia, Haixia; Wang, Hongli; Liu, Qiang; Su, Fengxi; Jia, Weijuan

    2017-01-06

    This study evaluated the distribution pattern of the Ki67-labeling index (LI) among patients at a Chinese breast cancer center, and analyzed its prognostic significance in the 2015 St Gallen consensus breast cancer classification, estrogen receptor-positive and human epidermal growth factor receptor 2-negative(ER + /HER2 - )subtype. We classified 939 women with ER + /HER2 - breast cancer into three groups by Ki67-LI levels, and followed their clinicopathologic characteristics and prognoses. In the 939 eligible subjects, 342 had Ki67-LI ≤10% (Ki67 Low ), 281 had Ki67-LI between 10 and 30% (Ki67 Medium ), and 316 had Ki67-LI ≥30% (Ki67 High ). Although the Ki67 High group had less favorable clinicopathologic factors, the Ki67 Medium group's factors varied considerably. Kaplan-Meier estimates showed that disease-free survival(DFS) for the Ki67 Medium group was significantly shorter than the Ki67 Low group but longer than the Ki67 High group. Ki67-LI had independent prognostic significance in multivariate analysis. Other diagnostic factors, including tumor size >2 cm, positive lymph nodes, and grade III disease, were significantly associated with poorer disease-free survival only in the Ki67 Medium group. For patients with ER + /HER2 - breast cancer, we confirmed three distinct risk patterns by Ki67-LI levels according to the 2015 St Gallen consensus. For patients with clearly low or high Ki67-LI, straightforward clinical decisions could be offered, but for patients with intermediate Ki67-LI, other factors might provide valuable information.

  11. Impact of tissue sampling on accuracy of Ki67 immunohistochemistry evaluation in breast cancer.

    Science.gov (United States)

    Besusparis, Justinas; Plancoulaine, Benoit; Rasmusson, Allan; Augulis, Renaldas; Green, Andrew R; Ellis, Ian O; Laurinaviciene, Aida; Herlin, Paulette; Laurinavicius, Arvydas

    2016-08-30

    Gene expression studies have identified molecular subtypes of breast cancer with implications to chemotherapy recommendations. For distinction of these types, a combination of immunohistochemistry (IHC) markers, including proliferative activity of tumor cells, estimated by Ki67 labeling index is used. Clinical studies are frequently based on IHC performed on tissue microarrays (TMA) with variable tissue sampling. This raises the need for evidence-based sampling criteria for individual IHC biomarker studies. We present a novel tissue sampling simulation model and demonstrate its application on Ki67 assessment in breast cancer tissue taking intratumoral heterogeneity into account. Whole slide images (WSI) of 297 breast cancer sections, immunohistochemically stained for Ki67, were subjected to digital image analysis (DIA). Percentage of tumor cells stained for Ki67 was computed for hexagonal tiles super-imposed on the WSI. From this, intratumoral Ki67 heterogeneity indicators (Haralick's entropy values) were extracted and used to dichotomize the tumors into homogeneous and heterogeneous subsets. Simulations with random selection of hexagons, equivalent to 0.75 mm circular diameter TMA cores, were performed. The tissue sampling requirements were investigated in relation to tumor heterogeneity using linear regression and extended error analysis. The sampling requirements were dependent on the heterogeneity of the biomarker expression. To achieve a coefficient error of 10 %, 5-6 cores were needed for homogeneous cases, 11-12 cores for heterogeneous cases; in mixed tumor population 8 TMA cores were required. Similarly, to achieve the same accuracy, approximately 4,000 nuclei must be counted when the intratumor heterogeneity is mixed/unknown. Tumors of low proliferative activity would require larger sampling (10-12 TMA cores, or 6,250 nuclei) to achieve the same error measurement results as for highly proliferative tumors. Our data show that optimal tissue sampling for

  12. Distribution pattern of the Ki67 labelling index in breast cancer and its implications for choosing cut-off values.

    Science.gov (United States)

    Cserni, Gábor; Vörös, András; Liepniece-Karele, Inta; Bianchi, Simonetta; Vezzosi, Vania; Grabau, Dorthe; Sapino, Anna; Castellano, Isabella; Regitnig, Peter; Foschini, Maria Pia; Zolota, Vassiliki; Varga, Zsuzsanna; Figueiredo, Paulo; Decker, Thomas; Focke, Cornelia; Kulka, Janina; Kaya, Handan; Reiner-Concin, Angelika; Amendoeira, Isabel; Callagy, Grace; Caffrey, Emer; Wesseling, Jelle; Wells, Clive

    2014-06-01

    The Ki67 labelling index (LI - proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Targeted light-inactivation of the Ki-67 protein using theranostic liposomes leads to death of proliferating cells

    Science.gov (United States)

    Rahmanzadeh, Ramtin; Rai, Prakash; Gerdes, Johannes; Hasan, Tayyaba

    2010-02-01

    Nanomedicine is beginning to impact the treatment of several diseases and current research efforts include development of integrated nano-constructs (theranostics) which serve as probes for imaging and therapy in addition to delivering macromolecules intracellularly. In cancer, there is a vital unmet need for effective alternative treatments with high specificity and low systemic toxicity. This can be achieved by targeting key molecular markers associated with cancer cells with reduced effective drug doses. Here, we show an innovative proof-of-principle approach for efficient killing of proliferating ovarian cancer cells by inactivating a protein associated with cell proliferation namely, the nuclear Ki-67 protein (pKi-67), using nanotechnology-based photodynamic therapy (PDT). Antibodies against pKi-67 are widely used as prognostic tools for tumor diagnosis. In this work, anti pKi-67 antibodies were first conjugated to fluorescein isothiocyanate (FITC) and then encapsulated inside liposomes. After incubation of OVCAR-5 ovarian cancer cells with these liposomes, confocal microscopy confirmed the localization of the antibodies to the nucleoli of the cells. Irradiation with a 488 nm laser led to a significant loss of cell viability. The specificity of this approach for pKi-67 positive cells was demonstrated in confluent human lung fibroblasts (MRC-5) where only a small population of cells stain positive for pKi-67 and only minimal cell death was observed. Taken together, our findings suggest that pKi-67 targeted with nano-platform is an attractive therapeutic target in cancer therapy.

  14. Immunohistochemical detection of Ki67 in breast cancer correlates with transcriptional regulation of genes related to apoptosis and cell death.

    Science.gov (United States)

    Tan, Puay-Hoon; Bay, Boon-Huat; Yip, George; Selvarajan, Sathiyamoorthy; Tan, Patrick; Wu, Jeanie; Lee, Chee-How; Li, Kuo-Bin

    2005-03-01

    Ki67 is a nuclear protein that is tightly linked to the cell cycle. It is a marker of cell proliferation and has been used to stratify good and poor prognostic categories in invasive breast cancer. Its correlation with gene expression patterns has not been fully elucidated. In this study, Ki67 immunohistochemistry using the MIB-1 antibody was performed on sections cut from 21 formalin-fixed, paraffin-embedded invasive breast cancers. Scoring was determined as nil (no immunostaining), low (10% or less immunopositivity) or high (>10% immunoreactive cells) respectively. The relationship of Ki67 immunohistochemical detection with clinicopathologic parameters was evaluated. Using Affymetrix U133A GeneChips, expression profiles for these tumors were generated and correlated with Ki67 immunohistochemical findings. Analysis of variance was used to define genes that were differentially regulated between the groups. Real-time polymerase chain reaction (PCR) was used to confirm the presence of a downregulated gene. Our results showed high, low and nil Ki67 immunostaining in nine (43%), six (28.5%) and six (28.5%) invasive breast cancers respectively, with increased Ki67 protein expression correlating with high histologic grade (P=0.02), mitotic score (P=0.001) and estrogen receptor immunonegativity (P=0.002). Expression profiling trends of the Ki67 gene mirrored the observed proportions of immunostained cells when the Ki67 immunoscore was >10%. Genes related to apoptosis and cell death (bcl2, MAP2K4, TNF10) were noted to be downregulated in tumors that disclosed >40% Ki67 immunostaining (Pbreast cancers.

  15. Prognostic impact of discrepant Ki67 and mitotic index on hormone receptor-positive, HER2-negative breast carcinoma

    Science.gov (United States)

    Rossi, L; Laas, E; Mallon, P; Vincent-Salomon, A; Guinebretiere, J-M; Lerebours, F; Rouzier, R; Pierga, J-Y; Reyal, F

    2015-01-01

    Background: Inconsistencies between mitotic index (MI) and Ki67 measures have been identified in many breast tumour samples. The aim of this study was to describe the prognosis of hormone receptor-positive (HR+) HER2− tumours having discrepant MI and Ki67. Methods: We included a cohort of breast cancer patients initially treated by surgery between 2001 and 2005 in the Institut Curie. Breast cancer-specific survival (BCSS) and disease-free survival (DFS) were analysed according to three proliferation groups: high MI/high Ki67 (MI=3, Ki67>20%), low MI/low Ki67 (MIKi67⩽20%) and discrepant (high MI/low Ki67 or low MI/high Ki67). Results: Among the 1430 patients, 19.6% had discrepant Ki67 and MI, 11.6% had high markers and 68.8% had low markers. The 5-year BCSS was 95.8%, 95% CI (0.93–0.98) in the discrepant group, 99.3%, 95% CI (0.993–0.999) in the low-proliferation group and 91.8%, 95% CI (0.88–0.96) in the high-proliferation group. In multivariate analysis, the survival of the discrepant group was lower than that of the low-proliferation group: BCSS hazard ratio (HR)=3.01 (1.32–6.84; P=0.008) and DFS HR=2.07, 95% CI (1.31–3.26; P=0.002). Among grade 2 tumours in multivariate analysis, DFS of the discrepant group was lower than that of the low MI/low Ki67 group: HR=1.98, 95% CI (1.14–3.46), P=0.02. Regarding BCSS, the obtained results were similar. Conclusion: The prognosis of patients with discrepant MI and Ki67 appears intermediate between that of low MI/low Ki67 and high MI/high Ki67 groups. These markers should be jointly analysed to clarify prognosis. PMID:26379080

  16. Predictive Role of p53 Protein as a Single Marker or Associated to Ki67 Antigen in Oral Carcinogenesis

    OpenAIRE

    Montebugnoli, L.; Felicetti, L.; Gissi, D.B.; Cervellati, F.; Servidio, D.; Marchetti, C.; Prati, C.; Flamminio, F.; Foschini, M.P.

    2008-01-01

    p53 over-expression has been proposed as a reliable marker associated to oral carcinogenesis, although only about 50% of oral carcinomas (OSCC) are associated with p53 over-expression and even p53-negative lesions can progress to OSCC. The aim of the study was to determine whether the combination of p53 over-expression and p53 low-expression associated with Ki67 over-expression (high Ki67/p53 ratio) could lead to a more sensitive parameter. Immunohistochemical expression of Ki67 and p53 was m...

  17. Hot spot detection for breast cancer in Ki-67 stained slides: image dependent filtering approach

    Science.gov (United States)

    Niazi, M. Khalid Khan; Downs-Kelly, Erinn; Gurcan, Metin N.

    2014-03-01

    We present a new method to detect hot spots from breast cancer slides stained for Ki67 expression. It is common practice to use centroid of a nucleus as a surrogate representation of a cell. This often requires the detection of individual nuclei. Once all the nuclei are detected, the hot spots are detected by clustering the centroids. For large size images, nuclei detection is computationally demanding. Instead of detecting the individual nuclei and treating hot spot detection as a clustering problem, we considered hot spot detection as an image filtering problem where positively stained pixels are used to detect hot spots in breast cancer images. The method first segments the Ki-67 positive pixels using the visually meaningful segmentation (VMS) method that we developed earlier. Then, it automatically generates an image dependent filter to generate a density map from the segmented image. The smoothness of the density image simplifies the detection of local maxima. The number of local maxima directly corresponds to the number of hot spots in the breast cancer image. The method was tested on 23 different regions of interest images extracted from 10 different breast cancer slides stained with Ki67. To determine the intra-reader variability, each image was annotated twice for hot spots by a boardcertified pathologist with a two-week interval in between her two readings. A computer-generated hot spot region was considered a true-positive if it agrees with either one of the two annotation sets provided by the pathologist. While the intra-reader variability was 57%, our proposed method can correctly detect hot spots with 81% precision.

  18. Prognostic significance of MCM2, Ki-67 and gelsolin in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Yang, Jun; Tan, Dongfeng; Ramnath, Nithya; Moysich, Kirsten B; Asch, Harold L; Swede, Helen; Alrawi, Sadir J; Huberman, Joel; Geradts, Joseph; Brooks, John SJ

    2006-01-01

    Uncontrolled proliferation and increased motility are hallmarks of neoplastic cells, therefore markers of proliferation and motility may be valuable in assessing tumor progression and prognosis. MCM2 is a member of the minichromosome maintenance (MCM) protein family. It plays critical roles in the initiation of DNA replication and in replication fork movement, and is intimately related to cell proliferation. Ki-67 is a proliferation antigen that is expressed during all but G 0 phases of the cell cycle. Gelsolin is an actin-binding protein that regulates the integrity of the actin cytoskeletal structure and facilitates cell motility. In this study, we assessed the prognostic significance of MCM2 and Ki-67, two markers of proliferation, and gelsolin, a marker of motility, in non-small cell lung cancer (NSCLC). 128 patients with pathologically confirmed, resectable NSCLC (stage I-IIIA) were included. Immunohistochemistry was utilized to measure the expressions of these markers in formalin-fixed, paraffin-embedded tumor tissues. Staining and scoring of MCM2, Ki-67 and gelsolin was independently performed. Analyses were performed to evaluate the prognostic significance of single expression of each marker, as well as the prognostic significance of composite expressions of MCM2 and gelsolin. Cox regression and Kaplan-Meier survival analysis were used for statistical analysis. Of the three markers, higher levels of gelsolin were significantly associated with an increased risk of death (adjusted RR = 1.89, 95% CI = 1.17–3.05, p = 0.01), and higher levels of MCM2 were associated with a non-significant increased risk of death (adjusted RR = 1.36, 95% CI = 0.84–2.20, p = 0.22). Combined, adjusted analyses revealed a significantly poor prognostic effect for higher expression of MCM2 and gelsolin compared to low expression of both biomarkers (RR = 2.32, 95% CI = 1.21–4.45, p = 0.01). Ki-67 did not display apparent prognostic effect in this study sample. The results suggest

  19. Ki67 expression in invasive breast cancer: the use of tissue microarrays compared with whole tissue sections.

    Science.gov (United States)

    Muftah, Abir A; Aleskandarany, Mohammed A; Al-Kaabi, Methaq M; Sonbul, Sultan N; Diez-Rodriguez, Maria; Nolan, Chris C; Caldas, Carlos; Ellis, Ian O; Rakha, Emad A; Green, Andrew R

    2017-07-01

    Although the prognostic value of Ki67 in breast cancer is well documented, using optimal cut-points for patient stratification, reproducibility of the scoring and interpretation of the results remains a matter of debate particularly when using tissue microarrays (TMAs). This study aims to assess Ki67 expression assessed on TMAs and their matched whole tissue sections (WTS). Moreover, whether the cut-off used for WTS is reproducible on TMA in BC molecular classes and the association between Ki67 expression cut-off, assessed on TMAs and WTS, and clinicopathological parameters and patient outcome were tested. A large series (n = 707) of primary invasive breast tumours were immunostained for Ki67 using both TMA and WTS and assessed as percentage staining and correlated with each other, clinicopathological parameters and patient outcome. In addition, MKI67 mRNA expression was correlated with Ki67 protein levels on WTS and TMAs in a subset of cases included in the METABRIC study. There was moderate concordance in Ki67 expression between WTS and TMA when analysed as a continuous variable (Intraclass correlation coefficient = 0.61) and low concordance when dichotomised (kappa value = 0.3). TMA showed low levels of Ki67 with mean percentage of expression of 35 and 22% on WTS and TMA, respectively. MKI67 mRNA expression was significantly correlated with protein expression determined on WTS (Spearman Correlation, r = 0.52) and to a lesser extent on TMA (r = 0.34) (p Ki67 at 10, 15, 20, 25 or 30% in TMA. Using TMA, ≥20% Ki67 provided the best prognostic cut-off particularly in triple-negative and HER2-positive classes. Ki67 expression in breast cancer can be evaluated using TMA although different cut-points are required to emulate results from WTS. A cut-off of ≥20% for Ki67 expression in BC provides the best prognostic correlations when TMAs are used.

  20. Correlation Between GATA-3, Ki67 and p53 Expressions to Histopathology Grading of Breast Cancer in Makassar, Indonesia

    OpenAIRE

    Rosdiana Natzir, Rosdiana Natzir

    2016-01-01

    - Abstract: Background: During the last two decades, research about GATA-3, Ki-67, p53 expressions have been done, but it is still a debate on their use in predicting breast cancer patients1 prognosis and survival rate. Expressions of GATA-3 decreased with increasing of histopathology grading of breast cancer and increase with decrease of histopathology grading of breast cancer. The level expression of Ki-67 has a positive relation with breast cancer histopathology grading. p53 has no corr...

  1. Prognostic value of the proliferation marker Ki-67 in laryngeal carcinoma : Results of the Accelerated Radiotherapy with Carbogen Breathing and Nicotinamide phase III randomized trial

    NARCIS (Netherlands)

    Rademakers, Saskia E.; Hoogsteen, Ilse J.; Rijken, Paul F.; Terhaard, Chris H.; Doornaert, Patricia A.; Langendijk, Johannes A.; van den Ende, Piet; van der Kogel, Albert J.; Bussink, Johan; Kaanders, Johannes H.

    BackgroundThe prognostic and predictive value of the proliferation marker Ki-67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma. MethodsLabeling index of Ki-67 (Li Ki-67) in

  2. Prognostic value of the proliferation marker Ki-67 in laryngeal carcinoma : Results of the Accelerated Radiotherapy with Carbogen Breathing and Nicotinamide phase III randomized trial

    NARCIS (Netherlands)

    Rademakers, Saskia E.; Hoogsteen, Ilse J.; Rijken, Paul F.; Terhaard, Chris H.; Doornaert, Patricia A.; Langendijk, Johannes A.; Van Den Ende, Piet; Van Der Kogel, Albert J.; Bussink, Johan; Kaanders, Johannes H.

    2015-01-01

    Background The prognostic and predictive value of the proliferation marker Ki-67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma. Methods Labeling index of Ki-67 (Li Ki-67)

  3. The potential of ki67 and p53 assessment in development of individualized targeted therapy in breast cancer patients.

    Science.gov (United States)

    Ormenisan, C; Kubik, M; Legrand, S; Kraemer, D; Smotherman, C; Masood, S

    2015-01-01

    Despite the improvement of diagnostic methods and chemotherapeutic regimens in breast cancer, overall 5-year survival significantly depends on the stage of the disease. Over expression of tumor suppressor gene p53 and the marker for cellular proliferation Ki67 in breast cancer may have prognostic significance. We evaluated 675 patients diagnosed with breast cancer at UF Health Jacksonville between January 2000 and June 2007 with up to 5-year follow up. The aim of the study was to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 may predict outcome, the 'hazard' of dying. Cox's proportional hazards models were used to control for age (ki67 was considered in the model, the hazard of dying was significantly higher for ki67 positive compared to ki67 negative (Hazard ratio = 1.64, 95% CI 1.08, 2.49, p = 0.021). Neither of the two markers, nor their interaction was significant when all variables were considered in the model. This study confirms the expression of p53 and Ki67 as strong individual indicators of patient outcome. However, when controlling for the other variables, the two markers are not independent predictors. Future studies that will include these markers might help design targeted therapy.

  4. Differences in Ki67 expressions between pre- and post-neoadjuvant chemotherapy specimens might predict early recurrence of breast cancer.

    Science.gov (United States)

    Tokuda, Emi; Horimoto, Yoshiya; Arakawa, Atsushi; Himuro, Takanori; Senuma, Koji; Nakai, Katsuya; Saito, Mitsue

    2017-05-01

    The prognosis of breast cancer patients not obtaining a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC) is poorer than that of pCR patients. Identifying new prognostic factors for non-pCR patients is important because fractions of this population might benefit from novel adjuvant treatments currently under development. High Ki67 expression in remnant disease after NAC has been described as a poor prognostic factor. Studies have shown that a reduction in Ki67 expression is more often observed in good responders to chemotherapy. We hypothesized that the change in Ki67 expression might be useful for predicting patient outcomes and thus retrospectively examined pairs of biopsy and surgical specimens of breast tissue from individual patients. One hundred sixteen patients with remnant invasive disease in the breast, who received NAC and underwent surgery at our institution, were retrospectively examined. Differences in Ki67 expression between pre- and post-NAC specimens were analyzed in relation to patient outcomes. The mean Ki67 expression value after NAC was higher in patients who developed metastasis than in those without metastasis (PKi67 expression in the surgical than in the biopsy specimen were more frequent in patients with metastasis (PKi67 expressions after versus before NAC might be an important predictor of early metastasis. Evaluating not only absolute Ki67 values, but also any changes in response to NAC, may improve the prediction of patient outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Suprabasal expression of Ki-67 as a marker for the severity of oral epithelial dysplasia and oral squamous cell carcinoma

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    Nidhi Dwivedi

    2013-01-01

    Full Text Available Background: Transition of the normal oral epithelium to dysplasia and to malignancy is featured by increased cell proliferation. To evaluate the hypothesis of distributional disturbances in proliferating and stem cells in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC. Aim: To evaluate layer wise expression of Ki-67 in oral epithelial dysplasia and in OSCC. Materials and Methods: Thirty histologically confirmed cases of oral epithelial dysplasia, fifteen cases of OSCC and five cases of normal buccal mucosa were immunohistochemically examined and nuclear expression of Ki-67 was counted according to basal, parabasal, and suprabasal layers in epithelial dysplasia and number of positive cells per 100 cells in OSCC as labeling index (LI. Results: Suprabasal expression of Ki-67 increased according to the severity of epithelial dysplasia and the difference was statistically significant ( P < 0.001. The mean Ki-67LI was 12.78 for low risk lesions, 28.68 for high risk lesions, 39.45 for OSCC and 13.6 for normal buccal mucosa. Conclusion: The results of the present study demonstrate the use of proliferative marker Ki-67 in assessing the severity of epithelial dysplasia. Suprabasal expression of Ki-67 provides an objective criteria for determining the severity of epithelial dysplasia and histological grading of OSCC.

  6. The role of Ki67 proliferation assessment in predicting local control in bladder cancer patients treated by radical radiation therapy

    International Nuclear Information System (INIS)

    Lara, P.C.; Gonzalez, G.; Rey, A.; Apolinario, R.; Santana, C.; Afonso, J.L.; Diaz, J.M.

    1998-01-01

    Purpose: To assess whether tumour proliferation as measured by Ki67 immunostaining has any predictive value for local control in bladder cancer patients treated by radiotherapy. Patients and methods: Fifty-five patients suffering from infiltrating bladder carcinoma recommended for radical radiotherapy (66 Gy/6-7weeks) were included in this study. Paraffin-embedded pre-treatment tumour sections were stained with the Ki67 antibody. The percentage of Ki67-positive nuclei was correlated with established prognostic factors, local control and survival. Results27%) Ki67 expression indices (31.5%) (P<0.05; log-rank test). Conclusions: Ki67 immunostaining was a feasible method to estimate tumour proliferation. Patients with very low proliferating tumours seemed to achieve better local control after fractionated radiotherapy compared to other patients. Further studies are needed with a greater number of patients to accurately define the role of Ki67 expression in predicting tumour repopulation during fractionated radiotherapy. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  7. Immunohistochemical distribution of Ki67 in epidermis of thick glabrous skin of human digits.

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    Petrovic, Aleksandar; Petrovic, Vladimir; Milojkovic, Bobana; Nikolic, Ivan; Jovanovic, Dragan; Antovic, Aleksandra; Milic, Miroslav

    2018-01-01

    The glabrous skin on the flexor sides of hands and feet, compared to other integument regions, has thicker epidermis and more complex pattern of epidermal ridges, wherefore in microscopy is denominated as thick skin. The epidermis of this skin type has individually unique and permanent superficial patterns, called dermatoglyphics, which are maintained by regenerative potential of deep epidermal rete ridges, that interdigitate with adjacent dermis. Using light microscopy, we analyzed cadaveric big toes thick skin samples, described histology of deep epidermal ridges (intermediate, limiting, and transverse), and quantitatively evidenced their pattern of proliferation by immunohistochemical assessment of Ki67. Immunohistochemical distribution of Ki67 was confined to basal and suprabasal layers, with pattern of distribution specific for intermediate, limiting and transverse ridges that gradually transform within epidermal height. Deep epidermal ridges, interdigitating with dermal papillae, participate in construction of intricate epidermal base, whose possible role in epidermal regeneration was also discussed. Having a prominent morphology, this type of epidermis offers the best morphological insight in complexities of skin organization, and its understanding could challenge and improve currently accepted models of epidermal organization.

  8. Role of Ki-67 proliferation index in the assessment of patients with neuroendocrine neoplasias regarding the stage of disease.

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    Miller, H C; Drymousis, P; Flora, R; Goldin, R; Spalding, D; Frilling, A

    2014-06-01

    Neuroendocrine neoplasias (NEN) of the gastroenteropancreatic (GEP) system frequently present with metastatic deposits. The proliferation marker Ki-67 is used for diagnosis and to assess the prognosis of disease. The aim of our study was to evaluate the usefulness of Ki-67 % in the assessment of NEN patients with regard to their disease stage in clinical practice. Additionally, a comparative analysis of Ki-67 levels among different sites of disease was performed. This retrospective study included patients with GEP NEN referred to our center from 2010 to 2012. The NEN diagnosis was confirmed by standard histopathology. Ki-67 immunohistochemistry was done on paraffin-embedded sections using an automated Leica immunohistochemistry machine. NEN grading was carried out according to European Neuroendocrine Tumor Society recommendations (low grade [G1] to intermediate grade [G2], well to moderately differentiated neuroendocrine neoplasms; high-grade [G3], moderately to poorly differentiated neuroendocrine neoplasms). Results of tumor staging and grading were correlated. In a subgroup of cases, comparative analysis of Ki-67 levels in different sites of disease was carried out. One hundred sixty-one GEP NEN patients were included in the study. Metastatic disease was seen in 46.1 % (53/115) of G1 tumors, 77.8 % (28/36) of G2 tumors, and 100 % of (10/10) G3 tumors (p = 0.0002). When stratified according to primary tumor site, metastatic disease was documented in 42.9 % (36/84) of patients with pancreatic NEN and in 91.9 % (34/37) of those with small intestinal primary. Stage IV metastatic disease was present in 27.8 % (32/115) and 72.2 % (26/36) of the G1 and G2 tumors, respectively, and in 90 % (9/10) of the G3 tumors. Assessment of the Ki-67 index for a subset of cases at metastatic sites as well as the primary tumor site showed discrepancies in 35.3 % cases. In 7/9 (77.8 %) patients with liver metastases, Ki-67 % was higher in the liver lesions than in the primary tumor

  9. Efficacy of endocrine therapy in relation to progesterone receptor and Ki67 expression in advanced breast cancer.

    Science.gov (United States)

    Rocca, Andrea; Farolfi, Alberto; Maltoni, Roberta; Carretta, Elisa; Melegari, Elisabetta; Ferrario, Cristiano; Cecconetto, Lorenzo; Sarti, Samanta; Schirone, Alessio; Fedeli, Anna; Andreis, Daniele; Pietri, Elisabetta; Ibrahim, Toni; Montalto, Erika; Amadori, Dino

    2015-07-01

    We assessed whether progesterone receptor (PgR) and Ki67 in primary tumors and/or matched metastases are predictors of clinical benefit from first-line endocrine therapy (ET) in advanced breast cancer. We evaluated patients treated at our institute with first-line ET (2002-2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with >2 lines of chemotherapy. A cut-off of 20 % immunostained cells was used for PgR and Ki67. The main endpoint was time-to-progression (TTP). Groups were compared by the log-rank test and Cox multivariate analysis. In the 135 assessable patients (93 % were receiving an aromatase inhibitor; biomarker assessment had been performed on primary tumors in 77 cases, on metastases in 23 and on both in 35), median TTP was 16 months (median follow-up 43 months). The overall discordance rate between primary tumors and metastases was 23 % for Ki67 and 31 % for PgR. A longer median TTP (24 vs. 12 months, P = 0.012) was seen for PgR >20 % in metastases. Ki67 showed a trend for TTP prediction in the entire case series (P = 0.062). Patients with high Ki67 and low PgR in metastases had a median TTP of only 5 months. High Ki67 in primary tumors (P = 0.026) or metastases (P = 0.01) predicted disease progression at the first evaluation. PgR in metastases remained a significant independent predictor of TTP at multivariate analysis (HR 2.45). In an ER-high population, PgR >20 % in metastases identified patients with a long TTP on endocrine treatment, while Ki67 >20 % was associated with an increased risk of non-response.

  10. Clinicopathological Significance of the Proliferation Markers Ki67, RacGAP1, and Topoisomerase 2 Alpha in Breast Cancer.

    Science.gov (United States)

    Şahin, Sevinç; Işık Gönül, İpek; Çakır, Aslı; Seçkin, Selda; Uluoğlu, Ömer

    2016-10-01

    Objectives The aims of this study are to evaluate expressions of Ki67, RacGAP1 (MgcRacGAP) and topoisomerase 2 alpha (TOP2a), the markers related with cell proliferation that have been proposed to affect the prognosis in the literature and correlate the results with clinicopathological parameters of breast cancer patients. Methods Ki67, RacGAP1, and TOP2a antibodies were applied immunohistochemically to the tissue micrarray blocks of 457 female breast cancer patients. The results were correlated with clinical, prognostic, histopathological features, and other immunohistochemical findings (estrogen receptor [ER], progesterone receptor [PR], HER2, cytokeratin [CK]5/6, CK14, epidermal growth factor receptor [EGFR] and vimentin), statistically. Results Ki67 expression demonstrated direct correlation with TOP2a expression, mitotic count, tumor grade, geographic necrosis, basal-like phenotype. RacGAP1 expression was directly correlated with TOP2a expression, nipple invasion, and number of metastatic lymph nodes, and it was inversely correlated with PR expression. TOP2a expression was directly correlated with vimentin and Ki67 expressions, mitotic count, tumor grade, and geographic necrosis, and nipple invasion, and negatively correlated with ER and PR expressions. Higher TOP2a and Ki67 expressions were correlated with shorter overall survival. Higher TOP2a expression and RacGAP1 positivity were directly correlated with shorter disease-free survival. Conclusion This study showed that the overexpressions of Ki67, RacGAP1, and TOP2a affect the prognosis adversely, thus to develop target therapies against RacGAP1 and TOP2a as well as using Ki67 as a part of routine pathology practice might be beneficial in breast cancer therapy and prediction of prognosis. © The Author(s) 2016.

  11. Comparison between Manual and Automated Methods for Ki-67 Immunoexpression Quantification in Ameloblastomas

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    Rogelio González-González

    2016-01-01

    Full Text Available Ameloblastoma is a common and unpredictable odontogenic tumor with high relapse rates. Several studies assessing the proliferative capacity of these neoplasms have been published, mainly using the protein Ki-67. Cell counts must be completed to determine the cell proliferation rate. Multiple methods have been developed for this purpose. The most widely used method is the labeling index, which has undergone changes over time to better facilitate cell counting. Here, we compared manual cell counting methods with automated cell counting (ImmunoRatio to determine the relative effectiveness of these methods. The results suggest that ImmunoRatio, a free software tool, may be highly advantageous and provide results similar to manual cell counting methods when used with the appropriate calibration. However, ImmunoRatio has flaws that may affect the labeling index results. Therefore, this automated cell counting method must be supplemented with manual cell counting methods.

  12. Predictors of sentinel lymph node metastases in breast cancer-radioactivity and Ki-67.

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    Thangarajah, Fabinshy; Malter, Wolfram; Hamacher, Stefanie; Schmidt, Matthias; Krämer, Stefan; Mallmann, Peter; Kirn, Verena

    2016-12-01

    Since the introduction of the sentinel node technique for breast cancer in the 1990s patient's morbidity was reduced. Tracer uptake is known to be dependent from lymph node integrity and activity of macrophages. The aim of this study was to assess whether radioactivity of the tracer can predict sentinel lymph node metastases. Furthermore, a potential association with Ki-67 index was examined. Non-invasive prediction of lymph node metastases could lead to a further decrease of morbidity. We retrospectively analyzed patients with primary breast cancer who underwent surgery at the Department of Obstetrics and Gynecology in the University Hospital of Cologne between 2012 and 2013. Injection of radioactive tracer was done a day before surgery in the department of Nuclear Medicine. Clinical data and radioactivity of the sentinel node measured the day before and intraoperatively were abstracted from patient's files. Of 246 patients, 64 patients had at least one, five patients had two and one patient had three positive sentinel lymph nodes. Occurrence of sentinel lymph node metastases was not associated with preoperative tracer activity (p = 0,319), intraoperative tracer activity of first sentinel node (p = 0,086) or with loss of tracer activity until operation (p = 0,909). There was no correlation between preoperative Ki-67 index and occurrence of lymph node metastases (p = 0,403). In our cohort, there was no correlation between radioactivity and sentinel node metastases. Tracer uptake might not only be influenced by lymph node metastases and does not predict metastatic lymph node involvement. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Correlation between the Expression of Topo IIα and Ki67 in breast cancer and its clinical Pathological characteristics.

    Science.gov (United States)

    Jin, Jihai; Zheng, Dongxing; Liu, Yujuan

    2017-01-01

    To investigate the expression of Topo IIα and Ki67 and its clinical significance. The clinical pathological data of one hundred and sixteen invasive breast cancer patients who were admitted into our hospital from July 2013 to December 2015 and underwent radical mastectomy were retrospectively analyzed. The expression of topoisomerase (Topo) IIα and Ki67 was detected using immunohistochemical method, and the correlation between the two kinds of proteins and the general clinical pathological characteristics of the patients was analyzed. The positive expression rates of Topo IIα and Ki67 in breast cancer were 58.6% and 75% respectively. The expression of Topo IIα was in no apparent correlation with the age, tumor size, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) (P>0.05), but in a correlation with the number of metastatic lymph glands (PKi67 was in no apparent correlation with the age, tumor size, EP and HER-2, but in a correlation with the number of metastatic lymph glands and PR (PKi67 positive expression. Topo IIα and Ki67 can be regarded as the indicators for reflecting the proliferation activity of tumor cells, and the detection of Topo IIα and Ki67 expression is of great significance to the prognosis evaluation of breast cancer patients and clinical treatment.

  14. Predicting Lymph Node Metastasis in Endometrial Cancer Using Serum CA125 Combined with Immunohistochemical Markers PR and Ki67, and a Comparison with Other Prediction Models.

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    Bingyi Yang

    Full Text Available We aimed to evaluate the value of immunohistochemical markers and serum CA125 in predicting the risk of lymph node metastasis (LNM in women with endometrial cancer and to identify a low-risk group of LNM. The medical records of 370 patients with endometrial endometrioid adenocarcinoma who underwent surgical staging in the Obstetrics & Gynecology Hospital of Fudan University were collected and retrospectively reviewed. Immunohistochemical markers were screened. A model using serum cancer antigen 125 (CA125 level, the immunohistochemical markers progesterone receptor (PR and Ki67 was created for prediction of LNM. A predicted probability of 4% among these patients was defined as low risk. The developed model was externally validated in 200 patients from Shanghai Cancer Center. The efficiency of the model was compared with three other reported prediction models. Patients with serum CA125 50% and Ki67 < 40% in cancer lesion were defined as low risk for LNM. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.82. The model classified 61.9% (229/370 of patients as being at low risk for LNM. Among these 229 patients, 6 patients (2.6% had LNM and the negative predictive value was 97.4% (223/229. The sensitivity and specificity of the model were 84.6% and 67.4% respectively. In the validation cohort, the model classified 59.5% (119/200 of patients as low-risk, 3 out of these 119 patients (2.5% has LNM. Our model showed a predictive power similar to those of two previously reported prediction models. The prediction model using serum CA125 and the immunohistochemical markers PR and Ki67 is useful to predict patients with a low risk of LNM and has the potential to provide valuable guidance to clinicians in the treatment of patients with endometrioid endometrial cancer.

  15. A simple immunohistochemical panel comprising 2 conventional markers, Ki67 and p53, is a powerful tool for predicting patient outcome in luminal-type breast cancer

    Science.gov (United States)

    2013-01-01

    Background Ki67 is widely used in order to distinguish the “A” and “B” subtypes of luminal-type breast cancer. This study aimed to validate the prognostic value of adding p53 to Ki67 for characterizing luminal-type breast cancer. Methods Immunostaining for Ki67, p53, and the molecular markers HER2, CK5/6, CK14, EGFR, FOXA1, GATA3, and P-cadherin was examined hormone receptor (HR)-positive cancer tissues from 150 patients. The prognostic value of an immunohistochemical panel comprising Ki67 and p53 was compared with that of the single Ki67 labeling index (LI), and uni- and multivariate analyses were performed. Results Division of the patients based on the immunohistochemistry results into favorable- (low Ki67 LI, p53-negative) and unfavorable- (high Ki67 LI and/or p53-positive) phenotype groups yielded distinctly different Kaplan-Meier's curves of both disease-free (PKi67 LI vs. high Ki67LI curves. While the prognostic values of the other molecular markers were not significant, combined Ki67-p53 status was an independent prognostic factor by multivariate analysis. Conclusion These data indicate that an immunohistochemical panel comprising Ki67 and p53 is a practical tool for management of patients with HR-positive breast cancer. PMID:23384409

  16. Quantum dot-based immunofluorescent imaging of Ki67 and identification of prognostic value in HER2-positive (non-luminal) breast cancer.

    Science.gov (United States)

    Sun, Jin-Zhong; Chen, Chuang; Jiang, Guan; Tian, Wei-Qun; Li, Yan; Sun, Sheng-Rong

    2014-01-01

    The immunohistochemical assessment of Ki67 antigen (Ki67) is the most widely practiced measurement of breast cancer cell proliferation; however, it has some disadvantages and thus the prognostic value of Ki67 in breast cancer remains controversial. Our previous studies confirmed the advantages of quantum dots-based nanotechnology for quantitative analysis of biomarkers compared with conventional immunohistochemistry (IHC). This study was designed to assess Ki67 by quantum dot-immunohistochemistry (QD-IHC) and investigate the prognostic value of the Ki67 score in human epidermal growth factor receptor 2 (HER2)-positive (non-luminal) breast cancer. Ki67 expression in 108 HER2-positive (non-luminal) breast cancer specimens was detected by IHC and QD-IHC. Two observers assessed the Ki67 score independently and comparisons between the two methods were made. The prognostic value of the Ki67 score for five-year disease-free survival was estimated. The same antigen localization, high correlation of staining rates (r=0.993), and high agreement of measurements (κ=0.874) of Ki67 expression (cutoff: 30%) in breast cancer were found by QD-IHC and conventional IHC. The QD-IHC had a better interobserver agreement for the Ki67 score than conventional IHC (t=-7.280, PKi67 expression (cutoff: 30%) was associated with shorter disease-free survival (log-rank test; IHC, P=0.026; QD-IHC, P=0.001), especially in the lymph node-negative subgroups (log-rank test; IHC, P=0.017; QD-IHC, P=0.002). QD-IHC imaging of Ki67 was an easier and more accurate method for detecting and assessing Ki67. The Ki67 score was an independent prognosticator in the HER2-positive (non-luminal) breast cancer patients.

  17. Ki67 expression and the effect of neo-adjuvant chemotherapy on luminal HER2-negative breast cancer.

    Science.gov (United States)

    Horimoto, Yoshiya; Arakawa, Atsushi; Tanabe, Masahiko; Sonoue, Hiroshi; Igari, Fumie; Senuma, Koji; Tokuda, Emi; Shimizu, Hideo; Kosaka, Taijiro; Saito, Mitsue

    2014-07-30

    Patients with luminal HER2-negative tumours have a favourable prognosis. However, there is a subpopulation in which poorer outcomes are obtained with endocrine therapy alone. This subpopulation is considered to benefit from chemotherapy. However, the significance of chemotherapy for those with luminal tumours has decreased due to recent changes in treatment strategies. Thus, it is often difficult to determine whether we should recommend chemotherapy to such patients in clinical practice. We investigated Ki67 expression, as a means of predicting the responses of luminal HER2-negative breast cancer patients to neo-adjuvant chemotherapy (NAC), in order to identify a subpopulation that would benefit from these treatments. We enrolled 114 luminal HER2-negative breast cancer patients undergoing surgery after NAC. Biomarkers were examined using biopsy specimens obtained prior to treatment, to avoid any chemotherapy-related effects. Chemotherapy effects were determined employing operative specimens and we defined pathological complete response (pCR) as invasive nest disappearance, based only on the primary breast tumour. We applied receiver operating characteristic curve analysis to data from our 114 patients, to investigate Ki67 expression as a predictor of pCR. The pCR rate was significantly higher for tumours with high Ki67 expression (p Ki67 cut-off value which distinguishes those with a pCR from other cases. Another dataset, comprised of 196 patients with a median 29-month observation period, was recruited for validation. Disease-free survival was found to be significantly (p Ki67 expression was higher than 35%. Our results raise the possibility of the luminal HER2-negative subpopulation with Ki67 expression higher than 35% benefiting from chemotherapy, as evidenced by improved survival.

  18. Immunocytochemical results for HER2 and Ki67 in breast cancer touch-smear cell specimens are reliable.

    Science.gov (United States)

    Morimoto, Masami; Bando, Yoshimi; Nakagawa, Misako; Takechi, Hirokazu; Yoshida, Takahiro; Honda, Junko; Tadokoro, Yukiko; Moriya, Takuya; Sasa, Mitsunori; Tangoku, Akira

    2016-07-01

    Re-evaluation of the subtype of recurrent breast cancer is necessary for deciding the treatment approach, but it is often not performed due to the difficulty of obtaining tissue specimens from a recurrent lesion, etc. However, when a recurrent lesion is close to the body surface, fine-needle aspiration cells (FNA cells) can be easily obtained, and immunocytochemical (ICC) analysis of hormone receptors expression in FNA cells is said to be highly reliable. However, there is no consensus regarding ICC analysis of human epidermal growth factor receptor type 2 (HER2) expression and the Ki67 index using FNA cells. Touch-smear cells (TSC) were prepared from resected specimens from 36 patients with primary invasive ductal carcinoma of the breast. The TSC were fixed in 95 % ethanol and subjected to ICC analysis for HER2 using HercepTest™ (Dako) and Ki67 using MIB-1™ (Dako). HER2 expression and the Ki67 index for the TSC were compared with the results of immunohistochemical analysis of histological section (HS). Statistical analyses used the kappa test and Pearson's correlation coefficients. HER2 and Ki67 were analyzed in TSC from 36 and 28 patients, respectively. The HER2 expression scores in the TSC and HS groups showed good agreement (kappa value =0.640) and significant correlation (correlation coefficient =0.860, p Ki67 indexes in the TSC and HS groups also showed significant correlation (correlation coefficient =0.861, p Ki67 index using TSC were recognized.

  19. Ki67 proliferation in core biopsies versus surgical samples - a model for neo-adjuvant breast cancer studies.

    Science.gov (United States)

    Romero, Quinci; Bendahl, Pär-Ola; Klintman, Marie; Loman, Niklas; Ingvar, Christian; Rydén, Lisa; Rose, Carsten; Grabau, Dorthe; Borgquist, Signe

    2011-08-07

    An increasing number of neo-adjuvant breast cancer studies are being conducted and a novel model for tumor biological studies, the "window-of-opportunity" model, has revealed several advantages. Change in tumor cell proliferation, estimated by Ki67-expression in pre-therapeutic core biopsies versus post-therapeutic surgical samples is often the primary end-point. The aim of the present study was to investigate potential differences in proliferation scores between core biopsies and surgical samples when patients have not received any intervening anti-cancer treatment. Also, a lack of consensus concerning Ki67 assessment may raise problems in the comparison of neo-adjuvant studies. Thus, the secondary aim was to present a novel model for Ki67 assessment. Fifty consecutive breast cancer cases with both a core biopsy and a surgical sample available, without intervening neo-adjuvant therapy, were collected and tumor proliferation (Ki67, MIB1 antibody) was assessed immunohistochemically. A theoretical model for the assessment of Ki67 was constructed based on sequential testing of the null hypothesis 20% Ki67-positive cells versus the two-sided alternative more or less than 20% positive cells.. Assessment of Ki67 in 200 tumor cells showed an absolute average proliferation difference of 3.9% between core biopsies and surgical samples (p = 0.046, paired t-test) with the core biopsies being the more proliferative sample type. A corresponding analysis on the log-scale showed the average relative decrease from the biopsy to the surgical specimen to be 19% (p = 0.063, paired t-test on the log-scale). The difference was significant when using the more robust Wilcoxon matched-pairs signed-ranks test (p = 0.029). After dichotomization at 20%, 12 of the 50 sample pairs had discrepant proliferation status, 10 showed high Ki67 in the core biopsy compared to two in the surgical specimen (p = 0.039, McNemar's test). None of the corresponding results for 1000 tumor cells were

  20. Demonstration of the proliferation marker Ki-67 in renal biopsies: correlation to clinical findings.

    Science.gov (United States)

    Nabokov, A; Waldherr, R; Ritz, E

    1997-07-01

    Assessment of cell proliferation in renal biopsy samples is a potentially promising analytical tool to evaluate disease activity. So far no information is available on the correlation between proliferative activity in different anatomic compartments of the kidney and clinical symptoms. To elucidate this issue, we examined renal biopsy specimens from 20 patients with systemic vasculitis (15 Wegener's granulomatosis, five microscopic polyangiitis), 20 patients with immunoglobulin (Ig) A nephropathy (IgAN), 13 patients with minimal-change disease (MCD), 11 patients with tubulointerstitial nephritis, and five patients with diabetes mellitus. The streptavidin-biotin-peroxidase complex technique was applied to autoclave-pretreated, formalin-fixed, paraffin-embedded tissue sections to label different cell types with the antibody MIB1 directed against the Ki-67 antigen. Proliferation index (PI) was estimated as the number of positively stained nuclei per glomerular cross-section or per square millimeter section area. The interstitial cells were discriminated by additional staining of Ki-67-processed samples with specific immune markers. In patients with vasculitis, PI was considerably elevated in the extracapillary glomerular compartment (0.86), in proximal tubules (6.24), and in the interstitium (8.62). High proliferative activity was also noted in interstitium (3.98) and proximal tubules (1.35) of patients with IgAN. Of particular interest was the increased interstitial proliferative activity (15.0) in diabetic patients. Resident renal cells, but not infiltrating cells, seemed to constitute the majority of the proliferating cell population in the interstitium. In systemic vasculitis, clinical disease activity was significantly correlated to endocapillary (r(s) = 0.58), extracapillary (r(s) = 0.67), proximal tubular (r(s) = 0.67), and interstitial PI (r(s) = 0.61). By multiple linear regression analysis, proximal tubular PI was correlated to the presence of hematuria

  1. Prognostic significance of geminin expression levels in Ki67-high subset of estrogen receptor-positive and HER2-negative breast cancers.

    Science.gov (United States)

    Yagi, Tomoko; Inoue, Natsuko; Yanai, Ayako; Murase, Keiko; Imamura, Michiko; Miyagawa, Yoshimasa; Enomoto, Yukie; Nishimukai, Arisa; Takatsuka, Yuichi; Hirota, Seiichi; Akazawa, Kouhei; Miyoshi, Yasuo

    2016-03-01

    Indication for chemotherapy in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers is determined on the basis of Ki67 expression level. However, since Ki67-high cancers are not necessarily sensitive to chemotherapy, identification of such patients who do not need chemotherapy is an important issue. We used immunohistochemical staining to examine the expression levels of ER, progesterone receptor (PgR), Ki67, and geminin, a marker of S to G2/M phases, in 80 ER-positive/HER2-negative breast cancers. The labeling indices of Ki67 and geminin were determined and cutoff values were set at 15 and 6 %, respectively. Ki67 and geminin expression levels were significantly associated with nuclear grade. In the Ki67-low subset, 26 out of 28 (92.9 %) cancers were geminin low and in the Ki67-high subset, 31 out of 52 (59.6 %) were geminin high. Distant disease-free survival (DDFS) of the geminin-high subset was significantly poorer than that of the geminin-low subset (P = 0.009). In the Ki67-low subset, only one patient showed recurrence. Metastasis was detected in eight out of 31 (25.8 %) patients in the geminin-high group of the Ki67-high subset, but no recurrence was observed in the geminin-low group of the Ki67-high subset. Geminin-high breast cancers are significantly associated with worse prognosis. Since poorer prognosis was recognized only in the geminin-high group in Ki67-high cancers, we speculate that geminin may be useful for identifying patients in the Ki67-high subset who can avoid unnecessary chemotherapy.

  2. Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial.

    Science.gov (United States)

    Denkert, C; Loibl, S; Müller, B M; Eidtmann, H; Schmitt, W D; Eiermann, W; Gerber, B; Tesch, H; Hilfrich, J; Huober, J; Fehm, T; Barinoff, J; Jackisch, C; Prinzler, J; Rüdiger, T; Erbstösser, E; Blohmer, J U; Budczies, J; Mehta, K M; von Minckwitz, G

    2013-11-01

    The proliferation marker Ki67 has been suggested as a promising cancer biomarker. As Ki67 needs an exact quantification, this marker is a prototype of a new generation of tissue-based biomarkers. In this study, we have systematically evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort. We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial. We used the standardized cutoff-finder algorithm for three end points [response to neoadjuvant chemotherapy (pCR), disease-free (DFS) and overall-survival (OS)]. The analyses were stratified for hormone receptor (HR) and HER2 status by molecular subtype radar diagrams (MSRDs). A wide range of Ki67 cut points between 3%-94% (for pCR), 6%-46% (for DFS) and 4%-58% (for OS) were significant. The three groups of Ki67 ≤ 15% versus 15.1%-35% versus >35% had pCR-rates of 4.2%, 12.8%, and 29.0% (P Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive, but not triple-negative tumors. Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data-derived cut point optimization might not be possible. Ki67 could be used as a continuous marker; in addition, the scientific community could define standardized cut points for Ki67. Our analysis explains the variability observed for Ki67 cut points in previous studies; however, this should not be seen as weakness, but as strength of this marker. MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer. The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers.

  3. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry

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    Inwald, E. C.; Klinkhammer-Schalke, M.; Hofst?dter, F.; Zeman, F.; Koller, M.; Gerstenhauer, M.; Ortmann, O.

    2013-01-01

    The proliferation marker Ki-67 is one of the most controversially discussed parameters for treatment decisions in breast cancer patients. The purpose of this study was to evaluate the routine use and value of Ki-67 as a prognostic marker, and to analyze the associations between Ki-67 and common histopathological parameters in the routine clinical setting. Data from the clinical cancer registry Regensburg (Bavaria, Germany) were analyzed. Within the total data pool of 4,692 female patients, wh...

  4. Comparison of Visual and automated assessment of Ki-67 proliferative activity and their impact on outcome in primary operable invasive ductal breast cancer

    OpenAIRE

    Mohammed, Z M A; McMillan, D C; Elsberger, B; Going, J J; Orange, C; Mallon, E; Doughty, J C; Edwards, J

    2012-01-01

    Background: Immunohistochemistry of Ki-67 protein is widely used to assess tumour proliferation, and is an established prognostic factor in breast cancer. There is interest in automating the assessment of Ki-67 labelling index (LI) with possible benefits in handling increased workload, with improved accuracy and precision. Patients and methods: Visual and automated assessment of Ki-67 LI and survival were examined in patients with primary operable invasive ductal breast cancer. Tissue microar...

  5. An Advanced Deep Learning Approach for Ki-67 Stained Hotspot Detection and Proliferation Rate Scoring for Prognostic Evaluation of Breast Cancer

    OpenAIRE

    Saha, Monjoy; Chakraborty, Chandan; Arun, Indu; Ahmed, Rosina; Chatterjee, Sanjoy

    2017-01-01

    Being a non-histone protein, Ki-67 is one of the essential biomarkers for the immunohistochemical assessment of proliferation rate in breast cancer screening and grading. The Ki-67 signature is always sensitive to radiotherapy and chemotherapy. Due to random morphological, color and intensity variations of cell nuclei (immunopositive and immunonegative), manual/subjective assessment of Ki-67 scoring is error-prone and time-consuming. Hence, several machine learning approaches have been report...

  6. Neurotrophins, their receptors and KI-67 in human GH-secreting pituitary adenomas: an immunohistochemical analysis.

    Science.gov (United States)

    Artico, M; Bianchi, E; Magliulo, G; De Vincentiis, M; De Santis, E; Orlandi, A; Santoro, A; Pastore, F S; Giangaspero, F; Caruso, R; Re, M; Fumagalli, L

    2012-01-01

    Pituitary adenomas are a diverse group of tumors arising from the pituitary gland. Typically, they are small, slow-growing, hormonally inactive lesions that come to light as incidental findings on radiologic or postmortem examinations, although some small, slow-growing lesions with excessive hormonal activity may manifest with a clinical syndrome. The family of neurotrophins plays a key role in the development and maintenance of the pituitary endocrine cell function and in the regulation of hypothalamo-pituitary-adrenocortical axis activity. The objective of our experimental study is to investigate the localization of the neurotrophins, their relative receptors and to detect the expression level of Ki-67 to determine whether all these factors participate in the transformation and development of human pituitary adenomas. A very strong expression of Neurotrophin-3 (NT-3) and its receptor TrKC was observed in the extracellular matrix (ECM) and vessel endothelium, together with a clear/marked presence of Brain-derived neurotrophic factor (BDNF), and its receptor TrKB, thus confirming their direct involvement in the progression of pituitary adenomas. On the contrary, NGF (Nerve growth factor) and its receptor TrKA and p75NTR were weakly expressed in the epithelial gland cells and the ECM.

  7. Analysis of human mammary fibroadenoma by Ki-67 index in the follicular and luteal phases of menstrual cycle.

    Science.gov (United States)

    Rego, M F; Navarrete, M A L H; Facina, G; Falzoni, R; Silva, R; Baracat, E C; Nazario, A C P

    2009-04-01

    Fibroadenoma is the most common benign mammary condition among women aged 35 or younger. Expression of Ki-67 antigen has been used to compare proliferative activity of mammary fibroadenoma epithelium in the follicular and luteal phases of the menstrual cycle. Ninety eumenorrheic women were selected for tumour excision; they were assigned to either of the two groups, according to their phase of menstrual cycle. At the end of the study, 75 patients with 87 masses were evaluated by epithelial cell Ki-67 expression, blind (no information given concerning group to which any lesion belonged). Both groups were found to be homogeneous relative to age, menarche, body mass index, previous gestation, parity, breastfeeding, number of fibroadenomas, family history of breast cancer and tabagism. Median tumour size was 2.0 cm and no relationship between proliferative activity and nodule diameter was observed. No typical pattern was observed in the expression of Ki-67 in distinct nodules of the same patient. Average values for expression of Ki-67 (per 1000 epithelial cells) in follicular and luteal phases were 27.88 and 37.88, respectively (P = 0.116). Our findings revealed that proliferative activities in the mammary fibroadenoma epithelium did not present a statistically significant difference in the follicular and luteal phases. The present study contributes to clarifying that fibroadenoma is a neoplasm and does not undergo any change in the proliferative activity during the menstrual cycle.

  8. High-throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium.

    Science.gov (United States)

    Abubakar, Mustapha; Howat, William J; Daley, Frances; Zabaglo, Lila; McDuffus, Leigh-Anne; Blows, Fiona; Coulson, Penny; Raza Ali, H; Benitez, Javier; Milne, Roger; Brenner, Herman; Stegmaier, Christa; Mannermaa, Arto; Chang-Claude, Jenny; Rudolph, Anja; Sinn, Peter; Couch, Fergus J; Tollenaar, Rob A E M; Devilee, Peter; Figueroa, Jonine; Sherman, Mark E; Lissowska, Jolanta; Hewitt, Stephen; Eccles, Diana; Hooning, Maartje J; Hollestelle, Antoinette; Wm Martens, John; Hm van Deurzen, Carolien; Investigators, kConFab; Bolla, Manjeet K; Wang, Qin; Jones, Michael; Schoemaker, Minouk; Broeks, Annegien; van Leeuwen, Flora E; Van't Veer, Laura; Swerdlow, Anthony J; Orr, Nick; Dowsett, Mitch; Easton, Douglas; Schmidt, Marjanka K; Pharoah, Paul D; Garcia-Closas, Montserrat

    2016-07-01

    Automated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in studies from the Breast Cancer Association Consortium. We utilized 166 TMAs containing 16,953 tumour cores representing 9,059 breast cancer cases, from 13 studies, with information on other clinical and pathological characteristics. TMAs were stained for Ki67 using standard immunohistochemical procedures, and scanned and digitized using the Ariol system. An automated algorithm was developed for the scoring of Ki67, and scores were compared to computer assisted visual (CAV) scores in a subset of 15 TMAs in a training set. We also assessed the correlation between automated Ki67 scores and other clinical and pathological characteristics. Overall, we observed good discriminatory accuracy (AUC = 85%) and good agreement (kappa = 0.64) between the automated and CAV scoring methods in the training set. The performance of the automated method varied by TMA (kappa range= 0.37-0.87) and study (kappa range = 0.39-0.69). The automated method performed better in satisfactory cores (kappa = 0.68) than suboptimal (kappa = 0.51) cores (p-value for comparison = 0.005); and among cores with higher total nuclei counted by the machine (4,000-4,500 cells: kappa = 0.78) than those with lower counts (50-500 cells: kappa = 0.41; p-value = 0.010). Among the 9,059 cases in this study, the correlations between automated Ki67 and clinical and pathological characteristics were found to be in the expected directions. Our findings indicate that automated scoring of Ki67 can be an efficient method to obtain good quality data across large numbers of TMAs from multicentre studies. However, robust algorithm development and rigorous pre- and post-analytical quality control procedures are

  9. High‐throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium

    Science.gov (United States)

    Howat, William J; Daley, Frances; Zabaglo, Lila; McDuffus, Leigh‐Anne; Blows, Fiona; Coulson, Penny; Raza Ali, H; Benitez, Javier; Milne, Roger; Brenner, Herman; Stegmaier, Christa; Mannermaa, Arto; Chang‐Claude, Jenny; Rudolph, Anja; Sinn, Peter; Couch, Fergus J; Tollenaar, Rob A.E.M.; Devilee, Peter; Figueroa, Jonine; Sherman, Mark E; Lissowska, Jolanta; Hewitt, Stephen; Eccles, Diana; Hooning, Maartje J; Hollestelle, Antoinette; WM Martens, John; HM van Deurzen, Carolien; Investigators, kConFab; Bolla, Manjeet K; Wang, Qin; Jones, Michael; Schoemaker, Minouk; Broeks, Annegien; van Leeuwen, Flora E; Van't Veer, Laura; Swerdlow, Anthony J; Orr, Nick; Dowsett, Mitch; Easton, Douglas; Schmidt, Marjanka K; Pharoah, Paul D; Garcia‐Closas, Montserrat

    2016-01-01

    Abstract Automated methods are needed to facilitate high‐throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large‐scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in studies from the Breast Cancer Association Consortium. We utilized 166 TMAs containing 16,953 tumour cores representing 9,059 breast cancer cases, from 13 studies, with information on other clinical and pathological characteristics. TMAs were stained for Ki67 using standard immunohistochemical procedures, and scanned and digitized using the Ariol system. An automated algorithm was developed for the scoring of Ki67, and scores were compared to computer assisted visual (CAV) scores in a subset of 15 TMAs in a training set. We also assessed the correlation between automated Ki67 scores and other clinical and pathological characteristics. Overall, we observed good discriminatory accuracy (AUC = 85%) and good agreement (kappa = 0.64) between the automated and CAV scoring methods in the training set. The performance of the automated method varied by TMA (kappa range= 0.37–0.87) and study (kappa range = 0.39–0.69). The automated method performed better in satisfactory cores (kappa = 0.68) than suboptimal (kappa = 0.51) cores (p‐value for comparison = 0.005); and among cores with higher total nuclei counted by the machine (4,000–4,500 cells: kappa = 0.78) than those with lower counts (50–500 cells: kappa = 0.41; p‐value = 0.010). Among the 9,059 cases in this study, the correlations between automated Ki67 and clinical and pathological characteristics were found to be in the expected directions. Our findings indicate that automated scoring of Ki67 can be an efficient method to obtain good quality data across large numbers of TMAs from multicentre studies. However, robust algorithm development and rigorous pre‐ and post

  10. p16(INK4a)/Ki-67 dual stain cytology for cervical cancer screening in Thika district, Kenya.

    Science.gov (United States)

    Ngugi, Caroline Wangari; Schmidt, Dietmar; Wanyoro, Karanja; Boga, Hamadi; Wanzala, Peter; Muigai, Anne; Mbithi, John; von Knebel Doeberitz, Magnus; Reuschenbach, Miriam

    2015-01-01

    The identification of suited early detection tests is one among the multiple requirements to reduce cervical cancer incidence in developing countries. We evaluated p16(INK4a)/Ki-67 dual-stain cytology in a screening population in Thika district, Kenya and compared it to high-risk human papillomavirus (HR-HPV) DNA testing and visual inspection by acetic acid (VIA) and Lugol's iodine (VILI). Valid results for all tests could be obtained in 477 women. 20.9 % (100/477) were tested positive for HR-HPV DNA, 3.1 % (15/477) had positive VIA/VILI and 8.2 % (39/477) positive p16(INK4a)/Ki-67 cytology. Of 22 women that showed up for colposcopy and biopsy, 6 women were diagnosed with CIN3 and two with CIN2. All women with CIN2/3 were negative in VIA/VILI screening and positive by HR-HPV DNA testing. But HPV was also positive in 91.7 % (11/12) of women with normal histology. p16(INK4a)/Ki-67 cytology was positive in all 6 women with CIN3, in one of the two CIN2 and in only 8.3 % (1/12) of women with normal histology. p16(INK4a)/Ki-67 cytology is an interesting test for further studies in developing countries, since our findings point to a lower fraction of false positive test results using p16(INK4a)/Ki-67 cytology compared to HPV DNA testing in a Kenyan screening population. VIA/VILI missed all histology-proven CIN2/3.

  11. Importance of P53, Ki-67 expression in the differential diagnosis of benign/malignant phyllodes tumors of the breast

    Directory of Open Access Journals (Sweden)

    Ulku Kucuk

    2013-01-01

    Full Text Available Background: Conventionally growth pattern, stromal overgrowth, stromal cellularity and stromal mitotic activity are the main parameters in the grading of phyllodes tumors (PTs. Recent studies revealed that both p53 and Ki-67 expressions are correlated with grade of PTs of the breast. Expression of hormone receptors and overexpression/amplification of HER2 has been studied in PTs to discover the roles of these markers as new treatment modalities. Materials and Method: We studied 26 PT cases. Seventeen benign and nine malignant PTs were re-evaluated as regards stromal cellularity mitotic activity, p53/Ki-67 expression rates and the relation between these parameters. Estrogen receptor and progesterone receptor (ER, PR positivity were determined by counting nuclear staining in five high-power fields. Also, the presence of any HER2 staining and staining patterns were documanted. Results: Stromal cellularity, mitotic rate, p53 and Ki-67 expression rates were all correlated with benign and malignant histologic subgroups (P = 0.000-0.001. Ki-67 and p53 expressions were statistically significantly correlated with histologic subgroups, stromal cellularity and mitotic rate (P < 0.005. ER and PR expressions in the epithelial component were not statistically significant between the two groups. HER2 showed different staining patterns in the epithelial component, and there was no staining in the stromal component. Conclusion: Ki-67 and p53 expression rates were statistically significantly correlated with grade of mammary PTs; therefore, they can be used in the determination of tumor grade, especially for the differential diagnosis of benign and malignant tumors. Malignant and benign tumors did not differ significantly in terms of hormone receptor and HER2 expression. HER2 expression showed different patterns in the epithelial component of the PTs.

  12. MCM-2 and MCM-5 expression in gastric adenocarcinoma: clinical significance and comparison with Ki-67 proliferative marker.

    Science.gov (United States)

    Giaginis, Constantinos; Giagini, Athina; Tsourouflis, Gerasimos; Gatzidou, Elisavet; Agapitos, Emmanuel; Kouraklis, Gregorios; Theocharis, Stamatios

    2011-03-01

    Minichromosome maintenance (MCM) proteins are essential components of DNA replication, being related to cell proliferation, and serve as useful biomarkers for cancer screening, surveillance and prognosis. The aim of the present study was to evaluate the clinical significance of MCM-2 and MCM-5 expression in gastric adenocarcinoma in comparison with Ki-67 proliferative marker. MCM-2, MCM-5 and Ki-67 expression was assessed immunohistochemically in 66 tumoral samples of gastric adenocarcinoma patients and was statistically analyzed in relation to clinicopathological characteristics and patient survival. MCM-2 expression did not show significant associations with any clinicopathological parameters, while Ki-67 expression was merely significantly associated with tumor size (P = 0.0150). MCM-2 and Ki-67 expression were more frequently in intestinal (median values: 67.5 and 60%) compared to diffuse-type (median values: 60 and 45%) gastric adenocarcinoma cases without though reaching statistical significance (P > 0.05). MCM-5 expression was significantly associated with tumor size (P = 0.0295), presence of lymph node metastases (P = 0.0216) and tumor histopathological stage (P = 0.0098). Patients presenting high MCM-5 expression had significantly shorter survival times (log-rank test, P = 0.0042), whereas neither MCM-2 nor Ki-67 expression showed significant prognostic value (log-rank test, P = 0.9618 and P = 0.7174, respectively). In multivariate analysis, patient age, histopathological stage and grade of differentiation, but not MCM-5 expression, were identified as independent prognostic factors (Cox regression analysis, P = 0.0097, P = 0.0195, P = 0.0035 and P = 0.3245, respectively). The present study showed that MCM-5 expression was associated with clinicopathological parameters in gastric adenocarcinoma. However, further studies highlighting the distinct impact of the two histopathological types, intestinal and diffuse, are warranted to delineate whether MCMs could

  13. Quantum dot-based multispectral fluorescent imaging to quantitatively study co-expressions of Ki67 and HER2 in breast cancer.

    Science.gov (United States)

    Xiang, Qing-Ming; Wang, Lin-Wei; Yuan, Jing-Ping; Chen, Jia-Mei; Yang, Fang; Li, Yan

    2015-08-01

    Both Ki67 and HER2 are key prognostic molecules for invasive breast cancer (BC), but the individual relative impacts on prognosis of these molecules are not known. This study was aimed at establishing a quantum dot (QD)-based double-color in-situ quantitative imaging technique to study the co-expressions of Ki67 and HER2, and delineate the individual impacts of these molecules on prognosis. The QD-based fluorescent immunostaining technique could simultaneously image the co-expressions of Ki67 and HER2 in BC specimens, with the former stained as clear red fluorescence in cancer cell nucleus, and the latter as bright green fluorescence on cancer cell membrane. Both Ki67 and HER2 expressions were significantly correlated with 8-year disease free survival (8-DFS) (PKi67 High-HER2 subgroup than Low-Ki67 High-HER2 subgroup (11.7 vs. 60.1months, PKi67 Low-HER2 subgroup than Low-Ki67 Low-HER2 subgroup (16.4 vs. 96.0months, PKi67 High-HER2 subgroup than Low-Ki67 Low-HER2 subgroup (11.7 vs. 96.0months, PKi67 Low-HER2 subgroup and High-Ki67 High-HER2 subgroup (11.7 vs. 16.4months, P=0.586). The hazard ratio (HR) of Ki67 negative impact on 8-DFS was about 3 fold of that of HER2 (HR 4.493 vs. 1.481). This study demonstrated that QD-based fluorescent imaging technique could help the quantitative study on the co-expressions of Ki67 and HER2 in BC, and Ki67 has a greater negative impact on BC prognosis than HER2. Copyright © 2015. Published by Elsevier Inc.

  14. Prognostic Value of Proliferation Markers: Immunohistochemical Ki-67 Expression and Cytometric S-Phase Fraction of Women with Breast Cancer in Libya

    Directory of Open Access Journals (Sweden)

    Eramah Ermiah, Abdelbaset Buhmeida, Fathi Abdalla, Ben Romdhane Khaled, Nada Salem, Seppo Pyrhönen, Yrjö Collan

    2012-01-01

    Full Text Available Background: We evaluated the association of the immunohistochemical Ki-67 expression, and S-phase fraction with clinicopathological variables and patient outcome.Patients and methods: Histological samples from 100 primary Libyan breast carcinoma patients were retrospectively studied with monoclonal antibody to Ki-67. S-phase fraction was determined by DNA image cytometry.Results: The median Ki-67 percentage for all tumors was 27.5%, ranging from 1 to 80% and the median S-phase fraction (SPF was 11%, ranging from 0 to 62 %. Tumors with high Ki-67 expression were found in 76% of patients and with high SPF values in 56%. Ki-67 expression was more frequent in tumors with high SPF than low SPF. High Ki-67 and high SPF were associated with advanced stages, poor differentiation of tumors, positive lymph nodes, and distant metastasis. The Ki-67 was associated with hormone receptor negative tumors. The SPF was higher in young patients (<50 years than in older patients. In the overall population (median follow-up 49 months, patients with high Ki-67 and high SPF had shorter survival time and predicted recurrence than patients with low Ki-67 and low SPF. In a Cox multivariate analysis, high SPF (p= 0.007, hormonal status (p= 0.001 and clinical stage (p=0.005 were independent predictors of disease-specific survival. The Ki-67 (p=0.065 in borderline significance proved to be independent predictor of disease-free survival. The SPF showed more statistically significance with a high grade of malignancy and survival time than Ki-67.Conclusions: The SPF value is useful cell proliferation marker to assess tumor prognosis. These markers may reflect the aggressive behavior of Libyan breast cancer and predict of the recurrence. It is therefore important to take these markers into consideration to select a high risk subgroup of the patients for intensive treatment.

  15. MCM - 2 and Ki - 67 as proliferation markers in renal cell carcinoma: A quantitative and semi - quantitative analysis.

    Science.gov (United States)

    Mehdi, Muhammad Zain; Nagi, Abdul Hanan; Naseem, Nadia

    2016-01-01

    Fuhrman nuclear grade is the most important histological parameter to predict prognosis in a patient of renal cell carcinoma (RCC). However, it suffers from inter-observer and intra-observer variation giving rise to need of a parameter that not only correlates with nuclear grade but is also objective and reproducible. Proliferation is the measure of aggressiveness of a tumour and it is strongly correlated with Fuhrman nuclear grade, clinical survival and recurrence in RCC. Ki-67 is conventionally used to assess proliferation. Mini-chromosome maintenance 2 (MCM-2) is a lesser known marker of proliferation and identifies a greater proliferation faction. This study was designed to assess the prognostic significance of MCM-2 by comparing it with Fuhrman nuclear grade and Ki-67. n=50 cases of various ages, stages, histological subtypes and grades of RCC were selected for this study. Immunohistochemical staining using Ki-67(MIB-1, Mouse monoclonal antibody, Dako) and MCM-2 (Mouse monoclonal antibody, Thermo) was performed on the paraffin embedded blocks in the department of Morbid anatomy and Histopathology, University of Health Sciences, Lahore. Labeling indices (LI) were determined by two pathologists independently using quantitative and semi-quantitative analysis. Statistical analysis was carried out using SPSS 20.0. Kruskall-Wallis test was used to determine a correlation of proliferation markers with grade, and Pearson's correlate was used to determine correlation between the two proliferation markers. Labeling index of MCM-2 (median=24.29%) was found to be much higher than Ki-67(median=13.05%). Both markers were significantly related with grade (p=0.00; Kruskall-Wallis test). LI of MCM-2 was found to correlate significantly with LI of Ki-67(r=0.0934;p=0.01 with Pearson's correlate). Results of semi-quantitative analysis correlated well with quantitative analysis. Both Ki-67 and MCM-2 are markers of proliferation which are closely linked to grade. Therefore, they

  16. Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women

    NARCIS (Netherlands)

    Ebisch, R.M.F.; Horst, J.; Hermsen, M.; Rijstenberg, L.L.; Vedder, J.E.; Bulten, J.; Bosgraaf, R.P.; Verhoef, V.M.; Heideman, D.A.; Snijders, P.J.; Meijer, C.J.W.; Kemenade, F.J. van; Massuger, L.F.; Melchers, W.J.; Bekkers, R.L.M.; Siebers, A.G.

    2017-01-01

    The aim of this study was to evaluate the clinical utility of p16/Ki-67 dual staining, for the identification of CIN in high-risk HPV-positive women from a non-responder screening cohort. P16/Ki-67 dual staining, Pap cytology, and HPV16/18 genotyping were performed on physician-taken liquid-based

  17. Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3, MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma

    International Nuclear Information System (INIS)

    Ladstein, Rita G; Bachmann, Ingeborg M; Straume, Oddbjørn; Akslen, Lars A

    2010-01-01

    Tumor cell proliferation is a predictor of survival in cutaneous melanoma. The aim of the present study was to evaluate the prognostic impact of mitotic count, Ki-67 expression and novel proliferation markers phosphohistone H3 (PHH3), minichromosome maintenance protein 4 (MCM4) and mitosin, and to compare the results with histopathological variables. 202 consecutive cases of nodular cutaneous melanoma were initially included. Mitotic count (mitosis per mm 2 ) was assessed on H&E sections, and Ki-67 expression was estimated by immunohistochemistry on standard sections. PHH3, MCM4 and mitosin were examined by staining of tissue microarrays (TMA) sections. Increased mitotic count and elevated Ki-67 expression were strongly associated with increased tumor thickness, presence of ulceration and tumor necrosis. Furthermore, high mitotic count and elevated Ki-67 expression were also associated with Clark's level of invasion and presence of vascular invasion. High expression of PHH3 and MCM4 was correlated with high mitotic count, elevated Ki-67 expression and tumor ulceration, and increased PHH3 frequencies were associated with tumor thickness and presence of tumor necrosis. Univariate analyses showed a worse outcome in cases with elevated Ki-67 expression and high mitotic count, whereas PHH3, MCM4 and mitosin were not significant. Tumor cell proliferation by Ki-67 had significant prognostic impact by multivariate analysis. Ki-67 was a stronger and more robust prognostic indicator than mitotic count in this series of nodular melanoma. PHH3, MCM4 and mitosin did not predict patient survival

  18. Valor prognóstico do Ki-67 no carcinoma indiferenciado de grandes células de glândula salivar maior: estudo de 11 casos Prognostic significance of Ki-67 in great cell undifferentiated carcinoma of the major salivary glands: study of 11 cases

    Directory of Open Access Journals (Sweden)

    Túlio V. Barbosa

    2003-10-01

    cases of Undifferentiated Carcinoma of Major Salivary Glands were diagnosed and treated at the Head and Neck and Otorhinolaryngology Department of Hospital Heliópolis, Hosphel, São Paulo, from 1977 to 2000. These specimens were reviewed through histological and imunohistochemical procedures, and sub classified for positivity profile of citokeratines (high and low molecular weights. Then, it was defined a bi-directional pattern of histogenetic differentiation (mucoepidermoid type and unidirectional pattern (epidermoid or ductal/glandular types, and its relation to clinic-demographic, mitotic index and cellular imunoproliferation (Ki- 67 clone MB-1, concerning to biological behaviour of these neoplasias. RESULTS: showed the predominance of patients withy more than 40 years old, white, parotid gland location and aggressiveness since early stages (T1 e T2. The mitotic and cellular imunoproliferative index (Ki-67 revealed values of high malignancy neoplasias (p<0,01 as mucoepidemoid, cystic adenoid and acinar carcinoma. CONCLUSION: The imunohistochemical subclassification positivity for citokeratines, did not show statistical differences between mitotic and cellular imunoproliferative index (Ki-67, relating to predictive prognosis of these neoplasias.

  19. Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Mitra, A V; Jameson, C; Barbachano, Y

    2010-01-01

    Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic...... feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant...... a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all...

  20. A methodology to ensure and improve accuracy of Ki67 labelling index estimation by automated digital image analysis in breast cancer tissue.

    Science.gov (United States)

    Laurinavicius, Arvydas; Plancoulaine, Benoit; Laurinaviciene, Aida; Herlin, Paulette; Meskauskas, Raimundas; Baltrusaityte, Indra; Besusparis, Justinas; Dasevicius, Darius; Elie, Nicolas; Iqbal, Yasir; Bor, Catherine

    2014-01-01

    Immunohistochemical Ki67 labelling index (Ki67 LI) reflects proliferative activity and is a potential prognostic/predictive marker of breast cancer. However, its clinical utility is hindered by the lack of standardized measurement methodologies. Besides tissue heterogeneity aspects, the key element of methodology remains accurate estimation of Ki67-stained/counterstained tumour cell profiles. We aimed to develop a methodology to ensure and improve accuracy of the digital image analysis (DIA) approach. Tissue microarrays (one 1-mm spot per patient, n = 164) from invasive ductal breast carcinoma were stained for Ki67 and scanned. Criterion standard (Ki67-Count) was obtained by counting positive and negative tumour cell profiles using a stereology grid overlaid on a spot image. DIA was performed with Aperio Genie/Nuclear algorithms. A bias was estimated by ANOVA, correlation and regression analyses. Calibration steps of the DIA by adjusting the algorithm settings were performed: first, by subjective DIA quality assessment (DIA-1), and second, to compensate the bias established (DIA-2). Visual estimate (Ki67-VE) on the same images was performed by five pathologists independently. ANOVA revealed significant underestimation bias (P Ki67-Count, in particularfor the clinically relevant interval of Ki67-Count Ki67-LI estimation by DIA, based on proper validation, calibration, and measurement error correction procedures, guided by quantified bias from reference values obtained by stereology grid count. This basic validation step is an important prerequisite for high-throughput automated DIA applications to investigate tissue heterogeneity and clinical utility aspects of Ki67 and other immunohistochemistry (IHC) biomarkers.

  1. Ki-67 Is an Independent Predictor of Metastasis and Cause-Specific Mortality for Prostate Cancer Patients Treated on Radiation Therapy Oncology Group (RTOG) 94-08

    Energy Technology Data Exchange (ETDEWEB)

    Verhoven, Bret [University of Wisconsin Carbone Cancer Center, Madison, Wisconsin (United States); Yan, Yan [RTOG Statistical Center, Philadelphia, Pennsylvania (United States); Ritter, Mark, E-mail: ritter@humonc.wisc.edu [University of Wisconsin Carbone Cancer Center, Madison, Wisconsin (United States); Khor, Li-Yan [Case Medical Center, Cleveland, Ohio (United States); Hammond, Elizabeth [LDS Hospital, Salt Lake City, Utah (United States); Jones, Christopher [Radiological Associates of Sacramento, Sacramento, California (United States); Amin, Mahul [Cedars-Sinai Medical Center, Los Angeles, California (United States); Bahary, Jean-Paul [Centre Hospitalier de l' Université de Montréal-Notre Dame, Montreal, Ontario (Canada); Zeitzer, Kenneth [Albert Einstein Medical Center, Philadelphia, Pennsylvania (United States); Pollack, Alan [University of Miami Miller School of Medicine, Miami, Florida (United States)

    2013-06-01

    Purpose: The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08. Methods and Materials: 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria. Results: In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation. Conclusions: High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.

  2. Breastfeeding and Immunohistochemical Expression of ki-67, p53 and BCL2 in Infiltrating Lobular Breast Carcinoma.

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    Angel Gonzalez-Sistal

    Full Text Available Invasive lobular breast carcinoma is the second most common type of breast cancer after invasive ductal carcinoma. According to the American Cancer Society, more than 180,000 women in the United States find out they have invasive breast cancer each year. Personal history of breast cancer and certain changes in the breast are correlated with an increased breast cancer risk. The aim of this work was to analyze breastfeeding in patients with infiltrating lobular breast carcinoma, in relation with: 1 clinicopathological parameters, 2 hormonal receptors and 3 tissue-based tumor markers.The study included 80 women with ILC, 46 of which had breastfeed their children. Analyzed parameters were: age, tumor size, axillary lymph node (N, distant metastasis (M, histological grade (HG, estrogen receptor (ER, progesterone receptor (PR, androgen receptor (AR, Ki-67, p53 and BCL2.ILC of non-lactating women showed a larger (p = 0.009, lymph node involvement (p = 0.051 and distant metastasis (p = 0.060. They were also more proliferative tumors measured by Ki-67 (p = 0.053. Breastfeeding history did not influence the subsequent behavior of the tumor regardless of histological subtype.Lactation seems to influence the biological characteristics of ILC defining a subgroup with more tumor size, axillary lymph node involvement, distant metastasis and higher proliferation measured by ki-67 expression.

  3. Prognostic Evaluation of Vimentin Expression in Correlation with Ki67 and CD44 in Surgically Resected Pancreatic Ductal Adenocarcinoma

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    Despoina Myoteri

    2017-01-01

    Full Text Available Purpose. Radical surgical resection with adjuvant chemotherapy or chemo-radiotherapy is the most effective treatment for pancreatic ductal adenocarcinoma (PDAC. However, relatively few studies investigate the prognostic significance of biological markers in PDAC. This study aims to look into the expressions of vimentin, Ki67, and CD44 in PDAC surgical specimens and their potential prognostic implications in survival. Method. The study was designed as retrospective, and vimentin, Ki67, and CD44 expressions were evaluated by immunohistochemistry in 53 pancreatic ductal adenocarcinoma cases. Overall survival was assessed by the Kaplan–Meier method. Results. Patients’ median age was 68 years. The median survival was 18 months. The tumors were T3-4 in 40/53 (75.5%, and metastases in lymph nodes were found in 42 out of 53 (79.2% cases. On multivariate analysis, the size of primary tumor (p<0.001, the surgical resection margin status (p=0.042, and vimentin expression (p=0.011 were independently correlated with overall survival. Conclusions. Long-term survival after resection of PDAC is still about 15%. Vimentin expression is a potential independent adverse prognostic molecular marker and should be included in histopathological reports. Also, CD44 expression correlates with high Ki67, vimentin positivity, and N stage and may represent a potential target of novel therapeutic modalities in pancreatic adenocarcinoma patients.

  4. Reduction in Ki-67 in Benign Breast Tissue of High Risk Women with the Lignan Secoisolariciresinol Diglycoside (SDG)

    Science.gov (United States)

    Fabian, Carol J.; Kimler, Bruce F.; Zalles, Carola M.; Klemp, Jennifer R.; Petroff, Brian K.; Khan, Qamar J.; Sharma, Priyanka; Setchell, Kenneth D. R.; Zhao, Xueheng; Phillips, Teresa A.; Metheny, Trina; Hughes, Jennifer R.; Yeh, Hung-Wen; Johnson, Karen A.

    2010-01-01

    Preclinical and correlative studies suggest reduced breast cancer with higher lignan intake or blood levels. We conducted a pilot study of modulation of risk biomarkers for breast cancer in premenopausal women after administration of the plant lignan secoisolariciresinol given as the diglycoside (SDG). Eligibility criteria included regular menstrual cycles, no oral contraceptives, a greater than 3-fold increase in 5 year risk, and baseline Ki-67 ≥2% in areas of hyperplasia in breast tissue sampled by random periareolar fine needle aspiration (RPFNA) during the follicular phase of the menstrual cycle. SDG 50 mg daily was given for 12 months, followed by repeat RPFNA. The primary endpoint was change in Ki-67. Secondary endpoints included change in cytomorphology, mammographic breast density, serum bioavailable estradiol, and testosterone IGF-I and IGFBP-3, and plasma lignan levels. Forty-five of 49 eligible women completed the study with excellent compliance (median = 96%) and few serious side effects (4% grade 3). Median plasma enterolactone increased ~ 9-fold, and total lignans 16 fold. Thirty-six (80%) of the 45 evaluable subjects demonstrated a decrease in Ki-67, from a median of 4% (range 2–16.8 %) to 2% (range 0–15.2%) (pSDG vs. placebo in premenopausal women. PMID:20724470

  5. Estudo citofotométrico da expressão dos marcadores tumorais Caspase-3 e Ki-67 no adenocarcinoma gástrico Cytophotometric study of the expression of tumoral markers Caspase-3 and Ki-67 in gastric adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Pedro Manuel Gonzales Cuellar

    2007-06-01

    Full Text Available RACIONAL: A carcinogênese gástrica é processo complexo e depende de fatores genéticos, ambientais e infecciosos. Nos últimos anos, houve grandes avanços nos campos da genética e da biologia molecular, sobre o desenvolvimento dos tumores. Os marcadores tumorais são substâncias ausentes nos tecidos normais e que podem ser identificadas em tecidos com câncer. Através de procedimentos imunoistoquímicos eles podem ser estudados. OBJETIVOS: Descrever a expressão citofotométrica do marcador tumoral Ki-67 analisando a densidade óptica e o índice de marcagem no adenocarcinoma de estômago. Descrever a expressão citofotométrica do marcador tumoral Caspase-3 analisando a densidade óptica e o índice de marcagem no adenocarcinoma de estômago. Comparar o índice de marcagem e densidade óptica dos marcadores tumorais Ki-67 e Caspase-3 no adenocarcinoma de estômago. MÉTODO: Foram selecionados, inicialmente, 58 blocos com espécime de adenocarcinoma gástrico coletados nos Serviços de Anátomo-Patologia do Hospital do Gama - Brasília (DF e Hospital Dom Orione - Araguaina (TO, e analizados no Laboratório de Citologia e Histopalogia Ltda - CITOLAB, Curitiba (PR. Foram aproveitados 31 blocos para o estudo histológico e imunoistoquímico realizado pelo sistema de análise computarizado SAMBA 4000. RESULTADOS: Das 31 lâminas estudas, 15 (48% foram marcadas pelo marcador Ki-67, 22 (71% foram marcadas pelo marcador Caspase-3 e 14 (45% marcaram com os dois marcadores. CONCLUSÕES: A expressão citofométrica do marcador Ki-67 foi observada em 15 lâminas da amostra estudada e apresentaram média do índice de marcagem de 36,85%, enquanto a densidade óptica apresentou média de 29,33 pixels. A expressão citofotométrica do marcador Caspase-3 foi observada em 22 lâminas da amostra estudada e apresentaram média do índice de marcagem de 87,71% e 60,74 pixels de média para a densidade óptica. Na comparação do índice de marcagem dos

  6. In vivo dynamics and kinetics of pKi-67: Transition from a mobile to an immobile form at the onset of anaphase

    International Nuclear Information System (INIS)

    Saiwaki, Takuya; Kotera, Ippei; Sasaki, Mitsuho; Takagi, Masatoshi; Yoneda, Yoshihiro

    2005-01-01

    A cell proliferation marker protein, pKi-67, distributes to the chromosome periphery during mitosis and nucleolar heterochromatin in the interphase. We report here on the structural domains of pKi-67 that are required for its correct distribution. While both the LR domain and the conserved domain were involved in localization to the nucleolar heterochromatin, both the LR domain and the Ki-67 repeat domain were required for its distribution to the mitotic chromosome periphery. Using in vivo time-lapse microscopy, GFP-pKi-67 was dynamically tracked from the mitotic chromosome periphery to reforming nucleoli via prenucleolar bodies (PNBs). The signals in PNBs then moved towards and fused into the reforming nucleoli with a thin string-like fluorescence during early G1 phase. An analysis of the in vivo kinetics of pKi-67 using photobleaching indicated that the association of pKi-67 with chromatin was progressively altered from 'loose' to 'tight' after the onset of anaphase. These findings indicate that pKi-67 dynamically alters the nature of the interaction with chromatin structure during the cell cycle, which is closely related to the reformation process of the interphase nucleolar chromatin

  7. Evaluation of Ki67 expression across distinct categories of breast cancer specimens: a population-based study of matched surgical specimens, core needle biopsies and tissue microarrays.

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    Gøril Knutsvik

    Full Text Available Tumor cell proliferation in breast cancer is strongly prognostic and may also predict response to chemotherapy. However, there is no consensus on counting areas or cut-off values for patient stratification. Our aim was to assess the matched level of proliferation by Ki67 when using different tissue categories (whole sections, WS; core needle biopsies, CNB; tissue microarrays, TMA, and the corresponding prognostic value.We examined a retrospective, population-based series of breast cancer (n = 534 from the Norwegian Breast Cancer Screening Program. The percentage of Ki67 positive nuclei was evaluated by visual counting on WS (n = 534, CNB (n = 154 and TMA (n = 459.The median percentage of Ki67 expression was 18% on WS (hot-spot areas, 13% on CNB, and 7% on TMA, and this difference was statistically significant in paired cases. Increased Ki67 expression by all evaluation methods was associated with aggressive tumor features (large tumor diameter, high histologic grade, ER negativity and reduced patient survival.There is a significant difference in tumor cell proliferation by Ki67 across different sample categories. Ki67 is prognostic over a wide range of cut-off points and for different sample types, although Ki67 results derived from TMA sections are lower compared with those obtained using specimens from a clinical setting. Our findings indicate that specimen specific cut-off values should be applied for practical use.

  8. Evaluation of Ki67 expression across distinct categories of breast cancer specimens: a population-based study of matched surgical specimens, core needle biopsies and tissue microarrays.

    Science.gov (United States)

    Knutsvik, Gøril; Stefansson, Ingunn M; Aziz, Sura; Arnes, Jarle; Eide, Johan; Collett, Karin; Akslen, Lars A

    2014-01-01

    Tumor cell proliferation in breast cancer is strongly prognostic and may also predict response to chemotherapy. However, there is no consensus on counting areas or cut-off values for patient stratification. Our aim was to assess the matched level of proliferation by Ki67 when using different tissue categories (whole sections, WS; core needle biopsies, CNB; tissue microarrays, TMA), and the corresponding prognostic value. We examined a retrospective, population-based series of breast cancer (n = 534) from the Norwegian Breast Cancer Screening Program. The percentage of Ki67 positive nuclei was evaluated by visual counting on WS (n = 534), CNB (n = 154) and TMA (n = 459). The median percentage of Ki67 expression was 18% on WS (hot-spot areas), 13% on CNB, and 7% on TMA, and this difference was statistically significant in paired cases. Increased Ki67 expression by all evaluation methods was associated with aggressive tumor features (large tumor diameter, high histologic grade, ER negativity) and reduced patient survival. There is a significant difference in tumor cell proliferation by Ki67 across different sample categories. Ki67 is prognostic over a wide range of cut-off points and for different sample types, although Ki67 results derived from TMA sections are lower compared with those obtained using specimens from a clinical setting. Our findings indicate that specimen specific cut-off values should be applied for practical use.

  9. The value of phosphohistone H3 as a proliferation marker for evaluating invasive breast cancers: A comparative study with Ki67

    Science.gov (United States)

    Kim, Ji-Ye; Jeong, Hyang Sook; Chung, Taek; Kim, Moonsik; Lee, Ji Hee; Jung, Woo Hee; Koo, Ja Seung

    2017-01-01

    Background Established measurements of proliferation in breast cancer are Ki67 and mitotic-activity-index (MAI), with problems in reproducibility and prognostic accuracy. Phosphohistone H3 (PHH3), a relatively novel IHC marker is specific for mitosis with good reproducibility. We hypothesized that PHH3 would be more reproducible and better represent proliferation than Ki67. Results PHH3 identified easily-missed mitosis by MAI, as demonstrated by upgrading M grade at diagnosis (n = 29/218, evenly distributed). PHH3 accurately found hot-spots, supported by mitotic count agreement between low-power and 10HPFs (R2 = 0.999; P = 0.001). PHH3 was more reproducible than Ki67, measured by five-rater inter-class correlation coefficient (0.904 > 0.712; P = 0.008). Finally, despite a relatively short follow-up (median 46 months; 7 recurrences) PHH3 was the only variable correlated with disease-free survival (P = 0.043), while all other conventional clinicopathologic variables, including Ki67 (P = 0.356), did not. Materials and Methods We compared Ki67 and PHH3 for 218 breast cancer surgical cases diagnosed from 2012 to 2013 at Severance hospital. The most representative invasive breast cancer surgical slides were immunohistochemically stained for Ki67 and PHH3. Conclusions Poor reproducibility and inadequate representation of proliferation of Ki67 and MAI may be improved by PHH3, allowing better accuracy in breast cancer diagnostics. PMID:29029412

  10. Low Ki67/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer.

    Science.gov (United States)

    Feng, Xiaolan; Li, Haocheng; Kornaga, Elizabeth N; Dean, Michelle; Lees-Miller, Susan P; Riabowol, Karl; Magliocco, Anthony M; Morris, Don; Watson, Peter H; Enwere, Emeka K; Bebb, Gwyn; Paterson, Alexander

    2016-12-27

    This study was designed to investigate the combined influence of ATM and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (breast tumors were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using fluorescence and brightfield immunohistochemistry respectively, and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome. Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p = 0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02). These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC.

  11. The use of automated Ki67 analysis to predict Oncotype DX risk-of-recurrence categories in early-stage breast cancer.

    Science.gov (United States)

    Thakur, Satbir Singh; Li, Haocheng; Chan, Angela M Y; Tudor, Roxana; Bigras, Gilbert; Morris, Don; Enwere, Emeka K; Yang, Hua

    2018-01-01

    Ki67 is a commonly used marker of cancer cell proliferation, and has significant prognostic value in breast cancer. In spite of its clinical importance, assessment of Ki67 remains a challenge, as current manual scoring methods have high inter- and intra-user variability. A major reason for this variability is selection bias, in that different observers will score different regions of the same tumor. Here, we developed an automated Ki67 scoring method that eliminates selection bias, by using whole-slide analysis to identify and score the tumor regions with the highest proliferative rates. The Ki67 indices calculated using this method were highly concordant with manual scoring by a pathologist (Pearson's r = 0.909) and between users (Pearson's r = 0.984). We assessed the clinical validity of this method by scoring Ki67 from 328 whole-slide sections of resected early-stage, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. All patients had Oncotype DX testing performed (Genomic Health) and available Recurrence Scores. High Ki67 indices correlated significantly with several clinico-pathological correlates, including higher tumor grade (1 versus 3, PKi67 indices were also significantly correlated with higher Oncotype DX risk-of-recurrence group (low versus high, PKi67 index was the major contributor to a machine learning model which, when trained solely on clinico-pathological data and Ki67 scores, identified Oncotype DX high- and low-risk patients with 97% accuracy, 98% sensitivity and 80% specificity. Automated scoring of Ki67 can thus successfully address issues of consistency, reproducibility and accuracy, in a manner that integrates readily into the workflow of a pathology laboratory. Furthermore, automated Ki67 scores contribute significantly to models that predict risk of recurrence in breast cancer.

  12. Clinical significance of pretherapeutic Ki67 as a predictive parameter for response to neoadjuvant chemotherapy in breast cancer: is it equally useful across tumor subtypes?

    Science.gov (United States)

    Sueta, Aiko; Yamamoto, Yutaka; Hayashi, Mitsuhiro; Yamamoto, Satoko; Inao, Toko; Ibusuki, Mutsuko; Murakami, Keiichi; Iwase, Hirotaka

    2014-05-01

    Ki67 has been identified as a prognostic and predictive marker for breast cancer and it was suggested that it may contribute to pathologic complete response (pCR) after neoadjuvant chemotherapy. It is unclear whether expression of Ki67 is particularly helpful for prediction of pCR across tumor subtypes. Pretherapeutic Ki67 was evaluated in a series of 121 breast cancer core biopsies. After neoadjuvant chemotherapy, we used postoperative specimens to evaluate the pCR status. Several parameters predictive of pCR were identified using logistic regression analysis. We investigated subgroups defined by estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2, in which predicting pCR with Ki67 might be feasible. Ki67 was found to be an independent predictor of pCR in multivariate analysis (odds ratio [OR], 3.62; 95% CI, 1.21-10.8). When stratified by ER, the above significance was exclusive to ER-positive tumors (OR, 6.24; 95% CI, 1.40-27.7). Using an receiver-operating characteristic curve, we obtained moderate discriminative accuracy with an area under the curve of 0.7752 for Ki67 prediction of pCR in ER-positive tumors. In subgroup analysis, patients with high Ki67 showed significantly improved pCR rate in luminal-type disease, with a median Ki67 value of 43% in the patients who achieved pCR, versus 29% for those without pCR (P = .018), whereas no associations were observed in other subtypes. Our results suggest that stratification according to Ki67 levels might improve predictive significance of the response in hormone-responsive breast cancer. Even in these subtypes assumed to be less chemosensitive, some patients with highly proliferative tumors derive a significant benefit from chemotherapy, and consequently it is important to identify them. Copyright © 2014 Mosby, Inc. All rights reserved.

  13. Correlation between semi-quantitative {sup 18}F-FDG PET/CT parameters and Ki-67 expression in small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Park, So Yeon; Lee, Eun Sub; Eo, Jae Seon [Dept. of Nuclear Medicine, Korea University Guro Hospital, Seoul (Korea, Republic of); Rhee, Seung Hong; Cho, Jae Hyuk; Choi, Sun Ju; Pahk, Kisso; Choe, Jae Gol; Kim, Sung Geun [Dept. of Nuclear Medicine, Korea University Anam Hospital, Seoul (Korea, Republic of); Lee, Si Nae [Dept. of Nuclear Medicine, G Sam Hospital, Gunpo (Korea, Republic of)

    2016-03-15

    The aim of this study was to evaluate the relationship between semiquantitative parameters on {sup 18}F-FDG PET/CT including maximum standardized uptake value (SUV{sub max}), mean standardized uptake value (SUV{sub mean}), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and the expression level of Ki-67 in small-cell lung cancer (SCLC). Ninety-four consecutive patients with SCLC were enrolled in this study. They underwent {sup 18}F-FDG PET/CT for initial evaluation of SCLC, and we measured SUV{sub max}, {sub avg}SUV{sub mean}, MTV{sub sum}, and TLGtotal on {sup 18}F-FDG PET/CT images. The protein expression of Ki-67 was examined by immunohistochemical staining. Significant correlations were found between the MTVsum and Ki-67 labeling index (r=0.254, p=0.014) and the TLGtotal and Ki-67 labeling index (r=0.239, p=0.020). No correlation was found between the SUVmax and Ki-67 labeling index (r=0.116, p=0.264) and the {sub avg}SUV{sub mean} and Ki-67 labeling index (r=0.031, p=0.770). Dividing the Ki-67 expression level into three categories, it was suggested that increasing Ki-67 expression level caused a stepwise increase in the MTV{sub sum} and TLGtotal. (p=0.028 and 0.039, respectively), but not the SUV{sub max} and {sub avg}SUV{sub mean} (p=0.526 and 0.729, respectively). In conclusion, the volume-based parameters of {sup 18}F-FDG PET/CT correlate with immunohistochemical staining of Ki-67 in SCLC. Measurement of the MTV{sub sum} and TLGtotal by {sup 18}F-FDG PET/CT might be a simple, noninvasive, and useful method to determine the proliferative potential of cancer cells.

  14. Quantum dots-based double imaging combined with organic dye imaging to establish an automatic computerized method for cancer Ki67 measurement

    OpenAIRE

    Wang, Lin-Wei; Qu, Ai-Ping; Liu, Wen-Lou; Chen, Jia-Mei; Yuan, Jing-Ping; Wu, Han; Li, Yan; Liu, Juan

    2016-01-01

    As a widely used proliferative marker, Ki67 has important impacts on cancer prognosis, especially for breast cancer (BC). However, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study is to establish quantum dots (QDs)-based double imaging of nuclear Ki67 as red signal by QDs-655, cytoplasmic cytokeratin (CK) as yellow signal by QDs-585, and organic dye imaging of cell nucleus as blue signal by 4?,6-diamidino-2-phenylindole (DAPI), an...

  15. Expressão citofotométrica dos marcadores tumorais Ki-67 e CD34 no adenocarcinoma de estômago Citophotometric expression of tumoral markers: Ki67 and CD34 in stomach adenocarcinoma

    Directory of Open Access Journals (Sweden)

    José Augusto Menezes Freitas de Campos

    2007-09-01

    Full Text Available RACIONAL: O câncer de estômago ocupa o terceiro lugar das neoplasias malignas em todo o mundo e é a segunda causa de morte por câncer. No entanto, sua incidência está em declínio nos últimos anos, principalmente em paises como Estados Unidos, Inglaterra e Austrália, assim como onde a sua incidência sempre foi alta - Japão, China, Coréia e Leste da Ásia -, com estimativa de 780 casos anuais por 100 mil habitantes. OBEJTIVOS: Descrição da expressão citofotométrica dos marcadores Ki-67 e CD34 e comparação entre a expressão deles no adenocarcinoma de estômago. MÉTODOS: Foram selecionados inicialmente 60 blocos com espécime de adenocarcinoma gástrico coletados nos serviços de patologia do Hospital do Gama - Brasília, DF e Hospital Dom Orione - Araguaina,TO. A imunoistoquímica com os marcadores Ki-67 e CD34 foi feita no Laboratório de Citologia e Histopalogia Ltda - CITOLAB, Curitiba, PR. Foram aproveitados do total 35 blocos para o estudo histológico e imunoistoquímico que foram analisados pelo sistema de citometria de imagem computarizado SAMBA 4000 no Instituto de Pesquisas Médicas do Hospital Universitário Evangélico de Curitiba. Foram estudados o índice de marcagem e a densidade óptica para ambos os marcadores analisados separadamente e depois comparados. RESULTADOS: Das 35 lâminas, 15 (42,85% marcaram o Ki-67; 26 (74,28% o CD34 e 12 lâminas (34,28% marcaram com os dois marcadores. Quando se comparou o índice de marcagem entre Ki-67 e CD34, observou-se que existe diferença significativa (PBACKGROUND: Stomach cancer is rated as the third malignant neoplasm in the world, being the second most frequent cause of death. However, its incidence has been declining in the last few years in countries like the United States, England and Australia, and in countries where its incidence has always been high - Japan, China, Korea and in the Eastern part of Asia, which has an estimated 780 cases per year per 100

  16. Immunohistochemical study of ki-67 and bcl-2 expression in some odontogenic cystic lesions with different clinical behaviors

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    Seyed Hossein Tabatabaei

    2016-11-01

    Full Text Available Background: Cystic lesions with odontogenic epithelial origin and similar clinicoradiographic appearance, show different clinical behaviors. Objective: To compare some factors related to cell proliferation and escape from apoptosis in epithelium covering two groups of odontogenic cystic lesions with different clinical behaviors. Methods: In this cross-sectional study 11 paraffin-embedded samples were selected of each lesions radicular cyst, dentigerous cyst, odontogenic keratocyst, and unicystic ameloblastoma. The sample underwent immunohistochemical staining for investigating the expression of ki-67 antigen and bcl-2 protein. Data analyzed with SPSS17 software and Kruskal–Wallis and chi-square statistical tests. Findings: Most of ki-67 positive cells were observed in parabasal layer of odontogenic keratocyst [35.50±26.29%; P=0.001]. The average of ki-67-LI was more in parabasal layer of aggressive group (26.80±37.79% compared to non-aggressive group (4.04±3.38%, was not being statistically significant. The highest average of bcl-2-LI was 95±6.70% in basal layer of odontogenic keratocyst (P=0.001. In all layers, the average of bcl-2-LI was more in aggressive lesions compared to non-aggressive ones and the highest amount was found in basal layer (72.45±3.94×10% which was statistically significant (P=0.001. Conclusion: According to the results of this study, more expression of the markers related to escape from apoptosis in aggressive lesions group compared to non-aggressive group, suggests that escape from apoptosis had a more critical role in aggressive behavior of odontogenic cystic lesions.

  17. p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplant patients.

    Science.gov (United States)

    Guzman, Grace; Alagiozian-Angelova, Victoria; Layden-Almer, Jennifer E; Layden, Thomas J; Testa, Guiliano; Benedetti, Enrico; Kajdacsy-Balla, André; Cotler, Scott J

    2005-11-01

    Patients with hepatocellular carcinoma who undergo orthotopic liver transplantation (OLT) are at risk for post-transplant tumor recurrence. The aim of this study was to evaluate whether expression of p53 and Ki-67 in hepatocellular carcinoma lesions present in explanted liver tissue was associated with time to tumor recurrence after OLT. Subjects consisted of 20 consecutive patients who underwent OLT and were found to have hepatocellular carcinoma in the liver explant. Immunostaining for p53 and Ki-67 was performed by standard methods. The presence of nuclear immunostaining in >10% of the tumor tissue was considered positive. Time to recurrence of hepatocellular carcinoma after OLT was compared between patients with positive and negative immunostaining by the log rank test. Multivariate analysis was performed using a Cox regression model to control for potentially confounding clinical factors. Time to post-transplant hepatocellular carcinoma recurrence was significantly more rapid in p53+ (P=0.0007) and Ki-67+ cases (P=0.001). These associations remained significant in multivariate analysis. Furthermore, time to recurrent hepatocellular carcinoma was significantly shorter in patients with a serum alpha feto-protein (AFP) level >or=100 ng/ml at time of diagnosis, compared to those with an AFP level or=100 ng/ml were associated with more rapid recurrence of hepatocellular carcinoma after OLT. Identification of patients at risk for early post-transplant recurrence could be used to guide surveillance and adjuvant treatment strategies. Modern Pathology (2005) 18, 1498-1503. doi:10.1038/modpathol.3800458; published online 8 July 2005.

  18. Evaluating TIMP-1, Ki67, and HER2 as markers for non-sentinel node metastases in breast cancer patients with micrometastases to the sentinel node

    DEFF Research Database (Denmark)

    Tvedskov, Tove Filtenborg; Bartels, Annette; Jensen, Maj-Britt

    2011-01-01

    The aim was to investigate whether the biochemical prognostic markers TIMP-1, Ki67, and HER2 could predict metastatic spread to non-sentinel nodes (NSN) in breast cancer patients with micrometastases to sentinel node (SN). We included all breast cancer patients with micrometastases to SN operated...... and tumor characteristics were retrieved from the Danish Breast Cancer Cooperative Group database. Immunohistochemical analyses of TIMP-1 and Ki67 and measurements of HER2 on formalin-fixed paraffin-embedded tumor tissue were performed. No significant differences in the immunoreactivity of TIMP-1 and Ki67...... were found between patients with and without NSN metastases. Six of seven HER2 positive patients did not have NSN metastases, but the results did not reach statistical significance. Despite being prognostic markers in breast cancer, TIMP-1 and Ki67 could not predict NSN metastases in women...

  19. The use of automated Ki67 analysis to predict Oncotype DX risk-of-recurrence categories in early-stage breast cancer.

    Directory of Open Access Journals (Sweden)

    Satbir Singh Thakur

    Full Text Available Ki67 is a commonly used marker of cancer cell proliferation, and has significant prognostic value in breast cancer. In spite of its clinical importance, assessment of Ki67 remains a challenge, as current manual scoring methods have high inter- and intra-user variability. A major reason for this variability is selection bias, in that different observers will score different regions of the same tumor. Here, we developed an automated Ki67 scoring method that eliminates selection bias, by using whole-slide analysis to identify and score the tumor regions with the highest proliferative rates. The Ki67 indices calculated using this method were highly concordant with manual scoring by a pathologist (Pearson's r = 0.909 and between users (Pearson's r = 0.984. We assessed the clinical validity of this method by scoring Ki67 from 328 whole-slide sections of resected early-stage, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. All patients had Oncotype DX testing performed (Genomic Health and available Recurrence Scores. High Ki67 indices correlated significantly with several clinico-pathological correlates, including higher tumor grade (1 versus 3, P<0.001, higher mitotic score (1 versus 3, P<0.001, and lower Allred scores for estrogen and progesterone receptors (P = 0.002, 0.008. High Ki67 indices were also significantly correlated with higher Oncotype DX risk-of-recurrence group (low versus high, P<0.001. Ki67 index was the major contributor to a machine learning model which, when trained solely on clinico-pathological data and Ki67 scores, identified Oncotype DX high- and low-risk patients with 97% accuracy, 98% sensitivity and 80% specificity. Automated scoring of Ki67 can thus successfully address issues of consistency, reproducibility and accuracy, in a manner that integrates readily into the workflow of a pathology laboratory. Furthermore, automated Ki67 scores contribute significantly to models that

  20. Comprehensive Analysis of the Association of Clinically Relevant Values of Ki-67 Labeling Index with Clinicopathologic and Immunohistochemical Criteria in Female Invasive Breast Carcinoma

    Directory of Open Access Journals (Sweden)

    Saba El-Gendi

    2018-03-01

    Full Text Available Objective: Breast cancer aggressiveness is related to tumor cell proliferation. Despite this, the Ki-67 index is not recommended for routine use in newly diagnosed breast carcinomas. Material and Methods: A total of 164 invasive breast carcinomas were stratified into the intrinsic molecular subtypes based on estrogen receptor, progesterone receptor (PR, HER2, and Ki-67 immunostaining. We studied the distribution of Ki-67 among the molecular subtypes and correlated it with clinicopathologic parameters. Furthermore, the change in the Ki-67 index with tumor size, grade and lymph node (LN status among the molecular subtypes was examined. Results: As a continuous variable, the median Ki-67 did not show significant differences with the clinicopathological variables. At a cutoff ≥14%, it correlated significantly with the mitotic index. At a cutoff ≥20%, it additionally correlated with the PR status. The median Ki-67 level varied significantly between luminal A and all other molecular subtypes. The median Ki-67 level in T1/T2 tumors compared to T3/T4 tumors was slightly higher in luminal B HER2+, slightly lower in HER2 enriched, and nearly similar among luminal A, triple negative and luminal B HER2-subtypes, yet without statistical significance. The median Ki-67 was lower in G1/G2 compared to G3 tumors in all-except luminal B HER2-positive subtype but without statistical significance. The Ki-67 distribution change between N0/N1 and N2/N3 cases among the molecular subtypes was significant. Conclusions: The impact of Ki-67 as a proliferation marker on the biological behavior of breast carcinomas is context dependent, and its clinical utility increases when interpreted in combination with other prognostic markers in the context of the molecular subtypes. Further studies, on larger sample sizes are recommended to unravel how the molecular types can affect the relation between Ki-67 and clinicopathological characteristics, particularly the LN status. [J

  1. Prognostic significance of Ki67 in Chinese women diagnosed with ER+/HER2? breast cancers by the 2015?St. Gallen consensus classification

    OpenAIRE

    Hu, Yue; Gu, Ran; Zhao, Jinghua; Yang, Yaping; Liu, Fengtao; Jin, Liang; Chen, Kai; Jia, Haixia; Wang, Hongli; Liu, Qiang; Su, Fengxi; Jia, Weijuan

    2017-01-01

    Background This study evaluated the distribution pattern of the Ki67-labeling index (LI) among patients at a Chinese breast cancer center, and analyzed its prognostic significance in the 2015?St Gallen consensus breast cancer classification, estrogen receptor-positive and human epidermal growth factor receptor 2-negative(ER+/HER2?)subtype. Methods We classified 939 women with ER+/HER2? breast cancer into three groups by Ki67-LI levels, and followed their clinicopathologic characteristics and ...

  2. Optimal Ki67 cut-off for luminal breast cancer prognostic evaluation: a large case series study with a long-term follow-up.

    Science.gov (United States)

    Bustreo, Sara; Osella-Abate, Simona; Cassoni, Paola; Donadio, Michela; Airoldi, Mario; Pedani, Fulvia; Papotti, Mauro; Sapino, Anna; Castellano, Isabella

    2016-06-01

    Although Ki67 index suffers from poor reproducibility, it is one of the most important prognostic markers used by oncologists to select the treatment of estrogen receptor (ER) positive breast cancer patients. In this study, we aim to establish the optimal Ki67 cut-offs for stratifying patient prognosis and to create a comprehensive prognostic index for clinical applications. A mono-institutional cohort of 1.577 human epidermal growth factor receptor 2 negative/ER+ breast cancer patients having complete clinical, histological, and follow-up data was collected. The 14 and 20 % Ki67 cut-offs were correlated to disease-free interval (DFI) and disease-specific survival (DSS). To create a comprehensive prognostic index, we used independent variables selected by uni/multivariate analyses. In terms of DFI and DSS, patients bearing tumors with Ki67 Ki67 values between 14 and 20 %. Patients with tumor with Ki67 > 20 % showed the poorest prognosis. Moreover, to tumor size, the number of metastatic lymph nodes and Ki67 > 20 % was given a score value, varying depending on definite cut-offs and used to create a prognostic index, which was applied to the population. Patients with a prognostic index ≥3 were characterized by significant risk of relapse [DFI: Hazard Ratio (HR) = 4.74, p Ki67 cut-off is the best to stratify high-risk patients in luminal breast cancers, and we suggest to integrate it with other prognostic factors, to better stratify patients at risk of adverse outcome.

  3. A methodology for comprehensive breast cancer Ki67 labeling index with intra-tumor heterogeneity appraisal based on hexagonal tiling of digital image analysis data.

    Science.gov (United States)

    Plancoulaine, Benoit; Laurinaviciene, Aida; Herlin, Paulette; Besusparis, Justinas; Meskauskas, Raimundas; Baltrusaityte, Indra; Iqbal, Yasir; Laurinavicius, Arvydas

    2015-10-19

    Digital image analysis (DIA) enables higher accuracy, reproducibility, and capacity to enumerate cell populations by immunohistochemistry; however, the most unique benefits may be obtained by evaluating the spatial distribution and intra-tissue variance of markers. The proliferative activity of breast cancer tissue, estimated by the Ki67 labeling index (Ki67 LI), is a prognostic and predictive biomarker requiring robust measurement methodologies. We performed DIA on whole-slide images (WSI) of 302 surgically removed Ki67-stained breast cancer specimens; the tumour classifier algorithm was used to automatically detect tumour tissue but was not trained to distinguish between invasive and non-invasive carcinoma cells. The WSI DIA-generated data were subsampled by hexagonal tiling (HexT). Distribution and texture parameters were compared to conventional WSI DIA and pathology report data. Factor analysis of the data set, including total numbers of tumor cells, the Ki67 LI and Ki67 distribution, and texture indicators, extracted 4 factors, identified as entropy, proliferation, bimodality, and cellularity. The factor scores were further utilized in cluster analysis, outlining subcategories of heterogeneous tumors with predominant entropy, bimodality, or both at different levels of proliferative activity. The methodology also allowed the visualization of Ki67 LI heterogeneity in tumors and the automated detection and quantitative evaluation of Ki67 hotspots, based on the upper quintile of the HexT data, conceptualized as the "Pareto hotspot". We conclude that systematic subsampling of DIA-generated data into HexT enables comprehensive Ki67 LI analysis that reflects aspects of intra-tumor heterogeneity and may serve as a methodology to improve digital immunohistochemistry in general.

  4. Correlation of Preoperative Ki67 and Serum CA15.3 Levels with Outcome in Early Breast Cancers a Multi Institutional Study.

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    Rasmy, A; Abozeed, W; Elsamany, S; Baiomy, M El; Nashwa, A; Amrallah, A; Hasaan, E; Alzahrani, A; Faris, M; Alsaleh, K; AlFaraj, A

    2016-01-01

    To investigate the association between preoperative pathological Ki67 labeling index and serum tumor marker cancer antigen 153 (CA 153) with clinicpathological parameters and treatment outcomes in early breast cancer. A retrospective study at 4 cancer centers in Saudi Arabia and Egypt was performed. Data were collected for female patients diagnosed with unilateral early breast cancer between March 2010 and October 2013. Cases treated with neoadjuvant chemotherapy (NACT) followed by surgery and radiotherapy were included. NACT included 68 cycles of anthracycline and taxane based regimens. Trastuzumab and hormonal treatments were added according to HER2 and hormone receptor status. Baseline serum CA15.3 and pathological Ki67 levels were evaluated and correlated with disease free survival (DFS) and overall survival (OS). A total of 280 pts was included. The median age was 49 years (3866 y) and median overall survival was 35 (2038) months (mo). Estrogen receptors (ER), progesterone receptors (PR) and HER 2 receptors were positive in 233 (83.2%), 198 (70%) and 65 cases (23.2%), respectively. High preoperative Ki67 and CA15.3 were noted in 177 (63.2%) and 131 (46.8%). A total of 45 (16%) patients had distal or local recurrence and 24 (8.6%) died of their disease. Most of the relapsed cases had high preoperative Ki67 (n=41, 91%) and CA15.3 (n=28, 62%) values. All of the patients who died had a high Ki67 but CA15.3 was high in 9 (37%) only. Mean DFS/OS in patients with high preoperative Ki67 was 32 months /32 months as compared to 37 months/35 months in those with normal Ki67 (pKi67 can be a predictive and prognostic marker. Higher levels are associated with poor DFS and OS in patients with early BC.

  5. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer.

    Science.gov (United States)

    Carbognin, Luisa; Sperduti, Isabella; Brunelli, Matteo; Marcolini, Lisa; Nortilli, Rolando; Pilotto, Sara; Zampiva, Ilaria; Merler, Sara; Fiorio, Elena; Filippi, Elisa; Manfrin, Erminia; Pellini, Francesca; Bonetti, Franco; Pollini, Giovanni Paolo; Tortora, Giampaolo; Bria, Emilio

    2016-03-22

    The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between 'pure' or 'mixed' histology ILC and Ki67. At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8%, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21%); 10-years DFS and OS were 75.1, 66.5, and 30.2% (p = 0.01) and 84.3, 76.4 and 59% (p = 0.003), for patients with a Ki67 21%, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85%, OS 100%). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with 'pure' ILC performed worse than 'mixed' histology. Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with 'pure' ILC.

  6. Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3, MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma

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    Bachmann Ingeborg M

    2010-04-01

    Full Text Available Abstract Background Tumor cell proliferation is a predictor of survival in cutaneous melanoma. The aim of the present study was to evaluate the prognostic impact of mitotic count, Ki-67 expression and novel proliferation markers phosphohistone H3 (PHH3, minichromosome maintenance protein 4 (MCM4 and mitosin, and to compare the results with histopathological variables. Methods 202 consecutive cases of nodular cutaneous melanoma were initially included. Mitotic count (mitosis per mm2 was assessed on H&E sections, and Ki-67 expression was estimated by immunohistochemistry on standard sections. PHH3, MCM4 and mitosin were examined by staining of tissue microarrays (TMA sections. Results Increased mitotic count and elevated Ki-67 expression were strongly associated with increased tumor thickness, presence of ulceration and tumor necrosis. Furthermore, high mitotic count and elevated Ki-67 expression were also associated with Clark's level of invasion and presence of vascular invasion. High expression of PHH3 and MCM4 was correlated with high mitotic count, elevated Ki-67 expression and tumor ulceration, and increased PHH3 frequencies were associated with tumor thickness and presence of tumor necrosis. Univariate analyses showed a worse outcome in cases with elevated Ki-67 expression and high mitotic count, whereas PHH3, MCM4 and mitosin were not significant. Tumor cell proliferation by Ki-67 had significant prognostic impact by multivariate analysis. Conclusions Ki-67 was a stronger and more robust prognostic indicator than mitotic count in this series of nodular melanoma. PHH3, MCM4 and mitosin did not predict patient survival.

  7. Limitations in predicting PAM50 intrinsic subtype and risk of relapse score with Ki67 in estrogen receptor-positive HER2-negative breast cancer.

    Science.gov (United States)

    Fernandez-Martinez, Aranzazu; Pascual, Tomás; Perrone, Giuseppe; Morales, Serafin; de la Haba, Juan; González-Rivera, Milagros; Galván, Patricia; Zalfa, Francesca; Amato, Michela; Gonzalez, Lucia; Prats, Miquel; Rojo, Federico; Manso, Luis; Paré, Laia; Alonso, Immaculada; Albanell, Joan; Vivancos, Ana; González, Antonio; Matito, Judit; González, Sonia; Fernandez, Pedro; Adamo, Barbara; Muñoz, Montserrat; Viladot, Margarita; Font, Carme; Aya, Francisco; Vidal, Maria; Caballero, Rosalía; Carrasco, Eva; Altomare, Vittorio; Tonini, Giuseppe; Prat, Aleix; Martin, Miguel

    2017-03-28

    PAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%.

  8. Digital image analysis of Ki67 proliferation index in breast cancer using virtual dual staining on whole tissue sections: clinical validation and inter-platform agreement.

    Science.gov (United States)

    Koopman, Timco; Buikema, Henk J; Hollema, Harry; de Bock, Geertruida H; van der Vegt, Bert

    2018-01-18

    The Ki67 proliferation index is a prognostic and predictive marker in breast cancer. Manual scoring is prone to inter- and intra-observer variability. The aims of this study were to clinically validate digital image analysis (DIA) of Ki67 using virtual dual staining (VDS) on whole tissue sections and to assess inter-platform agreement between two independent DIA platforms. Serial whole tissue sections of 154 consecutive invasive breast carcinomas were stained for Ki67 and cytokeratin 8/18 with immunohistochemistry in a clinical setting. Ki67 proliferation index was determined using two independent DIA platforms, implementing VDS to identify tumor tissue. Manual Ki67 score was determined using a standardized manual counting protocol. Inter-observer agreement between manual and DIA scores and inter-platform agreement between both DIA platforms were determined and calculated using Spearman's correlation coefficients. Correlations and agreement were assessed with scatterplots and Bland-Altman plots. Spearman's correlation coefficients were 0.94 (p Ki67 proliferation index in breast cancer, as an alternative to manual scoring of whole sections in clinical practice. Inter-platform agreement between two different DIA platforms was excellent, suggesting vendor-independent clinical implementability.

  9. Prognostic value of tissue protein expression levels of MIB-1 (Ki-67) in Danish ovarian cancer patients. From the 'MALOVA' ovarian cancer study

    DEFF Research Database (Denmark)

    Heeran, Mel C; Høgdall, Claus K; Kjaer, Susanne K

    2013-01-01

    The primary objective of this study was to assess the expression of MIB-1 (Ki-67) in tumour tissues from 808 patients with epithelial ovarian tumours. The second was to evaluate, whether MIB-1 (Ki-67) tissue expression levels correlate with clinicopathological parameters and prognosis of the dise......The primary objective of this study was to assess the expression of MIB-1 (Ki-67) in tumour tissues from 808 patients with epithelial ovarian tumours. The second was to evaluate, whether MIB-1 (Ki-67) tissue expression levels correlate with clinicopathological parameters and prognosis...... of the disease. Using tissue arrays (TA), we analysed the MIB-1 (Ki-67) expression levels in tissues from 202 women with borderline ovarian tumours (BOT) (177 stage I, 5 stage II, 19 stage III, 1 stage IV) and 606 ovarian cancer (OC) patients (177 stage I, 64 stage II, 311 stage III, 54 stage IV). Using a 10...... different distribution of MIB-1 (Ki-67) positive and negative tumours were found in adenocarcinoma NOS, serous adenocarcinomas, mucinous adenocarcinomas, endometrioid adenocarcinomas, non-epithelial and clear-cell carcinomas (p = 0.016). Univariate Kaplan-Meier survival analysis performed on all OC cases...

  10. An Advanced Deep Learning Approach for Ki-67 Stained Hotspot Detection and Proliferation Rate Scoring for Prognostic Evaluation of Breast Cancer.

    Science.gov (United States)

    Saha, Monjoy; Chakraborty, Chandan; Arun, Indu; Ahmed, Rosina; Chatterjee, Sanjoy

    2017-06-12

    Being a non-histone protein, Ki-67 is one of the essential biomarkers for the immunohistochemical assessment of proliferation rate in breast cancer screening and grading. The Ki-67 signature is always sensitive to radiotherapy and chemotherapy. Due to random morphological, color and intensity variations of cell nuclei (immunopositive and immunonegative), manual/subjective assessment of Ki-67 scoring is error-prone and time-consuming. Hence, several machine learning approaches have been reported; nevertheless, none of them had worked on deep learning based hotspots detection and proliferation scoring. In this article, we suggest an advanced deep learning model for computerized recognition of candidate hotspots and subsequent proliferation rate scoring by quantifying Ki-67 appearance in breast cancer immunohistochemical images. Unlike existing Ki-67 scoring techniques, our methodology uses Gamma mixture model (GMM) with Expectation-Maximization for seed point detection and patch selection and deep learning, comprises with decision layer, for hotspots detection and proliferation scoring. Experimental results provide 93% precision, 0.88% recall and 0.91% F-score value. The model performance has also been compared with the pathologists' manual annotations and recently published articles. In future, the proposed deep learning framework will be highly reliable and beneficial to the junior and senior pathologists for fast and efficient Ki-67 scoring.

  11. Preoperative Prediction of Ki-67 Labeling Index By Three-dimensional CT Image Parameters for Differential Diagnosis Of Ground-Glass Opacity (GGO.

    Directory of Open Access Journals (Sweden)

    Mingzheng Peng

    Full Text Available The aim of this study was to predict Ki-67 labeling index (LI preoperatively by three-dimensional (3D CT image parameters for pathologic assessment of GGO nodules. Diameter, total volume (TV, the maximum CT number (MAX, average CT number (AVG and standard deviation of CT number within the whole GGO nodule (STD were measured by 3D CT workstation. By detection of immunohistochemistry and Image Software Pro Plus 6.0, different Ki-67 LI were measured and statistically analyzed among preinvasive adenocarcinoma (PIA, minimally invasive adenocarcinoma (MIA and invasive adenocarcinoma (IAC. Receiver operating characteristic (ROC curve, Spearman correlation analysis and multiple linear regression analysis with cross-validation were performed to further research a quantitative correlation between Ki-67 labeling index and radiological parameters. Diameter, TV, MAX, AVG and STD increased along with PIA, MIA and IAC significantly and consecutively. In the multiple linear regression model by a stepwise way, we obtained an equation: prediction of Ki-67 LI=0.022*STD+0.001* TV+2.137 (R=0.595, R's square=0.354, p<0.001, which can predict Ki-67 LI as a proliferative marker preoperatively. Diameter, TV, MAX, AVG and STD could discriminate pathologic categories of GGO nodules significantly. Ki-67 LI of early lung adenocarcinoma presenting GGO can be predicted by radiologic parameters based on 3D CT for differential diagnosis.

  12. Multiple Bone Metastasis of Sclerosing Epithelioid Fibrosarcoma 12 Years after Initial Surgery—Increasing Ki-67 Labeling Index

    Directory of Open Access Journals (Sweden)

    Atsuko Kanno

    2009-01-01

    Full Text Available Sclerosing epithelioid fibrosarcoma (SEF is a rare sarcoma of low-grade malignancy. There has been no report to describe the comparison of histological features of SEF between primary and metastatic lesions in spite of high local recurrence rate. We report the histological changes and increasing Ki-67 labeling index of the primary and metastatic lesions of SEF. The patient was a 31-year-old man. At 18, a tumor in the abdominal wall was excised. At 23, the tumor recurred which was removed again. At 30, he was referred to our hospital because of swelling and pain in the chest. Histological examination of the chest wall tumor showed epithelioid cells arranged like alveolar pattern with dense collagen stroma. These findings were consistent with those of SEF. Abdominal and the rib tumors showed the same immunohistochemistrical expression. It is noteworthy that the tumor cells of the rib lesion showed increased cellularity, and its Ki-67 activity was higher as compared with the abdominal tumor, suggestive of progression of malignancy of SEF.

  13. Correlation of18F-FDG uptake on PET/CT with Ki67 immunohistochemistry in pre-treatment epithelial ovarian cancer.

    Science.gov (United States)

    Mayoral, M; Paredes, P; Saco, A; Fusté, P; Perlaza, P; Tapias, A; Fernandez-Martinez, A; Vidal, L; Ordi, J; Pavia, J; Martinez-Roman, S; Lomeña, F

    Standardised uptake value (SUV) and volumetric parameters such as metabolic tumour volume (MTV) and total lesion glycolysis (TLG) from 18 F-FDG PET/CT are useful criteria for disease prognosis in pre-operative and post-treatment epithelial ovarian cancer (EOC). Ki67 is another prognostic biomarker in EOC, associated with tumour aggressiveness. The aim of this study is to evaluate the association between 18 F-FDG PET/CT measurements and Ki67 in pre-treatment EOC to determine if PET/CT parameters could non-invasively predict tumour aggressiveness. A pre-treatment PET/CT was performed on 18 patients with suspected or newly diagnosed EOC. Maximum SUV (SUVmax), mean SUV (SUVmean), whole-body MTV (wbMTV), and whole-body TLG (wbTLG) with a threshold of 30% and 40% of the SUVmax were obtained. Furthermore, Ki67 index (mean and hotspot) was estimated in tumour tissue specimens. Immunohistochemical findings were correlated with PET parameters. The mean age was 57.0 years old (standard deviation 13.6 years). A moderate correlation was observed between mean Ki67 index and SUVmax (r=0.392), SUVmean 30% (r=0.437), and SUVmean 40% (r=0.443), and also between hotspot Ki67 index and SUVmax (r=0.360), SUVmean 30% (r=0.362) and SUVmean 40% (r=0.319). There was a weaker correlation, which was inversely negative, between mean and hotspot Ki67 and volumetric PET parameters. However, no statistical significant differences were found for any correlations. SUVmax and SUVmean were moderately correlated with Ki67 index, whereas volumetric PET parameters overall, showed a weaker correlation. Thus, SUVmax and SUVmean could be used to assess tumour aggressiveness in pre-treatment EOC. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  14. Prognostic Significance of Bcl-2 and p53 Protein Expressions and Ki67 Proliferative Index in Diffuse Large B-cell Lymphoma

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    Betül Bolat Küçükzeybek

    2013-09-01

    Full Text Available Objective: Diffuse large B-cell lymphoma (DLBCL is a high-grade neoplasm that has heterogeneous properties in clinical, morphological, and immunophenotypic aspects. In the present study the effects of p53, Bcl-2, and Ki67 on prognosis and their relationships with clinical parameters were examined. Materials and Methods: Thirty-five patients who had been diagnosed with nodally located DLBCL at İzmir Atatürk Training and Research Hospital between January 1999 and June 2006 were included in the study. The Ann Arbor classification system was used to determine the stage of the patients. The patients were evaluated according to age, sex, stage, B symptoms, extranodal involvement, and lactate dehydrogenase (LDH level as well as immunohistochemically. P53 protein and Bcl-2 oncoprotein expressions and Ki67 proliferation index were assessed immunohistochemically. Results: High Bcl-2 expression was found in 9 patients (25.7%, high p53 expression was found in 10 patients (28.6%, and high Ki67 was observed in 23 patients (65.7%. There was no significant correlation between p53 expression, Bcl-2 expression, or Ki67 proliferation index and age, sex, stage, B symptoms, extranodal involvement, LDH level, and overall survival (p>0.05. We did not find a relationship among p53 expression, Bcl-2 expression, Ki67 proliferation index, and prognosis (p>0.05. There was no significant relationship between overall survival and age, sex, stage, B symptoms, extranodal involvement, or LDH level (p>0.05. Our results revealed that Bcl-2 and p53 protein expressions and Ki67 proliferation index have no effect on overall survival of patients with DLBCL. Conclusion: The prognostic importance of p53 and Bcl-2 protein expressions and Ki67 proliferation index in DLBCL, which has biological and clinical heterogeneity, can be understood in a large series of studies that have subclasses and immunohistochemical markers with optimal cut-off values.

  15. Low-level Ki-67 expression as an independent predictor of bladder tumour recurrence in patients with primary upper tract urothelial carcinoma after radical nephroureterectomy.

    Science.gov (United States)

    Wu, Pengjie; Liu, Shengjie; Zhang, Wei; Zhang, Yaoguang; Zhu, Gang; Wei, Dong; Wan, Ben; Wang, Jianye

    2015-12-01

    To evaluate the association of molecular markers and conventional clinicopathological factors with bladder tumour recurrence in patients with primary upper tract urothelial carcinoma after radical nephroureterectomy. The expressions of Ki-67 and P53 were measured by immunohistochemical staining prospectively in 115 consecutive patients with primary upper tract urothelial carcinoma from March 2004 to February 2014. The Cox proportional hazards regression model was used to identify independent predictors. The association between Ki-67 expression and clinicopathological variables was assessed by the χ(2) test. Intravesical recurrence occurred in 13 out of 115 (11.3%) patients with a mean follow-up of 54.2 months (range: 7-130). Low-level Ki-67 expression (P = 0.010), older age (>65, P = 0.040) and lower ureter tumour (P = 0.001) were independent predictors of bladder tumour recurrence in Cox regression analysis. Ki-67 expression was elevated with the progression of tumour grade (P = 0.004) but not with stage (P = 0.186). Ki-67 overexpression was also significantly higher in aggressive pathological types (P = 0.008), but only shows an inclination towards poor oncologic outcomes in the cancer-specific survival rate (P = 0.107) and the overall survival rate (P = 0.063). Low-level Ki-67 expression was an independent predictor for bladder tumour recurrence, while Ki-67 overexpression was associated with adverse clinicopathological parameters and poor prognosis in patients with primary upper tract urothelial carcinoma after radical nephroureterectomy. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Genotyping of high-risk human papillomaviruses in p16/Ki-67-positive urothelial carcinoma cells: even a worm will turn.

    Science.gov (United States)

    Advenier, A-S; Casalegno, J-S; Mekki, Y; Decaussin-Petrucci, M; Mège-Lechevallier, F; Ruffion, A; Piaton, E

    2015-04-01

    Co-expression of p16INK4a protein and Ki-67 (p16/Ki-67) is noted in almost all high-grade urothelial lesions. However, the aetiological role or, conversely, the absence of causative effect of high-risk human papillomaviruses (hr-HPVs) has not been documented. The purpose of this study is to evaluate HPV DNA in p16/Ki-67-positive, high-grade urothelial tumour cells. Fifty-seven urine samples collected from 50 patients, including 55 histologically proven high-grade proliferations and two cases with clinical evidence of malignancy, were analysed for p16/Ki-67. Immunolabelling was performed in destained Papanicolaou-stained slides after ThinPrep(®) processing. HPV genotyping was performed by polymerase chain reaction (PCR) using a DNA microarray for 35 HPV types. Confirmation of the presence (or absence) of HPV in tissue samples was verified using a reasoned approach combining PCR and in situ hybridization (ISH) for hr-HPVs. Co-expression of p16/Ki-67 was noted in 43 of 57 (75.4%) cases. In these, hr-HPVs 16, 31 and 70, and low risk HPV 84, were detected in the urine in four patients (8%). Upregulation of p16INK4a protein was confirmed on bladder biopsy or transurethral resection specimens, but PCR and ISH for hr-HPVs were both negative on the tissue sections. Our results show a low prevalence of HPV infection in the urinary tract of patients with p16/Ki-67-positive urothelial malignancy. The study confirms that the deregulated cell cycle, as demonstrated by p16/Ki-67 dual labelling, is independent of the oncogenic action of hr-HPVs in high-grade urothelial proliferations. © 2014 John Wiley & Sons Ltd.

  17. Ki-67 Expression in Sclerosing Adenosis and Adjacent Normal Breast Terminal Ductal Lobular Units: A Nested Case-Control Study from the Mayo Benign Breast Disease Cohort

    Science.gov (United States)

    Nassar, Aziza; Hoskin, Tanya L.; Stallings-Mann, Melody L.; Degnim, Amy C.; Radisky, Derek C.; Frost, Marlene H.; Vierkant, Robert A.; Hartmann, Lynn C.; Visscher, Daniel W.

    2015-01-01

    Purpose Sclerosing adenosis (SA) increases risk for invasive breast cancer (BC) 2.1 times relative to that in the general population. Here, we sought to evaluate whether the proliferation marker Ki-67 stratifies risk among women with SA. Methods A nested case-control sample of patients with SA was obtained from the Mayo Clinic Benign Breast Disease Cohort. Ki-67 expression was evaluated in SA lesions and in the adjacent normal terminal duct lobular units (TDLU) in women who did (cases, n =133) or did not (controls, n =239) develop BC. Ki67 was scored by intensity and number of positively stained cells per one high-power field (magnification, ×40) (40×HPF) for both SA and normal TDLU. Associations of Ki-67 expression with case-control status were assessed using conditional logistic regression. Results Higher Ki-67 expression was significantly associated with case-control status in both SA (P=.03) and normal background TDLU (P=.006). For the SA lesion, >2 average positively stained cells/40×HPF showed an adjusted odds ratio (OR) of 1.9 (95% CI, 1.1–3.4) compared to samples with an average of ≤2 positively stained cells. For background TDLU, lobules with >2 but ≤6 average positively stained cells showed an adjusted OR of 1.3 to 1.5, whereas those with an average of >6 positively stained cells had an OR of 2.4 (95% CI, 1.1–5.3) compared to those with an average of <2 positively stained cells. Conclusions Among women with SA, increased Ki-67 expression in either the SA lesion or the normal background TDLU carried an approximately 2-fold increased odds of subsequent BC as compared to lower Ki-67 expression. PMID:25863475

  18. Prognostic value of Ki67 and p53 in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer: Validation of the cut-off value of the Ki67 labeling index as a predictive factor.

    Science.gov (United States)

    Ohara, Masahiro; Matsuura, Kazuo; Akimoto, Etsushi; Noma, Midori; Doi, Mihoko; Nishizaka, Takashi; Kagawa, Naoki; Itamoto, Toshiyuki

    2016-04-01

    The aim of this study was to evaluate the significance of the Ki67 labeling index and p53 status as prognostic and predictive indicators of operable estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Among 697 consecutive patients with primary breast cancer who underwent curative surgery between 2002 and 2013, 308 patients with ER-positive and HER2-negative breast cancer were assessed. The results of the multivariate Cox analysis demonstrated that a high Ki67 labeling index was significantly associated with a short recurrence-free interval (RFI) (p=0.004) and was marginally associated with a worse overall survival (p=0.074). A positive p53 status was not associated with worse outcomes. To validate the cut-off values of the Ki67 labeling index for identifying patients who may benefit from additional chemotherapy, prognostic factors were investigated in breast cancer patients treated postoperatively with endocrine therapy alone. Analysis of receiver operating characteristic curves demonstrated that a Ki67 labeling index cut-off of 20.0% was optimal for predicting recurrence among patients who did not receive adjuvant chemotherapy. The 5-year RFIs for patients with Ki67 Ki67 labeling index (≥20%) was significantly associated with large tumors (pKi67 labeling index ≥20%, lymph node metastasis and progesterone receptor negativity were significant worse prognostic factors for RFI (p=0.0333, 0.0116 and 0.0573, respectively). The Ki67 labeling index was found to be a useful prognostic factor in patients with ER-positive and HER2-negative breast cancer and the cut-off values of the Ki67 labeling index for making a decision regarding adjuvant treatment were validated.

  19. Estrogen receptor-negative breast ductal carcinoma: clinicopathological features and MIB-1 (Ki-67 proliferative index association.

    Directory of Open Access Journals (Sweden)

    Noorasmaliza Mdpaiman

    Full Text Available Breast cancer estrogen receptor (ER status is one of the strong additional factors in predicting response of patients towards hormonal treatment. The main aim of this study was to assess the morphological characteristics and proliferative activity using MIB-1(Ki-67 of estrogen receptor negative invasive breast ductal carcinoma (NOS type as well as to correlate these features with clinicopathological data. We also aim to study the expression of c-erbB2 in ER negative breast tumors. High proliferative rate (MIB-1 above 20% was observed in 63 (63.6% of 99 ER negative tumors and that these tumors were associated with high expression of c-erbB2 (57.6%. We observed that MIB-1 is a reliable independent prognostic indicator for ER negative infiltrating ductal carcinoma in this study.

  20. [Effect of yanghe huayan decoction on precancerosis of breast cancer, protein and mRNA expression of ki67: an experimental research].

    Science.gov (United States)

    Li, Jing-Wei; Liu, Xiao-Fei; Chen, Hong-Zhi; Chen, Han-Han; Shi, Guang-Xi; Wang, Shi-Jun

    2014-08-01

    To explore the effect of Yanghe Huayan Decoction (YHD, a representative recipe for warming yang mass dissipating) in inhibiting precancerosis of breast cancer (PBC) and on the protein and mRNA expression of ki67. The PBC rat model was established by dimethylbenzanthracene (DMBA), and 9 weeks later rats were randomly divided into the blank control group, the model group, the YHD group, the Sanjie Huatan Decoction group (SHD), the Pingxiao Tablet group (PT), and the tamoxifen group. Rats in the model group were administered with water by gastrogavage. Rats in the YHD group received YHD (deglued antler powder 12 g, prepared rhizome of rehmannia 9 g, cassia bark 6 g, white mustard seed 3 g, zedoary root 12 g, appendiculate cremastra pseudobulb 15 g, chekiang fritillary bulb 9 g, licorice root 6 g) at the daily dose of 7.2 g/kg by gastrogavage. Rats in the SHD group received SHD (oldenlandia diffusa 15 g, Scutellaria Barbata 15 g, Trichosanthes Kirilowii 15 g, pinellia 9 g) at the daily dose of 5.4 g/kg by gastrogavage. Rats in the PT group received PT at the daily dose of 144 mg/kg by gastrogavage. Those in the tamoxifen group received tamoxifen at the daily dose of 4 mg/kg by gastrogavage. Pathomorphological changes of the breast tissue were observed by HE staining. The positive rate and the gray value of ki67 expression were detected by immunohistochemical assay. And the expression of ki67 mRNA was detected by q-PCR. Compared with the model group, the general hyperplasia and the occurrence rate of precancerous lesion were higher and the occurrence rate of invasive carcinoma was lower in each treatment group (P ki67 grey value increased in each treatment group (P ki67 and mRNA expression of ki67 increased in the rest treatment groups (P 0.05). The positive rate of ki67 expression and mRNA expression of ki67 increased in the PT group, showing statistical difference (P canceration of breast cancer. It also could inhibit ki67 protein and mRNA expression. Its effect was

  1. Prognostic impact of proliferation for resected early stage 'pure' invasive lobular breast cancer: Cut-off analysis of Ki67 according to histology and clinical validation.

    Science.gov (United States)

    Carbognin, Luisa; Sperduti, Isabella; Fabi, Alessandra; Dieci, Maria Vittoria; Kadrija, Dzenete; Griguolo, Gaia; Pilotto, Sara; Guarneri, Valentina; Zampiva, Ilaria; Brunelli, Matteo; Orvieto, Enrico; Nortilli, Rolando; Fiorio, Elena; Parolin, Veronica; Manfrin, Erminia; Caliò, Anna; Nisticò, Cecilia; Pellini, Francesca; Scarpa, Aldo; Pollini, Giovanni Paolo; Conte, Pierfranco; Tortora, Giampaolo; Bria, Emilio

    2017-10-01

    The intent of this analysis was to investigate and validate the prognostic potential of Ki67 in a multi-center series of patients affected by early stage 'pure' invasive lobular carcinoma (ILC). Clinical-pathological data of patients affected by ILC were correlated with overall survival and disease-free survival (OS/DFS); data from a parallel invasive ductal carcinoma (IDC) patients' cohort were gathered as well. The maximally selected Log-Rank statistics analysis was applied to Ki67 continuous variable to estimate the appropriate cut-off. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed as well. Data from overall 1097 (457/222 ILC: training/validation set; 418 IDC) patients were gathered. The identified optimal Ki67 cut-offs were 4% and 14% for DFS in ILC and IDC cohort, respectively. In ILC patients, the Ki67 cut-off was an independent OS predictor. Ten-years OS and DFS were 89.9% and 77.2% (p = 0.007) and 79.4% and 69.2% (p = 0.03) for patients with Ki67 ≤ 4% and >4%, respectively. In IDC patients, 10-years OS was 93.8% and 71.7%, p = 0.02, DFS was 84.0% and 52.6%, p = 0.0003, for patients with Ki67 ≤ 14% and >14%, respectively. In the validation set, the optimal Ki67 OS cut-off was 5%. The STEPP analysis showed that in the presence of low Ki67 values, IDC patients have a better DFS than ILC patients, while with the increase of values the prognosis tends to overlap. Despite the retrospective design of the study, the prognostic relevance of Ki67 (as well as its optimal cut-off) seems to significantly differ according to breast cancer histology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. High Ki-67 Immunohistochemical Reactivity Correlates With Poor Prognosis in Bladder Carcinoma: A Comprehensive Meta-Analysis with 13,053 Patients Involved.

    Science.gov (United States)

    Luo, Yihuan; Zhang, Xin; Mo, Meile; Tan, Zhong; Huang, Lanshan; Zhou, Hong; Wang, Chunqin; Wei, Fanglin; Qiu, Xiaohui; He, Rongquan; Chen, Gang

    2016-04-01

    Ki-67 is considered as one of prime biomarkers to reflect cell proliferation and immunohistochemical Ki-67 staining has been widely applied in clinical pathology. To solve the widespread controversy whether Ki-67 reactivity significantly predicts clinical prognosis of bladder carcinoma (BC), we performed a comprehensive meta-analysis by combining results from different literature. A comprehensive search was conducted in the Chinese databases of WanFang, China National Knowledge Infrastructure and Chinese VIP as well as English databases of PubMed, ISI web of science, EMBASE, Science Direct, and Wiley online library. Independent studies linking Ki-67 to cancer-specific survival (CSS), disease-free survival (DFS), overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS) were included in our meta-analysis. With the cut-off values literature provided, hazard ratio (HR) values between the survival distributions were extracted and later combined with STATA 12.0. In total, 76 studies (n = 13,053 patients) were eligible for the meta-analysis. It was indicated in either univariate or multivariate analysis for survival that high Ki-67 reactivity significantly predicted poor prognosis. In the univariate analysis, the combined HR for CSS, DFS, OS, PFS, and RFS were 2.588 (95% confidence interval [CI]: 1.623-4.127, P Asian and European-American patients (P Asian patients, for CSS, DFS, PFS, and RFS in European-American patients (P literature with low cut-off value (<20%) demonstrated that high Ki-67 reactivity predicted shorter DFS, PFS, and RFS in BC patients (P < 0.05). In the subgroup analysis of high cut-off value (≥20%), our meta-analysis indicated that high Ki-67 reactivity, in either univariate or multivariate analysis, significantly correlated with all five clinical outcomes in BC patients (P < 0.05). The meta-analysis indicates that high Ki-67 reactivity significantly correlates with deteriorated clinical outcomes

  3. Expression of Ki-67, Oct-4, γ-tubulin and α-tubulin in human tooth development.

    Science.gov (United States)

    Kero, Darko; Novakovic, Josip; Vukojevic, Katarina; Petricevic, Josko; Kalibovic Govorko, Danijela; Biocina-Lukenda, Dolores; Saraga-Babic, Mirna

    2014-11-01

    To analyze factors controlling cell proliferation and differentiation, and appearance of primary cilia during the cap and bell stages of incisor or/and canine human enamel organs. Qualitative and quantitative analysis of proliferating Ki-67 positive cells and expression of γ-tubulin, α-tubulin and Oct-4 was immunohistochemically analyzed in the cap an bell stages of 10 developing human incisor and canine germs, 8-21 weeks old. During the analyzed period, ratio of Ki-67 positive cells changed in outer enamel epithelium from 48.86% to 24.52%, in inner enamel epithelium increased from 56.11% to 60.06% and then dropped to 44.24%. While in dental papilla proliferation first increased from 46.26% to 55.45%, and then dropped to 22.08%, a constant decrease of proliferation characterized enamel reticulum (from 46.26% to 15.49%). Strong cytoplasmic Oct-4 expression characterized epithelial parts of enamel organ, particularly the differentiating ameloblasts. During further development, Oct-4 expression shifted to both nuclear and cytoplasmic expression in mesenchymal tooth components. Primary cilia characterized most of the cells in developing enamel organ. While non-ciliated (proliferating) cells mainly contained two centrioles (γ-tubulin), the primary cilia (α-tubulin) were arising from basal bodies (γ-tubulin) of non-proliferating cells. We suggest that increase in cell proliferation enables growth of enamel organ, while its selective decrease leads to disintegration of some tooth parts. Drop of proliferation coincided with initiation of ameloblast and odontoblast differentiation. Additionally, cell differentiation was accompanied by increased expression of Oct-4 and probably by signalling via primary cilia, both regulating processes of cell proliferation and differentiation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Serum follicle-stimulating hormone level is associated with human epidermal growth factor receptor type 2 and Ki67 expression in post-menopausal females with breast cancer.

    Science.gov (United States)

    Zhou, Jun; Chen, Yiding; Huang, Yiting; Long, Jinpei; Wan, Fang; Zhang, Suzhan

    2013-10-01

    The present study aimed to determine the association between levels of the gender hormones, follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P) and prolactin (PRL), and two breast cancer molecular markers, human epidermal growth factor receptor 2 (Her-2) and Ki67, in post-menopausal patients with breast cancer. A retrospective study of the serum hormone levels of FSH, LH, P and PRL and the expression status of Her-2 and Ki67 was performed using 187 post-menopausal females with breast cancer. Her-2 + breast cancer patients exhibited higher serum FSH levels compared with Her-2 - patients (69.47±3.219 vs. 58.56±1.516 IU/l). The patients with high Ki67 expression [immunohistochemistry (IHC), 3+] displayed higher FSH (72.51±4.616 vs. 60.53±1.476 IU/l) and LH (32.33±1.916 vs. 26.98±0.8852 IU/l) levels than those with lower Ki67 expression. No correlation was identified between the FSH, LH, P and PRL hormone levels, tumor stages and lymphovascular invasion (LVI). In conclusion, a higher serum FSH level was identified in Her-2 + post-menopausal patients with breast cancer. Higher serum FSH and LH levels were also observed in breast cancer patients with high Ki67 expression. FSH and LH may function in the progression of breast cancer.

  5. Study of COX-2, Ki67, and p53 expression to predict effectiveness of 5-flurouracil, epirubicin and cyclophosphamide with celecoxib treatment in breast cancer patients.

    Science.gov (United States)

    Chow, L W C; Loo, W T Y; Wai, C C Y; Lui, E L H; Zhu, L; Toi, M

    2005-10-01

    Cyclooxygenase-2 (COX-2) affects cell proliferation, apoptosis, and metastasis of breast cancer, and may also be involved in tumor angiogenesis through vascular endothelial growth factor. Ki67 and p53 are common markers of proliferation and apoptosis in tumor cells. This study investigated the change in expression of COX-2, Ki67, and p53 in solid tumors after the administration of chemotherapeutic drugs. Fifty patients were eligible to be treated with preoperative 5-fluorouracil, epirubicin, and cyclophosphamide, with celecoxib (FECC). Tumor tissue samples from 10 patients who, diagnosed with invasive ductal carcinoma, completed chemotherapy were examined immunohistochemically for COX-2, Ki67, and p53. From the 60% of patients who expressed COX-2 and 90% who expressed Ki67 and p53 before treatment, 90% of patients revealed a lower intensity staining for each marker after FECC treatment. However, changes in expression of the three markers did not significantly correlate with tumor size, grade, axillary lymph node status. Immunostained slides clearly showed that the diaminobenzidine intensity was markedly reduced after the three-cycle FECC treatment, which implied the combined regimens be effective to the cancer patients. This study demonstrates a novel relationship between COX-2, Ki67, and p53 expression of human breast invasive ductal carcinomas. This functional relationship provides support for a potential therapeutic role of COX-2 inhibitors in human breast cancer.

  6. [Clinicopathologic study and immunohistochemistry comparison of Pax2, p53 and Ki-67 in low- and high-grade ovarian serous carcinomas].

    Science.gov (United States)

    Shen, Xu-xia; Yu, Lin; Bi, Rui; Yang, Wen-tao

    2011-08-01

    To evaluate the two-tier system for the grading of ovarian serous carcinomas, and to analyze Pax2, p53, Ki-67 protein expression and their prognostic values for low- and high-grade ovarian serous carcinomas. A total of 38 cases of low-grade and 100 cases of high-grade ovarian serous carcinomas were selected based on the two-tier grading system. Immunohistochemistry was used to detect Pax2, p53 and Ki-67 protein expression in all cases. Correlation of the two-tier system with immunohistochemical results and prognostic parameters were performed. (1) The overall survival, disease-free survival and 5-year survival rates were significantly higher in the low-grade serous carcinoma cases than in the high-grade cases (P carcinomas. The high-grade serous carcinomas had a significantly higher expression level of p53 (55.0% vs 13.2%, P carcinomas had a significantly higher expression level of Pax2 (65.8% vs 13.0%, P p53 and Ki-67 were found to have little correlation with overall survival and disease-free survival (P > 0.05). The two-tier system for the grading of ovarian serous carcinomas has a good prognostic value. There are significantly differences in expressions of Pax2, p53 and Ki-67 between low- and high-grade ovarian serous carcinomas. Compared with p53 and Ki-67, Pax2 is likely a better prognostic indicator for ovarian serous carcinoma.

  7. Telomeric 1p36.3 deletion and Ki-67 expression in B-Non-Hodgkin's Lymphoma patients associated with chronic hepatitis C virus infection.

    Science.gov (United States)

    Mosad, E; Said Abd El-Rahman Allam, M; Moustafa, H M; Mohammed, A Eliaw; El kebeer, A M; Abdel-Moneim, S S

    2014-12-01

    The hepatitis C virus (HCV) core protein is able to accumulate genetic p53 mutations and may be considered co-oncogenic. This study investigates 1p36.3 telomere deletion in B-non-Hodgkin's lymphoma (NHL) patients with chronic HCV infection using fluorescence in situ hybridization (FISH) in relation to survival to assess Ki-67 antigen expression. A study group and a control group of 100 patients with B-NHL (50 HCV positive and 50 HCV negative) and 60 control bone marrow biopsies were subjected to FISH for the detection of 1P36.3 deletion and to immunohistochemical staining with Ki-67 antigens. 1p36.3 deletion by FISH was detected in 40% of the study group, and Ki-67 was expressed in approximately 74% of patients. A significant difference was found between positive and negative HCV patients in their overall survival, the qualitative expression of Ki-67 and the quantitative detection of 1p36.3 deletion by FISH. The overall survival was shorter with the presence of an 1p36 deletion by FISH and HCV positive. We concluded that the coexistence of Ki-67 positivity, HCV positivity and 1p36.3 deletion may contribute to infection-related cancers at the 1p36.3 locus. © 2014 John Wiley & Sons Ltd.

  8. Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer.

    Science.gov (United States)

    Sonnenblick, Amir; Francis, Prudence A; Azim, Hatem A; de Azambuja, Evandro; Nordenskjöld, Bo; Gutiérez, Jorge; Quinaux, Emmanuel; Mastropasqua, Mauro G; Ameye, Lieveke; Anderson, Michael; Lluch, Ana; Gnant, Michael; Goldhirsch, Aron; Di Leo, Angelo; Barnadas, Agusti; Cortes-Funes, Hernan; Piccart, Martine; Crown, John

    2015-08-01

    Breast International Group (BIG) 2-98 is a randomised phase III trial that tested the effect of adding docetaxel, either in sequence to or in combination with anthracycline-based adjuvant chemotherapy, in women with node-positive breast cancer (BC). Here, we present the 10-year final trial safety and efficacy analyses. We also report an exploratory analysis on the predictive value of Ki67 for docetaxel efficacy, in the BIG 2-98 and using a pooled analysis of three other randomised trials. 2887 patients were randomly assigned in a 2×2 trial design to one of four treatments. The primary objective was to evaluate the overall efficacy of docetaxel on disease free survival (DFS). Secondary objectives included comparisons of sequential docetaxel versus sequential control arm, safety and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry. After a median follow-up of 10.1years, the addition of docetaxel did not significantly improve DFS or OS (hazard ratio (HR)=0.91, 95% confidence interval (CI)=0.81-1.04; P=0.16 and HR=0.88, 95% CI=0.76-1.03; P=0.11, respectively). Sequential docetaxel did not improve DFS compared to the sequential control arm (HR=0.86, 95% CI=0.72-1.03; P=0.10). In oestrogen receptor (ER)-positive tumours with Ki67⩾14%, the addition of docetaxel resulted in 5.4% improvement in 10-year OS (P=0.03, test for interaction=0.1). In a multivariate model, there was a trend for improved DFS and OS in ER-positive patients with high Ki67 and treated with docetaxel (HR=0.79, 95% CI=0.63-1.01; P=0.05 and HR=0.76, 95% CI=0.57-1.01; P=0.06, respectively). A pooled analysis of four randomised trials showed a benefit of taxanes in highly proliferative ER-positive disease but not in low proliferating tumours (interaction test P=0.01). The DFS benefit previously demonstrated with sequential docetaxel is no longer observed at 10years. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly

  9. Immunohistological expression of HIF-1α, GLUT-1, Bcl-2 and Ki-67 in consecutive biopsies during chemoradiotherapy in patients with rectal cancer

    DEFF Research Database (Denmark)

    Havelund, Birgitte Mayland; Sørensen, Flemming Brandt; Pløen, John

    2013-01-01

    The aim of this study was to describe the dynamics of HIF-1α, GLUT-1, Bcl-2 and Ki-67 during chemoradiotherapy (CRT) of rectal cancer, and to investigate the fluctuation of these biomarkers in relation to pathological response to CRT. The study included 86 patients with rectal adenocarcinoma...... receiving preoperative CRT (>50.4 Gy and Uracil/Tegafur). Immunohistological expressions of HIF-1α, GLUT-1, Bcl-2 and Ki-67 were investigated in biopsies taken before treatment, after 2, 4 and 6 weeks of CRT and in specimens from the operation. Decreasing expressions of HIF-1α, Bcl-2 and Ki-67 were observed...... during CRT, whereas GLUT-1 overall was unchanged. No significant changes of the markers were observed in the interval between CRT and surgery. A significant association was observed between the presence of residual carcinoma after 6 weeks of treatment and pathological response to CRT, but no association...

  10. Multi-level gene expression signatures, but not binary, outperform Ki67 for the long term prognostication of breast cancer patients.

    Science.gov (United States)

    Tobin, Nicholas P; Lindström, Linda S; Carlson, Joseph W; Bjöhle, Judith; Bergh, Jonas; Wennmalm, Kristian

    2014-05-01

    Proliferation-related gene signatures have been proposed to aid breast cancer management by providing reproducible prognostic and predictive information on a patient-by-patient basis. It is unclear however, whether a less demanding assessment of cell division rate (as determined in clinical setting by expression of Ki67) can function in place of gene profiling. We investigated agreement between literature-, distribution-based, as well as signature-derived values for Ki67, relative to the genomic grade index (GGI), 70-gene signature, p53 signature, recurrence score (RS), and the molecular subtype models of Sorlie, Hu, and Parker in representative sets of 253 and 159 breast cancers with a median follow-up of 13 and 14.5 years, respectively. The relevance for breast cancer specific survival was also addressed in uni- and bivariate Cox models. Taking both cohorts into account, our broad approach identified ROC optimized Ki67 cutoffs in the range of 8-28%. With optimum signature-reproducing cutoffs, similarity in classification of individual tumors was higher for binary signatures (72-85%), than multi-level signatures (67-73%). Consistent with strong agreement, no prognostic superiority was noted for either Ki67 or the binary GGI, 70-gene and p53 signatures in the Uppsala dataset by bivariate analyses. In contrast, Ki67-independent prognostic capacity could be demonstrated for RS and molecular subtypes according to Sorlie, Hu and Parker in both datasets. Our results show that the added prognostic value of binary proliferation-related gene signatures is limited for Ki67-assessed breast cancers. More complex, multi-level descriptions have a greater potential in short- and long-term prognostication for biologically relevant breast cancer subgroups. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  11. Digital imaging in the immunohistochemical evaluation of the proliferation markers Ki67, MCM2 and Geminin, in early breast cancer, and their putative prognostic value.

    Science.gov (United States)

    Joshi, Shalaka; Watkins, Johnathan; Gazinska, Patrycja; Brown, John P; Gillett, Cheryl E; Grigoriadis, Anita; Pinder, Sarah E

    2015-07-25

    Immunohistochemical assessment of proliferation may provide additional prognostic information in early breast cancer. However, due to a lack of methodological standards proliferation markers are still not routinely used for determining therapy. Even for Ki67, one of the most widely-studied markers, disagreements over the optimal cutoff exist. Improvements in digital microscopy may provide new avenues to standardise and make data more reproducible. We studied the immunohistochemical expression of three markers of proliferation: Ki67, Mini-Chromosome Maintenance protein 2 and Geminin, by conventional light microscope and digital imaging on triplicate TMAs from 309 consecutive cases of primary breast cancers. Differences between the average and the maximum percentage reactivity in tumour cell nuclei from the three TMA cores were investigated to assess the validity of the approach. Time-dependent Receiver Operating Characteristic curves were utilized to obtain optimal expression level cut-offs, which were then correlated with clinico-pathological features and survival. High concordance between conventional and digital scores was observed for all 3 markers (Ki67: rs = 0.87, P Ki67 or MCM2; analysis of two or three cores produced comparable results. Higher levels of all three proliferation markers were significantly associated with higher grade (P Ki67, MCM2 and Geminin respectively. All 3 proliferation marker cutoffs were predictive of 15-year breast cancer-specific survival in univariable Cox regression analyses. In multivariable analysis only lymph node status (HR = 3.9, 95 % CI = 1.79-8.5, P = 0.0006) and histological grade (HR = 1.84, 95 % CI = 1-3.38, P = 0.05) remained significantly prognostic. Here we show that. MCM2 is a more sensitive marker of proliferation than Ki67 and should be examined in future studies, especially in the lymph node-negative, hormone receptor-positive subgroup. Further, digital microscopy can be used effectively as a high-throughput method

  12. Value of Breast Cancer Molecular Subtypes and Ki67 Expression for the Prediction of Efficacy and Prognosis of Neoadjuvant Chemotherapy in a Chinese Population.

    Science.gov (United States)

    Wang, Jiayu; Sang, Die; Xu, Binghe; Yuan, Peng; Ma, Fei; Luo, Yang; Li, Qing; Zhang, Pin; Cai, Ruigang; Fan, Ying; Chen, Shanshan; Li, Qiao

    2016-05-01

    The aim of the study was to determine the predictive role of breast cancer subtypes in the efficacy and prognosis of neoadjuvant chemotherapy (NCT) regimens combining taxanes and anthracyclines.Data from 240 patients with breast cancer who received surgery after 4 to 6 weeks of NCT were retrospectively analyzed. The patients were classified into luminal A, luminal B, HER2 overexpression, and triple negative breast cancer (TNBC) as well as low Ki67 (≤ 14%) and high Ki67 (> 14%) expression groups using immunohistochemistry. NCT outcome parameters were pathological complete response (pCR), clinical complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) 4 weeks after surgery. Long-term outcome parameters were disease-free survival (DFS) with a follow-up time of 3 to 56 months.pCR rates were 1.6%, 13.4%, 22.6%, and 23.8% in patients with luminal A, luminal B, HER2, and TNBC cancers, respectively. High pCR rates correlated with high Ki67 expression (> 40%) (P breast cancer was the highest compared to all other groups, but only significantly higher compared to luminal B (P = 0.035, HR = 1.480, 95% CI: 1.060-1.967) patients and correlated with Ki67 expression > 40% (P = 0.005).Luminal A type patients derived the least benefit from neoadjuvant chemotherapy but had better long-term prognoses. ER status and Ki67 expression served as efficacy predictors for NCT, whereas only Ki67 expression > 40% correlated with long-term treatment outcomes.

  13. Expressão imuno-histoquímica dos marcadores pcna, KI67 e p53 em carcinomas epidermóides do trato aerodigestivo superior

    Directory of Open Access Journals (Sweden)

    João Paulo Esposito

    Full Text Available OBJETIVO: Os carcinomas epidermóides do trato aerodigestivo superior são tumores de comportamento biológico heterogêneo. O objetivo deste trabalho é verificar se a expressão imuno-histoquímica dos marcadores Ki67, PCNA e P53 apresenta correlações com parâmetros prognósticos clínico-patológicos. MÉTODOS: Determinação da expressão imuno-histoquímica dos antígenos Ki67, PCNA e P53 em espécimes tumorais fixados e embebidos em parafina de 53 pacientes com carcinoma epidermóide em diferentes sítios primários do trato aerodigestivo superior. RESULTADOS: Os marcadores tiveram altos índices de expressão imuno-histoquímica, sendo 46,5% para o Ki67, 66,5% para o PCNA e 36,5% para o P53. Não houve correlação da expressão do Ki67 e do PCNA com o estadiamento TNM (AJCC, nem com o grau de malignidade. A expressão do Ki67 apresentou correlação positiva com a expressão do PCNA (p = 0,037. O mesmo aconteceu para o PCNA e o número de mitoses por campo (p = 0,001. CONCLUSÕES: De acordo com estes resultados, concluiu-se que a determinação da imunorreatividade dos marcadores Ki67 e PCNA é um método objetivo e quantificável para avaliar proliferação celular que pode subsidiar as informações prognósticas.

  14. Changes in the ER, PgR, HER2, p53 and Ki-67 biological markers between primary and recurrent breast cancer: discordance rates and prognosis

    Directory of Open Access Journals (Sweden)

    Tashima Rumiko

    2011-10-01

    Full Text Available Abstract Background In breast cancer, ER/PgR, HER2, and Ki-67 are important biological markers for predicting prognosis and making effective treatment decisions. In addition, changes in markers due to relapse are also clinically experienced; however, the frequency and clinical significance are still not fully understood. Thus, changes in markers and their correlations with prognosis were investigated. Patients and Methods Out of the patients with relapse from 1997 to March 2011, there were 97 consecutive patients from whom the lesion was resected and evaluated by immunostaining. The biopsy sites were chest wall, lymph node, ipsilateral breast tumor recurrence, lungs, bones, ovaries and brain. The markers sought were ER, PgR, HER2, p53 and Ki-67. Results The hormone receptor positive rate from the primary tumor to recurrence decreased from 63.9% to 57.7% and from 56.7% to 43.3% for ER and PgR, respectively. Changes in the positive/negative evaluation were seen at the rate of 10.3% and 25.8% for ER and PgR, respectively. The Ki-67 index increased significantly from a mean of 29.1% at primary tumor to 36.3% at relapse. When divided into 2 groups ( Conclusion Estrogen receptor and PgR decreased while Ki-67 increased due to relapse; however, the rate of change was high for PgR and Ki-67. Change in the subtypes was seen in 25%. In addition, PgR at relapse and Ki-67 at primary tumor were significant factors for post-relapse prognosis while PgR becoming negative was a poor prognostic factor. These findings are important for making effective treatment decisions.

  15. Correlation between the Uptake of 18F-Fluorodeoxyglucose (18F-FDG and the Expression of Proliferation-Associated Antigen Ki-67 in Cancer Patients: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Sheng-Ming Deng

    Full Text Available To study the correlation between 18F-FDG uptake and cell proliferation in cancer patients by meta-analysis of published articles.We searched PubMed (MEDLINE included, EMBASE, and Cochrane Database of Systematic Review, and selected research articles on the relationship between 18F-FDG uptake and Ki-67 expression (published between August 1, 1994-August 1, 2014, according to the literature inclusion and exclusion criteria. The publishing language was limited to English. The quality of included articles was evaluated according to the Quality Assessment of Diagnosis Accuracy Studies-2 (QUADAS-2. The correlation coefficient (r was extracted from the included articles and processed by Fisher's r-to-z transformation. The combined correlation coefficient (r and the 95% confidence interval (CI were calculated with STATA 11.0 software under a random-effects model. Begg's test was used to analyze the existence of publication bias and draw funnel plot, and the sources of heterogeneity were explored by sensitivity and subgroup analyses.According to the inclusion and exclusion criteria, 79 articles were finally included, including 81 studies involving a total of 3242 patients. All the studies had a combined r of 0.44 (95% CI, 0.41-0.46, but with a significant heterogeneity (I2 = 80.9%, P<0.01. Subgroup analysis for different tumor types indicated that most subgroups showed a reduced heterogeneity. Malignant melanoma (n = 1 had the minimum correlation coefficient (-0.22 between 18F-FDG uptake and Ki-67 expression, while the thymic epithelial tumors (TETs; n = 2 showed the maximum correlation coefficient of 0.81. The analytical results confirmed that correlation between 18F-FDG uptake and Ki-67 expression was extremely significant in TETs, significant in gastrointestinal stromal tumors (GISTs, moderate in patients with lung, breast, bone and soft tissue, pancreatic, oral, thoracic, and uterine and ovarian cancers, average in brain, esophageal and colorectal

  16. The Relationship of Race, Oncotype DX, and Ki67 in a Population Highly Screened For Breast Cancer.

    Science.gov (United States)

    Guth, Amber A; Chun Kim, Jennifer; Schwartz, Shira; Montes, Jennifer; Snyder, Rebecca Akiko; Axelrod, Deborah; Schnabel, Freya

    2017-03-01

    Oncotype DX recurrence score (ODX) can predict risk of invasive breast cancer recurrence and benefit of chemotherapy. Literature is limited on the relationship of ODX and race in women with hormone receptor positive and node negative/positive disease. Our study examines the relationship between race and clinical characteristics within a population of highly screened women with newly diagnosed breast cancer. The institutional Breast Cancer Database was queried for patients with newly diagnosed breast cancer between January2010 and March2015. We analyzed clinical and tumor characteristics including ODX. Statistical analyses included Pearson's Chi-Square and Fisher's Exact Tests. There were 2,092 women in our study cohort. The majority had college-level education (84%), regular screening (78%), and clinical breast exams (88%). The majority had invasive ductal carcinoma (IDC) (62%), early stage (0, I, II) tumors (93%), ER+ (84%), PR+ (71%), Her2 negative (86%), and node negative disease (83%). There was a significantly higher proportion of later stage disease among African-Americans (p = 0.001) and Asians (p = 0.006) and more triple negative breast cancers among African-Americans (p Ki67. Therefore we recommend that further research be focused on refining management algorithms by ethnicity. © 2017 Wiley Periodicals, Inc.

  17. Nogo-B receptor expression correlates negatively with malignancy grade and ki-67 antigen expression in invasive ductal breast carcinoma.

    Science.gov (United States)

    Pula, Bartosz; Olbromski, Mateusz; Owczarek, Tomasz; Ambicka, Aleksandra; Witkiewicz, Wojciech; Ugorski, Maciej; Rys, Janusz; Zabel, Maciej; Dziegiel, Piotr; Podhorska-Okolow, Marzena

    2014-09-01

    Nogo-B receptor (NgBR) has been shown to be involved in endothelial cell chemotaxis and morphogenesis. However, few studies analyzing its expression in cancer cells have been performed. We examined NgBR expression in 233 patients with invasive ductal breast carcinoma (IDC) and corresponding non-malignant breast tissues (NMBT) on mRNA (real-time polymerase chain reaction) and protein levels (immunohistochemistry; IHC and western-blot analysis). NgBR expression was found also analyzed in breast cancer cell lines of varying invasiveness. NgBR expression was increased in IDC compared to NMBT on the mRNA (p=0.0007) and protein level (p=0.018). NgBR expression decreased significantly with IDC malignancy grade and correlated negatively with the Ki-67 antigen expression (r=-0.18; p=0.0005). High NgBR mRNA expression was associated with estrogen receptor negativity (p=0.0023) and the triple-negative phenotype of the tumors (p=0.0129). NgBR may be involved in IDC development, however, its role in its progression requires further research. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. Influence of intra-tumoral heterogeneity on the evaluation of BCL2, E-cadherin, EGFR, EMMPRIN, and Ki-67 expression in tissue microarrays from breast cancer

    DEFF Research Database (Denmark)

    Tramm, Trine; Kyndi, Marianne; Sørensen, Flemming B

    2018-01-01

    -tumoral heterogeneity as well as inter-observer variability on the evaluation of various IHC markers with potential prognostic impact in breast cancer (BCL2, E-cadherin, EGFR, EMMPRIN and Ki-67). MATERIAL AND METHODS: From each of 27 breast cancer patients, two tumor-containing paraffin blocks were chosen. Intra...... was found. EMMPRIN and Ki-67 showed a more heterogeneous expression with moderate to substantial intra-block agreements. For both stainings, there was a moderate inter-block agreement that improved slightly for EMMPRIN, when using WS instead of TMA cores. Inter-observer agreements were found to be almost...... perfect for BCL2, E-cadherin and EGFR (WS: κ > 0.82, TMAs: κ > 0.90), substantial for EMMPRIN (κ > 0.63), but only fair to moderate for Ki-67 (WS: κ = 0.54, TMAs: κ = 0.33). CONCLUSIONS: BCL2, E-cadherin and EGFR were found to be homogeneously expressed, whereas EMMPRIN and Ki-67 showed a more pronounced...

  19. Brief fixation does not hamper the reliability of Ki67 analysis in breast cancer core-needle biopsies : A double-centre study

    NARCIS (Netherlands)

    Kalkman, Shona; Bulte, Joris P.; Halilovic, Altuna; Bult, Peter; van Diest, Paul J.

    2015-01-01

    Aims: Immunohistochemical assessment of Ki67 expression in core-needle biopsies (CNBs) is increasingly playing a role in therapeutic decision-making for breast cancer patients. Within the framework of same-day diagnosis of breast lesions, fixation times are markedly decreased. We therefore attempted

  20. Brief fixation does not hamper the reliability of Ki67 analysis in breast cancer core-needle biopsies: a double-centre study

    NARCIS (Netherlands)

    Kalkman, S.; Bulte, J.P.; Halilovic, A.; Bult, P.; Diest, P.J. van

    2015-01-01

    AIMS: Immunohistochemical assessment of Ki67 expression in core-needle biopsies (CNBs) is increasingly playing a role in therapeutic decision-making for breast cancer patients. Within the framework of same-day diagnosis of breast lesions, fixation times are markedly decreased. We therefore attempted

  1. Brief fixation does not hamper the reliability of Ki67 analysis in breast cancer core-needle biopsies: a double-centre study.

    Science.gov (United States)

    Kalkman, Shona; Bulte, Joris P; Halilovic, Altuna; Bult, Peter; van Diest, Paul J

    2015-02-01

    Immunohistochemical assessment of Ki67 expression in core-needle biopsies (CNBs) is increasingly playing a role in therapeutic decision-making for breast cancer patients. Within the framework of same-day diagnosis of breast lesions, fixation times are markedly decreased. We therefore attempted to validate Ki67 analysis in briefly fixed breast cancer CNBs. CNBs of 136 consecutive patients with invasive breast cancer diagnosed through the same-day diagnosis programme of both the University Medical Centre Utrecht (UMCU) and the Radboud University Medical Centre (RUMC) were included. CNBs were fixed in formaldehyde for approximately 45 min at the UMCU and for between 60 and 90 min at the RUMC. Immunohistochemistry for Ki67 expression was compared between the briefly fixed CNBs and conventionally fixed resection specimens of the same tumour. The overall agreement between CNBs and resections was 122 of 142 (85.9%) (κ = 0.71; 95% CI 0.60-0.83). Positive and negative predictive values were 79.7% (95% CI 67-88%) and 91.0% (95% CI 82-96%), respectively. Overall agreement for Ki67 expression was good between briefly fixed CNBs and conventionally fixed resection specimens, and within the range of studies comparing conventionally fixed CNBs and resections. © 2014 John Wiley & Sons Ltd.

  2. Ki-67 and PCNA Expression in Canine Mammary Tumors and Adjacent Nonneoplastic Mammary Glands: Prognostic Impact by a Multivariate Survival Analysis.

    Science.gov (United States)

    Carvalho, M I; Pires, I; Prada, J; Lobo, L; Queiroga, F L

    2016-11-01

    The assessment of tumor proliferation has been considered a determining prognostic factor in canine mammary tumors (CMTs). However, no studies have assessed the prognostic importance of proliferation in adjacent nonneoplastic mammary glands. We included 64 CMTs (21 benign and 43 malignant) and studied the proliferation index (PI) of Ki-67 and proliferating cell nuclear antigen (PCNA) together with several clinicopathological characteristics. A positive and statistically significant correlation between the PI of Ki-67 and PCNA in tumors and adjacent nonneoplastic mammary glands was observed in benign and malignant tumors. Tumor size, skin ulceration, histological type, mitotic index, nuclear grade, differentiation grade, histological grade of malignancy, lymph node metastasis, Ki-67, and PCNA expression in tumors and adjacent nonneoplastic mammary glands were statistically associated with overall survival by univariate analysis in malignant cases (n = 43). Histological grade of malignancy and high intratumoral PCNA retained their significance by multivariate analysis arising as independent predictors of overall survival. Interestingly, the PI of Ki-67 and PCNA of adjacent nontumoral mammary glands were associated with clinicopathological features of tumor aggressiveness and shorter overall survival, demonstrating the need to better explore this adjacent non-neoplastic tissue. © The Author(s) 2016.

  3. Triaging borderline/mild dyskaryotic Pap cytology with p16/Ki-67 dual-stained cytology testing: Cross-sectional and longitudinal outcome study

    NARCIS (Netherlands)

    M.H. Uijterwaal (Margot); B.I. Witte (Birgit); F.J. van Kemenade (Folkert); D.C. Rijkaart (Dorien); R. de Ridder (Rogier); J. Berkhof (Johannes); G.A.M.A. Balfoort-Van Der Meij (G. A M A); M.C.G. Bleeker; P.J.F. Snijders (Peter); C.J.L.M. Meijer (Chris J. L.)

    2014-01-01

    textabstractBackground: Women with borderline/mildly dyskaryotic (BMD) cytology smears are currently followed up with repeat testing at 6 and 18 months. The objective of this study is to analyse the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the detection of

  4. Comparison of visual assessment and image analysis in the evaluation of Ki-67 expression and their prognostic significance in immunohistochemically defined luminal breast carcinoma.

    Science.gov (United States)

    Arihiro, Koji; Oda, Miyo; Ohara, Masahiro; Kadoya, Takayuki; Osaki, Akihiko; Nishisaka, Takashi; Shiroma, Noriyuki; Kobayashi, Yoshie

    2016-12-01

    To compare the Ki-67 labeling index value obtained through immunohistochemistry analysis by human examiners to that obtained from computer-assisted image analysis, and to establish a cut-off value for Ki-67 labeling index for each method in luminal B breast carcinoma. Immunohistochemistry analysis for Ki-67 was performed on the formalin-fixed, paraffin-embedded tissue samples from 403 patients with primary luminal breast cancers. Whole slide images were obtained using the NanoZoomer (Hamamatsu Photonics, Hamamatsu, Japan) and thoroughly analyzed using the Definiens Tissue Studio version 1.1 (Definiens AG, Munich, Germany) to detect the percentage of positively-stained nuclei of carcinoma cells. Although a significant correlation was found between the Ki-67 labeling index obtained by manual assessment and computer-assisted image analysis (Spearman rank correlation coefficient, P visual counting (cut-off value: 28.5%; P visual counting (cut-off value: 19.7%, P visual counting could equally predict disease-free survival in patients with luminal B breast carcinoma, including those who received endocrine therapy. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Combination of CK20 and Ki-67 immunostaining analysis predicts recurrence, progression, and cancer-specific survival in pT1 urothelial bladder cancer.

    Science.gov (United States)

    Bertz, Simone; Otto, Wolfgang; Denzinger, Stefan; Wieland, Wolf F; Burger, Maximilian; Stöhr, Robert; Link, Stefan; Hofstädter, Ferdinand; Hartmann, Arndt

    2014-01-01

    The prognostic value of CK20, Ki-67, and p53 has been investigated for non-muscle-invasive urothelial bladder cancers but not for the distinct and clinically challenging subset of pT1 bladder cancers. To evaluate the prognostic value of CK20, Ki-67, and p53 within the largest series of pT1 urothelial bladder cancers. Data from 309 patients with pT1 urothelial bladder cancer from one single urologic centre were collected. Adjuvant instillation of bacillus Calmette-Guérin was performed in each patient. A second resection was performed after 4-8 wk. A total of 76 patients underwent cystectomy. We conducted histomorphologic analysis; immunohistochemistry for CK20, Ki-67, and p53; and univariate and multivariate Cox regression models including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS). At a median follow-up of 49 mo, we found recurrence and progression and disease-specific mortality rates of 22.7%, 20.1%, and 15.9%, respectively. CK20 expression was significantly correlated with RFS in multivariate analysis (hazard ratio [HR]: 5.89; 95% confidence interval [CI], 1.44-24.15; p=0.014). In multivariate analysis, Ki-67 was the only marker significantly correlated with PFS (HR: 2.80; 95% CI, 1.45-5.43, p=0.002). Ki-67 (HR: 3.83; 95% CI, 1.59-9.26; p=0.003), and CK20 (HR: 8.44; 95% CI,1.16-61.34; p=0.035) were significantly correlated with CSS in multivariate analysis. The combination of CK20 and Ki-67 showed significantly worse RFS (p=0.026), PFS (p=0.003), and CSS (plimitation of this study. Our present analysis of the largest series of patients with pT1 urothelial bladder cancer published to date found Ki-67 and CK20 to be potential prognostic markers improving the risk stratification of pT1 bladder tumours. They are reliable indicators of biologic aggressiveness and may contribute to decision making on therapeutic strategy for pT1 bladder carcinomas. Copyright © 2012 European Association of Urology. Published by

  6. Evaluation of an Optimal Cut-Off Point for the Ki-67 Index as a Prognostic Factor in Primary Breast Cancer: A Retrospective Study.

    Directory of Open Access Journals (Sweden)

    Rumiko Tashima

    Full Text Available The Ki-67 index is an important biomarker for indicating the proliferation of cancer cells and is considered to be an effective prognostic factor for breast cancer. However, a standard cut-off point for the Ki-67 index has not yet been established. Therefore, the aim of this retrospective study was to determine an optimal cut-off point in order to establish it as a more accurate prognostic factor. Immunohistochemical analysis of the Ki-67 index was performed on 4329 patients with primary breast cancer from August 1987 to March 2012. Out of this sample, there were 3186 consecutive cases from September 1997 with simultaneous evaluations of ER, PgR and HER2 status. Cox's proportional hazard model was used to perform univariate and multivariate analyses of the factors related to OS. The hazard ratios (HR and the p values were then compared to determine the optimal cut-off point for the Ki-67 index. The median Ki-67 index value was 20.5% (mean value 26.2%. The univariate analysis revealed that there was a statistically significant negative correlation with DFS and OS and the multivariate analysis revealed that the Ki-67 index value was a significant factor for DFS and OS. The top seven cut-off points were then carefully chosen based on the results of the univariate analysis using the lowest p-values and the highest HR as the main selection criteria. The multivariate analysis of the factors for OS showed that the cut-off point of 20% had the highest HR in all of the cases. However, the cutoff point of 20% was only a significant factor for OS in the Luminal/HER2- subtype. There was no correlation between the Ki-67 index value and OS in any of the other subtypes. These data indicate that the optimal cut-off point of 20% is the most effective prognostic factor for Luminal/HER2- breast cancer.

  7. Advantages of adjuvant chemotherapy for patients with triple-negative breast cancer at Stage II: usefulness of prognostic markers E-cadherin and Ki67

    Science.gov (United States)

    2011-01-01

    Introduction Triple-negative breast cancer (TNBC), which is characterized by negativity for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2), is a high risk breast cancer that lacks specific targets for treatment selection. Chemotherapy is, therefore, the primary systemic modality used in the treatment of this disease, but reliable parameters to predict the chemosensitivity of TNBC have not been clinically available. Methods A total of 190 TNBC patients who had undergone a curative resection of a primary breast cancer were enrolled. The adjuvant chemotherapy was performed for 138 (73%) of 190 TNBC cases; 60 cases had an anthracyclin-based regimen and 78 a 5-fluorouracil-based regimen. The prognostic value of E-cadherin, Ki67 and p53 expression in the outcome of TNBC patients with adjuvant chemotherapy was evaluated by immunohistochemistry. Results The adjuvant therapy group, especially those with Stage II TNBC, had a more favorable prognosis than the surgery only group (P = 0.0043), while there was no significant difference in prognosis between the anthracyclin-based regimen and 5-fluorouracil-based regimen. Patients with E-cadherin-negative and Ki67-positive expression showed significantly worse overall survival time than those with either E-cadherin-positive or Ki67-negative expression (P Ki67-positive expression was strongly predictive of poor overall survival (P = 0.004) in TNBC patients receiving adjuvant chemotherapy. In contrast, p53 status was not a specific prognostic factor. Conclusions Adjuvant therapy is beneficial for Stage II TNBC patients. The combination of E-cadherin and Ki67 status might be a useful prognostic marker indicating the need for adjuvant chemotherapy in Stage II TNBC patients. PMID:22126395

  8. Co-Expression of p16, Ki67 and COX-2 Is Associated with Basal Phenotype in High-Grade Ductal Carcinoma In Situ of the Breast.

    Science.gov (United States)

    Perez, Amanda Arantes; Balabram, Débora; Rocha, Rafael Malagoli; da Silva Souza, Átila; Gobbi, Helenice

    2015-06-01

    We assessed the co-expression of cell cycle-related biomarkers in a series of 121 consecutive cases of high-grade ductal carcinoma in situ (DCIS), pure or associated with invasive carcinoma, and their associations with the different immunoprofiles of DCIS. Cases were identified from the histopathology files of the Breast Pathology Laboratory, Federal University of Minas Gerais, Brazil, from 2003 to 2008. The expression of estrogen receptor, progesterone receptor, HER2 overexpression, cytokeratin 5, epidermal growth factor receptor 1, cyclooxygenase-2, p16 and Ki67 were assessed. Tumors were placed into five subgroups according to their immunohistochemical profile: luminal A, luminal B, HER2, basal-like and "not classified". We found that the basal phenotype was associated with a higher frequency of p16-positive cases (83%) and the luminal A phenotype showed a higher frequency of p16-negative cases (93%; p=0.000). The association of biomarkers p16(+)/Ki67(+)/COX2(+) was expressed in 02/06 cases (33.3%) of the basal phenotype but in only 01/70 cases (1.4%) of the luminal A phenotype (p=0.01). The co-expression of p16(+)/Ki67(+)/COX2(-) was associated with a basal phenotype (p=0.004). P16 expression, p16(+)/Ki67(+)/COX2(+) and p16(+)/Ki67(+)/COX2(-) co-expression showed significant associations with the basal phenotype and these profiles could be used to guide more aggressive treatment strategies in patients with high-grade DCIS. © The Author(s) 2015.

  9. An inter-observer Ki67 reproducibility study applying two different assessment methods: on behalf of the Danish Scientific Committee of Pathology, Danish breast cancer cooperative group (DBCG).

    Science.gov (United States)

    Laenkholm, Anne-Vibeke; Grabau, Dorthe; Møller Talman, Maj-Lis; Balslev, Eva; Bak Jylling, Anne Marie; Tabor, Tomasz Piotr; Johansen, Morten; Brügmann, Anja; Lelkaitis, Giedrius; Di Caterino, Tina; Mygind, Henrik; Poulsen, Thomas; Mertz, Henrik; Søndergaard, Gorm; Bruun Rasmussen, Birgitte

    2018-01-01

    In 2011, the St. Gallen Consensus Conference introduced the use of pathology to define the intrinsic breast cancer subtypes by application of immunohistochemical (IHC) surrogate markers ER, PR, HER2 and Ki67 with a specified Ki67 cutoff (>14%) for luminal B-like definition. Reports concerning impaired reproducibility of Ki67 estimation and threshold inconsistency led to the initiation of this quality assurance study (2013-2015). The aim of the study was to investigate inter-observer variation for Ki67 estimation in malignant breast tumors by two different quantification methods (assessment method and count method) including measure of agreement between methods. Fourteen experienced breast pathologists from 12 pathology departments evaluated 118 slides from a consecutive series of malignant breast tumors. The staining interpretation was performed according to both the Danish and Swedish guidelines. Reproducibility was quantified by intra-class correlation coefficient (ICC) and Lights Kappa with dichotomization of observations at the larger than (>) 20% threshold. The agreement between observations by the two quantification methods was evaluated by Bland-Altman plot. For the fourteen raters the median ranged from 20% to 40% by the assessment method and from 22.5% to 36.5% by the count method. Light's Kappa was 0.664 for observation by the assessment method and 0.649 by the count method. The ICC was 0.82 (95% CI: 0.77-0.86) by the assessment method vs. 0.84 (95% CI: 0.80-0.87) by the count method. Although the study in general showed a moderate to good inter-observer agreement according to both ICC and Lights Kappa, still major discrepancies were identified in especially the mid-range of observations. Consequently, for now Ki67 estimation is not implemented in the DBCG treatment algorithm.

  10. Comparison of PTCH1, COX-2, p53, and Ki-67 protein expression in basal cell carcinomas of nodular and superficial subtypes arising on the head and trunk.

    Science.gov (United States)

    Khalesi, Mohammad; Waterhouse, Mary; Whiteman, David C; Johns, Richard; Rosendahl, Cliff; Hackett, Timothy; Pollak, Thomas; Kimlin, Michael G; Hacker, Elke; Neale, Rachel E

    2016-10-01

    There is some evidence that basal cell carcinomas (BCCs) arising on different anatomic sites and developing to different histological subtypes differ in their pathophysiology. The expression of a number of proteins, including PTCH1, COX-2, p53, and Ki-67, is frequently altered in BCC development. This study sought to determine whether protein expression differs between BCCs at different anatomic sites and of different histological subtypes. Expression of PTCH1, COX-2, p53, and Ki-67 proteins was compared between: (i) BCCs arising on the head (n = 55) and trunk (n = 53), and (ii) nodular (n = 52) and superficial (n = 43) BCCs. The intensity of immunohistochemistry (IHC) staining (low, moderate, strong, very strong) for PTCH1 and COX-2 proteins was measured and the proportions of p53- and Ki-67-positive cells quantified. The proportion of cells expressing Ki-67 was higher in tumor tissue than in non-malignant epidermis, whereas the opposite was found for PTCH1. The IHC staining intensity for PTCH1 was substantially greater in truncal BCCs than in BCCs on the head (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.63-8.96). The intensity of staining for PTCH1 was greater for superficial than for nodular BCCs (OR 3.70, 95% CI 1.53-8.97), and superficial BCCs showed a higher proportion of Ki-67-positive cells (OR 5.57, 95% CI 1.66-18.67). These differences suggest that the pathophysiology of BCC differs between lesions on the head and trunk and between nodular and superficial subtypes, perhaps indicating differences in their etiology. © 2016 The International Society of Dermatology.

  11. Long-term prognostic performance of Ki67 rate in early stage, pT1-pT2, pN0, invasive breast carcinoma.

    Directory of Open Access Journals (Sweden)

    Fabien Reyal

    Full Text Available BACKGROUND: Molecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1-pT2, pN0 breast cancer patients. METHODS: 456 patients treated in 1995-1996 were identified in the Institut Curie database. Ki67 (MIB1 was retrospectively assessed by immunohistochemistry for all cases. The prognostic value of this index was compared to that of histological grade (HG, Estrogen receptor (ER and HER2 status. Distant disease free interval, loco-regional recurrence, time-lapse from first metastatic diagnosis to death were analyzed. RESULTS: All 456 patients were treated by lumpectomy plus axillary dissection and radiotherapy. 27 patients (5.9% received systemic treatment. Tumors were classified as HG1 in 35%, HG2 in 42% and HG3 in 23% of cases. ER was expressed in 86% of the tumors, HER2 in 5% and 14% were triple negative. The median follow-up was 151 [5-191] months. Distant and loco-regional disease recurrences were observed in 16% and 18%, respectively. High (>20% Ki67 rate [HR = 3 (1.8-4.8, p<10e-06] and HG3 [HR = 4.4 (2.2-8.6, p = 0.00002] were associated with an increased rate of distant relapse. In multivariate analysis, the Ki67 remained the only significant prognostic factor in the subgroups of ER positive HER2 negative [HR = 2.6 (1.5-4.6, p = 0.0006] and ER positive HER2 negative HG2 tumors [HR = 2.2 (1.01-4.8, p = 0.04]. CONCLUSIONS: We validate the prognosis value of the Ki67 rate in small size node negative breast cancer. We conclude that Ki67 is a potential cost-effective decision marker for adjuvant therapy in early-stage HG2, pT1-pT2, pN0, breast cancers.

  12. Comparison between Ki67 labeling index determined using image analysis software with virtual slide system and that determined visually in breast cancer.

    Science.gov (United States)

    Maeda, Ichiro; Abe, Kayoko; Koizumi, Hirotaka; Nakajima, Chika; Tajima, Shinya; Aoki, Hiromi; Tsuchiya, Junichi; Tsuchiya, Seiko; Tsuchiya, Kyoko; Shimo, Arata; Tsugawa, Koichiro; Ueno, Takahiko; Tatsunami, Shinobu; Takagi, Masayuki

    2016-09-01

    In recent papers, Ki67 labeling index (LI) has been used to classify breast cancer patients into the low and high Ki67LI groups for comparison studies, which showed significant differences in many prognostic factors. It has not been clarified whether image analysis software can be used for calculating LI in breast cancer. In our study, we examined whether Ki67LI in breast cancer calculated using image analysis software correlates with that measured on the basis of visual. Fifty patients were randomly selected among breast cancer patients who underwent surgical operation from March, 2010 to May, 2010 in our hospital without preoperative chemotherapy. In this study, for the virtual slide system (VSS: VS120-L100, Olympus, Tokyo, Japan), the high-resolution VSs of all the 50 patients were prepared as samples. The image analysis software use for calculating LI was Tissuemorph Digital Pathology (Tissuemorph DP: Visiopharm, Hoersholm, Denmark). The calculated LI was extracted from 3 to 5 views containing hot spots. The LI calculated using Tissuemorph DP was designed as LI/image/T. The digital image of 3 to 5 LI/image/T views was printed out, and on the digital photograph, we counted visually the number of Ki67-immunopositive cells in exactly the same area, and the percentage of Ki67-immunopositive cells was designed as LI/direct. Moreover, a pathologist's assistant (PA) determined the tumor area in the same specimen using VSS and calculated LI using Tissuemorph DP, which was designed as LI/image/PA. The chief pathologist (CP) similarly calculated LI which was designed as LI/image/CP. We evaluated the degree of agreement between different data sets "LI/image/T and LI/direct" and "LI/image/T, LI/image/CP, and LI/image/PA" by using interclass correlation coefficient (ICC). The average counts of cells were as follows: LI/direct, 3209.7 ± 1970.4 (SD); LI/image/T, 2601.6 ± 1697.1; LI/image/PA, 2886.5 ± 2027.5; LI/image/CP, 18805.5 ± 22293.4. The values of LI

  13. Immunohistological expression of HIF-1α, GLUT-1, Bcl-2 and Ki-67 in consecutive biopsies during chemoradiotherapy in patients with rectal cancer

    DEFF Research Database (Denmark)

    Havelund, Birgitte Mayland; Sørensen, Flemming Brandt; Pløen, John

    2013-01-01

    The aim of this study was to describe the dynamics of HIF-1α, GLUT-1, Bcl-2 and Ki-67 during chemoradiotherapy (CRT) of rectal cancer, and to investigate the fluctuation of these biomarkers in relation to pathological response to CRT. The study included 86 patients with rectal adenocarcinoma...... during CRT, whereas GLUT-1 overall was unchanged. No significant changes of the markers were observed in the interval between CRT and surgery. A significant association was observed between the presence of residual carcinoma after 6 weeks of treatment and pathological response to CRT, but no association...... was seen between the fluctuations of any of the markers and response to CRT. This unique material containing specimens before, after and during CRT for rectal cancer demonstrated biological dynamics in HIF-1α, Bcl-2 and Ki-67, but not GLUT-1, expression during CRT, and a significant association was seen...

  14. Estudo citofotométrico da expressão dos marcadores tumorais Ki-67 e CD34 no adenocarcinoma de próstata

    Directory of Open Access Journals (Sweden)

    Paulo Faria Barbosa

    Full Text Available OBJETIVO: Quantificar a porcentagem da imunomarcação no índice de marcagem e densidade óptica do Ki-67 e CD34 no adenocarcinoma de próstata e compará-las entre si. MÉTODOS: Foram estudados, através de imunoistoquímica, o Ki-67 e o CD34 em 34 casos de adenocarcinoma de próstata provenientes de prostatectomia radical no período de 2000 a 2005 realizado no Hospital Regional do Gama em Brasília. Estes marcadores foram quantificados através do software SAMBA 4000 ® Sistema de Análise Microscópica de Busca Automática e do software IMMUNO® para análise das variáveis índice de marcagem e densidade óptica. Para avaliação da associação entre as expressões do marcador, foi estimado o coeficiente de correlação de Spearman. Para a comparação do tipo de lesão, foi usado o teste t de Student em amostras pareadas e não paramétrico de Wilcoxon. RESULTADOS: Dos 34 blocos que foram para leitura dos marcadores tumorais, 15 marcaram expressão com Ki-67, 34 com CD34 e 14 com ambos os marcadores. O índice de marcagem do CD34 teve valor mediano de 72,72%, valor mínimo 5,14% e valor máximo 88,81%. O índice de marcagem do Ki-67 teve mediana de 73,78%, mínimo de 16,87% e máximo de 87,47%. A densidade óptica do CD34 teve mediana de 48,33, mínimo de 35,65 e máximo de 85,86. Na densidade óptica do Ki-67 o valor da mediana foi 40,03 sendo a mínima de 21,53 e a máxima de 52,43. CONCLUSÃO: A expressão citofotométrica do Ki-67 teve índice médio de marcação de 64,04% e o CD34 de 61,64%. A expressão citofotométrica da densidade óptica média do Ki-67 foi de 39,49 e no CD34 de 53,69. Há diferença significativa entre a imunomarcação do Ki-67 e CD34 em relação à densidade óptica (p=0,025, não havendo diferença significativa no índice de marcagem (p=0,470.

  15. [Expression of Ki-67 and estrogen receptor in the uterus of mice with autoimmune premature ovarian failure induced by peptide zona pellucida 3].

    Science.gov (United States)

    Cai, Huihua; Fu, Xiafei; Ren, Xuwen; Chen, Xiazhu; Zhang, Dongmei; He, Yuanli

    2015-07-01

    To investigate the histomorphology and the expressions of the proliferation marker Ki-67 and estrogen receptor in the uterus of mice with autoimmune premature ovarian failure (POF) induced by zona pellucida 3 peptide (pZP3). Autoimmune POP models were established in 20 female BALB/c mice (7-8 weeks old) by immunization with pZP3 and another 20 mice served as the control group. The POP models were verified by vaginal cytology, serum sex hormones, ovary histomorphology and ZP3 antibody immunohistochemistry. The histomorphology and expressions of Ki-67, estrogen receptor α and estrogen receptor β in the uterus of the mice were detected. Autoimmune POP models were established successfully in 80% of the mice at 8 weeks after the immunization. Compared with those in the control group, the mice in the model group showed a smaller volume of the uterus, thinner endometrium and a reduced number of glands. The luminal epithelial cells, glandular epithelial cells and stromal cells in the uterus of the model mice all presented with a lower expression of Ki-67 than those in the control group, and Ki-67 translocation from the nuclei to the cytoplasm was found in the model group. The luminal epithelial cells, glandular epithelial cells and stromal cells showed positive ERα immunoreactivity in the model group but not in the control group. No obvious ERβ expression was found in the uterus in either of the groups. pZP3 can induce autoimmune POP, cause suppressed proliferation of the endometrial epithelial cells and stromal cells, and reduce the cellular expression of ERα in the uterus of mice.

  16. Immunohistochemical assessment of Ki67 with antibodies SP6 and MIB1 in primary breast cancer: a comparison of prognostic value and reproducibility.

    Science.gov (United States)

    Ekholm, Maria; Beglerbegovic, Sanda; Grabau, Dorthe; Lövgren, Kristina; Malmström, Per; Hartman, Linda; Fernö, Mårten

    2014-08-01

    To compare SP6 and MIB1 antibodies for assessment of Ki67 in primary breast cancer with regard to prognostic value and reproducibility. A cohort of 237 premenopausal women with node-negative breast cancer, mainly (87%) not treated with adjuvant systemic therapy, was used. Assessment of Ki67 (SP6 and MIB1) was performed on tissue microarray by three different investigators. The seventh decile was applied for cut-off. Distant disease-free survival (DDFS) was chosen as endpoint and the follow-up was restricted to 5 years. Eighty-nine per cent of the samples were classified into the same proliferation group, irrespective of antibody used. For both antibodies, high Ki67 was associated with inferior DDFS in univariable analyses (SP6: HR 2.5, P = 0.01; and MIB1: HR 2.8, P = 0.004), but failed to reach statistical significance for DDFS in multivariable analyses adjusted for HER2, age, and tumour size (SP6: HR 2.0, P = 0.074; and MIB1: HR 2.2, P = 0.058). The agreement between different assessors was somewhat higher for MIB1 than for SP6 (κ 0.83-0.88 versus 0.72-0.77). SP6 was not superior to MIB1, but the two antibodies were comparable in the assessment of Ki67. Both MIB1 and SP6 could therefore be considered for prognostic use in primary breast cancer. © 2014 John Wiley & Sons Ltd.

  17. ER, PR, HER2, Ki-67 and CK5 in Early and Late Relapsing Breast Cancer—Reduced CK5 Expression in Metastases

    Directory of Open Access Journals (Sweden)

    Kristiina Joensuu

    2013-01-01

    Full Text Available Breast cancer can recur even decades after the primary therapy. Markers are needed to predict cancer progression and the risk of late recurrence. The estrogen receptor (ER, progesterone receptor (PR, human epidermal growth factor receptor-2 (HER2, proliferation marker Ki-67, and cytokeratin CK5 were studied to find out whether their expression or occurrence in subgroups of breast cancers correlated with the time of recurrence. The expression of HER2, ER, PR, Ki-67, and CK5 was studied by IHC in 72 primary breast cancers and their corresponding recurrent/metastatic lesions. The patients were divided into three groups according to the time of the recurrence/metastasis: before two years, after 5 years, and after 10 years. Based on their IHC profiles, the tumors were divided into surrogates of the genetically defined subgroups of breast cancers and the subtype definitions were as follows: luminal A (ER or PR+HER2–, luminal B (ER or PR+HER2+, HER2 overexpressing (ER–PR–HER2+, triple-negative (ER–PR–HER2–, basal-like (ER–PR–HER2–CK5+, non-classified (ER–PR–HER2–CK5– and luminobasal (ER or PR+CK5+. In multivariate analysis, tumor size and HER2 positivity were a significant risk of early cancer relapse. The metastases showed a significantly lower CK5 expression. CK5 positivity distinguished triple negative tumors into rapidly and slowly recurring cancers. The IHC subtype ER or PR+HER2– luminal A presented a significantly lower risk of early tumor recurrence. Ki-67 expression denoted early-relapsing tumors and correlated linearly with tumor progression, since Ki-67 positivity declined gradually from early-relapsing toward late-recurring cancers.

  18. High Ki67 predicts unfavourable outcomes in early breast cancer patients with a clinically clear axilla who do not receive axillary dissection or axillary radiotherapy.

    Science.gov (United States)

    Zurrida, S; Bagnardi, V; Curigliano, G; Mastropasqua, M G; Orecchia, R; Disalvatore, D; Greco, M; Cataliotti, L; D'Aiuto, G; Talakhadze, N; Goldhirsch, A; Viale, G

    2013-10-01

    Axillary dissection is increasingly forgone in early breast cancer patients with a clinically negative axilla. The GRISO 053 randomised trial recruited 435 patients of age over 45 years, tumour ≤1.4 cm and clinically negative axilla, to assess the importance of axillary radiotherapy versus no axillary radiotherapy in patients not given axillary dissection. In the present study on a subgroup GRISO cases our aim was to assess the prognostic importance of tumour biological factors after more than 10 years of follow-up. We retrospectively assessed biological factors in a subgroup of 285 GRISO cases (145 given axillary radiotherapy; 140 not given axillary radiotherapy) with complete biologic, therapeutic and follow-up information, using multivariable Cox proportional hazards regression modelling. Only 10-year cumulative incidence of distant metastasis was lower in the axillary radiotherapy (1%) than no axillary radiotherapy arm (7%) (p=0.037). Irrespective of study arm, hormone receptor positivity had significantly favourable effects on 10-year disease-free survival (DFS) and overall survival. human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes were associated with lower 10-year DFS (60% and 76%, respectively) than luminal A (96%) and B (91%) (p=0.001). Ten-year DFS for high (≥14%) Ki67 cancers was lower than for low Ki67 cancers (p=0.027); however, this effect was mainly confined to the no axillary radiotherapy arm. For patients with clinically node-negative small breast cancer not given axillary dissection, 10-year DFS is worsened by HER2 positivity, triple-negative phenotype and high Ki67. Axillary radiotherapy counteracts the negative prognostic effect of high Ki67 in patients not receiving axillary dissection. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Prognostic Value of Molecular Subtypes, Ki67 Expression and Impact of Postmastectomy Radiation Therapy in Breast Cancer Patients With Negative Lymph Nodes After Mastectomy

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    Selz, Jessica, E-mail: chaumontjessica@yahoo.fr [Department of Radiation Oncology, Institut Curie, Hopital Rene Huguenin, Saint Cloud (France); Stevens, Denise; Jouanneau, Ludivine [Department of Medical Statistics, Institut Curie, Hopital Rene Huguenin, Saint Cloud (France); Labib, Alain [Department of Radiation Oncology, Institut Curie, Hopital Rene Huguenin, Saint Cloud (France); Le Scodan, Romuald [Department of Radiation Oncology, Centre Hospitalier Prive Saint Gregoire, Saint Gregoire (France)

    2012-12-01

    Purpose: To determine whether Ki67 expression and breast cancer subtypes could predict locoregional recurrence (LRR) and influence the postmastectomy radiotherapy (PMRT) decision in breast cancer (BC) patients with pathologic negative lymph nodes (pN0) after modified radical mastectomy (MRM). Methods and Materials: A total of 699 BC patients with pN0 status after MRM, treated between 2001 and 2008, were identified from a prospective database in a single institution. Tumors were classified by intrinsic molecular subtype as luminal A or B, HER2+, and triple-negative (TN) using estrogen, progesterone, and HER2 receptors. Multivariate Cox analysis was used to determine the risk of LRR associated with intrinsic subtypes and Ki67 expression, adjusting for known prognostic factors. Results: At a median follow-up of 56 months, 17 patients developed LRR. Five-year LRR-free survival and overall survival in the entire population were 97%, and 94.7%, respectively, with no difference between the PMRT (n=191) and no-PMRT (n=508) subgroups. No constructed subtype was associated with an increased risk of LRR. Ki67 >20% was the only independent prognostic factor associated with increased LRR (hazard ratio, 4.18; 95% CI, 1.11-15.77; P<.0215). However, PMRT was not associated with better locoregional control in patients with proliferative tumors. Conclusions: Ki67 expression but not molecular subtypes are predictors of locoregional recurrence in breast cancer patients with negative lymph nodes after MRM. The benefit of adjuvant RT in patients with proliferative tumors should be further investigated in prospective studies.

  20. Effect of raloxifene on breast cancer cell Ki67 and apoptosis: a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients.

    Science.gov (United States)

    Dowsett, M; Bundred, N J; Decensi, A; Sainsbury, R C; Lu, Y; Hills, M J; Cohen, F J; Veronesi, P; O'Brien, M E; Scott, T; Muchmore, D B

    2001-09-01

    Raloxifene is a selective estrogen receptor (ER) modulator approved for prevention and treatment of postmenopausal osteoporosis. This is an exploratory study of raloxifene in primary breast cancer patients. Postmenopausal women (50-80 years of age), with histological or cytological diagnosis of stage I or II primary breast cancer, were randomly assigned to 14 days of placebo, 60 mg/day raloxifene, or 300 mg twice daily (600 mg/day) of raloxifene. A core biopsy of the primary tumor was obtained before therapy, and a representative sample of the excised tumor was obtained from the operative specimen after treatment. Paired baseline and endpoint biopsies from each patient were analyzed for Ki67, apoptosis, and estrogen and progesterone receptors. Treatment group differences in efficacy measurements were primarily evaluated for baseline-to-endpoint change and percentage change using a one-way ANOVA with treatment as the fixed effect. Of 167 enrolled patients, 143 had evaluable efficacy data. Most breast cancer cases were invasive (98.6%), stage I (76.6%), and ER-positive (83.2%). In patients with ER-positive tumors, Ki67 increased 7% from baseline on placebo and decreased by 21% on 60 mg/day raloxifene (P = 0.015 versus placebo) and by 14% on 600 mg/day raloxifene (P = 0.064 versus placebo). Raloxifene did not affect apoptosis. ER decreased significantly with 60 mg/day or 600 mg/day raloxifene compared with placebo (P Ki67 among patients with ER-negative tumors. There were no treatment differences in adverse events. In this exploratory trial, 60 mg/day raloxifene showed a significant antiproliferative effect in ER-positive breast cancer, demonstrated by the decrease in Ki67, with no effect in ER-negative cancer. This provides support for raloxifene having a breast cancer preventive effect in postmenopausal women.

  1. Assessment of p21, p53 expression, and Ki-67 proliferative activities in the gastric mucosa of children with Helicobacter pylori gastritis.

    Science.gov (United States)

    Saf, Coskun; Gulcan, Enver Mahir; Ozkan, Ferda; Cobanoglu Saf, Seyhan Perihan; Vitrinel, Ayca

    2015-02-01

    Helicobacter pylori that is generally acquired in childhood and infects the gastric mucosa is considered to be responsible for many pathobiological changes that are linked to the pathogenesis of gastric cancer. Although the majority of studies on the subject have been carried out in adults, there are a limited number of studies on children that reflect the early period of infection and may be of greater significance. We aimed to determine the role of H. pylori infection and/or gastritis in several histopathological changes, p53, p21, and cell proliferation-associated Ki-67 antigen expression in the gastric mucosa. We studied 60 patients with a mean age of 7.5 ± 4.5 years at referral. On the basis of endoscopic appearance and the evaluation of the gastric antral specimens, the patients were divided into three groups: patients without gastritis, patients with H. pylori-positive gastritis, and patients with H. pylori-negative gastritis. To determine the expression of p53, Ki-67, and p21 in gastric biopsy specimens, immunohistochemical stains were performed. The incidence of neutrophil activity, which was one of our histopathologic parameters, was significantly higher in the H. pylori-positive gastritis group than the other two groups. The presence of lymphoid aggregate was more frequent in H. pylori ± gastritis groups than the nongastritis group. p53 expression was found to be significantly higher in the H. pylori-positive gastritis group than the nongastritis group. Ki-67 and p21 expressions were significantly more frequent in the H. pylori-positive gastritis group than the other two groups. When we evaluated the density of H. pylori, as the density of bacteria increases, we found that the expressions of p53, p21, and Ki-67 increased significantly. Expression of the studied precancerous markers in significant amounts indicates the importance of childhood H. pylori infection in the constitution of gastric cancer in adulthood.

  2. An assessment of the diagnostic criteria for sessile serrated adenoma/polyps: SSA/Ps using image processing software analysis for Ki67 immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Fujimori Yukari

    2012-05-01

    Full Text Available Abstract Background Serrated polyps belong to a heterogeneous group of lesions that are generally characterized morphologically. This type of lesion is thought to be the precursor of sporadic carcinomas with microsatellite instability, and probably also the precursor for CpG island-methylated microsatellite-stable carcinomas. For practical purposes, according to the 2010 WHO classification, the diagnostic criteria for sessile serrated adenomas/polyps (SSA/Ps was established by the research project “Potential of Cancerization of Colorectal Serrated Lesions” led by the Japanese Society for Cancer of the Colon and Rectum. The aim of this study was to evaluate the validity of the morphologic characteristics established in Japan by using immunohistochemical staining for Ki-67. Methods To calculate the target cells, 2 contiguous crypts which could be detected from the bottom of the crypt to the surface of the colorectal epithelium were selected. To validate the proliferative activity, we evaluated the percentage and the asymmetrical staining pattern of Ki67 positive cells in each individual crypt. To examine the immunoreactivity of Ki67, computer-assisted cytometrical analysis was performed. Results SSA/Ps had a higher proliferative activity as compared to hyperplastic polyps (HPs based on the difference in incidence of Ki67 positive cells, and the former also exhibited a significantly higher asymmetric distribution of these cells as compared to HPs, even in lesions with a diameter Conclusion We conclude that assessment of the pathological findings of SSA/Ps, including crypt dilation, irregularly branching crypts, and horizontally arranged basal crypts (inverted T- and/or L-shaped crypts is appropriate to show a significantly higher proliferative activity as compared to HPs. Further, the use of two-dimensional image analysis software is an objective and reproducible method for this type of histological examination. Virtual slides The virtual

  3. Usefulness of p16ink4a, ProEX C, and Ki-67 for the diagnosis of glandular dysplasia and adenocarcinoma of the cervix uteri.

    Science.gov (United States)

    Negri, Giovanni; Bellisano, Giulia; Carico, Elisabetta; Faa, Gavino; Kasal, Armin; Antoniazzi, Sonia; Egarter-Vigl, Eduard; Piccin, Andrea; Dalla Palma, Paolo; Vittadello, Fabio

    2011-07-01

    Although the diagnostic criteria of in-situ and invasive adenocarcinomas of the cervix uteri are well established, the differentiation from benign mimics may be difficult and the morphologic features of the precursors of endocervical adenocarcinoma are still debated. In this study, we evaluated the usefulness of p16ink4a (p16), ProEX C, and Ki-67 for the diagnosis of endocervical adenocarcinoma and its precursors. Immunohistochemistry with p16, ProEX C, and Ki-67 was performed in 82 glandular lesions including 15 invasive adenocarcinomas, 29 adenocarcinomas in situ (AIS), 22 non-neoplastic samples, and 16 cases of glandular dysplasia (GD), which showed significant nuclear abnormalities but did not meet the diagnostic criteria for AIS. The immunohistochemical expression pattern was scored according to the percentage of the stained cells (0, 1+, 2+, and 3+ when 0% to 5%, 6% to 25%, 26% to 50%, and more than 50% of the cells were stained, respectively) and was evaluated for each antibody. p16 was at least focally expressed (1+ or more) in 14 of 15 invasive adenocarcinomas, in all AIS and in 7 negative samples. ProEX C and Ki-67 both scored 1+ or more in all adenocarcinomas and AIS and in 8 and 6 negative samples, respectively. Of the GD 15, 14, and 15 expressed p16, ProEX C, and Ki-67, respectively. The score differences between neoplastic and non-neoplastic samples were highly significant for each marker (Pcervix uteri and may also improve the diagnostic accuracy of endocervical GD. In particularly problematic cases, the combination of p16 and a proliferation marker can provide additional help for the interpretation of these lesions.

  4. FEAT expression correlates with tumor size, PR status, HER2 expression, Ki67 index, and molecular subtype and predicts recurrence in breast cancer.

    Science.gov (United States)

    Wang, S M; Ye, M; Zhou, J; Ni, S M; Wei, Q C

    2017-01-01

    FEAT protein is uniformly overexpressed in a variety of human cancers but weakly expressed in normal tissue. FEAT has antiapoptotic activity and plays a role in carcinogenesis; however, the correlation between FEAT and clinicopathologic characteristics in cancer has not been reported. Our study explores the expression of FEAT protein and its clinicopathologic significance in breast cancer. We examined the expression of FEAT in tissues from 131 cases of breast cancer by immunohistochemistry and analyzed the correlation between FEAT expression and clinicopathologic parameters. The difference in FEAT expression between normal breast tissues and breast cancer tissues was also investigated. Finally, we analyzed the association between FEAT expression and disease-free survival or overall survival. Our data showed that FEAT was expressed in the cytoplasm. The expression of FEAT protein was significantly higher in breast cancer tissues than in normal breast tissues. Moreover, the expression of FEAT protein was higher in breast cancer with a larger tumor size (>2 cm), negative PR, positive HER2, or higher Ki67 index (≥14%) than in breast cancer with a smaller tumor size (≤2 cm), positive PR, negative HER2, or lower Ki67 index (Ki67 index, and molecular subtype. Survival analysis showed that disease-free survival and overall survival were significantly shorter in breast cancer patients with high FEAT expression than in those with low expression of FEAT (Pbreast cancer, but not for survival. In conclusion, FEAT may be a potential biomarker for recurrence of breast cancer.

  5. 18F-fluorodeoxyglucose positron emission tomography in patients with recurrent ovarian cancer: in comparison with vascularity, Ki-67, p53, and histologic grade

    International Nuclear Information System (INIS)

    Cho, Song-Mee; Byun, Jae Young; Park, Yong Gyu; Lee, Joon Mo; Lee, Jae Mun; Lee, Kyo-Young; Park, Gyeong-Sin; Kim, Hyeon-Sook; Lee, Bae Young; Lee, Kang-Hoon; Song, Kyung-Sup

    2007-01-01

    The aim of this study was to assess the correlation between 18F-fluorodeoxyglucose positron emission tomography (FDG PET) positivity of tumor recurrence and vascularity, Ki-67, p53, and histologic grade in patients with ovarian cancer. Nineteen patients with recurrent ovarian cancer underwent FDG PET before second-look surgery. Archival paraffin-embedded tissue materials were used to assess histologic grade including architectural pattern, mitotic activity, and nuclear pleomorphism; intratumor microvessel density (MVD); Ki-67; and p53. Univariate analysis was used to evaluate the correlation between FDG PET positivity and each biomarker. Stepwise logistic regression analysis was used to determine the best parameter to explain FDG PET positivity. MVD revealed significant positive correlation with FDG PET positivity (p=0.0341). There was no significant correlation between FDG PET positivity and Ki-67 or p53 (p=0.4040, p=0.6027). Mitotic activity yielded statistically significant positive correlations with FDG PET positivity (p=0.0448) although histologic grade revealed no positive correlation (p=1). Stepwise logistic regression analysis revealed MVD to be the strongest parameter for FDG PET positivity (OR=0.696, 95% CI 0.487-0.993, p=0.0458). In conclusion, FDG PET positivity revealed positive correlation with MVD and mitotic activity. MVD was the strongest parameter in predicting positive tumor recurrence on FDG PET. (orig.)

  6. Correlation of 18F-fluorodeoxyglucose uptake on positron emission tomography with Ki-67 index and pathological invasive area in lung adenocarcinomas 30 mm or less in size

    International Nuclear Information System (INIS)

    Murakami, Shuji; Saito, Haruhiro; Sakuma, Yuji; Mizutani, Yumiko; Ishikawa, Yoshihiro; Kondou, Tetsuro; Oshita, Fumihiro; Yokose, Tomoyuki; Kameda, Youichi; Suga, Yasuhiro; Ito, Hiroyuki; Tsuboi, Masahiro; Nakayama, Haruhiko; Noda, Kazumasa; Yamada, Kouzo

    2010-01-01

    Background: 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is commonly used to distinguish benign from malignant lesion. Recently, maximum standardized uptake value (SUVmax) on FDG-PET has found to have prognostic value. We examined the relationship between SUVmax and proliferative activities as indicated by maximum diameter of tumor opacity on mediastinal-window images (TOM), Ki-67 index, and diameter of the pathological invasive area in lung adenocarcinomas ≤30 mm. Methods: Thin-section computed tomography (TS-CT) and FDG-PET were performed on 140 patients with resectable lung adenocarcinomas ≤30 mm between March 2006 and May 2008. Tumors were classified as air-type or solid-type based on TS-CT findings. In all resected specimens, diameter of the pathological invasive area and Ki-67 index were assessed. Results: SUVmax was significantly lower for air-type than for solid-type tumors (0.97 vs. 3.96, p 5 mm was determined as 2.15 by ROC analysis, with sensitivity of 88.3% and specificity of 84.6%. Conclusions: SUVmax correlated significantly with Ki-67 index and diameter of the pathological invasive area. The present results suggest the potential role of FDG-PET in predicting adenocarcinomas with invasive characteristics.

  7. Analysis of expression of cyclin E, p27kip1 and Ki67 protein in colorectal cancer tissues and its value for diagnosis, treatment and prognosis of disease.

    Science.gov (United States)

    Li, W; Zhang, G; Wang, H-L; Wang, L

    2016-12-01

    We conducted this study is to investigate the clinical application value of Cyclin E, p27kip1 and Ki67 protein expression in colorectal cancer tissues for diagnosis, treatment, and prognosis of this disease. The positive expression of Cyclin E, p27kip1 and Ki-67 in tissues of 200 patients with colorectal cancer and 200 patients with benign colorectal tumor or inflammation were detected by immunohistochemistry PowerVision two-step method. RT-PCR was used to detect the expression level of the corresponding mRNA, as well as to analyze the association with TNM staging, pathology type, free progression survival and median survival. The sensitivity, specificity, and accuracy of diagnosis were analyzed by ROC. The positive expression rate and positive degree of Cyclin E and Ki-67 of observation group were higher than those of the control group, while positive expression rate and positive degree of p27kipl was lower than that of the control group; the differences were statistically significant (pcolorectal cancer tissues was upregulated and p27kipl protein expression was downregulated, which were closely related to the TNM and pathological differentiation degree. These values were also closely associated with free progression survival and median survival of prognosis. Therefore, the above indexes can be used as highly sensitive, specific and accurate markers for the diagnosis of colorectal cancer.

  8. Low CD4 cells and viral co-infection increase the risk of VaIN: Use of SCCA1 and Ki67 as diagno-prognostic biomarkers.

    Science.gov (United States)

    Okoye, Jude Ogechukwu; Erinle, Charles; Ngokere, Antony Ajuluchukwu; Jimoh, Abimbola

    2018-03-01

    This study evaluated the correlation of SCCA1, Ki67 and CD4 cell expressions and classified vaginal smears in individuals co-infected with Human immunodeficiency virus (HIV), Herpes simplex virus 2 (HSV2), Epstein Barr virus (EBV) and Human Papilloma virus (HPV). This crossectional study included 173 participants within the age range of 20-70 years. Vaginal smears were stained by Papanicolaou technique and classified into high-grade squamous cell intraepithelial lesion (HSIL), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells of undetermined significance (ASCUS) and negative for intraepithelial lesion (NIL). Presence of immunoglobulin M and G antibodies for EBV, HIV, HPV and HSV2, and SCCA1 and Ki67 antigens were determined by ELISA method. Result showed that biomarkers SCCA1 had higher sensitivity (87.5%) to vaginal lesions when compared with Ki67 which had a sensitivity of 70.8% (p > .01). Assays revealed viral co-infections of 96.0% and 16.8% in smears positive and negative for vaginal lesions, respectively (p biomarkers for vaginal intraepithelial neoplasia (VaIN). Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Immunoexpression of Ki-67, MCM2, and MCM3 in Ameloblastoma and Ameloblastic Carcinoma and Their Correlations with Clinical and Histopathological Patterns.

    Science.gov (United States)

    Carreón-Burciaga, Ramón Gil; González-González, Rogelio; Molina-Frechero, Nelly; Bologna-Molina, Ronell

    2015-01-01

    Cell proliferation assays are performed using antibodies against nuclear proteins associated with DNA replication. These nuclear proteins have gained special interest to predict the biological and clinical behaviors of various tumors. The aim of this study was to analyze the presence of Ki-67 protein and the minichromosome maintenance-2 (MCM2) and maintenance-3 (MCM3) proteins in ameloblastoma. Materials and Methods. Cell proliferation marker expression levels were assessed via immunohistochemistry in 111 ameloblastoma cases (72 unicystic ameloblastoma samples, 38 solid/multicystic ameloblastoma samples, and 1 ameloblastic carcinoma). The label index was performed as described previously. Results. MCM2 and MCM3 showed higher proliferation indexes in all variants of ameloblastoma compared to the classic marker Ki-67. No correlation between the proliferation index and the clinical and protein expression data was observed. Conclusion. The results suggest that clinical features do not directly affect tumor cell proliferation. Moreover, the high levels of cellular proliferation of MCM2 and MCM3 compared with Ki-67 may indicate that MCM2 and MCM3 are more sensitive markers for predicting the growth rate and eventually might be helpful as a tool for predicting aggressive and recurrent behaviors in these tumors.

  10. Risk of progression of early cervical lesions is associated with integration and persistence of HPV-16 and expression of E6, Ki-67, and telomerase

    Directory of Open Access Journals (Sweden)

    Arianna Vega-Peña

    2013-01-01

    Full Text Available Background: Low-grade squamous intraepithelial lesions (LSIL are the earliest lesions of the uterine cervix, the persistence and integration of high-risk human papillomavirus (HR-HPV as type 16, which promotes the development of more aggressive lesions. Aim: To select more aggressive lesions with tendency to progress to invasive cervical cancer. Materials and Methods: A total of 75 cytological specimens in liquid base (Liqui-PREP were analyzed: 25 specimens were with no signs of SIL (NSIL and without HPV; 25 NSIL with HPV-16, and 25 with both LSIL and HPV-16. The expression of Ki-67, telomerase, and viral E6 was evaluated by immunocytochemistry; and the detection of viral DNA was done by polymerase chain reaction (PCR and restriction fragment length polymorphism (RFLPs for genotyping or sequencing of HPV-16. The physical state of HPV-16 was evaluated by in situ hybridization with amplification with tyramide. Results: Of the total group, 58.6% had LSIL associated with persistence and of these 59.3% was associated with integrated state of HPV as intense expression of E6, Ki-67 (P = 0.013, P = 0.055 has except for the expression of telomerase present a non-significant association (P<0.341. Conclusions: Overexpression of E6 and Ki-67 is associated with the integration of HPV-16, favoring viral persistence, and increasing the risk of progression in women with NSIL and LSIL.

  11. Female Adnexial Tumor of Probable Wolffian Origin (FATWO) without Ki-67 Expression Reflecting Low Malignant Potential in a 55-Year-Old Woman.

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    Kahyaoglu, Serkan; Kahyaoglu, Inci; Sirvan, Levent; Sengul, Ilker; Timur, Hakan; Mollamahmutoglu, Leyla

    2012-12-01

    Female adnexial tumors of probable Wolffian origin (FATWO) are rare tumors derived from the remnants of the mesonephric duct. These tumors generally exhibit a low malignant potential, but recurrence and or metastasis is possible during the course of the disease according to the tumors' possible malignant potential. We report a case of FATWO without estrogen and progesterone receptors and with negative immunostaining for Ki-67 (a proliferation marker) as a probable low-malignant-potential tumor. A 55-year-old woman presented with a complaint of heavy menstrual bleeding and pelvic pain. Pre-operative ultrasonographic evaluation revealed an intramural uterine leiomyoma of 4 cm in diameter and a right adnexial solid mass measuring 5 cm in diameter. Following total abdominal hysterectomy and bilateral salpingo-oophorectomy, immunostaining based on the labeled streptavidin-biotin method was performed on sections from representative blocks of paraffin-embedded tissues sampled from the mass, revealing a low mitotic index with negative Ki-67 immunostaining. Immunohistochemical staining with promising new markers and pathological investigation of the entire tumor are needed to determine the malignant behavior of an individual FATWO. Ki-67 is a helpful marker for determining Wolffian duct tumors' potential malignant behavior.

  12. Association of nucleolar organizing regions and Ki-67 expression with recurrence rate of hair follicle tumor in dogs Associação das regiões organizadoras de nucléolos e da expressão do Ki-67 com a taxa de recorrência dos tumores de folículo piloso em cães

    Directory of Open Access Journals (Sweden)

    P.C. Souza

    2008-10-01

    Full Text Available Mitotic index, nuclear diameter, number of nucleolar organizing regions, and Ki-67 expression, in hair follicle tumors of 82 dogs were evaluated. Tissue specimens were used to prepare sections for histological staining for number of nucleolar organizing region and immunohistochemical staining for Ki-67. Tumors were classified as trichoblastoma (n=32, benign trichoepithelioma (n=30, pilomatricoma (n=7, malignant trichoepithelioma (n=6, infundibular keratinizing acanthoma (n=5, and tricholemmoma (n=2. Head, dorsum, and limbs were the most affected sites. Malignant trichoepithelioma presented significantly higher mitotic index, number of nucleolar organizing regions and Ki-67 expression. Regarding benign neoplasms, trichoblastoma presented significantly higher mitotic index and number of nucleolar organizing regions. Ki-67 expression did not differ among hair follicle benign neoplasms. Recurrence was only observed in two cases, with one benign trichoepithelioma and one malignant trichoepithelioma. In the two cases, nodules have not been removed with clean surgical margin. It was concluded that in benign neoplasms of hair follicles, the number of nucleolar organizing regions and Ki-67 expression were significantly smaller than in malignant neoplasm. Clean surgical margins are suggested to be more responsible to tumor recurrences than the number of nucleolar organizing regions, expression of Ki-67, and the mitotic index.O objetivo deste trabalho foi avaliar o índice mitótico, o diâmetro nuclear, o número de regiões organizadoras de nucléolos e a expressão do Ki-67 em 82 tumores de folículo piloso de cães, entre 2000 e 2006. Os tumores foram classificados como tricoblastoma (n=32, tricoepitelioma benigno (n=30, tricoepitelioma maligno (n=6, pilomatricoma (n=7, acantoma infundibular ceratinizante (n=5 e tricolemoma (n=2. A cabeça, o dorso e os membros foram os locais mais frequentemente acometidos. O tricoepitelioma maligno apresentou

  13. Imunoexpressão da citoqueratina 16 e do antígeno nuclear Ki-67 no colesteatoma adquirido da orelha média Expression patterns of cytokeratin 16 and the nuclear antigen Ki-67 in acquired middle ear cholesteatoma

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    Celina S. B. Pereira

    2002-08-01

    Full Text Available Introdução: Ocolesteatoma da orelha média é caracterizado pela presença de epitélio escamoso estratificado queratinizado nesta cavidade, causando destruição óssea e podendo levar a complicações. Algumas substâncias como a citoqueratina 16 e o Ki-67, marcadores de proliferação celular, vêm sendo utilizadas para estudar essa doença. A CK 16 é um filamento protéico, situado no citoplasma das células epiteliais, característico de epitélios hiperproliferativos. O Ki-67 é um antígeno nuclear que aparece nas células em estágio de proliferação. Objetivo: O objetivo deste trabalho foi estudar a imunoexpressão da CK 16 e do Ki-67 no colesteatoma adquirido. Forma de estudo: Clínico prospectivo. Material e Método: Foram colhidas amostras de colesteatoma de 31 pacientes submetidos à cirurgia otológica, sendo 20 adultos e 11 crianças, no período de 1998 e 2000. Essas amostras foram submetidas à análise histológica e imuno-histoquímica para estudo da expressão da CK 16 e do Ki-67 na matriz do colesteatoma. Resultado: A análise dos resultados mostrou a presença da CK 16 nas camadas suprabasais da matriz do colesteatoma e, do Ki-67, na camada basal, estendendo-se para as camadas suprabasais e, inclusive, para a camada apical da matriz. A reação aos anticorpos anti-CK 16 e Ki-67 foi heterogênea. A correlação entre a CK 16 e o Ki-67 suprabasal com variáveis morfológicas, como acantose do epitélio e hiperplasia da camada basal formando cones epiteliais em direção à perimatriz, foi positiva e significativa. Também houve relação positiva e significativa entre a CK 16 e o Ki-67 suprabasal e apical. Conclusão: Esses resultados permitem concluir que o colesteatoma tem características hiperproliferativas, expressando a CK 16 e o Ki-67 na sua matriz.Introduction: Cholesteatomas of the middle ear are characterized by the presence of stratified squamous epithelium in this cavity presenting with highly invasive

  14. The frequency of p53, Ki67, CD99 and Fli-1 protein expression in paraffin-embedded tissue blocks in Ewing’s sarcoma

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    Bagheri Hossein-Abadi Z

    2011-06-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Ewing sarcoma family tumors (ESFTs are among the most malignant tumors in children and young adults. ESFTs include Ewing sarcoma (ES and peripheral primitive neuroectodermal tumors (pPNETs. As there seemed to be few studies on the molecular biology of ESFTs, we investigated the frequency of CD99, Ki67, p53 and Fli-1 protein expression in 15 Iranian patients with ESFTs. In addition, the correlation between expression rate of these proteins and various clinical factors, including age, sex and survival was computed."n"nMethods: The expression of the aforesaid proteins was studied by immunohisto-chemistry in formalin-fixed and paraffin-embedded blocks of 15 ESFTs specimens. Stained sections were classified according to the percentage of stained tumor cells."n"nResults: The results showed the membrane expression of CD99 protein in all of the specimens. The nuclear expression of Fli-1 protein was observed in 86.7% and the over-expression of p53 nuclear protein was seen in 53.3% of the specimens. The expression rate of Ki67 protein was 60%. Although a significant correlation was not shown between the expression levels of Ki67, p53 or Fli-1 proteins with age, sex or survival of the patients, there was a significant

  15. High Ki-67 and Vascular Endothelial Growth Factor (VEGF Protein Expression as Negative Predictive Factor for Combined Neoadjuvant Chemotherapy in Young Age Stage III Breast Cancer

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    I Wayan Sudarsa

    2016-05-01

    Full Text Available Background: Breast cancer was, in general, a heterogeneous disease with diverse biological characteristics, types, subtypes and clinical behavior. Its treatment and management need to be personalized and individualized. Breast cancer in young ages, although rare, is usually a unique and more aggressive cancer associated with poorer prognosis. The combination of young age and advanced stages of breast cancer would make this particular breast cancer harder to treat and cure. Unfortunately, majority of Breast Cancer Patients in Bali were in younger ages, and at advanced stages, that the mainstay of treatment was neo-adjuvant chemotherapy followed by other treatment modalities. Improve prognosis only, those patients who had had a complete pathological response involving primary tumor and regional lymph nodes in the axilla. Several factors had been studied and contributed to breast cancer response to combined neo-adjuvant chemotherapy. Usually, younger patients, was associated with high proliferation rate represented by Ki-67 and early distant metastasis represented by VEGF, which also had role as prognostic markers. The purpose of this study was to determine whether high Ki-67 and VEGF expression correlate with response to NAC and hence, they would be important predictive factors for response to NAC. Method: This study was a cross-sectional and a nested case-control study of stage III breast cancers affecting patients 40 years of age or less, at Sanglah General Hospital and Prima Medika Hospital, conducted from September 1st, 2012 until March 31st, 2014. Clinical and pathology reports were traced and recorded from both hospitals; routine Immunohistochemistry (IHC examinations were performed by both pathology labs. Statistical analysis was performed using Chi-Square test, Odds Ratio (OR, and logistic regression analysis with p<0.05. Results: There were 66 Stage III young breast cancer patients, where 35 (53% showed no or negative response and 31 (47

  16. Ki-67 and p53 correlation prognostic value in squamous cell carcinomas of the oral cavity and tongue Valor prognóstico da correlação do Ki-67 e p53 em carcinomas epidermoides da cavidade oral e língua

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    Rafael Da Ros Motta

    2009-08-01

    Full Text Available Epidermoid carcinomas represent from 90% to 95% of oral cavity malignant neoplasias, making up 13,470 cases/year. AIMS: To correlate p53 and Ki-67 expressions in mouth and tongue carcinomas with lymph node status, gender, histological grade, tumor volume and pathological stage. MATERIALS AND METHODS: We carried out a retrospective study of 28 cases of mouth and tongue epidermoid carcinomas. They were submitted to immunohistochemical study in order to check the expression of p53 and Ki-67 antibodies and statistically compare them in terms of lymph node status, gender, histological grade, tumor volume and pathological staging. RESULTS: The individually analyzed p53 proved to have statistical significance (pO carcinoma epidermoide representa 90% a 95% das neoplasias malignas da cavidade oral, responsável por 13.470 casos/ano. OBJETIVOS: Correlacionar a expressão do p53 e Ki-67 nos carcinomas epidermoides de cavidade oral e língua com o estado linfonodal, sexo, grau histológico, volume tumoral e estadiamento patológico. MATERIAIS E MÉTODOS: Foi realizado estudo retrospectivo de 28 casos de carcinomas epidermoides da cavidade oral e língua. Estes foram submetidos à técnica de imunoistoquímica para verificar a expressão dos anticorpos p53 e Ki-67 e compará-los estatisticamente quanto ao status linfonodal, sexo, grau histológico, volume tumoral e estadiamento patológico. RESULTADOS: O p53 analisado individualmente mostrou significância estatística (p<0,05 quando comparado com o volume tumoral (p=0,029. Apesar de uma forte tendência, a relação de p53 com estado linfonodal não foi significativa. Quando o p53 + Ki67 foram analisados, o volume tumoral mostrou p < 0,05 (p = 0,029. DISCUSSÃO: A literatura mostra que a expressão dos marcadores p53 e Ki-67 está relacionada com presença de metástases para linfonodos e pior prognóstico. CONCLUSÃO: Nos carcinomas epidermoides da cavidade oral e língua o p53 e o Ki-67 est

  17. Prognostic significance of Ki67 proliferation index, HIF1 alpha index and microvascular density in patients with non-small cell lung cancer brain metastases

    Energy Technology Data Exchange (ETDEWEB)

    Berghoff, A.S. [Medical University of Vienna, Institute of Neurology, Vienna (Austria); Medical University of Vienna, Comprehensive Cancer Center CNS Tumors Unit, Vienna (Austria); Medical University of Vienna, Department of Medicine I, Vienna (Austria); Ilhan-Mutlu, A.; Preusser, M. [Medical University of Vienna, Comprehensive Cancer Center CNS Tumors Unit, Vienna (Austria); Medical University of Vienna, Department of Medicine I, Vienna (Austria); Woehrer, A.; Hainfellner, J.A. [Medical University of Vienna, Institute of Neurology, Vienna (Austria); Medical University of Vienna, Comprehensive Cancer Center CNS Tumors Unit, Vienna (Austria); Hackl, M. [Austrian National Cancer Registry, Statistics Austria, Vienna (Austria); Widhalm, G. [Medical University of Vienna, Comprehensive Cancer Center CNS Tumors Unit, Vienna (Austria); Medical University of Vienna, Department of Neurosurgery, Vienna (Austria); Dieckmann, K. [Medical University of Vienna, Comprehensive Cancer Center CNS Tumors Unit, Vienna (Austria); Medical University of Vienna, Department of Radiotherapy, Vienna (Austria); Melchardt, T. [Paracelsus Medical University Hospital Salzburg, Third Medical Department, Salzburg (Austria); Dome, B. [Medical University of Vienna, Department of Surgery, Vienna (Austria); Heinzl, H. [Medical University of Vienna, Comprehensive Cancer Center CNS Tumors Unit, Vienna (Austria); Medical University of Vienna, Center for Medical Statistics, Informatics, and Intelligent Systems, Vienna (Austria); Birner, P. [Medical University of Vienna, Comprehensive Cancer Center CNS Tumors Unit, Vienna (Austria); Medical University of Vienna, Institute of Clinical Pathology, Vienna (Austria)

    2014-07-15

    Survival upon diagnosis of brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) is highly variable and established prognostic scores do not include tissue-based parameters. Patients who underwent neurosurgical resection as first-line therapy for newly diagnosed NSCLC BM were included. Microvascular density (MVD), Ki67 tumor cell proliferation index and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry. NSCLC BM specimens from 230 patients (151 male, 79 female; median age 56 years; 199 nonsquamous histology) and 53/230 (23.0 %) matched primary tumor samples were available. Adjuvant whole-brain radiation therapy (WBRT) was given to 153/230 (66.5 %) patients after neurosurgical resection. MVD and HIF-1 alpha indices were significantly higher in BM than in matched primary tumors. In patients treated with adjuvant WBRT, low BM HIF-1 alpha expression was associated with favorable overall survival (OS), while among patients not treated with adjuvant WBRT, BM HIF-1 alpha expression did not correlate with OS. Low diagnosis-specific graded prognostic assessment score (DS-GPA), low Ki67 index, high MVD, low HIF-1 alpha index and administration of adjuvant WBRT were independently associated with favorable OS. Incorporation of tissue-based parameters into the commonly used DS-GPA allowed refined discrimination of prognostic subgroups. Ki67 index, MVD and HIF-1 alpha index have promising prognostic value in BM and should be validated in further studies. (orig.) [German] Die Ueberlebensprognose von Patienten mit zerebralen Metastasen eines nicht-kleinzelligen Lungenkarzinoms (NSCLC) ist sehr variabel. Bisher werden gewebsbasierte Parameter nicht in die prognostische Beurteilung inkludiert. Neurochirurgische Resektate zerebraler NSCLC-Metastasen wurden in dieser Studie untersucht. Die Gefaessdichte (''microvascular density'', MVD), der Ki67-Proliferationsindex sowie der HIF-1α-Index wurden mittels

  18. Immunoexpression of TTF-1 and Ki-67 in a coexistent anaplastic and follicular thyroid cancer with rare long-life surviving.

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    Jerzy Sowinski

    2009-01-01

    Full Text Available We report the immunohistochemical diagnosis, including TTF-1 (thyroid transcription factor 1 and Ki-67, of a rare mixed thyroid neoplasm composed of minimally invasive well differentiated follicular areas and highly aggressive undifferentiated anaplastic areas. A 75 old female presented to our clinic with a rapidly growing neck mass. Considering the dynamics of the disease and the multiple challenges presented by the patient: advanced age, tumor size, history of a longstanding goiter we decided to transfer her to the department of surgery. The intraoperative findings were an enlarged right lobe with tracheal and surrounding tissues infiltration. Total thyroidectomy, radical neck lymph nodes dissection and tracheostomy were performed. The histopathological and immunohistochemical examination revealed a coexistent anaplastic and follicular thyroid carcinoma. The proliferation index Ki-67, a cell proliferation marker, was found to be significantly higher in the anaplastic areas (30 +/- 5% in the comparison with the follicular areas (2 +/- 1%. The evaluation of the thyroid transcription factor 1 (TTF-1 expression revealed a correlation with the tumor cells aggressiveness accordingly to the cancer areas. After a radical surgery an external adjuvant radiation was applied. The patient is alive and more than five years after diagnosis she presented an increase of the serum thyroglobulin level suggesting, probably, a recurrence of the follicular form of the cancer. According to our survey we suggest that in thyroid cancers TTF-1 and Ki-67 could provides useful information on the differentiation activities of thyroid tumor cells and may be helpful to distinguish well differentiated and undifferentiated areas in a mixed thyroid cancer.

  19. A prognostic model for triple-negative breast cancer patients based on node status, cathepsin-D and Ki-67 index.

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    Liang Huang

    Full Text Available OBJECTIVE: The aim of this study was to evaluate clinicopathologic factors that could possibly affect the outcome of patients with triple negative breast cancer and subsequently build a prognostic model to predict patients' outcome. METHODS: We retrospectively analyzed clinicopathologic characteristics and outcome of 504 patients diagnosed with triple-negative invasive ductal breast cancer. 185 patients enrolled between 2000 and 2002 were designated to the training set. The variables that had statistically significant correlation with prognosis were combined to build a model. The prognostic value of the model was further validated in the separate validation set containing 319 patients enrolled between 2003 and 2006. RESULTS: The median follow-up duration was 66 months. 174 patients experienced recurrence, and 111 patients died. Positivity for ≥4 lymph nodes, Cathepsin-D positivity, and Ki-67 index ≥20% were independent factors for DFS, while the lymph nodes status and Ki-67 index were the prognostic factors for OS. The prognostic model was established based on the sum of all three factors, where positivity for ≥4 lymph nodes, Cathepsin-D and Ki-67 index ≥20% would individually contribute 1 point to the risk score. The patients in the validation set were assigned to a low-risk group (0 and 1 point and a high-risk group (2 and 3 points. The external validation analysis also demonstrated that our prognostic model provided the independent high predictive accuracy of recurrence. CONCLUSION: This model has a considerable clinical value in predicting recurrence, and will help clinicians to design an appropriate level of adjuvant treatment and schedule adequate appointments of surveillance visits.

  20. β-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases.

    Science.gov (United States)

    Bleckmann, Annalen; Conradi, Lena-Christin; Menck, Kerstin; Schmick, Nadine Annette; Schubert, Antonia; Rietkötter, Eva; Arackal, Jetcy; Middel, Peter; Schambony, Alexandra; Liersch, Torsten; Homayounfar, Kia; Beißbarth, Tim; Klemm, Florian; Binder, Claudia; Pukrop, Tobias

    2016-04-01

    Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01-0.56) and high Ki67 (HR 3.68, 95 % CI 1.12-12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11-5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02-4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.

  1. The influence of Ki-67 proliferation index on Tc-99m-EDDA-HYNIC-TOC somatostatin receptor scintigraphy in patients with carcinoids

    OpenAIRE

    Vlajković Marina; Rajić Milena; Ilić Slobodan; Stević Miloš; Kojić Marko; Živković Vesna; Karanikolić Aleksandar; Matović Milovan

    2014-01-01

    The aim of this paper is to determine the influence of Ki-67 proliferation index on somatostatin receptor scintigraphy (SSRS) with Tc-99m-EDDA-HYNIC-TOC (Tc-99m-Tektrotyd) somatostatin analogue in patients with carcinoid tumors. Sixty-one patients (31 female, 30 male; age range: 33-76 years) were examined: 13 patients highly suspected of having a carcinoid, and 48 patients who had undergone the surgical removal of the tumor. Whole body SSRS at 4 h postinjection, spot scintigrams and SPECT of ...

  2. ERCC1 and Ki67 in Small Cell Lung Carcinoma and Other Neuroendocrine Tumors of the Lung Distribution and Impact on Survival

    DEFF Research Database (Denmark)

    Skov, Birgit Guldhammer; Holm, B.; Erreboe, A.

    2010-01-01

    .001). The difference between TC and AC was significant (p = 0.02), as was the difference between low grade (TC + AC) and high grade NE (LCNEC + SCLC) (p ... with platinum-based chemotherapy has no impact on survival. High expression of ERCC1 in TC might represent a clue to the failure of platinum-based therapy in these patients. ERCC1 expression has prognostic impact in lung carcinoids. Ki 67 might be considered as a supplementary test to the histopatologic...... classification of NE tumors...

  3. Ki-67, cyclin E, and p16INK4 are complimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia.

    Science.gov (United States)

    Keating, J T; Cviko, A; Riethdorf, S; Riethdorf, L; Quade, B J; Sun, D; Duensing, S; Sheets, E E; Munger, K; Crum, C P

    2001-07-01

    Prior studies of Ki-67, cyclin E, and p16 expression have suggested that these biomarkers may be preferentially expressed in cervical neoplasia. This study examined and compared the distribution of staining for these three antigens in 1) normal and reactive epithelial changes, 2) diagnostically challenging cases (atypical metaplasia and atypical atrophy), 3) squamous intraepithelial lesions (SIL), and 4) high-and low-risk human papilloma virus (HPV) type-specific SIL. One hundred four epithelial foci from 99 biopsies were studied, including low-grade squamous intraepithelial lesions (LSIL; 24), high-grade squamous intraepithelial lesions (HSIL; 36), mature or immature (metaplastic) squamous epithelium (29), and atrophic or metaplastic epithelium with atypia (15). Cases were scored positive for Ki-67 expression if expression extended above the basal one third of the epithelium, for cyclin E if moderate to strong staining was present, and for p16 if moderate to strong diffuse or focal staining was present. HPV status was scored by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of extracted DNA. Immunohistochemical findings were correlated with histologic and viral data. Overall, a histologic diagnosis of SIL correlated strongly with all of the biomarkers used (p biomarkers for HPV were 82.4%, 89.5%, and 91.4%, respectively. The positive predictive value for HPV of either cyclin E or p16 was 88.7%. Strong diffuse staining for p16 was significantly associated with high-risk HPV-associated lesions. Normal or reactive epithelial changes scored positive for the three biomarkers in 7.7%, 8.0%, and 12%, respectively. Limitations in specificity included minimal or no suprabasal staining for Ki-67 in immature condylomas and occasional suprabasal staining of reactive epithelial changes (10%), diffuse weak nuclear cyclin E staining in some normal or metaplastic epithelia, and diffuse weak basal p16 staining and occasional stronger focal

  4. Evaluation of estrogen receptor alpha and beta and progesterone receptor expression and correlation with clinicopathologic factors and proliferative marker Ki-67 in breast cancers

    DEFF Research Database (Denmark)

    Rosa, Fabíola E; Caldeira, José R F; Felipes, Joice

    2008-01-01

    To elucidate the molecular profile of hormonal steroid receptor status, we analyzed ER-alpha, ER-beta, and PGR mRNA and protein expression in 80 breast carcinomas using reverse transcriptase polymerase chain reaction (RT-PCR), quantitative RT-PCR, and immunohistochemical analysis. Qualitative...... difference was observed between lymph node status and ER-beta protein expression (P = .0208). In ER-alpha-negative tumors, we detected a correlation between ER-beta protein expression and high levels of Ki-67. These data suggest that ER-beta could be a prognostic marker in human breast cancer....

  5. DCE-MRI texture analysis with tumor subregion partitioning for predicting Ki-67 status of estrogen receptor-positive breast cancers

    KAUST Repository

    Fan, Ming

    2017-12-08

    Breast tumor heterogeneity is related to risk factors that lead to worse prognosis, yet such heterogeneity has not been well studied.To predict the Ki-67 status of estrogen receptor (ER)-positive breast cancer patients via analysis of tumor heterogeneity with subgroup identification based on patterns of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Retrospective study.Seventy-seven breast cancer patients with ER-positive breast cancer were investigated, of whom 51 had low Ki-67 expression.T1 -weighted 3.0T DCE-MR images.Each tumor was partitioned into multiple subregions using three methods based on patterns of dynamic enhancement: 1) time to peak (TTP), 2) peak enhancement rate (PER), and 3) kinetic pattern clustering (KPC). In each tumor subregion, 18 texture features were computed.Univariate and multivariate logistic regression analyses were performed using a leave-one-out-based cross-validation (LOOCV) method. The partitioning results were compared with the same feature extraction methods across the whole tumor.In the univariate analysis, the best-performing feature was the texture statistic of sum variance in the tumor subregion with early TTP for differentiating between patients with high and low Ki-67 expression (area under the receiver operating characteristic curves, AUC = 0.748). Multivariate analysis showed that features from the tumor subregion associated with early TTP yielded the highest performance (AUC = 0.807) among the subregions for predicting the Ki-67 status. Among all regions, the tumor area with high PER at a precontrast MR image achieved the highest performance (AUC = 0.722), while the subregion that exhibited the highest overall enhancement rate based on KPC had an AUC of 0.731. These three models based on intratumoral texture analysis significantly (P < 0.01) outperformed the model using features from the whole tumor (AUC = 0.59).Texture analysis of intratumoral heterogeneity has the potential to serve as a valuable

  6. Metastatic prolactinoma: case report with immunohistochemical assessment for p53 and Ki-67 antigens Prolactinoma metastático: relato de caso com avaliação imuno-histoquímica para os antígenos p53 e Ki-67

    Directory of Open Access Journals (Sweden)

    Paulo S. Crusius

    2005-09-01

    Full Text Available Pituitary carcinomas are rare neoplasms characterized by craniospinal and/or systemic metastases originated from the pituitary. Their histopathology is frequently indistinguishable from that of benign adenomas. The development of markers that better reflect their behavior is desirable. We present the case of a 47 year-old man with a prolactin-secreting macroadenoma who was submitted to surgeries, cranial radiation therapy, and bromocriptine treatment, but evolved to a fatal outcome after the disclosure of intracranial metastases. Tumor samples underwent p53 and Ki-67 immunohistochemical assessment. p53 was absent in all samples, a rare finding among pituitary carcinomas. Ki-67 proliferative index was 2.80% in the original tumor, 4.40% in the relapse, and 4.45% in the metastasis. The figure in the relapse is higher than the expected for a noninvasive adenoma. In conclusion, p53 staining is not positive in all pituitary carcinomas. A high Ki-67 proliferative index in a pituitary adenoma might indicate a more aggressive behavior.Carcinomas pituitários são neoplasias raras caracterizadas pela presença de metástases cranio-espinhais e/ou sistêmicas originadas da hipófise. Sua histopatologia é freqüentemente indistinguível daquela dos adenomas benignos. O desenvolvimento de marcadores que melhor reflitam o seu comportamento é desejável. Apresentamos o caso de um homem de 47 anos com um macroadenoma secretor de prolactina que foi submetido a procedimentos cirúrgicos, radioterapia e tratamento com bromocriptina, mas que evoluiu para o óbito após o descobrimento de metástases intracranianas. Amostras do tumor foram submetidas à análise imuno-histoquímica para os antígenos p53 e Ki-67. A coloração para p53 foi negativa em todas as amostras, um achado raro entre os carcinomas pituitários. O índice proliferativo Ki-67 foi 2,80% no tumor original, 4,40% na recidiva e 4,45% na metástase. O valor obtido na recidiva é maior que o

  7. Ki67 expression in the primary tumor predicts for clinical benefit and time to progression on first-line endocrine therapy in estrogen receptor-positive metastatic breast cancer.

    Science.gov (United States)

    Delpech, Y; Wu, Y; Hess, K R; Hsu, L; Ayers, M; Natowicz, R; Coutant, C; Rouzier, R; Barranger, E; Hortobagyi, G N; Mauro, D; Pusztai, L

    2012-09-01

    We examined whether baseline Ki67 expression in estrogen receptor-positive (ER+) primary breast cancer correlates with clinical benefit and time to progression on first-line endocrine therapy and survival in metastatic disease. Ki67 values and outcome information were retrieved from a prospectively maintained clinical database and validated against the medical records; 241 patients with metastatic breast cancer were included--who had ER+ primary cancer with known Ki67 expression level--and received first-line endocrine therapy for metastatic disease. Patients were assigned to low (25 %) Ki67 expression groups. Kaplan-Meier survival curves were plotted and multivariate analysis was performed to assess association between clinical and immunohistochemical variables and outcome. The clinical benefit rates were 81, 65, and 55 % in the low (n = 32), intermediate (n = 103), and high (n = 106) Ki67 expression groups (P = 0.001). The median times to progression on first-line endocrine therapy were 20.3 (95 % CI, 17.5-38.5), 10.8 (95 % CI, 8.9-18.8), and 8 (95 % CI, 6.1-11.1) months, respectively (P = 0.0002). The median survival times after diagnosis of metastatic disease were also longer for the low/intermediate compared to the high Ki67 group, 52 versus 30 months (P Ki67 expression in the primary tumor remained an independent adverse prognostic factor in metastatic disease (P = 0.001). Low Ki67 expression in the primary tumor is associated with higher clinical benefit and longer time to progression on first-line endocrine therapy and longer survival after metastatic recurrence.

  8. Ki-67 cell proliferation in familial and in esporadic unilateral retinoblastoma: case report Avaliação da proliferação celular com marcador ki-67 em pacientes com retinoblastoma unilateral esporádico e familiar: relato de caso

    Directory of Open Access Journals (Sweden)

    Maria Teresa Brizzi Chizzotti Bonanomi

    2007-03-01

    Full Text Available PURPOSE: Ki-67 is a nuclear protein that is expressed at all phases of the cell cycle except the resting phase. This study is a clinicopathologic observational case report that aims to report on the cell proliferation rates, as measured by the Ki-67 antigen, in two enucleated retinoblastoma eyes. METHODS: One unilateral familial (mother with unilateral disease - patient 1 and one unilateral sporadic retinoblastoma (patient 2 patients were submitted to enucleation without previous treatment. The tumor cell proliferation rate was assessed by the Ki-67 antigen labeling index (stained cells / 100 cells in five different fields of the tumor. RESULTS: Patient 1 was 23 months old and the tumor was exophytic with associated neovascularization of the iris; patient 2 was 6 years old and the tumor was endophytic with coarse vitreous seeds. Both enucleated eyes presented optic nerve with free surgical margins. Positive Ki-67 cell index in patient 1 varied from 75 to 90 (MD ± SD: 79.5 ± 6.61 and in patient 2 from 38 to 60 (MD ± SD: 46.6 ± 8.2. CONCLUSIONS: The familial retinoblastoma, besides the earlier age presentation, showed 45.8% more Ki-67 positive cells than the same stage sporadic one. This proliferation rate may explain the earlier presentation age of the tumor in the inherited disease.OBJETIVO: O Ki-67 é antígeno nuclear que se expressa em todas as fases do ciclo celular, exceto no período de repouso. Este é um estudo de casos com correlação clínico-patológica que visa avaliar a taxa de proliferação celular, medida pelo antígeno Ki-67, em 2 olhos enucleados com retinoblastoma. MÉTODOS: Um paciente com retinoblastoma unilateral familiar (mãe com doença unilateral - paciente 1 e outro com retinoblastoma unilateral esporádico (paciente 2 foram submetidos à enucleação ocular sem outro tratamento prévio. A taxa de proliferação celular foi avaliada segundo índice obtido pela contagem de células marcadas com Ki-67, em 5 campos

  9. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression.

    Science.gov (United States)

    Nitz, U; Gluz, O; Huober, J; Kreipe, H H; Kates, R E; Hartmann, A; Erber, R; Moustafa, Z; Scholz, M; Lisboa, B; Mohrmann, S; Möbus, V; Augustin, D; Hoffmann, G; Weiss, E; Böhmer, S; Kreienberg, R; Du Bois, A; Sattler, D; Thomssen, C; Kiechle, M; Jänicke, F; Wallwiener, D; Harbeck, N; Kuhn, W

    2014-08-01

    Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only. A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel 100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥ 20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. ClinicalTrials.gov, NCT02115204. © The Author 2014. Published by Oxford University Press on behalf of the European Society for

  10. Association of XRCC1 Trp194 allele with risk of breast cancer, and Ki67 protein status in breast tumor tissues.

    Science.gov (United States)

    Jalali, Chiya; Ghaderi, Bayazid; Amini, Sabrieh; Abdi, Mohammad; Roshani, Daem

    2016-06-01

    To evaluate the role of this polymorphism as a risk factor for breast cancer in Kurdish patients and to investigate the possible association between Arg194Trp x-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms with clinical and histopathological outcomes of patients with breast cancer. A total of 100 breast cancer patients and 200 cancer-free controls in Kurdish population of Kurdistan state admitted to Tohid Hospital, Sanandaj, Kurdistan, Iran between January 2012 and May 2015 were enrolled in this cross-sectional study. Tissue expression of estrogen receptor (ER), progesteron receptor (PR), human epidermal growth factor receptor 2 (Her2/neu), and Ki67 were evaluated by immunohistochemistry (IHC). The Arg194Trp genotypes were determined by polymerase chain reaction- restriction fragment length polymorphism method.  Our data showed that the risk for breast cancer increased significantly among the Trp variant of XRCC1. Statistically significant association was found between codon 194 polymorphisms and tissue expression of Ki67. The Trp allele of codon 194 XRCC1 is a potential risk factor for breast cancer in Kurdish ethnicity. Furthermore, effect of this polymorphism on clinical and histological features of breast cancer was significant.

  11. The comparison of nuclear ubiquitous casein and cyclin-dependent kinases substrate (NUCKS) with Ki67 proliferation marker expression in common skin tumors.

    Science.gov (United States)

    Zduniak, Krzysztof; Agrawal, Siddarth; Symonowicz, Krzysztof; Jurczyszyn, Kamil; Ziółkowski, Piotr

    2014-03-01

    Nuclear ubiquitous casein and cyclin-dependent kinases substrate (NUCKS) is a chromosomal protein of unknown function. Its amino acid composition and structure of its DNA binding domain resemble those of high mobility group A (HMGA) proteins which are associated with various malignancies. Since changes in expression of HMGA are considered as a marker of tumor progression, it is possible that similar changes in expression of NUCKS could be a useful tool in diagnosis of malignant skin tumors. To investigate this assumption we used specific antibodies against NUCKS for immunohistochemistry of squamous (SCC) and basal cell carcinoma (BCC) as well as keratoacanthoma (KA). We found high expression of NUCKS in nuclei of SCC and BCC cells which exceeded expression of the well-known proliferation marker Ki67. Expression of NUCKS in benign KA was much below that of malignant tumors. With the present study and based on our previous experience we would like to suggest the NUCKS protein as a novel proliferation marker for immunohistochemical evaluation of formalin-fixed and paraffin-embedded skin tumor specimens. We would like to emphasize that NUCKS abundance in malignant skin tumors is higher than that of the well-known proliferation marker Ki67, thus allowing more precise assessment of tumor proliferation potential.

  12. Image cytometry of aneuploidy, growth fraction (MoAb Ki-67) and hormone receptors (ER, PR) immunocytochemical assays in breast carcinomas.

    Science.gov (United States)

    Charpin, C; Andrac, L; Lavaut, M N; Andonian, C; Fraterno, M; Devictor, B; Perez-Castillo, A; Bonnier, P; Piana, L

    1990-10-01

    DNA nuclear content was assessed in human breast carcinomas (n = 132) using image cytometry. Optical density histograms of Feulgen stained cell imprints from fresh tissue samples, subsequently frozen for immunocytochemical assays, were determined by the SAMBA system and used for the DNA index, the ploidy balance (PB) and the proliferation index (PI) computation. The three parameters were correlated to (i) histological data (tumour grade, vascular and/or lymph node invasion) and to (ii) growth fraction (Ki67), hormone receptor antigenic sites (ER, PR) and intramedullar (bone marrow) biopsies and anti-KL1-positive epithelial cells. It was shown that 57% of breast carcinomas were aneuploid. Aneuploidy PI significantly correlated to the criteria of poor prognosis such as high tumour grade, vascular and lymphatic invasion and to increased Ki67-positive cells, and the absence of or low ER and PR. Since image cytometry is easy to handle and perfectly suitable for current diagnostic practice in pathology departments, particularly for tumour cell ploidy assessment and standardized analysis of immunostaining procedures with morphological control of the preparation, we conclude that image cytometry, as performed with the SAMBA, must be regarded as a relevant tool for prognosis evaluation and therapy guidance in individual patients.

  13. Octyl gallate reduces ATP levels and Ki67 expression leading HepG2 cells to cell cycle arrest and mitochondria-mediated apoptosis.

    Science.gov (United States)

    Lima, Kelly Goulart; Krause, Gabriele Catyana; da Silva, Elisa Feller Gonçalves; Xavier, Léder Leal; Martins, Léo Anderson Meira; Alice, Laura Manzoli; da Luz, Luiza Bueno; Gassen, Rodrigo Benedetti; Filippi-Chiela, Eduardo Cremonese; Haute, Gabriela Viegas; Garcia, Maria Claudia Rosa; Funchal, Giselle Afonso; Pedrazza, Leonardo; Reghelin, Camille Kirinus; de Oliveira, Jarbas Rodrigues

    2018-04-01

    Octyl gallate (OG) is an antioxidant that has shown anti-tumor, anti-diabetic and anti-amyloidogenic activities. Mitochondria play an important role in hepatocellular carcinoma, mainly by maintaining accelerated cellular proliferation through the production of ATP. Thus, the mitochondria may be a target for antitumor therapies. Here, we investigated the effects of OG in the hepatocarcinoma cell line (HepG2) and the mechanisms involved. We report, for the first time, that treatment with OG for 24h inhibited HepG2 cell growth by decreasing mitochondrial activity and mass, which led to the reduction of ATP levels. This reduction in the energy supply triggered a decrease in Ki67 protein expression, leading cells to cycle arrest. In addition, treatment with two doses of OG for 48h induced loss of mitochondrial functionality, mitochondrial swelling and apoptosis. Finally, we report that HepG2 cells had no resistance to treatment after multiple doses. Collectively, our findings indicate that metabolic dysregulation and Ki67 protein reduction are key events in the initial anti-proliferative action of OG, whereas mitochondrial swelling and apoptosis induction are involved in the action mechanism of OG after prolonged exposure. This suggests that OG targets mitochondria, thus representing a candidate for further research on therapies for hepatocarcinoma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Ki67 and lymphocytes in the pretherapeutic core biopsy of primary invasive breast cancer: positive markers of therapy response prediction and superior survival.

    Science.gov (United States)

    Schlotter, Claus M; Tietze, Lothar; Vogt, Ulf; Heinsen, Carlos Villena; Hahn, Antje

    2017-09-22

    Background Core needle biopsy plays a crucial role as diagnostic tool for BC. Both Ki67 and likely tumor-infiltrating lymphocytes (TILs) in the near future are determining the kind of systemic therapy. The role of TILs in BC is still an issue for clinical research, albeit preliminary results of neoadjuvant and adjuvant clinical studies already now highlight the crucial impact of TILs on therapy response and survival. Methods Evaluation of related publications (pubmed) and meeting abstracts (ASCO, SABCS). Results The monoclonal antibody Ki67 recognizing a nuclear antigene in proliferating cells is a positive marker of therapy response and superior survival. Endocrine responsive tumors of low proliferation (Ki67 19%) vs. tumors with lower proliferation after neoadjuvant chemotherapy (NAC). pCR-rates of up to 60% can be seen in TNBC and HR-, HER2+BC, lower pCR-rates, however, in HR+, HER2- BC. Increased stromal TILs are found in 30% of TNBC and in 19% of HR-, HER2+BC. The percentage of TILs is a significant independent parameter for pCR after NAC. Lymphocyte-predominant BC (LPBC) respond with higher pCR-rates than non-LPBC or tumors without any TILs. Increased TILs in TN and HR-, HER2+ subtypes predict benefit from addition of carboplatin to NAC. TILs are also associated with improved DFS and OS among patients with TNBC and HR-, HER2+ BC. Conversly and interestingly increased TILs in patients with HR+, HER2-(luminal) BC are associated with a 10% higher risk of death per 10% increase of TILs. Interactions between immune system and cancer are complex. The cancer-immunity cycle characterizes these interactions. BC subtypes with higher number of mutations such as TNBC and HR-, HER2+BC are considered to provide a raising number of tumor-associated antigens, thereby capable to build up a higher endogenous immune response. TILs may serve as surrogate marker of both an existing endogenous immune response and the probability to respond to cancer immune therapies. As cancer co

  15. Power of PgR expression as a prognostic factor for ER-positive/HER2-negative breast cancer patients at intermediate risk classified by the Ki67 labeling index.

    Science.gov (United States)

    Kurozumi, Sasagu; Matsumoto, Hiroshi; Hayashi, Yuji; Tozuka, Katsunori; Inoue, Kenichi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari; Kurosumi, Masafumi

    2017-05-22

    The Ki67 labeling index (LI) is regarded as a significant prognostic marker in ER-positive/HER2-negative breast cancer patients. The expression of PgR has recently been identified as another prognostic marker. In the present study, we investigated the prognostic utilities and most suitable cut-off values for Ki67 and PgR, and evaluated the relationship between Ki67 LI and PgR expression in ER-positive/HER2-negative breast cancer. In the present study, 177 consecutive Japanese women with ER-positive/HER2-negative invasive carcinoma of no special type who were treated between 2000 and 2001 were enrolled. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were analyzed according to Ki67 LI and PgR expression, and significant cut-off values for selecting patients with a poor prognosis were evaluated. The cut-off values for Ki67 LI as a prognostic marker plotted against P values showed bimodal peaks at 10% and 30%. Among the cut-off points examined for the PgR status, 20% PgR positivity was the most significant for predicting survival differences (RFS: P = 0.0003; CSS: P Ki67 LI of 10-30%, the low PgR breast cancer, and the most suitable cut-off value was found to be 20%. Furthermore, the PgR status is a powerful method for selecting patients with a poor prognosis among ER-positive/HER2-negative patients at intermediate risk, as assessed using Ki67 LI.

  16. Alterations in three biomarkers (estrogen receptor, progesterone receptor and human epidermal growth factor 2) and the Ki67 index between primary and metastatic breast cancer lesions.

    Science.gov (United States)

    Fujii, Kimihito; Watanabe, Rie; Ando, Takahito; Kousaka, Junko; Mouri, Yukako; Yoshida, Miwa; Imai, Tsuneo; Nakano, Shogo; Fukutomi, Takashi

    2017-12-01

    In recurrent breast cancer, the tumor phenotype, as assessed by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status, occasionally changes. This change, in addition to the Ki67 index were evaluated at sites of recurrence and the correlation between changes in tumor phenotype and survival were assessed in breast cancer patients. Comparisons in pathological parameters between primary and metastatic lesions were drawn between ER, PR, HER2, and the Ki67 index in 70 patients with recurrent breast cancer. The association between changes in tumor phenotype and patient survival was assessed. The hormone receptor status changed from positive, in the primary lesions, to negative, in the metastatic lesions in 19.8% (ER) and 39.5% (PR) of patients, respectively. Conversion from negative to positive status was confirmed in 27.2% (ER) and 31.2% (PR) of patients, respectively. A change in HER2 status from negative (primary lesion) to positive (metastatic lesion) occurred in seven patients (10%). The mean Ki67 index of primary lesions with positive hormone receptor status was significantly lower than at sites of recurrence with any hormone receptor status, from 10.9±9.8 standard deviation (SD) to 22.9±18.6 (P=0.031) and 12.2±10.5 SD to 27.4±20.9 (P=0.023), for ER and PR, respectively. The mean overall survival of patients with ER status conversion from positive to negative was 7.4±1.2 standard error (SE) years, and 14.8±1.4 SE years for patients who retained positive ER status (P=0.005, log-rank), with a hazard ratio of 3.44 (95% confidence interval, 1.36-8.33). This difference in survival based upon change in ER status was similarly observed in patients with PR status conversion in the same direction. Thus, ER and PR status conversion at the time of recurrence strongly impact survival, particularly if the change is from positive (primary lesion) to negative (metastatic lesion). Monitoring the biological behavior of breast

  17. Determination to genotypes of human papillomavirus and analysis with immunohistochemical marker Ki67 in biopsy with cervical dysplasia patients of Hospital Dr. Max Peralta in Cartago during 2013

    International Nuclear Information System (INIS)

    Blanco Chaves, Ana Lorely

    2014-01-01

    Cervical cancer is one of the leading causes of death among women worldwide, occupying in Costa Rica the fourth place. The human papillomavirus (HPV) is shown that is linked to at least 99.7% of cases, mainly associated with high risk genotypes. A study was conducted of type descriptive where were implemented molecular techniques such as: PCR, reverse hybridization for the determination of different HPV genotypes, and immunohistochemical detection of cell proliferation marker Ki67 in paraffin-embedded cervical biopsies from patients at the Hospital Dr. Max Peralta in Cartago, during the year 2013. The most frequent genotype that was determined among the study population has been 39, which was presented in 53% of cases. In addition, 65% of biopsies studied have showed mixed infections of HPV. (author) [es

  18. Valor prognóstico do Ki-67 no carcinoma indiferenciado de grandes células de glândula salivar maior: estudo de 11 casos

    OpenAIRE

    Barbosa, Túlio V.; Rosas, Marilene P.; Costa, Anderson C.; Rapoport, Abrão

    2003-01-01

    INTRODUÇÃO: Estabelecer a relação entre o comportamento biológico e o prognóstico nas neoplasias indiferenciadas das glândulas salivares maiores. OBJETIVO: Identificação de parâmetros clínicos, histopatológicos, imunohistoquímicos e de proliferação celular (Ki-67) no prognóstico destas neoplasias. FORMA DE ESTUDO: Análise de espécimes através de procedimentos histológicos e imunohistoquímicos e sua relação com o prognóstico destas neoplasias. MATERIAL E MÉTODO: Onze casos de carcinoma indifer...

  19. The Value of 18F-FDG PET/CT Imaging Combined With Pretherapeutic Ki67 for Early Prediction of Pathologic Response After Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer.

    Science.gov (United States)

    Luo, Jurui; Zhou, Zhirui; Yang, Zhaozhi; Chen, Xingxing; Cheng, Jinyi; Shao, Zhimin; Guo, Xiaomao; Tuan, Jeffrey; Fu, Xiaolong; Yu, Xiaoli

    2016-02-01

    To evaluate the value of F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG PET/CT) and pretherapeutic Ki67 in predicting pathologic response in locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NAC).As a training set, total 301 LABC patients treated with NAC were retrospectively analyzed to evaluate the potential predictive value of pretherapeutic Ki67 for pathologic complete response (pCR) after NAC. Another 60 LABC patients were prospectively included as a validation set to evaluate the value of Ki67 combined PET/CT as pCR predictors. Ki67 was assessed in pretherapy core needle biopsy specimens and PET/CT scans were performed at baseline (before initiating NAC), after the 2nd, and 4th cycle of NAC. Maximum standardized uptake value (SUVmax) and its changes relative to baseline (ΔSUVmax%) were used as parameters of PEC/CT.In the training set, Ki67 was a predictor of pCR to NAC, with area under the curve (AUC) of 0.624 (P = 0.003) in receiver-operating characteristic (ROC) analysis. In the validation set, Ki67 alone did not show significant value in predicting pCR in the validation set. ΔSUVmax% after then 2nd or 4th course are predictors of pCR to NAC with the AUC of 0.774 (P = 0.002) and 0.791 (P = 0.002), respectively. When combined with ΔSUVmax% after the 2nd and 4th course NAC, Ki67 increased the value of ΔSUVmax% in predicting pCR with the AUC of 0.824 (P = 0.001). Baseline SUVmax and after 2nd, 4th course NAC had no predictive value for pCR, but SUVmax after the 2nd and 4th course showed remarkable predictive value for nonpathologic response (Grade 1 in Miller-Payne Grading System) with the AUC of 0.898 (P = 0.0001) and 0.801 (P = 0.003).Both PET/CT and Ki67 can predict pCR to NAC in LABC patients in the early phases of treatment. PET/CT combined Ki67 is a better pCR predictor for response to NAC. This helps the physician to predict the probability of pCR, and facilitates the

  20. Hypoxia-inducible factor-2a is associated with ABCG2 expression, histology-grade and Ki67 expression in breast invasive ductal carcinoma

    Directory of Open Access Journals (Sweden)

    Xiang Lei

    2012-03-01

    Full Text Available Abstract Background Breast cancer is the most common cancer and the leading cause of cancer mortality in women worldwide. Hypoxia is an important factor involved in the progression of solid tumors and has been associated with various indicators of tumor metabolism, angiogenesis and metastasis. But little is known about the contribution of Hypoxia-Inducible Factor-2a (HIF-2a to the drug resistance and the clinicopathological characteristics in breast cancer. Methods Immunohistochemistry was employed on the tissue microarray paraffin sections of surgically removed samples from 196 invasive breast cancer patients with clinicopathological data. The correlations between the expression of HIF-2a and ABCG2 as well as other patients' clinicopathological data were investigated. Results The results showed that HIF-2a was expressed in different intensities and distributions in the tumor cells of the breast invasive ductal carcinoma. A positive staining for HIF-2a was defined as a brown staining observed mainly in the nucleus. A statistically significant correlation was demonstrated between HIF-2a expression and ABCG2 expression (p = 0.001, histology-grade (p = 0.029, and Ki67 (p = 0. 043 respectively. Conclusion HIF-2a was correlated with ABCG2 expression, histology-grade and Ki67 expression in breast invasive ductal carcinoma. HIF-2a could regulate ABCG2 in breast cancer cells, and could be a novel potential bio-marker to predict chemotherapy effectiveness. The hypoxia/HIF-2a/ABCG2 pathway could be a new mechanism of breast cancer multidrug-resistance. Virtual slides http://www.diagnosticpathology.diagnomx.eu/vs/2965948166714795

  1. Disturbance of Bcl-2, Bax, Caspase-3, Ki-67 and C-myc expression in acute and subchronic exposure to benzo(a)pyrene in cervix.

    Science.gov (United States)

    Gao, Meili; Li, Yongfei; Ji, Xiaoying; Xue, Xiaochang; Chen, Lan; Feng, Guodong; Zhang, Huqin; Wang, Huichun; Shah, Walayat; Hou, Zhanwu; Kong, Yu

    2016-03-01

    Epidemiological studies have demonstrated that cigarette smoking is an important cofactor or an independent risk factor for the development of cervical cancer. Benzo(a)pyrene (BaP) is one of the most potent tobacco smoke carcinogens in tobacco smoke. BaP induced DNA damage and over expression in p53 cervical tissue of mice as demonstrated in our previous study. Here we present the findings of exposure to BaP on the expression of Bcl-2, C-myc, Ki-67, Caspase-3 and Bax genes in mouse cervix. Acute intraperitoneal administration of BaP (12.5, 25, 50, 100mg/kg body weight) to ICR female mice induced a significant increase in Bcl-2, C-myc, Ki-67 mRNA and protein level till 72h except in Bcl-2 at 24h with 12.5, 25, 50mg/kg as well as at 48h with 12.5mg/kg body weight post treatment. A significant increase was also seen in Caspase-3 and Bax mRNA and protein level with peak level at 24h and gradual decrease till 72h, however, the expression of caspase-3 increased while that of Bax decreased with increasing dose of Bap after 24h. In sub chronic intraperitoneal and oral gavage administration of BaP (2.5, 5, 10mg/kg body weight), similar significant increase was observed for all the examined genes as compared to the control and vehicle groups, however the expression of Bax decreased in a dose dependent manner. The findings of this study will help in further understanding the molecular mechanism of BaP induced carcinogenesis of cervical cancer. Copyright © 2015 Elsevier GmbH. All rights reserved.

  2. Significado clínico-patológico das expressões citofotométricas do Ki-67 e Caspase-3 no carcinoma de células escamosas do esôfago Clinicopathologic significance of the Ki-67 and Caspase-3 cytophotometric expressions in the esophageal squamous cell carcinomal

    Directory of Open Access Journals (Sweden)

    Gilmar Pereira Silva

    2008-06-01

    Full Text Available RACIONAL: A escolha da forma de tratamento do carcinoma de células escamosa de esôfago ainda hoje é orientada pelo estadiamento tumoral, onde as características histopatológicas do tumor são o maior determinante. Parale-lamente, desenvolvem-se estudos para entender o comportamento da biologia tumoral por método imunoistoquímico de quantificação manual, avaliando a ati-vidade proliferativa ou apoptótica do tecido em análise. As desvantagens conti-das no modo manual fizeram surgir e desenvolver método computadorizado de análise de imagem. OBJETIVOS: Verificar as expressões dos marcadores KI-67 e Caspase-3 e correlacioná-las com as características clínico-patológicas do tumor. MÉTODOS: Foram estudados 29 blocos parafinados provenientes de pa-cientes portadores de carcinoma de células escamosas de esôfago submetidos à esofagectomia e pertencentes a acervos de laboratórios de patologia. Proce-deu-se preparo das lâminas por técnica imunoistoquímica convencional. A quantificação da imunorreatividade às proteínas Ki-67 e Caspase-3 foi realizada pelo software de análise de imagem computadorizada SAMBA (Systeme d'Analyse Microphotometrique a Balayage Automatique através do índice de marcagem encontrado. RESULTADOS: Predominaram na amostra o sexo mascu-lino (82,7%; maiores de 50 anos; tumores moderadamente diferenciados (68,98%; estágio III (72,42%; lesões >3cm e localizadas no ⅓ inferior do ór-gão. Os índices médios de marcagem identificados foram de 62,05% para o Ki-67 e 86,06% para a Caspase-3, e não mostraram correlação com as caracterís-ticas clínico-patológicas como sexo, idade, estadiamento tumoral, grau de pro-fundidade da lesão e comprometimento linfonodal. Houve significante diferença de expressão do Ki-67 entre os graus histológicos (P=0,047 e correlação entre os índices dos marcadores estudados (r=0,41 e P =0,032. CONCLUSÃO: Na presente investigação as atividades das proteínas estudadas

  3. Expression of p53, Ki-67 and c-erb B2 in growth hormone-and/or prolactin-secreting pituitary adenomas Expressão de p53, Ki-67 e c-erb B2 em adenomas hipofisários secretores de prolactina e/ou hormônio de crescimento

    Directory of Open Access Journals (Sweden)

    Carlos Henrique A. Botelho

    2006-03-01

    Full Text Available The subcellular events implicated on the formation and behavior of pituitary adenomas are not fully understood. In this study we investigated the presence of p53, Ki-67 and c-erb B2 in 38 pituitary adenomas with immunohistochemical positivity for GH and prolactin (n=26; 68.4%, for prolactin (n=9; 23.7% and for GH (n=3. 7.8%. The analyses revealed the following results: 24 (63.2% tumors expressed variable positivity for c-erb B2, 11 (28.9% expressed p53 positivity and 11 (28.9% tumors were variably positive for Ki-67. Our results demonstrated a high percentage of GH/prolactin-, prolactin- and GH-secreting tumors with immunohistochemical positivity for c-erb B2. Once this membrane receptor is related to growth factors EGF and TGFalpha and both have a definite effect on tumor growth, our data suggest a possible role for c-erb B2 on the evolution of these tumors.Os eventos subcelulares implicados na formação e comportamento dos adenomas hipofisários não são completamente compreendidos. Neste estudo nós investigamos a presença de p53, Ki-67 e c-erb B2 em 38 adenomas hipofisários com positividade imuno-histoquímica para GH e prolactina (n=26, 68,4%, para prolactina (n=9, 23,7% e para GH (n=3, 7,8%. A análise revelou os seguintes resultados: 24 tumores (63,2% expressaram positividade variável para c-erb B2, 11 (28,9% expressaram positividade para p53 e 11 tumores (28,9% foram variavelmente positivos para Ki-67. Nossos resultados demonstraram elevada percentagem de tumores secretores de GH/prolactina, prolactina e GH com positividade imuno-histoquímica para c-erb B2. Desde que este receptor de membrana está relacionado aos fatores de crescimento EGF e TGFalfa e ambos têm efeito definido no crescimento tumoral, nossos dados sugerem possível função para o c-erb B2 na evolução destes tumores.

  4. Analysis of the immunohistochemical expressions of p53, bcl-2 and Ki-67 in colorectal adenocarcinoma and their correlations with the prognostic factors Análise das expressões imunoistoquímicas da p53, bcl-2 e Ki-67 no adenocarcinoma colorretal e suas correlações com os fatores prognósticos

    Directory of Open Access Journals (Sweden)

    Hunaldo Lima de Menezes

    2010-06-01

    Full Text Available CONTEXT: Search of tumors markers that allow treatment with higher survival rates, and indicate the response to treatment and recurrence of cancer OBJECTIVE: To analyze the immunoexpression of the proteins p53, bcl-2 and Ki-67 in colorectal adenocarcinoma and correlate them with the clinical-pathological prognostic factors. METHOD: Tissue microarray paraffin blocks were made from colorectal adenocarcinoma tissue resected from 82 patients who had undergone surgery but not chemotherapy or radiotherapy, at "Hospital São Paulo", São Paulo, SP, Brazil, between 2002 and 2005. Thin sections (4 µm were subjected to immunohistochemical reactions, and immunoexpression staining scores were obtained. The scores were correlated with the degree of cell differentiation, staging, disease-free interval, recurrence, survival and specific mortality. The study variables were analyzed using the chi-square and Kaplan-Meier tests to investigate associations with the markers. The significance of the differences between the curves of the disease-free interval and survival was analyzed using the Logrank and Wilcoxon tests. RESULTS: The immunohistochemical expression of p53 was positive in 70 tumors (85.4% and negative in 12 (14.6%. The expression of bcl-2 was positive in 26 (31.7% and negative in 56 (68.3%. The expression of Ki-67 was positive in 62 (75.6% and negative in 20 (24.4%. There was no statistically significant correlation between the expressions of these markers separately or in conjunction, in relation to the degree of cell differentiation, staging, disease-free interval, survival and specific mortality. In relation to recurrence, there was a statistically significant correlation with positive expression of Ki-67 (P = 0.035. CONCLUSION: The immunohistochemical expression of Ki-67 in colorectal cancer is associated with recurrence of this disease.CONTEXTO: Pesquisa de marcadores tumorais que permitam tratamento com maiores índices de sobrevida, além de

  5. Expressão imunohistoquímica de P53 e Ki-67 na carcinogênese esofágica induzida pela dietilnitrosamina: modelo experimental

    Directory of Open Access Journals (Sweden)

    Miguel Angelo Martins de Castro Junior

    Full Text Available OBJETIVO: Avaliar a expressão imunohistoquímica de p53 e ki-67 na carcinogênese esofágica induzida quimicamente através do uso de dietilnitrosamina, em um grupo de 100 camundongos fêmeas. MÉTODOS: O estudo experimental foi realizado com quatro grupos de animais, onde os grupos I e II foram considerados controles, sendo diferenciados por gavagem esofágica, uma vez semana, com água fria (temperatura ambiente ou quente (60º-70ºC. E os grupos III e IV foram considerados estudos, os quais receberam dietilnitrosamina por três dias consecutivos semanalmente, também sendo diferenciados por gavagem, uma vez por semana, com água fria ou quente. O estudo apresentou datas progressivas de sacrifícios com coleta de peças esofágicas, que iniciava aos 30 dias de experimento e terminava aos 150 dias. Demonstrou-se que não houve diferença na incidência tumoral quando foi acrescida a variável temperatura da água; provavelmente devido ao episódio único semanal que era adicionado ao animal em experimentação. RESULTADOS: A análise imunohistoquímica do p53 não evidenciou diferença estatística durante a evolução da carcinogênese até 150 dias, porém quando analisado a relação com alterações patológicas demonstra-se que apresenta significância em relação à patologia baixo grau de displasia, alto grau e carcinoma. CONCLUSÃO: A análise imunohistoquímica do ki-67 demonstrou diferença estatística durante a evolução da carcinogênese a partir do dia 120 de experimento e quando analisada a relação com alterações patológicas demonstrou-se que apresenta significância também em relação à lesão intraepitelial de alto grau e carcinoma.

  6. Avaliação da caspase-3 e Ki-67 como marcadores prognósticos nas neoplasias mamárias em cadelas

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    Ana Carolina Bernardes Terzian

    2007-04-01

    Full Text Available A apoptose e a proliferação celular possuem uma participação importante na tumorigênese, determinando o crescimento tumoral e consequentemente sua agressividade. O presente estudo teve como objetivo avaliar a ocorrência da apoptose associada a proliferação celular em neoplasias mamárias em cadelas e a elas a evolução clínica do paciente. Setenta animais foram submetidos à exérese cirúrgica do tumor, sendo este submetido ao diagnóstico histopatológico e marcação imuno-histoquímica para caspase-3 e Ki-67. Estes marcadores de apoptose e proliferação celular demonstraram grande expressão nas neoplasias malignas, principalmente nos carcinomas, considerado o mais maligno dos tumores. Estes resultados corroboram os dados da literatura e contribuem para um prognóstico tumoral criterioso que complementa a classificação tumoral existente proporcionando uma melhor e maior sobrevida devido a uma adequação do procedimento terapêutico de cada paciente.

  7. Adaptive Localization of Focus Point Regions via Random Patch Probabilistic Density from Whole-Slide, Ki-67-Stained Brain Tumor Tissue

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    Yazan M. Alomari

    2015-01-01

    Full Text Available Analysis of whole-slide tissue for digital pathology images has been clinically approved to provide a second opinion to pathologists. Localization of focus points from Ki-67-stained histopathology whole-slide tissue microscopic images is considered the first step in the process of proliferation rate estimation. Pathologists use eye pooling or eagle-view techniques to localize the highly stained cell-concentrated regions from the whole slide under microscope, which is called focus-point regions. This procedure leads to a high variety of interpersonal observations and time consuming, tedious work and causes inaccurate findings. The localization of focus-point regions can be addressed as a clustering problem. This paper aims to automate the localization of focus-point regions from whole-slide images using the random patch probabilistic density method. Unlike other clustering methods, random patch probabilistic density method can adaptively localize focus-point regions without predetermining the number of clusters. The proposed method was compared with the k-means and fuzzy c-means clustering methods. Our proposed method achieves a good performance, when the results were evaluated by three expert pathologists. The proposed method achieves an average false-positive rate of 0.84% for the focus-point region localization error. Moreover, regarding RPPD used to localize tissue from whole-slide images, 228 whole-slide images have been tested; 97.3% localization accuracy was achieved.

  8. Evaluation of potential prognostic value of Bmi-1 gene product and selected markers of proliferation (Ki-67 and apoptosis (p53 in the neuroblastoma group of tumors

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    Katarzyna Taran

    2016-02-01

    Full Text Available Introduction: Cancer in children is a very important issue in pediatrics. The least satisfactory treatment outcome occurs among patients with clinically advanced neuroblastomas. Despite much research, the biology of this tumor still remains unclear, and new prognostic factors are sought. The Bmi-1 gene product is a currently highly investigated protein which belongs to the Polycomb group (PcG and has been identified as a regulator of primary neural crest cells. It is believed that Bmi‑1 and N-myc act together and are both involved in the pathogenesis of neuroblastoma. The aim of the study was to assess the potential prognostic value of Bmi-1 protein and its relations with mechanisms of proliferation and apoptosis in the neuroblastoma group of tumors.Material/Methods: 29 formalin-fixed and paraffin-embedded neuroblastoma tissue sections were examined using mouse monoclonal antibodies anti-Bmi-1, anti-p53 and anti-Ki-67 according to the manufacturer’s instructions.Results: There were found statistically significant correlations between Bmi-1 expression and tumor histology and age of patients.Conclusions: Bmi-1 seems to be a promising marker in the neuroblastoma group of tumors whose expression correlates with widely accepted prognostic parameters. The pattern of BMI-1 expression may indicate that the examined protein is also involved in maturation processes in tumor tissue.

  9. A Comparative Analysis of Biomarker Expression and Molecular Subtypes of Pure Ductal Carcinoma In Situ and Invasive Breast Carcinoma by Image Analysis: Relationship of the Subtypes with Histologic Grade, Ki67, p53 Overexpression, and DNA Ploidy

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    Venetia R. Sarode

    2011-01-01

    Full Text Available There is a paucity of data regarding molecular subtypes of pure ductal carcinoma in situ (pDCIS. We evaluated the expression of ER, PR, HER2, Ki67, and p53 and DNA ploidy in 118 pDCIS and 100 invasive breast carcinomas (IBCAs by routine IHC and classified them according to molecular subtypes. Quantification of biomarkers and DNA ploidy was performed by image analysis. Expression of ER, PR, and high ki67 was more frequent in pDCIS compared to IBCA. High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy. Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA. In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes. Molecular subtypes of IBCA are distinct from those of pDCIS. Invasion is characterized by change in phenotype in some tumors.

  10. Evaluation of p16INK4a/Ki-67 dual stain in comparison with an mRNA human papillomavirus test on liquid-based cytology samples with low-grade squamous intraepithelial lesion

    DEFF Research Database (Denmark)

    Waldstrom, M.; Christensen, R. K.; Ornskov, D.

    2013-01-01

    BACKGROUND: The objective of the current study was to investigate the clinical performance of detecting high-grade lesions with the CINtec PLUS p16INK4a/Ki-67 dual stain and the APTIMA human papillomavirus (HPV) Assay in a cohort of women with low-grade squamous intraepithelial lesion (LSIL) cyto...

  11. Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811.

    Science.gov (United States)

    Doll, Corinne M; Moughan, Jennifer; Klimowicz, Alexander; Ho, Clement K; Kornaga, Elizabeth N; Lees-Miller, Susan P; Ajani, Jaffer A; Crane, Christopher H; Kachnic, Lisa A; Okawara, Gordon S; Berk, Lawrence B; Roof, Kevin S; Becker, Mark J; Grisell, David L; Ellis, Robert J; Sperduto, Paul W; Marsa, Gerald W; Guha, Chandan; Magliocco, Anthony M

    2017-03-01

    To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFR high:low ) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFR high:low  ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFR high:low  ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. High Ki67ratio in EGFR high:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor

  12. Presence or Absence of Significant HPVE4 Expression in High-grade Anal Intraepithelial Neoplasia With p16/Ki-67 Positivity Indicates Distinct Patterns of Neoplasia: A Study Combining Immunohistochemistry and Laser Capture Microdissection PCR.

    Science.gov (United States)

    Leeman, Annemiek; Pirog, Edyta C; Doorbar, John; van de Sandt, Miekel M; van Kemenade, Folkert J; Jenkins, David; Quint, Wim G V

    2018-04-01

    Progression of anal intraepithelial neoplasia (AIN) involves transition from productive to transforming human papillomavirus (HPV) infection. Grading aims to distinguish productive low-grade AIN from high-grade anal intraepithelial neoplasia (HGAIN) with risk of cancer. We describe immunohistochemical patterns in AIN adding a novel marker for initiation of the productive phase of the HPV life cycle (panHPVE4) to those for cell cycle activity (Ki-67) and transforming activity of HPVE7 gene (p16). We studied 67 anal biopsies for suspected anal neoplasia (17 normal, 15 AIN1, 20 AIN2, 15 AIN3) from 54 men who have sex with men at New York Presbyterian Hospital, USA. Two pathologists generated consensus AIN and immunogrades. Whole tissue and laser capture microdissection samples from multiple HPV-infected biopsies were tested for HPV with SPF10-PCR-DEIA-LiPA25, version 1. (Para)basal Ki-67 expression distinguished normal from AIN (≥lower-third Ki-67) with sensitivity 0.92 and specificity 1.0. Ki-67 did not distinguish grades of AIN. Null/patchy p16 versus diffuse ≥lower-third patterns discriminated HGAIN (sensitivity, 1.0; specificity, 0.84). There was marked heterogeneity in E4 expression within HGAIN. Most AIN2 (14/20) was E4 versus 0/15 AIN3 (sensitivity, 0.70; specificity 1.0). HPV was detected in 63 (94%) biopsies, with 49 (77.8%) high-risk HPV. HPV16 was the most frequent (13%). Multiple HPV genotypes were found in 15 (24%) biopsies and laser capture microdissection -polymerase chain reaction confirmed specific HPV types in E4 +/- AIN. Although Ki-67 discriminated AIN and p16 HGAIN, E4/p16 staining shows that most AIN2 is different from transformed AIN3 in showing both entry into productive HPV infection and transforming activity.

  13. Valor prognóstico do Ki-67 no carcinoma indiferenciado de grandes células de glândula salivar maior: estudo de 11 casos Prognostic significance of Ki-67 in great cell undifferentiated carcinoma of the major salivary glands: study of 11 cases

    OpenAIRE

    Túlio V. Barbosa; Marilene P. Rosas; Anderson C. Costa; Abrão Rapoport

    2003-01-01

    INTRODUÇÃO: Estabelecer a relação entre o comportamento biológico e o prognóstico nas neoplasias indiferenciadas das glândulas salivares maiores. OBJETIVO: Identificação de parâmetros clínicos, histopatológicos, imunohistoquímicos e de proliferação celular (Ki-67) no prognóstico destas neoplasias. FORMA DE ESTUDO: Análise de espécimes através de procedimentos histológicos e imunohistoquímicos e sua relação com o prognóstico destas neoplasias. MATERIAL E MÉTODO: Onze casos de carcinoma indifer...

  14. Effects of Cyclooxygenase Inhibitors in Combination with Taxol on Expression of Cyclin D1 and Ki-67 in a Xenograft Model of Ovarian Carcinoma

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    Liang Wan

    2012-08-01

    Full Text Available The present study was designed to investigate the effects of cyclooxygenase (COX inhibitors in combination with taxol on the expression of cyclin D1 and Ki-67 in human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 100 mg/kg celecoxib (a COX-2 selective inhibitor alone, 3 mg/kg SC-560 (a COX-1 selective inhibitor alone by gavage twice a day, 20 mg/kg taxol alone by intraperitoneally (i.p. once a week, or celecoxib/taxol, SC-560/celecoxib, SC-560/taxol or SC-560/celecoxib/taxol, for three weeks. To test the mechanism of the combination treatment, the index of cell proliferation and expression of cyclin D1 in tumor tissues were determined by immunohistochemistry. The mean tumor volume in the treated groups was significantly lower than control (p < 0.05, and in the three-drug combination group, tumor volume was reduced by 58.27% (p < 0.01; downregulated cell proliferation and cyclin D1 expression were statistically significant compared with those of the control group (both p < 0.01. This study suggests that the effects of COX selective inhibitors on the growth of tumors and decreased cell proliferation in a SKOV-3 cells mouse xenograft model were similar to taxol. The three-drug combination showing a better decreasing tendency in growth-inhibitory effect during the experiment may have been caused by suppressing cyclin D1 expression.

  15. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance).

    Science.gov (United States)

    Ellis, Matthew J; Suman, Vera J; Hoog, Jeremy; Goncalves, Rodrigo; Sanati, Souzan; Creighton, Chad J; DeSchryver, Katherine; Crouch, Erika; Brink, Amy; Watson, Mark; Luo, Jingqin; Tao, Yu; Barnes, Michael; Dowsett, Mitchell; Budd, G Thomas; Winer, Eric; Silverman, Paula; Esserman, Laura; Carey, Lisa; Ma, Cynthia X; Unzeitig, Gary; Pluard, Timothy; Whitworth, Pat; Babiera, Gildy; Guenther, J Michael; Dayao, Zoneddy; Ota, David; Leitch, Marilyn; Olson, John A; Allred, D Craig; Hunt, Kelly

    2017-04-01

    Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for

  16. Non-Gaussian diffusion MR imaging of glioma: comparisons of multiple diffusion parameters and correlation with histologic grade and MIB-1 (Ki-67 labeling) index

    International Nuclear Information System (INIS)

    Yan, Ren; Haopeng, Pang; Xiaoyuan, Feng; Jiawen, Zhang; Zhenwei, Yao; Jinsong, Wu; Chengjun, Yao; Tianming, Qiu; Ji, Xiong; Mao, Sheng; Yueyue, Ding; Yong, Zhang; Jianfeng, Luo

    2016-01-01

    This study was conducted to compare the association of Gaussian and non-Gaussian magnetic resonance imaging (MRI)-derived parameters with histologic grade and MIB-1 (Ki-67 labeling) index (MI) in brain glioma. Sixty-five patients with pathologically confirmed glioma, who underwent diffusion-weighted MRI with 2 b values (0, 1000 s/mm 2 ) and 22 b values (≤5000 s/mm 2 ), respectively, were divided into three groups of grade II (n = 35), grade III (n = 8), and grade IV (n = 22). Comparisons by two groups were made for apparent diffusion coefficient (ADC), slow diffusion coefficient (Dslow), distributed diffusion coefficient (DDC), and heterogeneity index α. Analyses of receiver operating characteristic (ROC) curve were performed to maximize the area under the curve (AUC) for differentiating grade III + IV (high-grade glioma, HGG) from grade II (low-grade glioma, LGG) and grade IV (glioblastoma multiforme, GBM) from grade II + III (other grade glioma, OGG). Correlations with MI were analyzed for the MRI parameters. On tumor regions, the values of ADC, Dslow, DDC, and α were significantly higher in grade II [(1.37 ± 0.29, 0.70 ± 0.11, 1.39 ± 0.34) (x 10 -3 mm 2 /s) and 0.88 ± 0.05, respectively] than in grade III [(0.99 ± 0.13, 0.55 ± 0.07, 1.04 ± 0.20) (x 10 -3 mm 2 /s) and 0.80 ± 0.03, respectively] and grade IV [(1.03 ± 0.14, 0.50 ± 0.05, 1.02 ± 0.16) (x 10 -3 mm 2 /s) and 0.76 ± 0.04, respectively] (all P < 0.001). The parameter α showed the highest AUCs of 0.950 and 0.922 in discriminating HGG from LGG and GBM from OGG, respectively. Significant correlations with histologic grade and MI were observed for the MRI parameters. The non-Gaussian MRI-derived parameters α and Dslow are superior to ADC in glioma grading, which are comparable with ADC as reliable biomarkers in noninvasively predicting the proliferation level of glioma malignancy. (orig.)

  17. Non-Gaussian diffusion MR imaging of glioma: comparisons of multiple diffusion parameters and correlation with histologic grade and MIB-1 (Ki-67 labeling) index

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Ren; Haopeng, Pang; Xiaoyuan, Feng; Jiawen, Zhang; Zhenwei, Yao [Fudan University, Department of Radiology, Huashan Hospital, Shanghai (China); Jinsong, Wu; Chengjun, Yao; Tianming, Qiu [Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai (China); Ji, Xiong [Fudan University, Department of Neuropathology, Huashan Hospital, Shanghai (China); Mao, Sheng; Yueyue, Ding [Department of Imaging, Suzhou Children' s Hospital, Suzhou, Jiangsu (China); Yong, Zhang [MR Research, GE Healthcare, Shanghai (China); Jianfeng, Luo [Fudan University, Department of Biostatistics, Public Health School, Shanghai (China)

    2016-02-15

    This study was conducted to compare the association of Gaussian and non-Gaussian magnetic resonance imaging (MRI)-derived parameters with histologic grade and MIB-1 (Ki-67 labeling) index (MI) in brain glioma. Sixty-five patients with pathologically confirmed glioma, who underwent diffusion-weighted MRI with 2 b values (0, 1000 s/mm{sup 2}) and 22 b values (≤5000 s/mm{sup 2}), respectively, were divided into three groups of grade II (n = 35), grade III (n = 8), and grade IV (n = 22). Comparisons by two groups were made for apparent diffusion coefficient (ADC), slow diffusion coefficient (Dslow), distributed diffusion coefficient (DDC), and heterogeneity index α. Analyses of receiver operating characteristic (ROC) curve were performed to maximize the area under the curve (AUC) for differentiating grade III + IV (high-grade glioma, HGG) from grade II (low-grade glioma, LGG) and grade IV (glioblastoma multiforme, GBM) from grade II + III (other grade glioma, OGG). Correlations with MI were analyzed for the MRI parameters. On tumor regions, the values of ADC, Dslow, DDC, and α were significantly higher in grade II [(1.37 ± 0.29, 0.70 ± 0.11, 1.39 ± 0.34) (x 10{sup -3} mm{sup 2}/s) and 0.88 ± 0.05, respectively] than in grade III [(0.99 ± 0.13, 0.55 ± 0.07, 1.04 ± 0.20) (x 10{sup -3} mm{sup 2}/s) and 0.80 ± 0.03, respectively] and grade IV [(1.03 ± 0.14, 0.50 ± 0.05, 1.02 ± 0.16) (x 10{sup -3} mm{sup 2}/s) and 0.76 ± 0.04, respectively] (all P < 0.001). The parameter α showed the highest AUCs of 0.950 and 0.922 in discriminating HGG from LGG and GBM from OGG, respectively. Significant correlations with histologic grade and MI were observed for the MRI parameters. The non-Gaussian MRI-derived parameters α and Dslow are superior to ADC in glioma grading, which are comparable with ADC as reliable biomarkers in noninvasively predicting the proliferation level of glioma malignancy. (orig.)

  18. Chromogenic In Situ Hybridization and p16/Ki67 Dual Staining on Formalin-Fixed Paraffin-Embedded Cervical Specimens: Correlation with HPV-DNA Test, E6/E7 mRNA Test, and Potential Clinical Applications

    Directory of Open Access Journals (Sweden)

    Roberta Zappacosta

    2013-01-01

    Full Text Available Although HPV-DNA test and E6/E7 mRNA analyses remain the current standard for the confirmation of human papillomavirus (HPV infections in cytological specimens, no universally adopted techniques exist for the detection of HPV in formalin-fixed paraffin-embedded samples. Particularly, in routine laboratories, molecular assays are still time-consuming and would require a high level of expertise. In this study, we investigated the possible use of a novel HPV tyramide-based chromogenic in situ hybridization (CISH technology to locate HPV on tissue specimens. Then, we evaluate the potential usefulness of p16INK4a/Ki-67 double stain on histological samples, to identify cervical cells expressing HPV E6/E7 oncogenes. In our series, CISH showed a clear signal in 95.2% of the specimens and reached a sensitivity of 86.5%. CISH positivity always matched with HPV-DNA positivity, while 100% of cases with punctated signal joined with cervical intraepithelial neoplasia grade 2 or worse (CIN2+. p16/Ki67 immunohistochemistry gave an interpretable result in 100% of the cases. The use of dual stain significantly increased the agreement between pathologists, which reached 100%. Concordance between dual stain and E6/E7 mRNA test was 89%. In our series, both CISH and p16INK4a/Ki67 dual stain demonstrated high grade of performances. In particular, CISH would help to distinguish episomal from integrated HPV, in order to allow conclusions regarding the prognosis of the lesion, while p16INK4a/Ki67 dual stain approach would confer a high level of standardization to the diagnostic procedure.

  19. Chromogenic In Situ Hybridization and p16/Ki67 Dual Staining on Formalin-Fixed Paraffin-Embedded Cervical Specimens: Correlation with HPV-DNA Test, E6/E7 mRNA Test, and Potential Clinical Applications

    Science.gov (United States)

    Zappacosta, Roberta; Colasante, Antonella; Viola, Patrizia; D'Antuono, Tommaso; Lattanzio, Giuseppe; Capanna, Serena; Gatta, Daniela Maria Pia; Rosini, Sandra

    2013-01-01

    Although HPV-DNA test and E6/E7 mRNA analyses remain the current standard for the confirmation of human papillomavirus (HPV) infections in cytological specimens, no universally adopted techniques exist for the detection of HPV in formalin-fixed paraffin-embedded samples. Particularly, in routine laboratories, molecular assays are still time-consuming and would require a high level of expertise. In this study, we investigated the possible use of a novel HPV tyramide-based chromogenic in situ hybridization (CISH) technology to locate HPV on tissue specimens. Then, we evaluate the potential usefulness of p16INK4a/Ki-67 double stain on histological samples, to identify cervical cells expressing HPV E6/E7 oncogenes. In our series, CISH showed a clear signal in 95.2% of the specimens and reached a sensitivity of 86.5%. CISH positivity always matched with HPV-DNA positivity, while 100% of cases with punctated signal joined with cervical intraepithelial neoplasia grade 2 or worse (CIN2+). p16/Ki67 immunohistochemistry gave an interpretable result in 100% of the cases. The use of dual stain significantly increased the agreement between pathologists, which reached 100%. Concordance between dual stain and E6/E7 mRNA test was 89%. In our series, both CISH and p16INK4a/Ki67 dual stain demonstrated high grade of performances. In particular, CISH would help to distinguish episomal from integrated HPV, in order to allow conclusions regarding the prognosis of the lesion, while p16INK4a/Ki67 dual stain approach would confer a high level of standardization to the diagnostic procedure. PMID:24369532

  20. Protective effect of chronic caffeine intake on gene expression of brain derived neurotrophic factor signaling and the immunoreactivity of glial fibrillary acidic protein and Ki-67 in Alzheimer’s disease

    OpenAIRE

    Ghoneim, Fatma M; Khalaf, Hanaa A; Elsamanoudy, Ayman Z; Abo El-khair, Salwa M; Helaly, Ahmed MN; Mahmoud, El-Hassanin M; Elshafey, Saad H

    2015-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder with progressive degeneration of the hippocampal and cortical neurons. This study was designed to demonstrate the protective effect of caffeine on gene expression of brain derived neurotrophic factor (BDNF) and its receptor neural receptor protein-tyrosine kinase-β (TrkB) as well as glial fibrillary acidic protein (GFAP) and Ki-67 immunoreactivity in Aluminum chloride (AlCl3) induced animal model of AD. Fifty adult rats included in this...

  1. MET and PTEN gene copy numbers and Ki-67 protein expression associate with pathologic complete response in ERBB2-positive breast carcinoma patients treated with neoadjuvant trastuzumab-based therapy

    International Nuclear Information System (INIS)

    Calhoun, Benjamin C.; Portier, Bryce; Wang, Zhen; Minca, Eugen C.; Budd, G. Thomas; Lanigan, Christopher; Tubbs, Raymond R.; Morrison, Larry E.

    2016-01-01

    Pathologic complete response (pCR) after neoadjuvant chemotherapy for breast cancer is associated with improved prognosis in aggressive tumor subtypes, including ERBB2- positive tumors. Recent adoption of pCR as a surrogate endpoint for clinical trials in early stage breast cancer in the neoadjuvant setting highlights the need for biomarkers that, alone or in combination, help predict the likelihood of response to treatment. Biopsy specimens from 29 patients with invasive ductal carcinoma treated with trastuzumab-based therapy prior to definitive resection and pathologic staging were evaluated by dual color bright field in situ hybridization (dual ISH) using probes for MET, TOP2A, PTEN, and PIK3CA genes, each paired with centromeric probes to their respective chromosomes (chromosomes 7, 17, 10, and 3). Ki-67 expression was assessed by immunohistochemistry (IHC). Various parameters describing copy number alterations were evaluated for each gene and centromere probe to identify the optimal parameters for clinical relevance. Combinations of ISH parameters and IHC expression for Ki-67 were also evaluated. Of the four genes and their respective chromosomes evaluated by ISH, two gene copy number parameters provided statistically significant associations with pCR: MET gain or loss relative to chromosome 7 (AUC = 0.791, sensitivity = 92 % and specificity = 67 % at optimal cutoff, p = 0.0032) and gain of PTEN (AUC = 0.674, sensitivity = 38 % and specificity = 100 % at optimal cutoff, p = 0.039). Ki-67 expression was also found to associate significantly with pCR (AUC = 0.726, sensitivity = 100 % and specificity = 42 % at optimal cutoff, p = 0.0098). Combining gain or loss of MET relative to chromosome 7 with Ki-67 expression further improved the association with pCR (AUC = 0.847, sensitivity = 92 % and specificity = 83 % at optimal cutoffs, p = 0.0006). An immunogenotypic signature of low complexity comprising MET relative copy number and Ki-67 expression generated by dual

  2. Human epidermal growth factor receptor 2-positive breast cancer: heat shock protein 90 overexpression, Ki67 proliferative index, and topoisomerase II-α co-amplification as predictors of pathologic complete response to neoadjuvant chemotherapy with trastuzumab and docetaxel.

    Science.gov (United States)

    Bria, Emilio; Furlanetto, Jenny; Carbognin, Luisa; Brunelli, Matteo; Caliolo, Chiara; Nortilli, Rolando; Massari, Francesco; Pedron, Serena; Manfrin, Erminia; Pellini, Francesca; Bonetti, Franco; Sperduti, Isabella; Pollini, Giovanni Paolo; Scarpa, Aldo; Tortora, Giampaolo

    2015-02-01

    The combination of trastuzumab and chemotherapy is currently considered the standard of care for patients with locally advanced/operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The potential correlation between the pathologic complete response (pCR) and the overexpression of heat shock protein 90 (Hsp90), Ki67, and the amplification of topoisomerase II-α (TOPO2A) was investigated in a series of patients who received neoadjuvant treatment. HER2-amplified patients who received neoadjuvant trastuzumab-docetaxel were gathered. Baseline and postsurgical Hsp90 immunoscore, Ki67 proliferation index, and TOPO2A amplification were determined together with classic clinical-pathologic predictors and correlated with pCR and imaging data. A total of 24 patients were evaluated for response; pCR, clinical, and radiologic response were found in 4 patients (16.7%; 95% confidence interval [CI], 1.7-31.5), 9 patients (37.5%; 95% CI, 18.1-56.8), and 6 patients (25.0%; 95% CI, 7.6-42.3) patients, respectively. pCR was significantly higher in premenopausal (60.0% vs. 5.3%, P = .02) and negative hormonal receptor patients (50.0% vs. 5.6%, P = .03). A trend for patients with high Ki67 and TOPO2A/HER2 co-amplification was found (21.1% vs. none, P = .54; 50.0% vs. 12%, P = .16). pCR was significantly higher in patients with Hsp90 score 3+, in comparison with score 2+ and score 1+ (50.0% vs. 14.3% vs. none, P = .05). After treatment, a statistically significant lower Ki67 staining (30.0% vs. 17.5%, P = .005) and a trend for the decreased expression of high (score 3+) and moderate (score 2+) Hsp90 immunostaining (McNemar P = .25, Wilcoxon-Mann-Whitney P = .08) were found. Although underpowered, our data suggest that patients with HER2-positive breast cancer overexpressing Hsp90 should be investigated as a "newer" molecular subtype with a significantly higher chance of pCR when receiving anti-Her2 agents. Copyright © 2015 Elsevier Inc. All rights

  3. Fluorine-18-deoxyglucose positron emission tomography/computed tomography with Ki67 and GLUT-1 immunohistochemistry for evaluation of the radiosensitization effect of oleanolic acid on C6 rat gliomas.

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    Zhang, Yu; Xu, Huiqin; Wang, Hui; Yu, Wenjing; Zhao, Xuefeng; Xue, Yangyang

    2015-01-01

    The aim of this study was to investigate the radiosensitization effect of oleanolic acid (OA) in an in-vivo C6 rat glioma model using fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) and Ki67 and glucose transporter-1 (GLUT-1) immunohistochemistry(IHC) and evaluate the utility of 18F-FDG PET/CT in assessing early changes after radiotherapy. Tumor-bearing rats were divided into four groups: the control group (group A), the OA group(group B), the radiotherapy group (group C), and the OA combined with radiotherapy group (group D). 18F-FDG PET/CT images were obtained to monitor the tumor/muscle (T/M) ratio of 18F-FDG uptake before treatment,1 day after treatment, and 7 days after treatment. Tumor volume changes were also assessed, and hematoxylin and eosin staining and Ki67 and GLUT-1 IHC staining were also carried out. Before treatment, there were no obvious differences between the T/M ratios (F=0.147, P=0.931)and tumor volumes (F=0.177, P=0.911) among the four groups. At day 1 after treatment, statistical differences were observed in the T/M ratios (F=2.891, P=0.05), with decreased values in groups C and D compared with group A(tCA=2.354, tDA=2.356, PGLUT-1 in the four groups (F=16.667, 22.082, and 39.555,PGLUT-1, and our study also found a significant relationship between the expression of Ki67 and the expression of GLUT-1. OA has a radiosensitization effect on C6 rat glioma tumors in vivo, detected using 18F-FDG PET/CT and Ki67 and GLUT-1 IHC staining. 18F-FDG PET/CT is a potentially sensitive tool for the evaluation of early changes after radiotherapy.

  4. Intratumoral Heterogeneous F 18 Fluorodeoxyglucose Uptake Corresponds with Glucose Transporter 1 and Ki-67 Expression in a Case of Krukenberg Tumor: Localization of Intratumoral Hypermetabolic Focus by Fused PET/MR

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    Im, Hyung Jun; Kim, Youg il; Kim, Woo Ho; Kim, Seung Hyup; Kang, Keon Wook [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2011-06-15

    The expression of glucose transporters (Glut 1, Glut 3), Hexokinase II, and Ki-67 has been proposed to explain intratumoral heterogeneous F-18 fluorodeoxyglucose (FDG) uptake. We report a case of Krukenberg tumor with intratumoral heterogeneous FDG uptake which corresponded well with the expression tomography (PET)/magnetic resonance (MR) imaging was helpful for localizing the metabolically active area in the tumor specimen. This report elucidates the relationship between the intratumoral heterogeneous FDG uptake and biologic heterogeneity, and shows the usefulness of PET/MR in research on intratumoral heterogeneity.

  5. Protective effect of chronic caffeine intake on gene expression of brain derived neurotrophic factor signaling and the immunoreactivity of glial fibrillary acidic protein and Ki-67 in Alzheimer’s disease

    Science.gov (United States)

    Ghoneim, Fatma M; Khalaf, Hanaa A; Elsamanoudy, Ayman Z; Abo El-khair, Salwa M; Helaly, Ahmed MN; Mahmoud, El-Hassanin M; Elshafey, Saad H

    2015-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder with progressive degeneration of the hippocampal and cortical neurons. This study was designed to demonstrate the protective effect of caffeine on gene expression of brain derived neurotrophic factor (BDNF) and its receptor neural receptor protein-tyrosine kinase-β (TrkB) as well as glial fibrillary acidic protein (GFAP) and Ki-67 immunoreactivity in Aluminum chloride (AlCl3) induced animal model of AD. Fifty adult rats included in this study were classified into 5 group (10 rats each); negative and positive control groups (I&II), AD model group (III), group treated with caffeine from the start of AD induction (IV) and group treated with caffeine two weeks before AD induction (V). Hippocampal tissue BDNF and its receptor (TrkB) gene expression by real time RT-PCR in addition to immunohistochemical study of GFAP and Ki67 immunoreactivity were performed for all rats in the study. The results of this study revealed that caffeine has protective effect through improving the histological and immunohistochemical findings induced by AlCl3 as well as BDNF and its receptor gene expression. It could be concluded from the current study, that chronic caffeine consumption in a dose of 1.5 mg/kg body weight daily has a potentially good protective effect against AD. PMID:26339337

  6. Tumor size and proliferative marker geminin rather than Ki67 expression levels significantly associated with maximum uptake of 18F-deoxyglucose levels on positron emission tomography for breast cancers.

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    Arisa Nishimukai

    Full Text Available It has been well established that maximum standardized uptake value (SUVmax for 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT is clinically useful for evaluating treatment efficacy as well as predicting prognosis of breast cancer patients. Although SUVmax reflects increased glucose uptake and metabolism possibly induced by activation of growth factor signaling or TP53 dysfunction, tumor characteristics of SUVmax-high breast cancers remain to be elucidated. For the present study, we used immunohistochemical staining to investigate expressions of phospho-ribosomal protein S6 (pS6, downstream molecule of phosphatidyl inositol 3-kinase/Akt/mammalian target of the rapamycin/S6K pathway and phosphor-p44/42 mitogen-activated protein kinase (pMAPK. Expression levels of TP53 and proliferative marker geminin as well as Ki67 were also examined by means of immunostaining in 163 invasive breast cancers. Cutoff values were set at 10% for pS6, 20% for pMAPK and TP53, and 4% for geminin. The SUVmax levels were significantly higher in the pS6-positive (p = 0.0173, TP53-positive (p = 0.0207 and geminin-high cancers (p2cm and geminin-high showed SUVmax-high, while only 6 of 49 (12.2% breast cancers ≤2cm in size and with low geminin levels were SUVmax-high. In conclusion, we could determine that breast cancers with a large tumor and a geminin-high rather than Ki67-high proliferative marker were significantly associated with high levels of SUVmax. These findings may signify that SUVmax reflects tumor characteristics with high proliferative activity but not activation of mTOR/S6K and MAPK pathways or increased glucose metabolism due to dysfunction of TP53.

  7. Prolactin/androgen-inducible carboxypeptidase-D increases with nitrotyrosine and Ki67 for breast cancer progression in vivo, and upregulates progression markers VEGF-C and Runx2 in vitro.

    Science.gov (United States)

    Thomas, Lynn N; Chedrawe, Emily R; Barnes, Penelope J; Too, Catherine K L

    2017-07-01

    Carboxypeptidase-D (CPD) cleaves C-terminal arginine (Arg) to produce nitric oxide (NO). Upregulation of CPD and NO by 17β-estradiol, prolactin (PRL), and androgen increases survival of human breast cancer (BCa) cells in vitro. To demonstrate similar events in vivo, CPD, nitrotyrosine (NT, hallmark of NO action), androgen receptor (AR), prolactin receptor (PRLR), and phospho-Stat5a (for activated PRLR) levels were evaluated in benign and malignant human breast tissues, and correlated with cell proliferation (Ki67) and BCa progression (Cullin-3) biomarkers. Paraffin-embedded breast tissues were analyzed by immunohistochemistry (IHC). BCa progression markers in human MCF-7 and T47D BCa cell lines treated with NO donor SIN-1 or PRL, ±CPD inhibitors were analyzed by RT-qPCR and immunoblotting. IHC showed progressive increases in CPD, NT, Ki67, and Cullin-3 from low levels in benign tissues to high levels in ductal carcinoma in situ, low-grade, high-grade, and triple-negative BCa. CPD and NT staining were closely associated, implicating CPD in NO production. Phospho-Stat5a increased significantly from benign to high-grade BCa and was mostly nuclear. AR and PRLR were abundant in benign breast and BCa, including triple-negative tumors. SIN-1 and PRL increased VEGF-C and Runx2, but not Cullin-3, in BCa cell lines. PRL induction of VEGF-C and Runx2 was inhibited partly by CPD inhibitors, implicating NO, produced by PRL-regulated CPD, in BCa progression. The CPD-Arg-NO pathway contributes to BCa progression in vitro and in vivo. PRL/androgen activation of the pathway support combined AR and PRLR blockade as an additional therapy for BCa.

  8. Immunohistochemical evaluation of e-cadherin, Ki-67 and PCNA in canine mammary neoplasias: correlation of prognostic factors and clinical outcome Avaliação imuno-histoquímica da e-caderina, Ki-67 e PCNA nas neoplasias mamárias caninas: correlação dos fatores prognósticos com a evolução clínica

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    Debora A.P.C. Zuccari

    2008-04-01

    Full Text Available E-cadherin is a cell-cell adhesion molecule and low e-cadherin expression is related to invasiveness and may indicate a bad prognosis in mammary neoplasms. The expression of cell proliferation markers PCNA and especially Ki-67, has also proved to have a strong prognostic value in this tumor class. The expression of these markers was related to the clinical-pathological characteristics of 73 surgically removed mammary tumors in female dogs by immunohistochemistry. There was no statistical correlation between these markers and death by neoplasm, survival time and disease-free interval. However, the loss of e-cadherin expression and marked Ki-67 expression (p=0.016 were considered statistically significant for the diagnosis (p=0.032. When evaluated as independent factors, there was evidence of the relationship between the loss of e-cadherin expression and high PCNA expression with changes in the body status (divided into obese, normal and cachectic of female dogs (p=0.030; there was also evidence of the relationship between pseudopregnancy and e-cadherin alone (p=0.021 and for ulceration and PCNA alone (p=0.035. The significant correlation between the markers expression and these well known prognostic factors used individually or in combination suggests their prognostic value in canine mammary tumors.A e-caderina é uma molécula de adesão celular e a perda de sua expressão esta relacionada à invasão tumoral podendo indicar um prognóstico ruim nas neoplasias mamárias. A expressão dos marcadores de proliferação celular PCNA e especialmente o Ki-67, também têm mostrado forte valor prognóstico nesta classe tumoral. A expressão imuno-histoquímica destes marcadores foi relacionada com as características clinico-patológicas de 73 tumores removidos cirurgicamente de fêmeas caninas. Não houve correlação estatística entre estes marcadores e a morte por neoplasia, tempo de sobrevida e intervalo livre de doença. Entretanto, a perda da

  9. Automated Quantitative Analysis of p53, Cyclin D1, Ki67 and pERK Expression in Breast Carcinoma Does Not Differ from Expert Pathologist Scoring and Correlates with Clinico-Pathological Characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Cass, Jamaica D. [Division of Cancer Biology and Genetics, Cancer Research Institute, Queen’s University, Kingston K7L 3N6 (Canada); Varma, Sonal [Department of Pathology and Molecular Medicine, Queen’s University, Kingston K7L 3N6 (Canada); Day, Andrew G. [Kingston General Hospital, Kingston K7L 2V7 (Canada); Sangrar, Waheed [Division of Cancer Biology and Genetics, Cancer Research Institute, Queen’s University, Kingston K7L 3N6 (Canada); Rajput, Ashish B. [Department of Pathology and Molecular Medicine, Queen’s University, Kingston K7L 3N6 (Canada); Raptis, Leda H.; Squire, Jeremy [Division of Cancer Biology and Genetics, Cancer Research Institute, Queen’s University, Kingston K7L 3N6 (Canada); Madarnas, Yolanda [Department of Oncology, Queen’s University, Kingston K7L 3N6 (Canada); SenGupta, Sandip K. [Department of Pathology and Molecular Medicine, Queen’s University, Kingston K7L 3N6 (Canada); Elliott, Bruce E., E-mail: elliottb@queensu.ca [Division of Cancer Biology and Genetics, Cancer Research Institute, Queen’s University, Kingston K7L 3N6 (Canada); Department of Pathology and Molecular Medicine, Queen’s University, Kingston K7L 3N6 (Canada)

    2012-07-18

    There is critical need for improved biomarker assessment platforms which integrate traditional pathological parameters (TNM stage, grade and ER/PR/HER2 status) with molecular profiling, to better define prognostic subgroups or systemic treatment response. One roadblock is the lack of semi-quantitative methods which reliably measure biomarker expression. Our study assesses reliability of automated immunohistochemistry (IHC) scoring compared to manual scoring of five selected biomarkers in a tissue microarray (TMA) of 63 human breast cancer cases, and correlates these markers with clinico-pathological data. TMA slides were scanned into an Ariol Imaging System, and histologic (H) scores (% positive tumor area x staining intensity 0–3) were calculated using trained algorithms. H scores for all five biomarkers concurred with pathologists’ scores, based on Pearson correlation coefficients (0.80–0.90) for continuous data and Kappa statistics (0.55–0.92) for positive vs. negative stain. Using continuous data, significant association of pERK expression with absence of LVI (p = 0.005) and lymph node negativity (p = 0.002) was observed. p53 over-expression, characteristic of dysfunctional p53 in cancer, and Ki67 were associated with high grade (p = 0.032 and 0.0007, respectively). Cyclin D1 correlated inversely with ER/PR/HER2-ve (triple negative) tumors (p = 0.0002). Thus automated quantitation of immunostaining concurs with pathologists’ scoring, and provides meaningful associations with clinico-pathological data.

  10. Histomorfometria e índice proliferativo (Ki-67 no carcinoma escamocelular in situ de pregas vocais Histomorphometry and proliferative index in squamous cell carcinoma in situ of the vocal cords

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    Elisângela Barros Soares Mendonça

    2012-12-01

    Full Text Available INTRODUÇÃO: As displasias da laringe são precursoras do carcinoma escamocelular invasivo e constituem lesões pouco comuns, pois a maior parte dos casos é detectada como carcinoma invasor. OBJETIVO: Caracterizar as displasias acentuadas/carcinoma in situ da prega vocal quanto a área do epitélio, diâmetro dos núcleos e índice proliferativo, comparando esses dados com os obtidos no epitélio escamoso normal e de transição. MATERIAL E MÉTODO: Entre as 1.400 biópsias e peças cirúrgicas de lesões intraepiteliais e carcinomas invasivos de laringe (1994-2006, foram selecionados cinco casos (0,35% pareados com dois controles de epitélio normal e com a idade; todos foram submetidos a análise morfométrica e imuno--histoquímica (Ki-67. RESULTADOS: Comparando-se o epitélio displásico com o normal e de transição observou-se maior área e diâmetro nuclear no epitélio displásico; não houve diferenças significativas no diâmetro dos núcleos por camada entre o epitélio displásico e de transição; e o índice proliferativo foi maior no epitélio displásico com núcleos corados em todas camadas e menor com núcleos limitados a camada basal e parabasal no epitélio normal e de transição. CONCLUSÃO: verifica-se maior área no epitélio displásico. O diâmetro dos núcleos do epitélio displásico e do de transição são semelhantes, mas este apresenta núcleos uniformes em toda extensão em contraste com o pleomorfismo do epitélio displásico. O índice proliferativo (Ki-67 contribui para o diagnóstico diferencial das lesões escamosas da prega vocal, pois no carcinoma in situ/displasia acentuada observa-se maior número de núcleos marcados, os quais são vistos em todas as camadas no epitélio.INTRODUCTION: Laryngeal dysplasias, precursors of squamous cell carcinomas, are uncommon lesions, inasmuch as most cases are diagnosed as invasive carcinomas. OBJECTIVE: To characterize severe dysplasia/in situ carcinoma of the vocal

  11. Foco de criptas aberrantes e câncer da junção colorretal: análise da presença de lesões precoces microscópicas na periferia do câncer colorretal e correlação com a expressão da β-catenina e Ki-67

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    Daniel Cury Ogata

    Full Text Available OBJETIVO: Avaliar a presença de foco de criptas aberrantes (FCA em mucosa macroscopicamente normal, localizada na periferia de um câncer colorretal (CCR e correlacionar a progressão tumoral destes FCA para o CCR, por meio da expressão da β-catenina e o Ki-67. MÉTODOS: Utilizou-se 21 espécimes cirúrgicos contendo adenocarcinoma de junção retossigmóide. Foram coletadas amostras localizadas a 1 e 5 cm proximal e distal ao tumor, quando possível, bem como um fragmento da neoplasia. Os FCA foram selecionados. Subseqüentemente foi realizado estudo imunoistoquímico com os anticorpos β-catenina e o Ki-67. RESULTADOS: A expressão nuclear da β-catenina nos adenocarcinomas, revelou freqüência de 81%. O Ki-67 apresentou a mesma freqüência. Apesar disso o coeficiente Kappa revelou fraca concordância entre estes anticorpos. Foram observados 20 FCA, sendo que 13 destes focos localizavam-se nas proximidades do tumor. Nenhum dos FCA apresentou expressão da β-catenina nuclear, tampouco para o Ki-67. CONCLUSÃO: Nas áreas situadas a 1 cm da neoplasia colorretal, foi observada maior concentração de FCA em relação às áreas situadas a 5 cm do tumor. No entanto, não se observou correlação entre a expressão da β-catenina e ki-67 nos colonócitos das criptas aberrantes das áreas estudadas, com as células neoplásicas do adenocarcinoma.

  12. Acute sleep deprivation enhances avoidance learning and spatial memory and induces delayed alterations in neurochemical expression of GR, TH, DRD1, pCREB and Ki67 in rats.

    Science.gov (United States)

    Azogu, Idu; de la Tremblaye, Patricia Barra; Dunbar, Megan; Lebreton, Marianne; LeMarec, Nathalie; Plamondon, Hélène

    2015-02-15

    The current study investigated the effects of acute versus repeated periods of sleep deprivation on avoidance learning and spatial memory and on the expression of discrete biochemical brain signals involved in stress regulation, motivation and brain plasticity. Male Long-Evans rats were sleep deprived using the platform-over-water method for a single 4 h period (ASD) or for daily 4h RSD period on five consecutive days (CSD). The Y maze passive avoidance task (YM-PAT) and the Morris water maze (MWM) were used to determine learning and memory 1h following the last SD period. Region-specific changes in glucocorticoid receptors (GR), tyrosine hydroxylase (TH), dopamine 1 receptors (DRD1), phospho-CREB (pCREB) and Ki-67 expression were assessed in the hippocampal formation, hypothalamus and mesolimbic regions 72 h following RSD. Behaviorally, our findings revealed increased latency to re-enter the aversive arm in the YM-PAT and reduced distance traveled and latency to reach the platform in the MWM in ASD rats compared to all other groups, indicative of improved avoidance learning and spatial memory, respectively. Acute SD enhanced TH expression in the ventral tegmental area, nucleus accumbens and A11 neurons of the hypothalamus and DRD1 expression in the lateral hypothalamus. Cell proliferation in the subventricular zone and pCREB expression in the dentate gyrus and CA3 regions was also enhanced following acute SD. In contrast, repeated SD significantly elevated GR-ir at the hypothalamic paraventricular nucleus and CA1 and CA3 layers of the hippocampus compared to all other groups. Our study supports that a brief 4h sleep deprivation period is sufficient to induce delayed neurochemical changes. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Central registry in psychiatry: A structured review

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    Jyoti Prakash

    2014-01-01

    Full Text Available Background: Central registry in psychiatry is being practiced in few countries and has been found useful in research and clinical management. Role of central registry has also expanded over the years. Materials and Methods: All accessible internet database Medline, Scopus, Embase were accessed from 1990 till date. Available data were systematically reviewed in structured manner and analyzed. Results: Central registry was found useful in epidemiological analysis, association studies, outcome studies, comorbidity studies, forensic issue, effective of medication, qualitative analysis etc., Conclusion: Central registry proves to be effective tool in quantitative and qualitative understanding of psychiatry practice. Findings of studies from central registry can be useful in modifying best practice and evidence based treatment in psychiatry.

  14. ER, PgR, Ki67, p27Kip1, and histological grade as predictors of pathological complete response in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using taxanes followed by fluorouracil, epirubicin, and cyclophosphamide concomitant with trastuzumab

    International Nuclear Information System (INIS)

    Kurozumi, Sasagu; Inoue, Kenichi; Takei, Hiroyuki; Matsumoto, Hiroshi; Kurosumi, Masafumi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari

    2015-01-01

    Neoadjuvant chemotherapy (NAC) with taxanes followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), and concurrent trastuzumab is a potent regimen for HER2 over-expressing breast cancer. A high pathological complete response (pCR) rate has been achieved using this regimen; however, the predictive factors and prognostic effects of pCR currently remain unclear. In the present study, we determined whether pCR was related to histological grade (HG) and several biological factors including p27 Kip1 . We also assessed the prognosis of the pCR and non-pCR groups, and expected differences between those positive and negative for lymph node metastasis after chemotherapy. A total of 129 Japanese women with HER2-positive invasive breast cancer received either paclitaxel or docetaxel followed by FEC, with the concomitant administration of trastuzumab. The statuses of HG, ER, PgR, Ki67, and p27 Kip1 were evaluated to determine their relationship with pCR. Relapse-free survival (RFS) and overall survival (OS) were also analyzed for their relationship with pCR and pathological nodal involvement. pCR was obtained in 84 out of 129 patients and the pCR rate was 65.1 %. The pCR rates related to 5 factors were as follows: HG (grade 3, 70.0 % vs. grades 1–2, 36.8 %), ER (negative, 78.6 % vs. positive, 40.0 %), PgR (negative, 75.3 % vs. positive, 38.9 %), Ki67 (high, 72.0 % vs. low, 47.2 %), and p27 Kip1 (low, 71.0 % vs. high, 50.0 %). RFS was significantly better in the pCR group than in the non-pCR group (p = 0.018). Patients with remaining nodal disease in the pCR group had worse OS (p = 0.0002). High-HG, low-ER, low-PgR, high-Ki67, and low-p27 Kip1 were identified as predictive factors of pCR in NAC with trastuzumab, while pCR and negative nodes were predictive of better survivals. The online version of this article (doi:10.1186/s12885-015-1641-y) contains supplementary material, which is available to authorized users

  15. Expression and Clinical Significance of Claudin-7, PDL-1, PTEN, c-Kit, c-Met, c-Myc, ALK, CK5/6, CK17, p53, EGFR, Ki67, p63 in Triple-negative Breast Cancer-A Single Centre Prospective Observational Study.

    Science.gov (United States)

    Constantinou, Chloe; Papadopoulos, Savvas; Karyda, Eirini; Alexopoulos, Athanasios; Agnanti, Niki; Batistatou, Anna; Harisis, Haris

    2018-01-01

    To explore the relationship between p53, p63, c-kit, Ki67, cMet, claudin7, CK5/6, CK17, AR, PTEN, EGFR, ALK, PDL-1 and c-MYC expression with the clinicopathological features of triple- negative breast cancer. Immunohistochemistry was performed in 84 triple-negative breast cancer samples. A statistically significant relationship between tumour grade and claudin-7 (p=0.004) and between protein p53 and positive lymph nodes (p=0.015) was found. High expression of claudin-7 (OR=65.8, 95%CI=4.35-995.19, p-value=0.003) and low expression of c-kit (OR=0.14, 95%CI=0.025-0.793, p-value=0.026) and protein p63 (OR=0.18 95%CI=0.035-0.978, p-value=0.047) was associated with higher tumour grade. Higher AR expression (OR=13.44, 95%CI=1.28-141.56, p-value=0.031) and lower expression of CK5/6 cytokeratins was found in patients with positive lymphovascular invasion (LVI) (OR=0.072, 95%CI=0.007-0.732, p-value=0.026). Only the cell proliferation index (Ki67) has been proven to be statistically significant for disease-free survival (p-value=0.0378), and overall survival (p-value=0.0186). High expression of claudin-7 and low expression of c-kit and protein p63 are associated with higher tumour grade. AR and CK5/6 expression seem to be important in LVI. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. A Review of Select Centralized Pain Syndromes

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    David R. Spiegel

    2015-01-01

    Full Text Available Pain can be broadly divided into 3 classes, including nociceptive or inflammatory pain (protective, neuropathic (pathological, occurring after damage to the nervous system, or centralized (pathological, due to abnormal function but with no damage or inflammation to the nervous system. The latter has been posited to occur when descending analgesic pathways are attenuated and/or glutamatergic transmission is facilitated. Additionally, this “pain prone phenotype” can be associated with early life trauma and a suboptimal response to opiates. This article will review the relationships between centralized pain syndromes (ie, fibromyalgia, chronic low back pain, childhood sexual abuse, and opiate misuse. Finally, treatment implications, potentially effecting primary care physicians, will be discussed.

  17. Central Institutional Review Board Review for an Academic Trial Network

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    Kaufmann, Petra; O’Rourke, P. Pearl

    2016-01-01

    Problem Translating discoveries into therapeutics is often delayed by lengthy start-up periods for multicenter clinical trials. One cause of delay can be multiple institutional review board (IRB) reviews of the same protocol. Approach When developing the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT; hereafter, NN), the National Institute of Neurological Disorders and Stroke (NINDS) established a central IRB (CIRB) based at Massachusetts General Hospital, the academic medical center that received the NN clinical coordinating center grant. The 25 NN sites, located at U.S. academic institutions, agreed to required CIRB use for NN trials. Outcomes To delineate roles and establish legal relationships between the NN sites and the CIRB, the CIRB executed reliance agreements with the sites and their affiliates that hold federalwide assurance for the protection of human subjects (FWA); this took, on average, 84 days. The first NN protocol reviewed by the CIRB achieved full approval to allow participant enrollment within 56 days and went from grant award to the first patient visit in less than four months. The authors describe anticipated challenges related to institutional oversight responsibilities versus regulatory CIRB review as well as unanticipated challenges related to working with complex organizations that include multiple FWA-holding affiliates. Next Steps The authors anticipate that CIRB use will decrease NN trial start-up time and thus promote efficient trial implementation. They plan to collect data on timelines and costs associated with CIRB use. The NINDS plans to promote CIRB use in future initiatives. PMID:25406606

  18. CENTRAL BANKS AND FINANCIAL STABILITY - Literature review

    Directory of Open Access Journals (Sweden)

    Adina APÃTÃCHIOAE

    2013-06-01

    Full Text Available Financial stability is a feature of the financial system, reflecting its ability to determine an efficient allocation of the resources and to manage financial risk by its own self-regulating mechanisms. Since the condition of financial systems changes over time, due to various shocks that components suffers, financial stability is a dynamic feature, but the system itself is constantly attempting to recover under the action of specific auto regulatory mechanisms. It is generally accepted that central banks play an important role in ensuring financial stability, there are a number of specific features that can help them achieve financial stability. Recent phenomena such as deregulation, globalization, the intensification of innovation, and so on, have supplemented the functions of central banks and at the same time, led to an intensification of links between banking and other large sectors of the financial system: insurance and financial markets.The objective of this article is to present the different views in the literature on the role of the central bank in ensuring financial stability and the new challenges that she must confront in assuming this new mandate. The role of central banks in ensuring financial stability is in the forefront and should be expanded beyond the traditional functions of stability, which determined that monetary and stability policies to converge. Moreover, due to vulnerabilities manifested by the financial markets in recent decades and that capital flows have become more intense, these vulnerabilities may spread rapidly, increasing the fragility of all markets and, for this reason, ensuring financial stability has become a key objective of public policies. Especially, since the stability of financial systems stimulates economic development and improved living standards, the competent authorities pays a particular attention to these issues

  19. Centralized National Ethical Review of Clinical Trials in Croatia

    Science.gov (United States)

    Vitezić, Dinko; Lovrek, Maja; Tomić, Siniša

    2009-01-01

    Aim To present the Croatian system of ethical review of clinical trials and assessment outcomes of the applications reviewed by the Croatian Central Ethics Committee. Methods Clinical trial applications reviewed by the Croatian Central Ethics Committee, which has the legal mandate to review clinical trials of medicinal products and medical devices, were retrospectively analyzed from May 2004 to the end of 2008 according to the number, research area, and type of opinion issued. Applications from 2008 were analyzed separately according to the study phase, participants (adult trials vs pediatric trials), and sponsor (commercial trials vs academic trials). Data were analyzed by descriptive statistics. Results Since its establishment in 2004, the Croatian Central Ethics Committee has reviewed 407 trials. The greatest number of clinical trials was in the field of oncology (n = 69), mental and behavioral disorders (n = 52), and endocrine, nutritional, and metabolic diseases (n = 50). In the initial assessment of clinical trials, 60% applications received a conditionally positive opinion. In 28% of applications, the opinion had to be postponed because additional documentation or explanations were required. In 2008, the Croatian Central Ethics Committee reviewed 99 trials, most of which were phase III trials (n = 57). Five clinical trials included pediatric population and 3 were academic clinical trials. Conclusion The model of centralized clinical trial review seems to be appropriate for the current number of clinical trials conducted in Croatia. The efficient and standardized review process of clinical trials by the Central Ethics Committee may positively affect the increasing number of clinical trials conducted in Croatia. Future development includes the transparency of the clinical trials through a publically available database and establishing the basis for conducting academic clinical trials. PMID:19399943

  20. Field review of fish habitat improvement projects in central Idaho

    International Nuclear Information System (INIS)

    Beschta, R.L.; Griffith, J.; Wesche, T.A.

    1993-05-01

    The goal of this field review was to provide information to the Bonneville Power Administration (BPA) regarding previous and ongoing fish habitat improvement projects in central Idaho. On July 14, 1992, the review team met at the Sawtooth National Recreation Area office near Ketchum, Idaho, for a slide presentation illustrating several habitat projects during their construction phases. Following the slide presentation, the review team inspected fish habitat projects that have been implemented in the last several years in the Stanley Basin and adjacent valleys. At each site the habitat project was described to the field team and a brief period for project inspection followed. The review team visited approximately a dozen sites on the Challis, Sawtooth, and Boise National Forests over a period of approximately two and a half days. There are two objectives of this review namely to summarize observations for specific field sites and to provide overview commentary regarding the BPA habitat improvement program in central Idaho

  1. Use of distributed ledger technology by central banks: A review

    Directory of Open Access Journals (Sweden)

    César del Río

    2017-12-01

    Full Text Available This paper reviews what stage the central banks of the world’s leading economies are at in their study and adoption of distributed ledger technology (DLT to reengineer their various systems and functions. A brief description of DLT will be given, followed by an analysis of central banks’ publications and pronouncements to determine what each central bank is doing on their journey to DLT adoption. It was found that of the central banks for which information was available, all of them have expressed interest in DLT and have evaluated it to some extent. Nevertheless, no central bank has an operational DLT-based system at this point. This is because some issues remain regarding the speed, cost of processing, security, transparency and privacy, legal settlement finality, scalability and network effects of the technology. As DLT matures, the expectation is that these issues will begin to be resolved.

  2. A review of neem biopesticide utilization and challenges in Central ...

    African Journals Online (AJOL)

    The status of neem biopesticide research, utilization and challenges in the central part of northern Nigeria was reviewed. In the sampled areas such as the Federal Capital Territory (FCT), Abuja and Niger State, the highest category of neem users (17.19%) were the rural farmers. Majority of the neem users obtained their ...

  3. Thiophene Scaffold as Prospective Central Nervous System Agent: A Review.

    Science.gov (United States)

    Deep, Aakash; Narasimhan, Balasubramanian; Aggarwal, Swati; Kaushik, Dhirender; Sharma, Arun K

    2016-01-01

    Heterocyclic compounds are extensively dispersed in nature and are vital for life. Various investigational approaches towards Structural Activity Relationship that focus upon the exploration of optimized candidates have become vastly important. Literature studies tell that for a series of compounds that are imperative in industrial and medicinal chemistry, thiophene acts as parent. Among various classes of heterocyclic compounds that have potential central nervous system activity, thiophene is the most important one. In the largely escalating chemical world of heterocyclic compounds showing potential pharmacological character, thiophene nucleus has been recognized as the budding entity. Seventeen Papers were included in this review article to define the central nervous system potential of thiophene. This review article enlightens the rationalized use and scope of thiophene scaffold as novel central nervous system activity such as anticonvulsant, acetylcholinesterase inhibitor, cyclin-dependent kinase 5 (cdk5/p25) inhibitors, CNS depressant, capability to block norepinephrine, serotonin and dopamine reuptake by their respective transporters etc. The Finding of this review confirm the importance of thiophene scaffold as potential central nervous system agents. From this outcome, ideas for future molecular modifications leading to the novel derivatives with better constructive pharmacological potential may be derived.

  4. Фактор пролиферации Ki-67 как показатель прогноза при раке молочной железы

    OpenAIRE

    ЛАЗУКИН АЛЕКСЕЙ ВАЛЕРЬЕВИЧ

    2014-01-01

    В обзоре проанализирована роль процессов пролиферации и апоптоза в развитии неоплазий, а также -роль пролиферативного онкомаркера Ki-67 как показателя прогноза при раке молочной железы. Обсуждается возможность использования маркера Ki-67 для таргетной терапии рака молочной железы. Показано, что комплексная терапия открывает новые перспективы для рационального лечения больных раком молочной железы....

  5. Central sensitization in chronic low back pain: A narrative review.

    Science.gov (United States)

    Sanzarello, Ilaria; Merlini, Luciano; Rosa, Michele Attilio; Perrone, Mariada; Frugiuele, Jacopo; Borghi, Raffaele; Faldini, Cesare

    2016-11-21

    Low back pain is one of the four most common disorders in all regions, and the greatest contributor to disability worldwide, adding 10.7% of total years lost due to this health state. The etiology of chronic low back pain is, in most of the cases (up to 85%), unknown or nonspecific, while the specific causes (specific spinal pathology and neuropathic/radicular disorders) are uncommon. Central sensitization has been recently recognized as a potential pathophysiological mechanism underlying a group of chronic pain conditions, and may be a contributory factor for a sub-group of patients with chronic low back pain. The purposes of this narrative review are twofold. First, to describe central sensitization and its symptoms and signs in patients with chronic pain disorders in order to allow its recognition in patients with nonspecific low back pain. Second, to provide general treatment principles of chronic low back pain with particular emphasis on pharmacotherapy targeting central sensitization.

  6. Role of carbohydrate in central fatigue: a systematic review.

    Science.gov (United States)

    Khong, T K; Selvanayagam, V S; Sidhu, S K; Yusof, A

    2017-04-01

    Carbohydrate (CHO) depletion is linked to neuromuscular fatigue during exercise. While its role at peripheral level is relatively well understood, less is known about its impact centrally. The aim of this systematic review was to critically analyze the effects of CHO on central fatigue (CF) assessed by various neurophysiological techniques. Four databases were searched using PRISMA guidelines through February 2016. The inclusion criteria were: CHO as intervention against a placebo control, fatigue induced by prolonged exercise and assessed using neurophysiological measures [voluntary activation (VA), superimposed twitch (SIT), M-wave, electromyography], alongside maximal voluntary contraction (MVC). Seven papers were reviewed, where exercise duration lasted between 115 and 180 min. CHO improved exercise performance in three studies, whereby two of them attributed it to CF via attenuation of VA and SIT reductions, while the other indicated peripheral involvement via attenuation of M-wave reduction. Although a few studies suggest that CHO attenuates CF, data on its direct effects on neurophysiological outcome measures are limited and mixed. Generally, measures employed in these studies were inadequate to conclude central contribution to fatigue. Factors including the techniques used and the lack of controls render additional confounding factors to make definitive deductions. Future studies should employ consistent techniques and appropriate neurophysiological controls to distinguish CHO effect at central level. The use of pharmacological intervention should be incorporated to elucidate involvement of central mechanisms. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Time to institutional review board approval with local versus central review in a multicenter pragmatic trial.

    Science.gov (United States)

    Neuman, Mark D; Gaskins, Lakisha J; Ziolek, Tracy

    2018-02-01

    Central institutional review board (IRB) review will be required for National Institutes of Health-funded multisite human subjects research as of January 2018, with similar requirements extending to most US multisite human research in 2020. Nonetheless, little is known regarding the relative efficiency of central versus local IRB review for multicenter studies. We compared the amount of time required for central versus local IRB review and approval for sites in one ongoing multicenter randomized trial. The REGAIN Trial (Regional versus General Anesthesia for Promoting Independence after Hip Fracture; clinicaltrials.gov number: NCT02507505) is an ongoing randomized trial comparing standard-care spinal anesthesia to standard-care general anesthesia for patients undergoing hip fracture surgery. After approval of the protocol by the sponsor IRB, each participating US site opted either to submit the protocol for local IRB review or to designate the sponsor IRB as the IRB of record (i.e. central IRB) via an authorization agreement after a limited local review. For each US REGAIN site approved through 18 April 2017, we assessed (1) the time in calendar days from protocol receipt to IRB submission, (2) the time in calendar days from IRB submission to IRB approval, and (3) the total time in calendar days from protocol receipt to IRB approval (i.e. time from protocol receipt to IRB submission plus time from IRB submission to IRB approval). The main study protocol was submitted to the sponsor IRB on 25 May 2015 and approved on 8 July 2015 (44 days). Out of 34 sites, 9 received initial approval from the central (sponsor) IRB; 25 sought initial approval via local review. The median time from protocol receipt to IRB submission was 39 days for sites approved by the central IRB (interquartile range: 35-134) versus 58 days for sites approved via local review (interquartile range: 41-105; p = 0.711). The median time from IRB submission to IRB approval for sites approved by

  8. Water Related Health Problems in Central Asia—A Review

    Directory of Open Access Journals (Sweden)

    Zakir Bekturganov

    2016-05-01

    Full Text Available The present paper provides an extensive literature review on water related health issues in Central Asia. Even though the per capita amount of available freshwater is substantial in all Central Asian states the uneven distribution in time and space creates problems for water availability. Due to this, the Central Asian economies are developing under increasing water deficiency. The degradation of water supply systems and sewage treatment plants is often severe leading to potentially high water loss rates and inadequate accessibility to safe water supply. In this context, rural areas are the most affected. Low tariffs in combination with absent metering and low collection rates for water fees mean that operation and maintenance costs for basic services of water supply and sanitation are not covered. Unsafe water supply contains both microbiological and non-microbiological contaminants. Helminthiasis and intestinal protozoa infections are of considerable public health importance in Central Asia. Agricultural and industrial pollution is especially affecting downstream areas of Amu Darya and Syr Darya rivers. In large areas copper, zinc, and chromium concentrations in water exceed maximum permissible concentration. Thus, there is an urgent need to strengthen the environmental monitoring system. Small-scale water supply and sanitation systems need to be developed in line with more efficient public spending on these.

  9. Central venous pressure monitoring via peripherally or centrally inserted central catheters: a systematic review and meta-analysis.

    Science.gov (United States)

    Sanfilippo, Filippo; Noto, Alberto; Martucci, Gennaro; Farbo, Marco; Burgio, Gaetano; Biasucci, Daniele G

    2017-07-14

    The central venous pressure (CVP) is the most commonly used static marker of preload for guiding fluid therapy in critically ill patients, though its usefulness remains controversial. Centrally inserted central catheters (CICCs) are the gold-standard devices for CVP monitoring but peripherally inserted central catheters (PICCs) may represent a valid alternative. We undertook a systematic review and meta-analysis with the aim to investigate whether the difference between PICC- and CICC-measured CVP is not significant. We searched for clinical studies published in PubMed and EMBASE databases from inception until December 21st 2016. We included studies providing data on paired and simultaneous CVP measurement from PICCs and CICCs. We conducted two analyses on the values of CVP, the first one according to the total number of CVP assessments, the second one considering the number of patients recruited. Four studies matched the inclusion criteria, but only three of them provided data for the meta-analyses. Both analyses showed non-significant differences between PICC-measured and CICC-measured CVP: 1489 paired simultaneous CVP assessments (MD 0.16, 95%CI -0.14, 0.45, p = 0.30) on a total of 57 patients (MD 0.22, 95%CI -1.46, 1.91, p = 0.80). Both analyses showed no heterogeneity (I2 = 0%). Available evidence supports that CVP monitoring with PICCs is accurate and reproduces similar values to those obtained from CICCs. The possibility to monitor CVP should not be used among clinical criteria for preferring a CICC over a PICC line.

  10. Measurement Properties of the Central Sensitization Inventory: A Systematic Review.

    Science.gov (United States)

    Scerbo, Thomas; Colasurdo, Joseph; Dunn, Sally; Unger, Jacob; Nijs, Jo; Cook, Chad

    2017-08-29

    Central sensitization (CS) is a phenomenon associated with several medical diagnoses, including postcancer pain, low back pain, osteoarthritis, whiplash, and fibromyalgia. CS involves an amplification of neural signaling within the central nervous system that results in pain hypersensitivity. The purpose of this systematic review was to gather published studies of a widely used outcome measure (the Central Sensitization Inventory [CSI]), determine the quality of evidence these publications reported, and examine the measurement properties of the CSI. Four databases were searched for publications from 2011 (when the CSI was developed) to July 2017. The Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist was applied to evaluate methodological quality and risk of bias. In instances when COSMIN did not offer a scoring system for measurement properties, qualitative analyses were performed. Fourteen studies met inclusion criteria. Quality of evidence examined with the COSMIN checklist was determined to be good to excellent for all studies for their respective measurement property reports. Interpretability measures were consistent when publications were analyzed qualitatively, and construct validity was strong when examined alongside other validated measures relating to CS. An assessment of the published measurement studies of the CSI suggest the tool generates reliable and valid data that quantify the severity of several symptoms of CS. © 2017 World Institute of Pain.

  11. Central presbycusis: a review and evaluation of the evidence.

    Science.gov (United States)

    Humes, Larry E; Dubno, Judy R; Gordon-Salant, Sandra; Lister, Jennifer J; Cacace, Anthony T; Cruickshanks, Karen J; Gates, George A; Wilson, Richard H; Wingfield, Arthur

    2012-09-01

    The authors reviewed the evidence regarding the existence of age-related declines in central auditory processes and the consequences of any such declines for everyday communication. This report summarizes the review process and presents its findings. The authors reviewed 165 articles germane to central presbycusis. Of the 165 articles, 132 articles with a focus on human behavioral measures for either speech or nonspeech stimuli were selected for further analysis. For 76 smaller-scale studies of speech understanding in older adults reviewed, the following findings emerged: (1) the three most commonly studied behavioral measures were speech in competition, temporally distorted speech, and binaural speech perception (especially dichotic listening); (2) for speech in competition and temporally degraded speech, hearing loss proved to have a significant negative effect on performance in most of the laboratory studies; (3) significant negative effects of age, unconfounded by hearing loss, were observed in most of the studies of speech in competing speech, time-compressed speech, and binaural speech perception; and (4) the influence of cognitive processing on speech understanding has been examined much less frequently, but when included, significant positive associations with speech understanding were observed. For 36 smaller-scale studies of the perception of nonspeech stimuli by older adults reviewed, the following findings emerged: (1) the three most frequently studied behavioral measures were gap detection, temporal discrimination, and temporal-order discrimination or identification; (2) hearing loss was seldom a significant factor; and (3) negative effects of age were almost always observed. For 18 studies reviewed that made use of test batteries and medium-to-large sample sizes, the following findings emerged: (1) all studies included speech-based measures of auditory processing; (2) 4 of the 18 studies included nonspeech stimuli; (3) for the speech-based measures

  12. A Review on Central Nervous System Effects of Gastrodin

    Directory of Open Access Journals (Sweden)

    Yuan Liu

    2018-02-01

    Full Text Available Rhizoma Gastrodiae (also known as Tian ma, the dried rhizome of Gastrodia elata Blume, is a famous Chinese herb that has been traditionally used for the treatment of headache, dizziness, spasm, epilepsy, stoke, amnesia and other disorders for centuries. Gastrodin, a phenolic glycoside, is the main bioactive constituent of Rhizoma Gastrodiae. Since identified in 1978, gastrodin has been extensively investigated on its pharmacological properties. In this article, we reviewed the central nervous system (CNS effects of gastrodin in preclinical models of CNS disorders including epilepsy, Alzheimer's disease, Parkinson's disease, affective disorders, cerebral ischemia/reperfusion, cognitive impairment as well as the underlying mechanisms involved and, where possible, clinical data that support the pharmacological activities. The sources and pharmacokinetics of gastrodin were also reviewed here. As a result, gastrodin possesses a broad range of beneficial effects on the above-mentioned CNS diseases, and the mechanisms of actions include modulating neurotransmitters, antioxidative, anti-inflammatory, suppressing microglial activation, regulating mitochondrial cascades, up-regulating neurotrophins, etc. However, more detailed clinical trials are still in need for positioning it in the treatment of neurological disorders.

  13. 78 FR 69426 - Submission for OMB Review; 30-Day Comment Request: NIH NCI Central Institutional Review Board...

    Science.gov (United States)

    2013-11-19

    ... Central Institutional Review Board (CIRB) Initiative (NCI) SUMMARY: Under the provisions of Section 3507(a... Evaluation Program, Operations and Informatics Branch, 9609 Medical Center Drive, Rockville, MD 20850 or call... Collection: NIH NCI Central Institutional Review Board (CIRB) Initiative (NCI), 0925-0625, Expiration Date 1...

  14. IMPACT OF CENTRAL SURGICAL REVIEW IN A STUDY OF MALIGNANT GERM CELL TUMORS

    Science.gov (United States)

    Billmire, Deborah F.; Rescorla, Frederick J.; Ross, Jonathan H.; Schlatter, Marc G.; Dicken, Bryan J.; Krailo, Mark D.; Rodriguez-Galindo, Carlos; Olson, Thomas A.; Cullen, John W.; Frazier, A. Lindsay

    2016-01-01

    BACKGROUND Verification of surgical staging has received little attention in clinical oncology trials for both children and adults. Central surgical review in a study of malignant pediatric germ cell tumors provided an opportunity to assess the impact of this process. METHODS Children’s Oncology Group study AGCT0132 data submission at study entry required operative note, surgical checklist, pathology and imaging reports. Central surgical review during the study included assessment for completeness of submitted data and confirmation of assigned stage. Review resulted in one of three conclusions: assigned status confirmed, assignment withheld pending review of additional information requested, or institutional assignment of stage disputed with reasons for recommended stage assignment explained. Changes in stage assignment based on central surgical review were left at the discretion of the enrolling institution. RESULTS 206 patients underwent central review. Failure to submit required data elements or need for clarification was noted in 40%. Disagreement with stage assignment occurred in 10%; the highest rate of discordance was in ovarian tumors submitted as stage I (34%). 17 of 21 discordant patients were reassigned to the stage recommended by central review. 4 patients with ovarian tumors not meeting central review criteria for Stage I remained in that stratum by institutional decision. Two-year event free survival (EFS) in Stage I ovarian tumor patients was 25% (1/4) for discordant patients compared to 57% (9/21) in patients who met Stage I criteria by central review. CONCLUSIONS Central review of stage assignment by a dedicated study surgeon improved collection of complete data and assignment of correct tumor stage at study entry, and allowed for prompt initiation of chemotherapy in patients determined not to have Stage I disease. PMID:25783295

  15. Review and Future Perspective of Central Receiver Design and Performance

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Guangdong; Libby, Cara

    2017-06-27

    Concentrating solar power (CSP) technology provides a commercial solar option to the utility-scale electricity market. CSP is unique in its ability to include low-cost thermal storage; thus, it can generate electricity when the sun is not available and dispatch electricity to meet varying load requirements. Within the suite of CSP technologies, the central receiver design represents the state-of-the-art technology, promising low cost, high performance, and dispatchable energy production. Current total capacity of central receiver plants worldwide is about 1.0 gigawatt (electric) with operating plants in Spain and the United States, as well as projects under construction in Asia, the Middle East, and North Africa. Central receiver technology has been under development since the 1950s, and a variety of central receiver designs have been explored. A distinguishing feature is the heat transfer medium. Central receiver designs exist that use dense fluids, gases, and solid particles in this role. Water/steam and molten salt receivers have been adopted in current commercial plants and are often coupled with a steam-Rankine power cycle with an operating temperature of less than 600 degrees C. Many new central receiver concepts, such as the volumetric air, supercritical carbon dioxide (sCO2), solid particle, and liquid-metal receiver designs, are under active research and development (R&D). New designs target operating temperatures generally higher than 700 degrees C-800 degrees C -- and even above 1000 degrees C -- so that higher-performance power cycles such as the sCO2-Brayton cycle or air-Brayton/steam-Rankine combined cycle can be used to promote greater overall system efficiency. Central receiver thermal storage provides dispatchability unavailable from variable-output renewables such as solar photovoltaic and wind power. Case study analysis of the California grid shows that there is a limit on the amount of non-dispatchable renewable generation that the grid can

  16. Review and future perspective of central receiver design and performance

    Science.gov (United States)

    Zhu, Guangdong; Libby, Cara

    2017-06-01

    Concentrating solar power (CSP) technology provides a commercial solar option to the utility-scale electricity market. CSP is unique in its ability to include low-cost thermal storage; thus, it can generate electricity when the sun is not available and dispatch electricity to meet varying load requirements. Within the suite of CSP technologies, the central receiver design represents the state-of-the-art technology, promising low cost, high performance, and dispatchable energy production. Current total capacity of central receiver plants worldwide is about 1.0 gigawatt (electric) with operating plants in Spain and the United States, as well as projects under construction in Asia, the Middle East, and North Africa. Central receiver technology has been under development since the 1950s, and a variety of central receiver designs have been explored. A distinguishing feature is the heat transfer medium. Central receiver designs exist that use dense fluids, gases, and solid particles in this role. Water/steam and molten salt receivers have been adopted in current commercial plants and are often coupled with a steam-Rankine power cycle with an operating temperature of less than 600°C. Many new central receiver concepts, such as the volumetric air, supercritical carbon dioxide (sCO2), solid particle, and liquid-metal receiver designs, are under active research and development (R&D). New designs target operating temperatures generally higher than 700°C-800°C—and even above 1000°C—so that higher-performance power cycles such as the sCO2-Brayton cycle or air-Brayton/steam-Rankine combined cycle can be used to promote greater overall system efficiency. Central receiver thermal storage provides dispatchability unavailable from variable-output renewables such as solar photovoltaic and wind power. Case study analysis of the California grid shows that there is a limit on the amount of non-dispatchable renewable generation that the grid can accommodate, beyond which

  17. Effect of hyperthermia on the central nervous system: a review

    NARCIS (Netherlands)

    Sminia, P.; van der Zee, J.; Wondergem, J.; Haveman, J.

    1994-01-01

    Experimental data show that nervous tissue is sensitive to heat. Animal data indicate that the maximum tolerated heat dose after local hyperthermia of the central nervous system (CNS) lies in the range of 40-60 min at 42-42 x 5 degrees C or 10-30 min at 43 degrees C. No conclusions concerning the

  18. The role of Ki-67 in breast cancer | Mannell | South African Journal ...

    African Journals Online (AJOL)

    South African Journal of Surgery. Journal Home · ABOUT · Advanced Search · Current Issue · Archives · Journal Home > Vol 54, No 2 (2016) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register · Download this PDF file. The PDF file you selected should load here if your ...

  19. Differences in Expression of EGFR, Ki67 and p-EPK in Oral Cavity ...

    African Journals Online (AJOL)

    Signaling through the PI3K/Akt/mTOR pathway is activated by growth factor ligand binding to receptor tyrosine kinases and regulates several cellular functions that are critical for tumorigenesis. The p-EPK, a tumor suppressor gene, negatively regulates the PI3K/Akt pathway. The loss of p-EPK function causes increased.

  20. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection

    NARCIS (Netherlands)

    Beuschlein, Felix; Weigel, Jens; Saeger, Wolfgang; Kroiss, Matthias; Wild, Vanessa; Daffara, Fulvia; Libé, Rosella; Ardito, Arianna; Ghuzlan, Abir Al; Quinkler, Marcus; Oßwald, Andrea; Ronchi, Cristina L.; De Krijger, Ronald; Feelders, Richard A.; Waldmann, Jens; Willenberg, Holger S.; Deutschbein, Timo; Stell, Anthony; Reincke, Martin; Papotti, Mauro; Baudin, Eric; Tissier, Frédérique; Haak, Harm R.; Loli, Paola; Terzolo, Massimo; Allolio, Bruno; Müller, Hans Helge; Fassnacht, Martin

    2015-01-01

    Background: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. Objective: The aim of this study was to identify markers with prognostic value for patients in this clinical setting. Design, Setting, and Participants: From the German ACC registry, 319

  1. Mini review of Central Exclusive Production at LHC

    CERN Document Server

    Brona, Grzegorz

    2009-01-01

    The LHC experiments provide an unprecedented coverage in pseudo-rapidity. This advantage and high LHC luminosity allow for broad studies of central exclusive production (CEP) processes such as exclusive production of ¡, di-leptons, di-photons and di-jets. Finally, with the proposed near beam detectors (FP420 and FP220) the exclusive Higgs and SUSY states will be also accesible. The discussion is focused on the CMS programme, as both CMS and ATLAS have similar kinematical coverage and may perform similar studies.

  2. Mini review of Central Exclusive Production at LHC

    CERN Document Server

    Brona, Grzegorz

    2009-01-01

    The LHC experiments provide an unprecedented coverage in pseudo-rapidity. This advantage and the high LHC luminosity allow for broad studies of central exclusive production (CEP) \\mbox{processes} such as exclusive production of $\\Upsilon$, di-leptons, di-photons and di-jets. With the proposed near beam detectors (FP420 and FP220) exclusive Higgs and SUSY states will be also \\mbox{accesible}. The \\mbox{discussion} is focused on the CMS programme, but both CMS and ATLAS have similar \\mbox{kinematical} coverage and may perform similar studies.

  3. Central giant cell granuloma: A case report and review

    Directory of Open Access Journals (Sweden)

    Krishnaveni Buduru

    2017-01-01

    Full Text Available Central giant cell granuloma (CGCG is a benign intra-osseous lesion of unknown etiology, and occurs in jaws. Clinically and radiographically difference between its nature - aggressive and non-aggressive can be made. It is characterized histologically by cellular fibrous tissue containing multiple foci of hemorrhage, aggregations of multinucleated giant cells, and occasionally, trabeculae of woven bone. Histologically, identical lesions occur in patients with known genetic defects such as cherubism, Noonan syndrome, or neurofibromatosis type I. It has an increased predilection for mandible and females in younger age group. Surgical curettage or resection is the most common therapy in aggressive lesions. The drawback is undesirable damage to the jaw or teeth, tooth germs, and frequent recurrences. Non-aggressive tumors respond well to such treatments. We are presenting a case of an aggressive type of CGCG of mandible in a young patient, who presented with massive swelling associated with loss of teeth in just 6 months duration.

  4. Role of ultrasound for central catheter tip localization in neonates: a review of the current evidence.

    Science.gov (United States)

    Sharma, Deepak; Farahbakhsh, Nazanin; Tabatabaii, Seyyed Ahmad

    2018-02-15

    Central catheters are known as "life lines" in intensive care units and are used frequently in neonatal intensive care unit (NICU) for multiple indications. The central catheters used in NICU includes umbilical venous catheter (UVC), umbilical arterial catheter (UAC) and peripherally inserted central catheter (PICC) lines. The tip of these central lines needs to be in a correct position as malpositioned central line tips lead to many neonatal complications. Radiograph either abdomen or chest is the most widely used modality for locating the tip of the central catheter. There are many disadvantages of radiographic confirmation of tip position and recently ultrasound (USG)/echocardiography has been used for localization of catheter tip. USG provides real-time assessment of the tip position with other added advantages like no radiation exposure, need for minimal training for performing USG, minimal handling of the neonate, identification of migration of central lines and making repositioning of central lines under USG guidance. The present evidence supports the use of USG/Echo for localization of central catheter tip and USG has shown to have good sensitivity, specificity, positive predictive value and negative predictive value when compared with a radiograph. In this review, we discuss about the role of USG/Echo in the identification of tip of central catheters in neonatal care.

  5. Postsecondary Transitions for Youth in Appalachia's Central Subregions: A Review of Education Research, 1995-2015

    Science.gov (United States)

    Kannapel, Patricia J.; Flory, Michael A.

    2017-01-01

    This article reviews research on issues surrounding postsecondary transitions for youth in middle (North Central, Central, and South Central) Appalachia, a region that faces numerous education challenges because of its geography, poverty, and economy. Examining published research and data from 1995 to 2015, the review seeks to inform education…

  6. Central obesity and the Mediterranean diet: A systematic review of intervention trials.

    Science.gov (United States)

    Bendall, C L; Mayr, H L; Opie, R S; Bes-Rastrollo, M; Itsiopoulos, C; Thomas, C J

    2017-10-17

    Central obesity is associated with chronic low-grade inflammation, and is a risk factor for cardiometabolic syndrome. The Mediterranean diet pattern has a convincing evidence-base for improving cardiometabolic health. This review investigated the impact of Mediterranean diet interventions on central obesity, specifically. A systematic literature search was conducted in the MEDLINE, CINAHL, EMBASE and Cochrane library databases. Search terms included: 'Mediterranean Diet', 'Mediterranean dietary pattern', 'central obesity' and 'visceral fat'. The search was limited to English language and humans ≥18 years. Eighteen articles met the eligibility criteria and reported at least one outcome measure of central obesity with Mediterranean diet intervention. Central obesity measures included waist circumference (16 studies), waist-hip ratio (5 studies) and visceral fat (2 studies). Thirteen (72%) of the studies, totaling 7186 subjects (5168 subjects assigned to a Mediterranean Diet), reported a significant reduction in central obesity with a Mediterranean-type diet. However, seven out of these 13 interventions employed energy restriction, and only three showed a statistically significant favorable effect of the Mediterranean diet relative to a control group. This systematic review highlights the potential for a Mediterranean diet intervention to reduce central obesity and in turn reduce obesity-related chronic disease risk and associated public health burden.

  7. Evidence for central sensitization in chronic whiplash: a systematic literature review.

    Science.gov (United States)

    Van Oosterwijck, J; Nijs, J; Meeus, M; Paul, L

    2013-03-01

    It has been suggested that sensitization of the central nervous system plays an important role in the development and maintenance of chronic (pain) complaints experienced by whiplash patients. According to the PRISMA guidelines, a systematic review was performed to screen and evaluate the existing clinical evidence for the presence of central sensitization in chronic whiplash. DATABASES AND DATA TREATMENT: Predefined keywords regarding central sensitization and chronic whiplash were combined in electronic search engines PubMed and Web of Science. Full text clinical reports addressing studies of central sensitization in human adults with chronic complaints due to a whiplash trauma were included and reviewed on methodological quality by two independent reviewers. From the 99 articles that were identified, 24 met the inclusion criteria, and 22 articles achieved sufficient scores on methodological quality and were discussed. These studies evaluated the sensitivity to different types of stimuli (mechanical, thermal, electrical). Findings suggest that although different central mechanisms seem to be involved in sustaining the pain complaints in whiplash patients, hypersensitivity of the central nervous system plays a significant role. Persistent pain complaints, local and widespread hyperalgesia, referred pain and (thoracic) allodynia, decreased spinal reflex thresholds, inefficient diffuse noxious inhibitory controls activation and enhanced temporal summation of pain were established in chronic whiplash patients. Although the majority of the literature provides evidence for the presence of central sensitization in chronic whiplash, underlying mechanisms are still unclear and future studies with good methodological quality are necessary. In addition, international guidelines for the definition, clinical recognition, assessment and treatment of central sensitization are warranted. © 2012 European Federation of International Association for the Study of Pain Chapters.

  8. The role of central sensitization in shoulder pain: A systematic literature review.

    Science.gov (United States)

    Sanchis, Marc N; Lluch, Enrique; Nijs, Jo; Struyf, Filip; Kangasperko, Maija

    2015-06-01

    Hyperexcitability of the central nervous system has been suggested to play an important role in pain experienced by patients with unilateral shoulder pain. A systematic literature review following the PRISMA guidelines was performed to evaluate the existing evidence related to the presence of central sensitization in patients with unilateral shoulder pain of different etiologies including those with chronic subacromial impingement syndrome. Studies addressing neuropathic pain (e.g., post-stroke shoulder pain) were not considered. Electronic databases PubMed, EBSCO, and Web of Science were searched to identify relevant articles using predefined keywords regarding central sensitization and shoulder pain. Articles were included till September 2013. Full-text clinical reports addressing studies of central sensitization in human adults with unilateral shoulder complaints including those diagnosed with subacromial impingement syndrome were included and screened for methodological quality by two independent reviewers. A total of 10 articles were retrieved for quality assessment and data extraction. All studies were cross-sectional (case-control) or longitudinal in nature. Different subjective and objective parameters, considered manifestations of central sensitization, were established in subjects with unilateral shoulder pain of different etiologies, including those receiving a diagnosis of subacromial impingement syndrome. Overall results suggest that, although peripheral mechanisms are involved, hypersensitivity of the central nervous system plays a role in a subgroup within the shoulder pain population. Although the majority of the literature reviewed provides emerging evidence for the presence of central sensitization in unilateral shoulder pain (including those diagnosed with subacromial impingement syndrome), our understanding of the role central sensitization plays in the shoulder pain population is still in its infancy. Future studies with high methodical quality

  9. Internationalisation of firms from Central and Eastern Europe: a systematic literature review

    OpenAIRE

    Caputo, Andrea; Pellegrini, Massimiliano M.; Dabic, Marina; Dana, Leo-Paul

    2016-01-01

    Purpose\\ud The purpose of this paper is to provide a systematic review of the literature addressing internationalisation of firms from Central and Eastern Europe (CEE).\\ud \\ud Design/methodology/approach\\ud This paper presents an inter-disciplinary systematic review of literature about the internationalisation of firms from CEE.\\ud \\ud Findings\\ud Three different clusters of research were identified. In the “Internationalisation Processes” cluster, containing many comparative studies, the foc...

  10. Ultrasound-guided central venous catheter placement : a structured review and recommendations for clinical practice

    NARCIS (Netherlands)

    Saugel, Bernd; Scheeren, Thomas W L; Teboul, Jean-Louis

    2017-01-01

    The use of ultrasound (US) has been proposed to reduce the number of complications and to increase the safety and quality of central venous catheter (CVC) placement. In this review, we describe the rationale for the use of US during CVC placement, the basic principles of this technique, and the

  11. Thrombosis prophylaxis in patient populations with a central venous catheter - A systematic review

    NARCIS (Netherlands)

    Klerk, Clara P. W.; Smorenburg, Susanne M.; Büller, Harry R.

    2003-01-01

    Background: Central venous catheters (CVCs) are used in a wide variety of patients. Associated complications are thrombosis and infection. It is a matter of debate whether thromboprophylaxis is beneficial. Methods: We performed a systematic review of 3 different patient populations to render the

  12. Book reviews:Bats of Southern and Central Africa: A Biogeographic ...

    African Journals Online (AJOL)

    Book reviews:Bats of Southern and Central Africa: A Biogeographic and Taxonomic Synthesis by Ara Monadjem, Peter John Taylor, F.P.D. (Woody) Cotterill & M. Corrie Schoeman. Wits University Press, Johannesburg. 2010. Pp. 564. Price R591.00 (paperback).ISBN.

  13. Phase 5 storage (Project W-112) Central Waste Complex operational readiness review, final report

    Energy Technology Data Exchange (ETDEWEB)

    Wight, R.H.

    1997-05-30

    This document is the final report for the RFSH conducted, Contractor Operational Readiness Review (ORR) for the Central Waste Complex (CWC) Project W-112 and Interim Safety Basis implementation. As appendices, all findings, observations, lines of inquiry and the implementation plan are included.

  14. Phase V storage (Project W-112) Central Waste Complex operational readiness review, final report

    International Nuclear Information System (INIS)

    Wight, R.H.

    1997-01-01

    This document is the final report for the RFSH conducted, Contractor Operational Readiness Review (ORR) for the Central Waste Complex (CWC) Project W-112 and Interim Safety Basis implementation. As appendices, all findings, observations, lines of inquiry and the implementation plan are included

  15. Book review: Vetter, H. 2005. Terralog. Turtles of the World. Vol. 3. Central and South America

    Directory of Open Access Journals (Sweden)

    2006-12-01

    Full Text Available Book review: Vetter, H. 2005. Terralog. Turtles of the World. Vol. 3. Central and South America/Schildkröten der Welt Band 3. Mittel- und Südamerika: 1-128, color pictures 606 + 9. Edition Chimaira, Frankfurt, Germany.ISBN 3-930612-82-8; 29.7 x 20.8 cm

  16. Central Venous Catheter-Related Tachycardia in the Newborn: Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Aya Amer

    2016-01-01

    Full Text Available Central venous access is an important aspect of neonatal intensive care management. Malpositioned central catheters have been reported to induce cardiac tachyarrhythmia in adult populations and there are case reports within the neonatal population. We present a case of a preterm neonate with a preexisting umbilical venous catheter (UVC, who then developed a supraventricular tachycardia (SVT. This was initially treated with intravenous adenosine with transient reversion. Catheter migration was subsequently detected, with the UVC tip located within the heart. Upon withdrawal of the UVC and a final dose of adenosine, the arrhythmia permanently resolved. Our literature review confirms that tachyarrhythmia is a rare but recognised neonatal complication of malpositioned central venous catheters. We recommend the immediate investigation of central catheter position when managing neonatal tachyarrhythmia, as catheter repositioning is an essential aspect of management.

  17. Central sensitization in patients with rheumatoid arthritis: a systematic literature review.

    Science.gov (United States)

    Meeus, Mira; Vervisch, Stijn; De Clerck, Luc S; Moorkens, Greta; Hans, Guy; Nijs, Jo

    2012-02-01

    The goal of the present study is to systematically review the scientific literature addressing central sensitization and central nociceptive processing in patients with rheumatoid arthritis (RA). To identify relevant articles, we searched PubMed and Web of Science. The search strategy was a combination of terms of the following groups: "Rheumatoid arthritis," inflammatory joint pain, or arthritis; AND (central) sensitization, (central) hypersensitivity, central hyperexcitability, pain modulation, pain processing, neural inhibition, or pain physiopathology; AND pain, nociception, hyperalgesia, pain threshold, or algometry. Articles fulfilling the inclusion criteria were screened for methodologic quality with specific checklists to evaluate different study designs (2 independent raters). Twenty-four full-text articles were included, of which the majority were case-control studies, followed by nonsystematic reviews, cross-sectional studies, and case reports. Methodologic quality was very heterogeneous. Preliminary evidence for generalized hyperalgesia in RA is available. In addition, the mechanism behind impaired central nociceptive processing remains rather obscure. The role of cytokines and neuropeptides especially remains to be elucidated. Windup appears to develop more easily in RA, but evidence in support of impaired nociceptive inhibition and cognitive emotional sensitization (sensitization due to cognitive bias) is scarce. The symmetrical manifestation of the disease, the poor relation between disease activity and symptoms, and the generalized hyperalgesia at both articular and nonarticular sites for different kinds of stimuli are indicative of the presence of central sensitization in RA patients. Further research is required to provide firm evidence in support of various aspects of central sensitization in humans with RA. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Herbal medicine for idiopathic central precocious puberty: A protocol for a systematic review of controlled trials.

    Science.gov (United States)

    Lee, Hye Lim; Lee, Yoo Been; Choi, Jun-Yong; Lee, Ju Ah

    2018-03-01

    Herbal medicine is widely used in East Asia to treat idiopathic central precocious puberty (ICPP). Most of the available clinical trials that investigated herbal medicine for ICPP have been included in this review. This systematic review will assess the efficacy and safety of herbal medicine for ICPP. Eleven databases, including Asian databases, will be searched for studies conducted through 2018. We will include randomized controlled trials assessing herbal medicine for ICPP. The risk of bias will be evaluated using the Cochrane risk of bias assessment tool, and confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation instrument. This systematic review will be published in a peer-reviewed journal and disseminated both electronically and in print. The review will be updated to inform and guide health care practices. PROSPER 2018 CRD42018087988.

  19. Index Case of Cutaneous Follicular Mycosis Fungoides With Central Nervous System Involvement and Review of Literature.

    Science.gov (United States)

    Nguyen, Giang Huong; Mohler, Alexander; Leppert, Michelle; Parra, Cindy; Zeng, Yue-Ping; Prok, Lori; Schowinsky, Jeffrey; Magro, Cynthia M; Pacheco, Theresa; Ney, Douglas

    2018-03-01

    Central nervous system involvement by mycosis fungoides (MF) is rare and is usually seen in advanced stages of the disease. We describe a patient with early-stage follicular MF who presented with changes in mental status. Despite an initial diagnosis of vasculitis based on clinical and brain biopsy results, the postmortem examination revealed extensive infiltration of MF cells throughout the brain with leptomeningeal involvement. This case in addition to the accompanied review of literature illustrates the importance of the awareness of central nervous system involvement by MF and highlights the need for an urgent neurologic evaluation in patients with a history of MF now presenting with neurologic signs or symptoms.

  20. Central sensitization syndrome and the initial evaluation of a patient with fibromyalgia: a review.

    Science.gov (United States)

    Fleming, Kevin C; Volcheck, Mary M

    2015-04-01

    In both primary care and consultative practices, patients presenting with fibromyalgia (FM) often have other medically unexplained somatic symptoms and are ultimately diagnosed as having central sensitization (CS). Central sensitization encompasses many disorders where the central nervous system amplifies sensory input across many organ systems and results in myriad symptoms. A pragmatic approach to evaluate FM and related symptoms, including a focused review of medical records, interviewing techniques, and observations, is offered here, giving valuable tools for identifying and addressing the most relevant symptoms. At the time of the clinical evaluation, early consideration of CS may improve the efficiency of the visit, reduce excessive testing, and help in discerning between typical and atypical cases so as to avoid an inaccurate diagnosis. Discussion of pain and neurophysiology and sensitization often proves helpful.

  1. Central Sensitization Syndrome and the Initial Evaluation of a Patient with Fibromyalgia: A Review

    Directory of Open Access Journals (Sweden)

    Kevin C. Fleming

    2015-04-01

    Full Text Available In both primary care and consultative practices, patients presenting with fibromyalgia (FM often have other medically unexplained somatic symptoms and are ultimately diagnosed as having central sensitization (CS. Central sensitization encompasses many disorders where the central nervous system amplifies sensory input across many organ systems and results in myriad symptoms. A pragmatic approach to evaluate FM and related symptoms, including a focused review of medical records, interviewing techniques, and observations, is offered here, giving valuable tools for identifying and addressing the most relevant symptoms. At the time of the clinical evaluation, early consideration of CS may improve the efficiency of the visit, reduce excessive testing, and help in discerning between typical and atypical cases so as to avoid an inaccurate diagnosis. Discussion of pain and neurophysiology and sensitization often proves helpful.

  2. Central coherence in eating disorders: an updated systematic review and meta-analysis.

    Science.gov (United States)

    Lang, Katie; Lopez, Carolina; Stahl, Daniel; Tchanturia, Kate; Treasure, Janet

    2014-12-01

    A bias towards local information over the global "gist" (weak central coherence, WCC), has been identified as a possible contributing and maintaining factor in eating disorders (ED). The present study aimed to provide an updated review of the WCC literature and examine the hypothesis that individuals with ED have WCC. The new search found 12 eligible studies. Meta-analyses were performed on nine of these 12 studies, the remaining three were commented on individually. Data were combined with data from the previous 2008 review, and meta- analyses were performed on 16 studies (nine studies from the new search and seven studies from 2008 review). Meta-analysis of the Group Embedded Figures Task provided evidence of superior local processing across all ED subtypes (pooled effect size of d = -0.62 (95% CI = -0.94, -0.31), P review has provided evidence of superior local processing, which supports the WCC hypothesis in ED.

  3. What indication, morbidity and mortality for central pancreatectomy in oncological surgery? A systematic review.

    Science.gov (United States)

    Santangelo, Michele; Esposito, Anna; Tammaro, Vincenzo; Calogero, Armando; Criscitiello, Carmen; Roberti, Giuseppe; Candida, Maria; Rupealta, Niccolò; Pisani, Antonio; Carlomagno, Nicola

    2016-04-01

    Conventional pancreatic resections for pancreatic neck and body diseases include pancreaticoduodenectomy, distal pancreatectomy with or without splenectomy, and total pancreatectomy. Recent studies have reported encouraging results of non-traditional pancreatic resections, including central pancreatectomy (CP), for central pancreatic disease. This surgical approach offers the potentials of low postoperative morbidity and preservation of metabolic functions. This study performs a systematic review on CP. A comprehensive literature search was conducted, for the period 1992-2015, on three worldwide databases: PubMed, Scopus, ISI-Web of Knowledge. We focused on indications, morbidity and mortality of this surgical procedure. The review shows that CP is particularly suitable for small-medium size diseases localized into the pancreatic body. This procedure is associated with an increased postoperative morbidity but an excellent postoperative pancreatic function. CP is a safe and effective procedure when performed following the right indications. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

  4. Does Acupuncture Alter Pain-related Functional Connectivity of the Central Nervous System? A Systematic Review.

    Science.gov (United States)

    Villarreal Santiago, María; Tumilty, Steve; Mącznik, Aleksandra; Mani, Ramakrishnan

    2016-08-01

    Acupuncture has been studied for several decades to establish evidence-based clinical practice. This systematic review aims to evaluate evidence for the effectiveness of acupuncture in influencing the functional connectivity of the central nervous system in patients with musculoskeletal pain. A systematic search of the literature was conducted to identify studies in which the central response of acupuncture in patients with musculoskeletal pain was evaluated by neuroimaging techniques. Databases searched were AMED, CINAHL, Cochrane Library, EMBASE, MEDLINE, PEDro, Pubmed, SCOPUS, SPORTDiscuss, and Web of Science. Included studies were assessed by two independent reviewers for their methodological quality by using the Downs and Black questionnaire and for their levels of completeness and transparency in reporting acupuncture interventions by using Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) criteria. Seven studies met the inclusion criteria. Three studies were randomized controlled trials (RCTs) and four studies were nonrandomized controlled trials (NRCTs). The neuroimaging techniques used were functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). Positive effects on the functional connectivity of the central nervous system more consistently occurred during long-term acupuncture treatment. The results were heterogeneous from a descriptive perspective; however, the key findings support acupuncture's ability to alter pain-related functional connectivity in the central nervous system in patients with musculoskeletal pain. Copyright © 2015. Published by Elsevier B.V.

  5. Risk factors for central venous catheter-related infections in a neonatal population - systematic review,

    OpenAIRE

    Rosado, Viviane; Camargos, Paulo A.M.; Anchieta, Lêni M.; Bouzada, Maria C.F.; Oliveira, Gabriela M. de; Clemente, Wanessa T.; Romanelli, Roberta M. de C.

    2018-01-01

    Abstract Objective: This was a systematic review of the incidence density and risk factors for central venous catheter-related infections in a neonatal population. Data source: The MEDLINE, Embase, Cochrane, BDENF, SciELO, and LILACS databases were used without date or language restriction. Studies that analyzed risk factors for bloodstream infections in newborns were identified. Data synthesis: A total of 134 articles were found that met the eligibility criteria. Of these articles, 14 wer...

  6. Risk factors for central venous catheter‐related infections in a neonatal population – systematic review

    OpenAIRE

    Viviane Rosado; Paulo A.M. Camargos; Lêni M. Anchieta; Maria C.F. Bouzada; Gabriela M. de Oliveira; Wanessa T. Clemente; Roberta M. de C. Romanelli

    2018-01-01

    Objective: This was a systematic review of the incidence density and risk factors for central venous catheter‐related infections in a neonatal population. Data source: The MEDLINE, Embase, Cochrane, BDENF, SciELO, and LILACS databases were used without date or language restriction. Studies that analyzed risk factors for bloodstream infections in newborns were identified. Data synthesis: A total of 134 articles were found that met the eligibility criteria. Of these articles, 14 were sele...

  7. Whole Tumor Histogram-profiling of Diffusion-Weighted Magnetic Resonance Images Reflects Tumorbiological Features of Primary Central Nervous System Lymphoma.

    Science.gov (United States)

    Schob, Stefan; Münch, Benno; Dieckow, Julia; Quäschling, Ulf; Hoffmann, Karl-Titus; Richter, Cindy; Garnov, Nikita; Frydrychowicz, Clara; Krause, Matthias; Meyer, Hans-Jonas; Surov, Alexey

    2018-04-01

    Diffusion weighted imaging (DWI) quantifies motion of hydrogen nuclei in biological tissues and hereby has been used to assess the underlying tissue microarchitecture. Histogram-profiling of DWI provides more detailed information on diffusion characteristics of a lesion than the standardly calculated values of the apparent diffusion coefficient (ADC)-minimum, mean and maximum. Hence, the aim of our study was to investigate, which parameters of histogram-profiling of DWI in primary central nervous system lymphoma can be used to specifically predict features like cellular density, chromatin content and proliferative activity. Pre-treatment ADC maps of 21 PCNSL patients (8 female, 13 male, 28-89 years) from a 1.5T system were used for Matlab-based histogram profiling. Results of histopathology (H&E staining) and immunohistochemistry (Ki-67 expression) were quantified. Correlations between histogram-profiling parameters and neuropathologic examination were calculated using SPSS 23.0. The lower percentiles (p10 and p25) showed significant correlations with structural parameters of the neuropathologic examination (cellular density, chromatin content). The highest percentile, p90, correlated significantly with Ki-67 expression, resembling proliferative activity. Kurtosis of the ADC histogram correlated significantly with cellular density. Histogram-profiling of DWI in PCNSL provides a comprehensible set of parameters, which reflect distinct tumor-architectural and tumor-biological features, and hence, are promising biomarkers for treatment response and prognosis. Copyright © 2018. Published by Elsevier Inc.

  8. Subjective endpoints in clinical trials: the case for blinded independent central review

    Directory of Open Access Journals (Sweden)

    Walovitch R

    2013-09-01

    Full Text Available Richard Walovitch,1 Bin Yao,2 Patrick Chokron,1 Helen Le,1 Glenn Bubley3 1WorldCare Clinical, LLC, Boston, MA, USA; 2Amgen, Inc, Thousand Oaks, CA, USA; 3Director of Genitourinary Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA Abstract: Primary efficacy and safety endpoints in clinical trials are often subjective assessments made by site personnel. For international confirmatory trials conducted over broad geographic regions and different clinical practice settings, variability in these subjective assessments can be substantial. Centralized endpoint assessment committees (EACs offer a mechanism through which to reduce assessment bias and potentially increase assessment precision and accuracy, particularly in open-label trials. An overview of regulatory agencies' rationales for an EAC is reviewed. In addition, the two main types of EACs, the blinded independent central review, and the consensus panel are compared. Selection of endpoints for EAC evaluation and design of EAC process to maximize EAC value proposition are also discussed. Keywords: endpoint assessment committee, FDA, central review, BICR, adjudication, consensus panel

  9. Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI.

    Science.gov (United States)

    Cagnie, Barbara; Coppieters, Iris; Denecker, Sien; Six, Jasmien; Danneels, Lieven; Meeus, Mira

    2014-08-01

    The aim of the present study was to systematically review the literature addressing pain-induced changes in the brain related to central sensitization in patients with fibromyalgia (FM) using specific functional (rs-fMRI and fMRI) and structural (voxel-based morphometry-VBM) brain MRI techniques. PubMed and Web of Science were searched for relevant literature using different key word combinations related to FM, brain MRI, and central sensitization. Full-text reports fulfilling the inclusion criteria were assessed on risk of bias and reviewed by two independent reviewers. From the 61 articles that were identified, 22 met the inclusion criteria and achieved sufficient methodological quality. Overall, eight articles examined structural brain (VBM) changes in patients with FM, showing moderate evidence that central sensitization is correlated with gray matter volume decrease in specific brain regions (mainly anterior cingulate cortex and prefrontal cortex). However, global gray matter volume remains unchanged. A total of 13 articles evaluated brain activity (fMRI) in response to a nociceptive stimulus. Findings suggest a higher but similar pattern of activation of the pain matrix in FM patients compared to controls. There is also evidence of decreased functional connectivity in the descending pain-modulating system in FM patients. Overall, two articles examined intrinsic brain connectivity in FM patients with rs-fMRI. In conclusion, there is moderate evidence for a significant imbalance of the connectivity within the pain network during rest in patients with FM. The included studies showed a moderate evidence for region-specific changes in gray matter volume, a decreased functional connectivity in the descending pain-modulating system, and an increased activity in the pain matrix related to central sensitization. More research is needed to evaluate the cause-effect relationship. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Natural history of treatment-emergent central sleep apnea on positive airway pressure: A systematic review.

    Science.gov (United States)

    Nigam, Gaurav; Riaz, Muhammad; Chang, Edward T; Camacho, Macario

    2018-01-01

    Treatment-emergent central sleep apnea (TECSA) is observed in some patients when they are treated with positive airway pressure (PAP) after significant resolution of the preexisting obstructive events in patients with obstructive sleep apnea. The objective of this study was to systematically review the literature for studies describing the natural history of TECSA. PubMed, Medline, Scopus, Web of Science, and Cochran Library databases were searched through June 29, 2017. Five studies were identified that discussed the natural history of TECSA. TECSA developed in 3.5%-19.8% of PAP-treated patients. Treatment-persistent central sleep apnea (TPCSA), representing protracted periods of PAP therapy-related central apneas, was noted in 14.3%-46.2% of patients with TECSA. Delayed-TECSA (D-TECSA) represents an anomalous TECSA entity appearing weeks to months after initial PAP therapy. D-TECSA was observed in 0.7%-4.2% of OSA patients undergoing PAP treatment (after at least 1 month). In patients with TECSA, a higher apnea-hypopnea index (AHI) and central apnea index at their baseline study or a higher residual AHI at their titration study may be associated with an increased likelihood of conversion to TPCSA. Overall, TECSA developed in 3.5%-19.8% of PAP-treated patients with OSA. The vast majority will experience complete resolution of central apneas over a few weeks to months. Unfortunately, about a third of patients with TECSA may continue to exhibit persistence of central sleep apnea on reevaluation. A small proportion may experience D-TECSA after few weeks to several months of initial exposure to PAP therapy.

  11. Role of centralized review processes for making reimbursement decisions on new health technologies in Europe.

    Science.gov (United States)

    Stafinski, Tania; Menon, Devidas; Davis, Caroline; McCabe, Christopher

    2011-01-01

    The purpose of this study was to compare centralized reimbursement/coverage decision-making processes for health technologies in 23 European countries, according to: mandate, authority, structure, and policy options; mechanisms for identifying, selecting, and evaluating technologies; clinical and economic evidence expectations; committee composition, procedures, and factors considered; available conditional reimbursement options for promising new technologies; and the manufacturers' roles in the process. A comprehensive review of publicly available information from peer-reviewed literature (using a variety of bibliographic databases) and gray literature (eg, working papers, committee reports, presentations, and government documents) was conducted. Policy experts in each of the 23 countries were also contacted. All information collected was reviewed by two independent researchers. Most European countries have established centralized reimbursement systems for making decisions on health technologies. However, the scope of technologies considered, as well as processes for identifying, selecting, and reviewing them varies. All systems include an assessment of clinical evidence, compiled in accordance with their own guidelines or internationally recognized published ones. In addition, most systems require an economic evaluation. The quality of such information is typically assessed by content and methodological experts. Committees responsible for formulating recommendations or decisions are multidisciplinary. While criteria used by committees appear transparent, how they are operationalized during deliberations remains unclear. Increasingly, reimbursement systems are expressing interest in and/or implementing reimbursement policy options that extend beyond the traditional "yes," "no," or "yes with restrictions" options. Such options typically require greater involvement of manufacturers which, to date, has been limited. Centralized reimbursement systems have become an

  12. Review article: Hydrological modeling in glacierized catchments of central Asia - status and challenges

    Science.gov (United States)

    Chen, Yaning; Li, Weihong; Fang, Gonghuan; Li, Zhi

    2017-02-01

    Meltwater from glacierized catchments is one of the most important water supplies in central Asia. Therefore, the effects of climate change on glaciers and snow cover will have increasingly significant consequences for runoff. Hydrological modeling has become an indispensable research approach to water resources management in large glacierized river basins, but there is a lack of focus in the modeling of glacial discharge. This paper reviews the status of hydrological modeling in glacierized catchments of central Asia, discussing the limitations of the available models and extrapolating these to future challenges and directions. After reviewing recent efforts, we conclude that the main sources of uncertainty in assessing the regional hydrological impacts of climate change are the unreliable and incomplete data sets and the lack of understanding of the hydrological regimes of glacierized catchments of central Asia. Runoff trends indicate a complex response to changes in climate. For future variation of water resources, it is essential to quantify the responses of hydrologic processes to both climate change and shrinking glaciers in glacierized catchments, and scientific focus should be on reducing uncertainties linked to these processes.

  13. Role of centralized review processes for making reimbursement decisions on new health technologies in Europe

    Directory of Open Access Journals (Sweden)

    Stafinski T

    2011-08-01

    Full Text Available Tania Stafinski1, Devidas Menon2, Caroline Davis1, Christopher McCabe31Health Technology and Policy Unit, 2Health Policy and Management, School of Public Health, University of Alberta, Edmonton, Alberta, Canada; 3Academic Unit of Health Economics, Leeds Institute for Health Sciences, University of Leeds, Leeds, UKBackground: The purpose of this study was to compare centralized reimbursement/coverage decision-making processes for health technologies in 23 European countries, according to: mandate, authority, structure, and policy options; mechanisms for identifying, selecting, and evaluating technologies; clinical and economic evidence expectations; committee composition, procedures, and factors considered; available conditional reimbursement options for promising new technologies; and the manufacturers' roles in the process.Methods: A comprehensive review of publicly available information from peer-reviewed literature (using a variety of bibliographic databases and gray literature (eg, working papers, committee reports, presentations, and government documents was conducted. Policy experts in each of the 23 countries were also contacted. All information collected was reviewed by two independent researchers.Results: Most European countries have established centralized reimbursement systems for making decisions on health technologies. However, the scope of technologies considered, as well as processes for identifying, selecting, and reviewing them varies. All systems include an assessment of clinical evidence, compiled in accordance with their own guidelines or internationally recognized published ones. In addition, most systems require an economic evaluation. The quality of such information is typically assessed by content and methodological experts. Committees responsible for formulating recommendations or decisions are multidisciplinary. While criteria used by committees appear transparent, how they are operationalized during deliberations

  14. Central sensitization in urogynecological chronic pelvic pain: a systematic literature review.

    Science.gov (United States)

    Kaya, Serap; Hermans, Linda; Willems, Tine; Roussel, Nathalie; Meeus, Mira

    2013-01-01

    Chronic pelvic pain (CPP) is a complex pain syndrome. Since its pathogenesis is still poorly understood and structural alterations in pain related brain regions may be present, there is a greater acceptance that sensitization of the central nervous system (CNS) plays an important role in the development and maintenance of chronicity. The purpose of this study is to systematically review the scientific evidence regarding central sensitization (CS) in female patients with urogynecological CPP. Systematic review of the literature. A systematic literature search was conducted in PubMed and Web of Science using different keyword combinations related to urogynecological CPP and central sensitization. Full text clinical reports addressing CS in adult women with urogynecological CPP were included and assessed for methodological quality by 2 independent reviewers. After screening for the eligibility, a total of 29 full-text articles with low to good methodological quality were retained. All studies were observational, 27 of which were case-control and 2 of which were cohorts. Sensitivity of the CNS was investigated by using a variety of methods. Although different central mechanisms seem to be involved in pain processing, the present evidence suggests hyperexcitability of the CNS in patients with urogynecological CPP. Altered brain morphology and function, generalized hyperalgesia to different type of stimuli, overactive bottom-up nociceptive mechanisms, and autonomic dysregulation were established in patients with urogynecological CPP. Nevertheless, diffuse noxious inhibitory control seemed normal, and therefore the contribution of an impaired endogenous pain inhibition mechanism to CPP requires further study. The same goes for the contribution of psychological factors. The level of evidence of retained studies is low due to the observational study designs and a wide range of diagnoses and assessment methods. Although the majority of the literature provides evidence for

  15. Mandibular Fracture Patterns at a Medical Center in Central Taiwan: A 3-Year Epidemiological Review.

    Science.gov (United States)

    Lin, Fu-Yu; Wu, Chao-I; Cheng, Hsu-Tang

    2017-12-01

    Mandibular fractures constitute a major portion of maxillofacial trauma and may lead to considerable functional and aesthetic sequelae if treatment is inadequate or delayed. An epidemiology study on mandibular fractures may guide the preventive efforts of the Taiwan public health care system. Therefore, a retrospective review was conducted at a medical center in central Taiwan to evaluate the current mandibular fracture epidemiology.The medical records and digitized radiographs of 198 patients who received treatment for mandibular fractures during a 3-year period (from October 2010 to September 2013) at a medical center in central Taiwan were reviewed to obtain demographic and injury data.The average age was 29.4 years (3-82 years). Patients aged 21 to 30 years sustained the most mandibular fractures (62 patients, 31.3%). The overall sex distribution (male to female) ratio was 1.8. Motor-vehicle accidents (MVAs) were the most common mechanism of injury (162 patients, 82%), and scooter and motorcycle riders wearing partial-coverage helmets constituted the majority of patients. A chart review identified 198 patients with 335 mandibular fractures; 113 patients (57.1%) had multiple mandibular fractures. The most common fracture sites were the symphysis and parasymphysis regions (38.9%), followed by the condyle (26.0%), angle (14.3%), body (14.3%), and ramus (6.6%).MVAs are the major cause of mandibular fractures in central Taiwan, and patients aged Taiwan. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

  16. Central pancreatectomy for the treatment of a benign pancreatic lesion: case report and literature review

    Directory of Open Access Journals (Sweden)

    Iván Domínguez-Sánchez

    Full Text Available We present the case of a 45 year old female patient with an incidental diagnosis of a cystic pancreatic lesion corresponding to a serous cystadenoma of 14 mm. During a 5-year follow-up (CT and MRT the lesion tripled in size and a surgical intervention was decided upon. The lesion was thought to have a benign pathology and, in an attempt to preserve the spleen and a major portion of pancreatic tissue, a central pancreatectomy with a diversion of the remaining distal pancreas was carried out. The authors reviewed national and international publications.

  17. The newest epidemic: a review of HIV/AIDS in Central and Eastern Europe.

    Science.gov (United States)

    Kelly, Jeffrey A; Amirkhanian, Yuri A

    2003-06-01

    HIV/AIDS has emerged as a grave public health threat in Central and Eastern Europe and in the Central Asian republics over the past five years. Massive political, social, cultural, and behavioural changes - along with economic upheaval and collapse of the public health infrastructure in many countries - have created circumstances conducive to the rapid spread of HIV. This paper reviews HIV and sexually transmitted disease (STD) data for all countries in the region, as well as behavioural, social, cultural, and other HIV epidemic enabling factors. The epidemiological picture of HIV in the region is mixed. Russia, Ukraine, Moldova and Belarus already have advanced epidemics. Some other countries in the region share similar enabling factors and have seen a very high proportion of their total number of HIV infections detected in only the past 18 months, indicating the emergence of recent epidemics. Several countries are more stable in their HIV incidence. Behavioural studies indicate that risky sexual and injection related practices are common in many vulnerable populations. HIV prevention steps, if taken quickly enough and on a large scale, can limit the scope of the HIV epidemic that is now unfolding in Central and Eastern Europe. This will require new models of government/non-governmental organization cooperation, policy approaches for addressing structural factors underlying the epidemic, and attention to human rights protection.

  18. A review on alcohol: from the central action mechanism to chemical dependency

    Directory of Open Access Journals (Sweden)

    João Victor Vezali Costardi

    2015-08-01

    Full Text Available SummaryIntroduction:alcohol is a psychotropic depressant of the central nervous system (CNS that promotes simultaneous changes in several neuronal pathways, exerting a profound neurological impact that leads to various behavioral and biological alterations.Objectives:to describe the effects of alcohol on the CNS, identifying the signaling pathways that are modified and the biological effects resulting from its consumption.Methods:a literature review was conducted and articles published in different languages over the last 15 years were retrieved.Results:the studies reviewed describe the direct effect of alcohol on several neurotransmitter receptors (gamma-aminobutyric acid [GABA], glutamate, endocannabinoids AEA and 2-AG, among others, the indirect effect of alcohol on the limbic and opioid systems, and the effect on calcium and potassium channels and on proteins regulated by GABA in the hippocampus.Discussion and conclusion:the multiple actions of alcohol on the CNS result in a general effect of psychomotor depression, difficulties in information storage and logical reasoning and motor incoordination, in addition to stimulating the reward system, a fact that may explain the development of addiction. Knowledge on the neuronal signaling pathways that are altered by alcohol allows the identification of effectors which could reduce its central action, thus, offering new therapeutic perspectives for the rehabilitation of alcohol addicts.

  19. Candida infection of the central nervous system following neurosurgery: a 12-year review.

    LENUS (Irish Health Repository)

    O'Brien, Deirdre

    2012-02-01

    BACKGROUND: Candida infection of the central nervous system (CNS) following neurosurgery is relatively unusual but is associated with significant morbidity and mortality. We present our experience with this infection in adults and discuss clinical characteristics, treatment options, and outcome. METHODS: All episodes of Candida isolated from the central nervous system were identified by searching our laboratory database. Review of the cases was performed by means of a retrospective chart review. RESULTS: Eleven episodes of Candida CSF infection following neurosurgery were identified over a 12-year period. Candida albicans was the predominant species isolated (n = 8, 73%). All infections were associated with foreign intracranial material, nine with external ventricular drains (82%), one with a ventriculoperitoneal shunt, one with a lumbar drain, and one with Gliadel wafers (1,3-bis [2-chloroethyl]-1-nitrosurea). Fluconazole or liposomal amphotericin B were the most common anti-fungal agents used. The mortality rate identified in our series was 27%. CONCLUSIONS: Candida infection following neurosurgery remains a relatively rare occurrence but one that causes significant mortality. These are complex infections, the management of which benefits from a close liaison between the clinical microbiologist and neurosurgeon. Prompt initiation of antifungal agents and removal of infected devices offers the best hope of a cure.

  20. Critical Review of Spatial Planning of CAT Watuputih, Rembang Zone, Central Java, Indonesia

    Science.gov (United States)

    Hadi, Sudharto P.

    2018-02-01

    The Act 26 of 2007 on spatial planning stipulates that spatial planning at national, provincial and local level must be based on environmental carrying capacity and environmental carrying capability. Provincial governments generally finished its spatial planning in 2010 and the city and regency's governments in 2011.This paper reviews the spatial planning of Central Java and Rembang Regency regarding the use of CAT (ground water basin) Watuputih, Rembang Zone. Both spatial planning determined that CAT Watuputih was allocated for conservation and for mining. The mixed use zoning stimulates conflict between private sector and government on one side and local people along with academician and NGOs on another side. The SEA (Strategic Environmental Assessment) studies initiated by central government found that CAT Watuputih has strong indication to be KBAK (natural landscape area of karst) need to be conserved while at the moment there have been 21 mining permit holders operating since 1998. The lesson learned from the review is that formulation of spatial planning must be conducted participatory by involving relevant stakeholder, objective and accountable.

  1. Central giant cell granulomas of the jaws: phenotype and proliferation-associated markers.

    Science.gov (United States)

    O'Malley, M; Pogrel, M A; Stewart, J C; Silva, R G; Regezi, J A

    1997-04-01

    Central giant cell granulomas (CGCGs) are jaw tumors of unknown origin that often exhibit an aggressive, though unpredictable, clinical course. The purpose of this study was to determine the immunoprofile of the mononuclear cells that seem to be responsible for the biologic behavior of these tumors. Numbers of cells in cell cycle were also determined and compared in clinically aggressive and non-aggressive CGCGs. Sixteen aggressive and 12 non-aggressive CGCGs were immunohistochemically stained with antibodies to CD34, CD68, factor XIIIa, alpha-smooth muscle actin, prolyl 4-hydroxylase, Ki-67, and p53 protein. Cell populations and numbers of cells in cell cycle were determined through microscopic quantitative assessment. CD34-positive cells were limited to support vessels. CD68-positive mononuclear cells constituted a small population of cells in all tumors. With two exceptions, factor XIIIa-positive cells were rarely seen. Alpha-smooth muscle actin staining was present in approximately half the tumors, and occasionally large numbers of positive cells were seen. Most mononuclear cells were positive for fibroblast-associated antigen. No phenotypic differences were detected between aggressive and non-aggressive tumors. P53 protein did not appear to be overexpressed in CGCGs. Ki-67 staining showed that only mononuclear cells were in cell cycle, and that there were no differences between aggressive and non-aggressive tumors. We conclude that CGCGs are primarily fibroblastic (and myofibroblastic) tumors in which macrophages appear to play a secondary role. Tumor cells show no differentiation toward endothelial cells or macrophage-related dendrocytes (factor XIIIa). Cellular phenotypes and numbers of cells in cell cycle are similar in both aggressive and non-aggressive tumors.

  2. Clinical effects of air pollution on the central nervous system; a review.

    Science.gov (United States)

    Babadjouni, Robin M; Hodis, Drew M; Radwanski, Ryan; Durazo, Ramon; Patel, Arati; Liu, Qinghai; Mack, William J

    2017-09-01

    The purpose of this review is to describe recent clinical and epidemiological studies examining the adverse effects of urban air pollution on the central nervous system (CNS). Air pollution and particulate matter (PM) are associated with neuroinflammation and reactive oxygen species (ROS). These processes affect multiple CNS pathways. The conceptual framework of this review focuses on adverse effects of air pollution with respect to neurocognition, white matter disease, stroke, and carotid artery disease. Both children and older individuals exposed to air pollution exhibit signs of cognitive dysfunction. However, evidence on middle-aged cohorts is lacking. White matter injury secondary to air pollution exposure is a putative mechanism for neurocognitive decline. Air pollution is associated with exacerbations of neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. Increases in stroke incidences and mortalities are seen in the setting of air pollution exposure and CNS pathology is robust. Large populations living in highly polluted environments are at risk. This review aims to outline current knowledge of air pollution exposure effects on neurological health. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Medicinal uses, pharmacology, and phytochemistry of Convolvulaceae plants with central nervous system efficacies: A systematic review.

    Science.gov (United States)

    Chen, Guang-Tong; Lu, Yun; Yang, Min; Li, Jian-Lin; Fan, Bo-Yi

    2018-01-22

    Central nervous system (CNS) disorders play a major impact on individual lives and place a severe strain on health care resources. Convolvulaceae is a family comprising approximately 1,600-1,700 species grouped in 55-60 genera, and many species are reported to have an effect on CNS functions. A systematic review of the literature studies was carried out to summarize available evidences on Convolvulaceae plants with CNS efficacies. This review is based on various data sources such as Google Scholar, Web of Science, Scopus, PubMed, and Wanfang Data. A total of 200 related articles were included in this review. According to the research result, 54 Convolvulaceae species are suggested to display CNS efficacies historically, and 46 species have been evaluated for their CNS efficacies. In addition, 67 compounds from 16 Convolvulaceae species are recognized to possess CNS efficacies. Despite great progress made through pharmacology and phytochemistry studies on CNS active Convolvulaceae species, more exploratory research is needed to gain a better understanding of the CNS efficacies of this plant family. Copyright © 2018 John Wiley & Sons, Ltd.

  4. Diagnostic performance of dual-staining cytology for cervical cancer screening: A systematic literature review.

    Science.gov (United States)

    Tjalma, Wiebren A A

    2017-03-01

    Cervical cancer screening saves lives. Secondary prevention in cervical cancer screening relies on the results of primary cytology and/or HPV testing. However, primary screening with cytology has a low sensitivity, and HPV screening has a low specificity. This means that either cancers are missed, or women are over-treated. To improve performance outcomes, the concept of dual-stain cytology (CINtec ® PLUS Cytology test) has been introduced. In this approach, additional staining with p16/Ki-67 is performed in cases where cytology results are abnormal (LSIL or ASCUS) and/or HPV-positive. Another way to describe this approach might be "diagnostic" cytology. In order to assess the value of this "diagnostic cytology", a systematic literature review was conducted of dual-stain cytology performance across multiple studies until May 2016. In a Belgian screening population (women age 25-65 years), dual-stain cytology was significantly more sensitive (66%) and slightly less specific (-1.0%) than cytology. In the population referred to colposcopy or with abnormal cytology (ASCUS, LSIL), dual-staining showed a significantly higher increase in specificity, and a slightly lower sensitivity than HPV testing. Specificity gains resulted in fewer false positives and an increase in the number of correct referrals to colposcopy. Dual-staining with p16/Ki-67 cytology is an attractive biomarker approach for triage in cervical cancer screening. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Advantages and disadvantages