Injection of Syngeneic Murine Melanoma Cells to Determine Their Metastatic Potential in the Lungs.

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Timmons, Joshua J; Cohessy, Sean; Wong, Eric T

2016-05-24

Approximately 90% of human cancer deaths are linked to metastasis. Despite the prevalence and relative harm of metastasis, therapeutics for treatment or prevention are lacking. We report a method for the establishment of pulmonary metastases in mice, useful for the study of this phenomenon. Tail vein injection of B57BL/6J mice with B16-BL6 is among the most used models for melanoma metastases. Some of the circulating tumor cells establish themselves in the lungs of the mouse, creating "experimental" metastatic foci. With this model it is possible to measure the relative effects of therapeutic agents on the development of cancer metastasis. The difference in enumerated lung foci between treated and untreated mice indicates the efficacy of metastases neutralization. However, prior to the investigation of a therapeutic agent, it is necessary to determine an optimal number of injected B16-BL6 cells for the quantitative analysis of metastatic foci. Injection of too many cells may result in an overabundance of metastatic foci, impairing proper quantification and overwhelming the effects of anti-cancer therapies, while injection of too few cells will hinder the comparison between treated and controls.

Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor.

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Chirivi, R G; Garofalo, A; Crimmin, M J; Bawden, L J; Stoppacciaro, A; Brown, P D; Giavazzi, R

1994-08-01

The synthetic matrix metalloproteinase inhibitor batimastat was tested for its ability to inhibit growth and metastatic spread of the B16-BL6 murine melanoma in syngeneic C57BL/6N mice. Intraperitoneal administration of batimastat resulted in a significant inhibition in the number of lung colonies produced by B16-BL6 cells injected i.v. The effect of batimastat on spontaneous metastases was examined in mice inoculated in the hind footpad with B16-BL6 melanoma. The primary tumor was removed surgically after 26-28 days. Batimastat was administered twice a day from day 14 to day 28 (pre-surgery) or from day 26 to day 44 (post-surgery). With both protocols, the median number of lung metastases was not significantly affected, but there was a significant reduction in the weight of the metastases. Finally, the effect of batimastat was examined on s.c. growth of B16-BL6 melanoma. Batimastat administered daily, starting at day of tumor transplantation, resulted in a significant growth delay, whereas treatment starting at advanced stage tumor only reduced tumor growth marginally. Our results indicate that a matrix metalloproteinase inhibitor can not only prevent the colonization of secondary organs by B16-BL6 cells but also limit the growth of solid tumors.

Toxicity and Immunogenicity in Murine Melanoma following Exposure to Physical Plasma-Derived Oxidants

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Sander Bekeschus

2017-01-01

Full Text Available Metastatic melanoma is an aggressive and deadly disease. Therapeutic advance has been achieved by antitumor chemo- and radiotherapy. These modalities involve the generation of reactive oxygen and nitrogen species, affecting cellular viability, migration, and immunogenicity. Such species are also created by cold physical plasma, an ionized gas capable of redox modulating cells and tissues without thermal damage. Cold plasma has been suggested for anticancer therapy. Here, melanoma cell toxicity, motility, and immunogenicity of murine metastatic melanoma cells were investigated following plasma exposure in vitro. Cells were oxidized by plasma, leading to decreased metabolic activity and cell death. Moreover, plasma decelerated melanoma cell growth, viability, and cell cycling. This was accompanied by increased cellular stiffness and upregulation of zonula occludens 1 protein in the cell membrane. Importantly, expression levels of immunogenic cell surface molecules such as major histocompatibility complex I, calreticulin, and melanocortin receptor 1 were significantly increased in response to plasma. Finally, plasma treatment significantly decreased the release of vascular endothelial growth factor, a molecule with importance in angiogenesis. Altogether, these results suggest beneficial toxicity of cold plasma in murine melanomas with a concomitant immunogenicity of potential interest in oncology.

Disseminated breast cancer cells acquire a highly malignant and aggressive metastatic phenotype during metastatic latency in the bone.

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Carolyn G Marsden

Full Text Available BACKGROUND: Disseminated tumor cells (DTCs in the bone marrow may exist in a dormant state for extended periods of time, maintaining the ability to proliferate upon activation, engraft at new sites, and form detectable metastases. However, understanding of the behavior and biology of dormant breast cancer cells in the bone marrow niche remains limited, as well as their potential involvement in tumor recurrence and metastasis. Therefore, the purpose of this study was to investigate the tumorigenicity and metastatic potential of dormant disseminated breast cancer cells (prior to activation in the bone marrow. METHODOLOGY/PRINCIPAL FINDINGS: Total bone marrow, isolated from mice previously injected with tumorspheres into the mammary fat pad, was injected into the mammary fat pad of NUDE mice. As a negative control, bone marrow isolated from non-injected mice was injected into the mammary fat pad of NUDE mice. The resultant tumors were analyzed by immunohistochemistry for expression of epithelial and mesenchymal markers. Mouse lungs, livers, and kidneys were analyzed by H+E staining to detect metastases. The injection of bone marrow isolated from mice previously injected with tumorspheres into the mammary fat pad, resulted in large tumor formation in the mammary fat pad 2 months post-injection. However, the injection of bone marrow isolated from non-injected mice did not result in tumor formation in the mammary fat pad. The DTC-derived tumors exhibited accelerated development of metastatic lesions within the lung, liver and kidney. The resultant tumors and the majority of metastatic lesions within the lung and liver exhibited a mesenchymal-like phenotype. CONCLUSIONS/SIGNIFICANCE: Dormant DTCs within the bone marrow are highly malignant upon injection into the mammary fat pad, with the accelerated development of metastatic lesions within the lung, liver and kidney. These results suggest the acquisition of a more aggressive phenotype of DTCs during

Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours.

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Buhles, Alexandra; Collins, Sara A; van Pijkeren, Jan P; Rajendran, Simon; Miles, Michelle; O'Sullivan, Gerald C; O'Hanlon, Deirdre M; Tangney, Mark

2009-03-09

The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metastasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate

A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

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Serrano, Fabiana A; Machado, Joel Jr; Santos, Edson L; Pesquero, João B; Martins, Rafael M; Travassos, Luiz R; Caires, Antonio CF; Rodrigues, Elaine G; Matsuo, Alisson L; Monteforte, Priscila T; Bechara, Alexandre; Smaili, Soraya S; Santana, Débora P; Rodrigues, Tiago; Pereira, Felipe V; Silva, Luis S

2011-01-01

Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd 2 [S (-) C 2 , N-dmpa] 2 (μ-dppe)Cl 2 } named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies. B16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a. Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells. The cyclopalladated C7a complex is

Corruption of the Fas pathway delays the pulmonary clearance of murine osteosarcoma cells, enhances their metastatic potential, and reduces the effect of aerosol gemcitabine.

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Gordon, Nancy; Koshkina, Nadezhda V; Jia, Shu-Fang; Khanna, Chand; Mendoza, Arnulfo; Worth, Laura L; Kleinerman, Eugenie S

2007-08-01

Pulmonary metastases continue to be a significant problem in osteosarcoma. Apoptosis dysfunction is known to influence tumor development. Fas (CD95, APO-1)/FasL is one of the most extensively studied apoptotic pathways. Because FasL is constitutively expressed in the lung, cells that express Fas should be eliminated by lung endothelium. Cells with low or no cell surface Fas expression may be able to evade this innate defense mechanism. The purpose of these studies was to evaluate Fas expression in osteosarcoma lung metastases and the effect of gemcitabine on Fas expression and tumor growth. Using the K7M2 murine osteosarcoma model, Fas expression was quantified using immunohistochemistry. High levels of Fas were present in primary tumors, but no Fas expression was present in actively growing lung metastases. Blocking the Fas pathway using Fas-associated death domain dominant-negative delayed tumor cell clearance from the lung and increased metastatic potential. Treatment of mice with aerosol gemcitabine resulted in increased Fas expression and subsequent tumor regression. We conclude that corruption of the Fas pathway is critical to the ability of osteosarcoma cells to grow in the lung. Agents such as gemcitabine that up-regulate cell surface Fas expression may therefore be effective in treating osteosarcoma lung metastases. These data also suggest that an additional mechanism by which gemcitabine induces regression of osteosarcoma lung metastases is mediated by enhancing the sensitivity of the tumor cells to the constitutive FasL in the lung.

Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade.

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Ouzounova, Maria; Lee, Eunmi; Piranlioglu, Raziye; El Andaloussi, Abdeljabar; Kolhe, Ravindra; Demirci, Mehmet F; Marasco, Daniela; Asm, Iskander; Chadli, Ahmed; Hassan, Khaled A; Thangaraju, Muthusamy; Zhou, Gang; Arbab, Ali S; Cowell, John K; Korkaya, Hasan

2017-04-06

It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We demonstrate here that monocytic (mMDSC) and granulocytic (gMDSC) subsets of myeloid-derived suppressor cells infiltrate in the primary tumour and distant organs with different time kinetics and regulate spatiotemporal tumour plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumour-infiltrated mMDSCs facilitate tumour cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and promoting tumour cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumour-bearing animals enhance metastatic growth of already disseminated tumour cells. MDSC-induced 'metastatic gene signature' derived from murine syngeneic model predicts poor patient survival in the majority of human solid tumours. Thus spatiotemporal MDSC infiltration may have clinical implications in tumour progression.

Rad51 expression levels predict synthetic lethality and metastatic potential in high grade breast cancers

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Wiegmans, A.P.; Al-Ejeh, F.; Khanna, K.K.

2012-01-01

Among women with breast cancer, 30-40% will develop metastatic disease and only achieve an overall survival of less than 5 years. Despite new-targeted therapy, breast tumors that harbour similar histology or molecular phenotype differ in their response to treatment. To uncover potential new therapeutic targets and improve outcome, we performed data mining of cancer micro array databases. We found that high expression of the homologous recombination protein, RAD51, was significantly associated with high-grade breast cancer, aggressive subtypes and increased risk of metastasis. We confirmed using immunohistochemistry that RAD5 1 was highly expressed in metastatic tumours and high-grade triple negative, HER2+ and luminal-B tumours. This provided a rationale for targeting RAD5 1 in high-grade, therapy-resistant breast cancers. Here, we report for the first time preclinical evaluation of RAD5 1 as a therapeutic target. We found that, in-vitro high RAD5 expressing cell lines were resistant to PARP inhibitor while knockdown reversed this resistance. In-vivo, knockdown of RAD5 1 inhibited metastatic progression using a syngeneic breast cancer model and the seeding of human xenografts to distant sites, including brain and lung. Concurrent PARP inhibition reduced primary tumor growth and delayed metastasis supporting synthetic lethality in-vivo. Together these insights provide pre-clinical data demonstrating RAD5 1 as a new biomarker and potential therapeutic target against aggressive metastatic breast cancer. (author)

Phorbol 12-myristate 13-acetate enhances nm23 gene expression in murine melanocytes but not in syngeneic B16-BL6 melanoma variants.

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Huijzer, J C; McFarland, M; Niles, R M; Meadows, G G

1996-03-01

The nm23 gene has been described as a potential metastasis suppressor gene in certain rodent and human tumors. We previously demonstrated that tyrosine and phenylalanine restriction suppresses metastatic heterogeneity of B16-BL6 murine melanoma and selects for tumor variants with decreased metastatic potential. In this study, we investigated nm23 expression in the highly metastatic B16-BL6 (ND) melanoma, its nutritionally derived poorly metastatic (LT) variant, and the syngeneic non-tumorigenic Mel-ab melanocytes. No differences in nm23 expression were observed between ND and LT cells, and nm23 expression varied between different isolates. Previously, we showed that metastatic potential of 1-ND cells decreases and is not altered in 1-LT cells after prolonged in vitro cell passage; however, nm23 expression is equivalently increased by 2-fold. In 2-ND and 2-LT cells, expression of nm23 is not different at higher in vitro cell passage. Expression of nm23 decreased about 2-fold when phorbol 12-myristate 13-acetate (PMA) was removed from Mel-ab cells, which induces these cells to become quiescent. Although membrane-associated protein kinase C (PKC) activity decreased after prolonged PMA treatment in all cells, neither nm23 expression nor proliferation of ND and LT cells was affected by PMA. These data indicate that nm23 expression is related to proliferative activity rather than to the suppression of metastatic potential.

Thioredoxin induces Tregs to generate an immunotolerant tumor microenvironment in metastatic melanoma

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Wang, Xiaogang; Dong, Haisheng; Li, Qi; Li, Yingxian; Hong, An

2015-01-01

Metastatic melanoma is a highly aggressive cancer that is very difficult to treat. Additionally, the antitumor immune reaction of melanoma is still unclear. Here we demonstrate an association between the expression and secretion of the antioxidant protein thioredoxin (TRX) and increasing tumor stage and metastasis in melanoma. To elucidate the role of TRX in melanoma, we assessed the correlation of TRX expression with different disease parameters in melanoma. We also examined the in vitro and in vivo effects of modulating TRX levels in melanoma cells using various methods of TRX depletion and augmentation. We further explored the effects of TRX on the cytokine milieu and the ability of TRX to regulate the proportion and specific activities of T-cell populations. We demonstrate that TRX expression correlates with Treg representation in clinical samples and, that modulation of TRX influences the induction of Tregs and the generation of an immunotolerant cytokine profile in mouse serum. Using a murine metastatic melanoma model, we identified a tumor immunoevasion mechanism whereby melanoma cell-secreted TRX enhances Treg infiltration. TRX displays chemotactic effects in recruiting Tregs, stimulates the conversion of conventional T cells to Tregs, and confers survival advantage to Tregs in the tumor microenvironment. In turn, this increase of Tregs generates immunotolerance in tissues and therefore decreases antitumor immune reactions. These results elucidate a mechanism by which TRX promotes metastatic melanoma in part through Treg recruitment to inhibit T-cell antitumor effects and suggest that TRX antibody may be useful in the clinic as a therapy against melanoma. PMID:26405597

Daphnetin inhibits invasion and migration of LM8 murine osteosarcoma cells by decreasing RhoA and Cdc42 expression

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Fukuda, Hiroki [Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto (Japan); Nakamura, Seikou [Department of Pharmacognosy, Kyoto Pharmaceutical University, Kyoto (Japan); Chisaki, Yugo [Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto (Japan); Takada, Tetsuya [Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto (Japan); Toda, Yuki [Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Kyoto (Japan); Murata, Hiroaki [Department of Orthopedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Department of Orthopedic Surgery, Matsushita Memorial Hospital, Osaka (Japan); Itoh, Kazuyuki [Department of Biology, Osaka Medical Center of Cancer and Cardiovascular Diseases, Osaka (Japan); Yano, Yoshitaka [Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto (Japan); Takata, Kazuyuki [Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto (Japan); Ashihara, Eishi, E-mail: ash@mb.kyoto-phu.ac.jp [Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto (Japan)

2016-02-26

Daphnetin, 7,8-dihydroxycoumarin, present in main constituents of Daphne odora var. marginatai, has multiple pharmacological activities including anti-proliferative effects in cancer cells. In this study, using a Transwell system, we showed that daphnetin inhibited invasion and migration of highly metastatic murine osteosarcoma LM8 cells in a dose-dependent manner. Following treatment by daphnetin, cells that penetrated the Transwell membrane were rounder than non-treated cells. Immunofluorescence analysis revealed that daphnetin decreased the numbers of intracellular stress fibers and filopodia. Moreover, daphnetin treatment dramatically decreased the expression levels of RhoA and Cdc42. In summary, the dihydroxycoumarin derivative daphnetin inhibits the invasion and migration of LM8 cells, and therefore represents a promising agent for use against metastatic cancer. - Highlights: • Daphnetin, a coumarin-derivative, inhibited invasion and migration of LM8 cells. • Stress fibers and filopodia were decreased by daphnetin treatment. • Daphnetin decreased RhoA and Cdc42 protein expression.

Daphnetin inhibits invasion and migration of LM8 murine osteosarcoma cells by decreasing RhoA and Cdc42 expression

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Fukuda, Hiroki; Nakamura, Seikou; Chisaki, Yugo; Takada, Tetsuya; Toda, Yuki; Murata, Hiroaki; Itoh, Kazuyuki; Yano, Yoshitaka; Takata, Kazuyuki; Ashihara, Eishi

2016-01-01

Daphnetin, 7,8-dihydroxycoumarin, present in main constituents of Daphne odora var. marginatai, has multiple pharmacological activities including anti-proliferative effects in cancer cells. In this study, using a Transwell system, we showed that daphnetin inhibited invasion and migration of highly metastatic murine osteosarcoma LM8 cells in a dose-dependent manner. Following treatment by daphnetin, cells that penetrated the Transwell membrane were rounder than non-treated cells. Immunofluorescence analysis revealed that daphnetin decreased the numbers of intracellular stress fibers and filopodia. Moreover, daphnetin treatment dramatically decreased the expression levels of RhoA and Cdc42. In summary, the dihydroxycoumarin derivative daphnetin inhibits the invasion and migration of LM8 cells, and therefore represents a promising agent for use against metastatic cancer. - Highlights: • Daphnetin, a coumarin-derivative, inhibited invasion and migration of LM8 cells. • Stress fibers and filopodia were decreased by daphnetin treatment. • Daphnetin decreased RhoA and Cdc42 protein expression.

Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion

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He Xianghuo

2010-07-01

Full Text Available Abstract Background The formation of metastasis is the most common cause of death in patients with lung cancer. A major implement to understand the molecular mechanisms involved in lung cancer metastasis has been the lack of suitable models to address it. In this study, we aimed at establishing a highly metastatic model of human lung cancer and characterizing its metastatic properties and underlying mechanisms. Methods The human lung adeno-carcinoma SPC-A-1 cell line was used as parental cells for developing of highly metastatic cells by in vivo selection in NOD/SCID mice. After three rounds of selection, a new SPC-A-1sci cell line was established from pulmonary metastatic lesions. Subsequently, the metastatic properties of this cell line were analyzed, including optical imaging of in vivo metastasis, immunofluorescence and immunohistochemical analysis of several epithelial mesenchymal transition (EMT makers and trans-well migration and invasion assays. Finally, the functional roles of fibronectin in the invasive and metastatic potentials of SPC-A-1sci cells were determined by shRNA analysis. Results A spontaneously pulmonary metastatic model of human lung adeno-carcinoma was established in NOD/SCID mice, from which a new lung cancer cell line, designated SPC-A-1sci, was isolated. Initially, the highly metastatic behavior of this cell line was validated by optical imaging in mice models. Further analyses showed that this cell line exhibit phenotypic and molecular alterations consistent with EMT. Compared with its parent cell line SPC-A-1, SPC-A-1sci was more aggressive in vitro, including increased potentials for cell spreading, migration and invasion. Importantly, fibronectin, a mesenchymal maker of EMT, was found to be highly expressed in SPC-A-1sci cells and down-regulation of it can decrease the in vitro and in vivo metastatic abilities of this cell line. Conclusions We have successfully established a new human lung cancer cell line with

Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion

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Jia, Deshui; Yao, Ming; Yan, Mingxia; Wang, Xiaomin; Hao, Xiangfang; Liang, Linhui; Liu, Lei; Kong, Hanwei; He, Xianghuo; Li, Jinjun

2010-01-01

The formation of metastasis is the most common cause of death in patients with lung cancer. A major implement to understand the molecular mechanisms involved in lung cancer metastasis has been the lack of suitable models to address it. In this study, we aimed at establishing a highly metastatic model of human lung cancer and characterizing its metastatic properties and underlying mechanisms. The human lung adeno-carcinoma SPC-A-1 cell line was used as parental cells for developing of highly metastatic cells by in vivo selection in NOD/SCID mice. After three rounds of selection, a new SPC-A-1sci cell line was established from pulmonary metastatic lesions. Subsequently, the metastatic properties of this cell line were analyzed, including optical imaging of in vivo metastasis, immunofluorescence and immunohistochemical analysis of several epithelial mesenchymal transition (EMT) makers and trans-well migration and invasion assays. Finally, the functional roles of fibronectin in the invasive and metastatic potentials of SPC-A-1sci cells were determined by shRNA analysis. A spontaneously pulmonary metastatic model of human lung adeno-carcinoma was established in NOD/SCID mice, from which a new lung cancer cell line, designated SPC-A-1sci, was isolated. Initially, the highly metastatic behavior of this cell line was validated by optical imaging in mice models. Further analyses showed that this cell line exhibit phenotypic and molecular alterations consistent with EMT. Compared with its parent cell line SPC-A-1, SPC-A-1sci was more aggressive in vitro, including increased potentials for cell spreading, migration and invasion. Importantly, fibronectin, a mesenchymal maker of EMT, was found to be highly expressed in SPC-A-1sci cells and down-regulation of it can decrease the in vitro and in vivo metastatic abilities of this cell line. We have successfully established a new human lung cancer cell line with highly metastatic potentials, which is subject to EMT and possibly

Molecular characterization of murine models of squamous carcinomas of preclinical application

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Bornachea Gomez, O.; Berdugo Zamora, A.

2015-01-01

The epidermis is a stratified epithelium affected by numerous pathologies, including cancer, being the tumors originated in this tissue more than half of the epithelial tumors diagnosed every year. Animal models are an essential tool for cancer research, as they provide information to understand how a homologous gene may cause or contribute to the disease in humans. The p53 CE and Rb CE; p53 CE murine models develop undifferentiated epidermal tumors with high metastatic potential that show a strong transcriptional similarity to many human tumors with poor prognosis. Numerous studies have associated the p53 tumor suppressor with deregulation of microRNAs involved in the epithelial-mesenchymal transition (EMT) and metastasis processes. Furthermore, tumors in p53 EC models show an early repression of p63 whose predominant isoform in keratinocytes of the basal layer is Np63. Our results indicate that miR21 helps to provide metastatic capacity to p53-deficient mouse skin tumors. The increased expression of miR21 correlates with active signaling pathways that can be inhibited pharmacologically. Moreover, miR21 expression is elevated in human metastatic lung tumors with poor prognosis. Besides, we also show that ?Np63? expression in p53-deficient cells partially reduces the metastatic behavior, most probably through the modulation microRNAs and transcription factors involved in the EMT process. These facts point to p53-deficient epidermal animal models as excellent candidates for preclinical analysis of human metastatic tumors characterized by TP53 alterations. Finally we developed a model in which the three members of the retinoblastoma family are ablated in the basal cells of stratified epithelia in a tamoxifen inducible manner: Rb1F/F ; Rbl2F/F;Rbl1-/-;K14CreErT2 (TKO). Previously our laboratory had shown that, in the absence of pRb, malignant conversion occurred when p53 is lost. At high doses of tamoxifen these animals show early lethality. When we adjust the dose

A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

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Elvington, Michelle; Huang, Yuxiang; Morgan, B. Paul; Qiao, Fei; van Rooijen, Nico; Atkinson, Carl

2012-01-01

Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcγR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer. PMID:22442351

Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer.

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Brown, Wells S; Tan, Li; Smith, Andrew; Gray, Nathanael S; Wendt, Michael K

2016-09-01

Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096-106. ©2016 AACR. ©2016 American Association for Cancer Research.

CRISPR-Cas9-Mediated Silencing of CD44 in Human Highly Metastatic Osteosarcoma Cells

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Tang Liu

2018-04-01

Full Text Available Background/Aims: Metastasis is the major cause of death in patients with osteosarcoma. There is an urgent need to identify molecular markers that promote metastasis. Cluster of differentiation 44 is a receptor for hyaluronic acid (HA and HA-binding has been proven to participate in various biological tumor activities, including tumor progression and metastasis. Methods: We performed a meta-analysis to investigate the relationship between CD44 expression, survival, and metastasis in patients with osteosarcoma. We then utilized the CRISPR-Cas9 system to specifically silence CD44 in highly metastatic human osteosarcoma cells (MNNG/HOS and 143B and further determined the functional effects of CD44 knockout in these cells. Results: The meta-analysis demonstrated that a high level of CD44 may predict poor survival and higher potential of metastasis in patients with osteosarcoma. The expression of CD44 in highly metastatic human osteosarcoma cell lines was efficiently blocked by CRISPR-Cas9. When CD44 was silenced, the proliferation and spheroid formation of these osteosarcoma cells was inhibited under 3-D culture conditions. Furthermore, the migratory and invasive functions were also impaired in these highly metastatic osteosarcoma cells. Conclusion: These results suggest that developing new strategies to target CD44 in osteosarcoma may prevent metastasis and improve the clinical outcome of osteosarcoma patients.

Specific expression of the human voltage-gated proton channel Hv1 in highly metastatic breast cancer cells, promotes tumor progression and metastasis

International Nuclear Information System (INIS)

Wang, Yifan; Li, Shu Jie; Pan, Juncheng; Che, Yongzhe; Yin, Jian; Zhao, Qing

2011-01-01

Highlights: → Hv1 is specifically expressed in highly metastatic human breast tumor tissues. → Hv1 regulates breast cancer cytosolic pH. → Hv1 acidifies extracellular milieu. → Hv1 exacerbates the migratory ability of metastatic cells. -- Abstract: The newly discovered human voltage-gated proton channel Hv1 is essential for proton transfer, which contains a voltage sensor domain (VSD) without a pore domain. We report here for the first time that Hv1 is specifically expressed in the highly metastatic human breast tumor tissues, but not in poorly metastatic breast cancer tissues, detected by immunohistochemistry. Meanwhile, real-time RT-PCR and immunocytochemistry showed that the expression levels of Hv1 have significant differences among breast cancer cell lines, MCF-7, MDA-MB-231, MDA-MB-468, MDA-MB-453, T-47D and SK-BR-3, in which Hv1 is expressed at a high level in highly metastatic human breast cancer cell line MDA-MB-231, but at a very low level in poorly metastatic human breast cancer cell line MCF-7. Inhibition of Hv1 expression in the highly metastatic MDA-MB-231 cells by small interfering RNA (siRNA) significantly decreases the invasion and migration of the cells. The intracellular pH of MDA-MB-231 cells down-regulated Hv1 expression by siRNA is obviously decreased compared with MDA-MB-231 with the scrambled siRNA. The expression of matrix metalloproteinase-2 and gelatinase activity in MDA-MB-231 cells suppressed Hv1 by siRNA were reduced. Our results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells.

ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer.

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Drosos, Yiannis; Escobar, David; Chiang, Ming-Yi; Roys, Kathryn; Valentine, Virginia; Valentine, Marc B; Rehg, Jerold E; Sahai, Vaibhav; Begley, Lesa A; Ye, Jianming; Paul, Leena; McKinnon, Peter J; Sosa-Pineda, Beatriz

2017-09-11

Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (Kras G12D ). We show that partial or total ATM deficiency cooperates with Kras G12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16 Ink4a and p19 Arf . However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.

Dual Role of Host Par2 in a Murine Model of Spontaneous Metastatic B16 Melanoma

Czech Academy of Sciences Publication Activity Database

Olejár, Tomáš; Větvička, D.; Zadinová, M.; Poučková, P.; Kukal, J.; Ježek, Petr; Matěj, R.

2014-01-01

Roč. 34, č. 7 (2014), s. 3511-3515 ISSN 0250-7005 R&D Projects: GA ČR(CZ) GAP302/10/0346 Institutional support: RVO:67985823 Keywords : PAR2 * melanoma * metastasis * murine model Subject RIV: EA - Cell Biology Impact factor: 1.826, year: 2014

Adherence of murine lymphocytes to high endothelial venules in vitro and its radiation effect

Energy Technology Data Exchange (ETDEWEB)

Lixin, Liu; Zijun, Mao; Zhiwei, Yin [Suzhou Medical Coll., JS (China). Dept. of Pathophysiology

1991-02-01

Using the assay of specific adhesion of lymphocytes to high endothelial venules (HEV) on cryostat sections of mesenteric lymph nodes (MLN), the effects of different doses (0, 1, 2, 4, 8 Gy) of {sup 60}Co {gamma}-ray irradiation of murine MLN lymphocytes in vitro on adhesion to normal HEV was observed. The results showed that in the irradiated murine MLN lymphocytes the ability to adhere to HEV of normal MLN was reduced. Statistical significance was revealed at 2, 4, 8 Gy irradiations. This results suggests that irradiation can inhibit the specific recognition and adhesion of lymphocytes to HEV to a certain extent.

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

Science.gov (United States)

2012-05-01

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

Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H).

Science.gov (United States)

Goldstein, J; Tran, B; Ensor, J; Gibbs, P; Wong, H L; Wong, S F; Vilar, E; Tie, J; Broaddus, R; Kopetz, S; Desai, J; Overman, M J

2014-05-01

The microsatellite instability-high (MSI-H) phenotype, present in 15% of early colorectal cancer (CRC), confers good prognosis. MSI-H metastatic CRC is rare and its impact on outcomes is unknown. We describe survival outcomes and the impact of chemotherapy, metastatectomy, and BRAF V600E mutation status in the largest reported cohort of MSI-H metastatic colorectal cancer (CRC). A retrospective review of 55 MSI-H metastatic CRC patients from two institutions, Royal Melbourne Hospital (Australia) and The University of Texas MD Anderson Cancer Center (United States), was conducted. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Median age was 67 years (20-90), 58% had poor differentiation, and 45% had stage IV disease at presentation. Median overall survival (OS) from metastatic disease was 15.4 months. Thirteen patients underwent R0/R1 metastatectomies, with median OS from metastatectomy 33.8 months. Thirty-one patients received first-line systemic chemotherapy for metastatic disease with median OS from the start of chemotherapy 11.5 months. No statistically significant difference in progression-free survival or OS was seen between fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. BRAF V600E mutation was present in 14 of 47 patients (30%). BRAF V600E patients demonstrated significantly worse median OS; 10.1 versus 17.3 months, P = 0.03. In multivariate analyses, BRAF V600E mutants had worse OS (HR 4.04; P = 0.005), while patients undergoing metastatectomy (HR 0.11; P = CRC do not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic factor in MSI-H metastatic CRC.

[High-dosed gestagen therapy of the metastatic mammary carcinoma (author's transl)].

Science.gov (United States)

Firusian, N; Becher, R

1981-12-01

Thirty patients with histologically proven metastatic mammary carcinoma were treated, after exhaustion of hormonal and cytostatic therapeutic means, with high-dosed medroxyprogesterone acetate (MPA) during a ten-day induction phase with 1000 mg MPAi.m. per day and then with 600 mg oral MPA per day. In eleven patients a complete or partial remission was achieved. The median period of remission comprised ten months. A positive relationship was found between the response to high-dosed MPA therapy and the length of free intervals. Side effects were tolerable.

High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma. Part 1: MRI vs. histopathology

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Sirin, Selma; Schlamann, Marc; Schweiger, Bernd; Goericke, Sophia L. [University Hospital Essen, Department of Diagnostic and Interventional Radiology and Neuroradiology, Essen (Germany); Metz, Klaus A. [University Hospital Essen, Department of Pathology and Neuropathology, Essen (Germany); Bornfeld, Norbert; Holdt, Markus [University Hospital Essen, Department of Ophthalmology, Essen (Germany); Temming, Petra; Schuendeln, Michael M. [University Hospital Essen, Department of Pediatric Hematology and Oncology, Essen (Germany)

2015-08-15

A reliable detection of metastatic risk factors is important for children with retinoblastoma to choose the right therapeutic regimen. First studies using high-resolution magnetic resonance imaging (MRI) with orbit surface coils were promising. The aim of this study was therefore to evaluate the ability of high-resolution MRI to detect metastatic and especially advanced metastatic risk factors in a large group of children with retinoblastoma. One hundred forty-three consecutive children with retinoblastoma (148 enucleated eyes, 64 girls, 79 boys, mean age 19.7 ± 15.3) who received pretherapeutical high-resolution MRI with orbit surface coils on 1.5 T MR scanner systems between 2007 and 2012 and subsequent primary enucleation within 14 days were included in this retrospective study. Image analysis was performed by two neuroradiologists experienced in ocular imaging in consensus. Histopathology served as gold standard. Sensitivity/specificity for the detection of metastatic risk factors using high-resolution MRI with orbit surface coils were 60 %/88.7 % for postlaminar optic nerve infiltration, 65.5 %/95.6 % for choroidal invasion, 100 %/99.3 % for scleral invasion, and 100 %/100 % for peribulbar fat invasion, respectively. The results increased for the detection of advanced metastatic risk factors, 81.8 %/89.1 % for deep postlaminar optic nerve infiltration, 70.6 %/97.6 % for massive choroidal invasion. High-resolution MRI is clinically valuable for the detection of metastatic, especially of advanced metastatic risk factors in children with retinoblastoma. (orig.)

Influence of WR-2721 on metastatic tumor spread after irradiation

International Nuclear Information System (INIS)

Ullrich, R.L.; Jernigan, M.C.; Yuhas, J.M.

1975-01-01

The Line 1 alveolar cell carcinoma is a transplantable murine tumor which, unlike most others, kills the host by means of metastatic spread. Attempts to cure this tumor with localized radiation therapy often fail, in spite of local tumor control, because the metastases evade the treatment. These facts suggest that host-tumor interactions may play a particularly important role in determining the ultimate survival of the tumor bearing animal. In order to initially evaluate the possible importance of normal regional tissues in host-tumor interactions the influence of WR-2721, a radioprotective drug, was examined for local tumor control and subsequent survival of the tumor bearing animal after localized radiation. Results indicated that WR-2721 can decrease metastasis. (U.S.)

Novel near-diploid ovarian cancer cell line derived from a highly aneuploid metastatic ovarian tumor.

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Ester Rozenblum

Full Text Available A new ovarian near-diploid cell line, OVDM1, was derived from a highly aneuploid serous ovarian metastatic adenocarcinoma. A metastatic tumor was obtained from a 47-year-old Ashkenazi Jewish patient three years after the first surgery removed the primary tumor, both ovaries, and the remaining reproductive organs. OVDM1 was characterized by cell morphology, genotyping, tumorigenic assay, mycoplasma testing, spectral karyotyping (SKY, and molecular profiling of the whole genome by aCGH and gene expression microarray. Targeted sequencing of a panel of cancer-related genes was also performed. Hierarchical clustering of gene expression data clearly confirmed the ovarian origin of the cell line. OVDM1 has a near-diploid karyotype with a low-level aneuploidy, but samples of the original metastatic tumor were grossly aneuploid. A number of single nucleotide variations (SNVs/mutations were detected in OVDM1 and the metastatic tumor samples. Some of them were cancer-related according to COSMIC and HGMD databases (no founder mutations in BRCA1 and BRCA2 have been found. A large number of focal copy number alterations (FCNAs were detected, including homozygous deletions (HDs targeting WWOX and GATA4. Progression of OVDM1 from early to late passages was accompanied by preservation of the near-diploid status, acquisition of only few additional large chromosomal rearrangements and more than 100 new small FCNAs. Most of newly acquired FCNAs seem to be related to localized but massive DNA fragmentation (chromothripsis-like rearrangements. Newly developed near-diploid OVDM1 cell line offers an opportunity to evaluate tumorigenesis pathways/events in a minor clone of metastatic ovarian adenocarcinoma as well as mechanisms of chromothripsis.

Emerging Therapies in Metastatic Prostate Cancer.

Science.gov (United States)

Sonnenburg, Daniel W; Morgans, Alicia K

2018-04-11

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

Treatment strategy for metastatic prostate cancer with extremely high PSA level: reconsidering the value of vintage therapy.

Science.gov (United States)

Yamada, Yasutaka; Sakamoto, Shinichi; Amiya, Yoshiyasu; Sasaki, Makoto; Shima, Takayuki; Komiya, Akira; Suzuki, Noriyuki; Akakura, Koichiro; Ichikawa, Tomohiko; Nakatsu, Hiroomi

2018-05-04

The prognostic significance of initial prostate-specific antigen (PSA) level for metastatic prostate cancer remains uncertain. We investigated the differences in prognosis and response to hormonal therapies of metastatic prostate cancer patients according to initial PSA levels. We analyzed 184 patients diagnosed with metastatic prostate cancer and divided them into three PSA level groups as follows: low (PSA progression-free survival (PFS) for first-line ADT and overall survival (OS) within each of the three groups. Furthermore, we analyzed response to antiandrogen withdrawal (AW) and alternative antiandrogen (AA) therapies after development of castration-resistant prostate cancer (CRPC). No significant differences in OS were observed among the three groups (P = 0.654). Patients with high PSA levels had significantly short PFS for first-line ADT (P = 0.037). Conversely, patients in the high PSA level group had significantly longer PFS when treated with AW than those in the low PSA level group (P = 0.047). Furthermore, patients with high PSA levels had significantly longer PFS when provided with AA therapy (P = 0.049). PSA responders to AW and AA therapies had significantly longer survival after CRPC development than nonresponders (P = 0.011 and P PSA level predicted favorable response to vintage sequential ADT and AW. The current data suggest a novel aspect of extremely high PSA value as a favorable prognostic marker after development of CRPC.

Scintigraphic detection of metastatic melanoma using indium 111/DTPA conjugated anti-gp240 antibody (ZME-018)

International Nuclear Information System (INIS)

Kirkwood, J.M.; Neumann, R.D.; Zoghbi, S.S.; Ernstoff, M.S.; Cornelius, E.A.; Shaw, C.; Ziyadeh, T.; Fine, J.A.; Unger, M.W.

1987-01-01

We evaluated the toxicity, pharmacokinetics, and localization of a monoclonal IgG2 alpha murine anti-human melanoma (gp240) antibody (ZME-018) that recognizes a tumor-associated cell surface glycoprotein of 240,000 molecular weight present in most melanomas. The antibody was conjugated with DTPA (diethylenetriamine pentaacetic acid) and labeled by chelation of 111 In. One mg of antibody labeled with 5 mCi of 111 In was infused, together with 0 to 40 mg of cold carrier ZME-018. The blood clearance, urinary excretion, and in vivo localization were determined in 26 patients. Scintigraphic images were obtained at 24 hours and 72 hours in all patients. Mild toxicity occurred in one patient. The half-time clearance of labeled monoclonal murine antibody (MoAb) from the blood increased from 16.1 hours at an antibody dose of 1 mg to 35.9 hours at 40 mg. Males showed faster clearance from the blood than did females or a single castrated male, perhaps due to selective concentration of antibody in the testes. Nonspecific uptake in liver, spleen, bone marrow, and intestine was seen in all patients. The percentage of known metastatic foci detected increased with the total dosage of antibody, from 23% at doses less than or equal to 5 mg, to 65%, 87% and 78% for 10, 20, and 40 mg, respectively. We conclude that at doses of greater than or equal to 10 mg, ZME-018 is a safe and potentially useful agent for the scintigraphic detection of metastatic malignant melanoma

In Vivo Detection of HSP90 Identifies Breast Cancers with Aggressive Behavior.

Science.gov (United States)

Osada, Takuya; Kaneko, Kensuke; Gwin, William R; Morse, Michael A; Hobeika, Amy; Pogue, Brian W; Hartman, Zachary C; Hughes, Philip F; Haystead, Timothy; Lyerly, H Kim

2017-12-15

Purpose: Hsp90, a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers. We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive breast cancers. Experimental Design: We exploited the uptake of an Hsp90 inhibitor by malignant cells to create an imaging probe (HS131) of Hsp90 activity by linking it to a near-infrared (nIR) dye. HS131 uptake into cells correlated with cell membrane expression of Hsp90 and was used to image molecular subtypes of murine and human breast cancers in vitro and in murine models. Results: HS131 imaging was both sensitive and specific in detecting the murine 4T1 breast cancer cell line, as well as subclones with differing metastatic potential. Highly metastatic subclones (4T07) had high HS131 uptake, but subclones with lower metastatic potential (67NR, 168FARN) had low HS131 uptake. We generated isogenic cell lines to demonstrate that overexpression of a variety of specific oncogenes resulted in high HS131 uptake and retention. Finally, we demonstrated that HS131 could be used to detect spontaneous tumors in MMTV-neu mice, as well as primary and metastatic human breast cancer xenografts. HS131 could image invasive lobular breast cancer, a histologic subtype of breast cancer which is often undetectable by mammography. Conclusions: An HSP90-targeting nIR probe is sensitive and specific in imaging all molecular subtypes of murine and human breast cancer, with higher uptake in aggressive and highly metastatic clones. Clinical studies with Hsp90-targeting nIR probes will be initiated shortly. Clin Cancer Res; 23(24); 7531-42. ©2017 AACR . ©2017 American Association for Cancer Research.

Stable and high expression of Galectin-8 tightly controls metastatic progression of prostate cancer

Science.gov (United States)

Gentilini, Lucas Daniel; Pérez, Ignacio González; Kotler, Monica Lidia; Chauchereau, Anne; Laderach, Diego Jose; Compagno, Daniel

2017-01-01

Two decades ago, Galectin-8 was described as a prostate carcinoma biomarker since it is only expressed in the neoplastic prostate, but not in the healthy tissue. To date, no biological function has been attributed to Galectin-8 that could explain this differential expression. In this study we silenced Galectin-8 in two human prostate cancer cell lines, PC3 and IGR-CaP1, and designed a pre-clinical experimental model that allows monitoring the pathology from its early steps to the long-term metastatic stages. We show for the first time that the natural and conserved expression of Gal-8 in tumour cells is responsible for the metastatic evolution of prostate cancer. In fact, Gal-8 controls the rearrangement of the cytoskeleton and E-Cadherin expression, with a major impact on anoikis and homotypic aggregation of tumour cells, both being essential processes for the survival of circulating tumour cells during metastasis. While localized prostate cancer can be cured, metastatic and advanced disease remains a significant therapeutic challenge, urging for the identification of prognostic markers of the metastatic process. Collectively, our results highlight Galectin-8 as a potential target for anti-metastatic therapy against prostate cancer. PMID:28591719

Percutaneous CT-guided high frequency induced thermotherapy as a treatment hepatocellular carcinoma and hepatic metastatic lesions

International Nuclear Information System (INIS)

Lu Ligong; Luo Pengfei; Chen Xiaoming

2004-01-01

Objective: To analyze the efficacy, side effects and complications of percutaneous high frequency induced thermotherapy (HiTT) performed under CT guidance involving 36 patients with hepatocellular carcinomas (HCC) and hepatic metastatic lesions. Methods: HiTT was performed in treatment of 36 patients (24 men and 12 women) with 42 hepatocellular carcinoma and hepatic metastatic carcinoma (six patient out of 36 had two nidi). The diameter of the tumors ranged from 1.6 to 7.8 cm (mean, 3.2 cm). The efficacy of HiTT was evaluated with triphasic spiral CT performed 1 month after the procedure. Results: The post-treatment CT scan showed complete necrosis in 33 nidi (78%) out of 42 nidi of hepatocellular carcinoma and hepatic metastatic carcinoma in 30 patients out of 36. Complete necrosis was obtained in 18 (95%) of 19 tumors no larger than 3 cm in diameter, 13 (72%) of 18 tumors between 3.0 and 5.0 cm in diameter. Eleven tumors showed incomplete necrosis. In our study, none of the patients experienced severe complications. All the patients are alive in the follow-up ranging from 2 to 12 months (mean, 7 months). Conclusion: Our research suggests that HiTT can be a safe and effective treatment of hepatocellular carcinomas and hepatic metastatic carcinoma when the lesion is no larger than 3 cm. The treatment is relatively effective for hepatocellular carcinoma between 3 and 5 cm in size. (authors)

High Genomic Instability Predicts Survival in Metastatic High-Risk Neuroblastoma

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Sara Stigliani

2012-09-01

Full Text Available We aimed to identify novel molecular prognostic markers to better predict relapse risk estimate for children with high-risk (HR metastatic neuroblastoma (NB. We performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR NBs. Children older than 1 year of age were categorized as “short survivors” (dead of disease within 5 years from diagnosis and “long survivors” (alive with an overall survival time ≥ 5 years. We reported that patients with less than three segmental copy number aberrations in their tumor represent a molecularly defined subgroup with a high survival probability within the current HR group of patients. The complex genomic pattern is a prognostic marker independent of NB-associated chromosomal aberrations, i.e., MYCN amplification, 1p and 11q losses, and 17q gain. Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is mainly associated with loss of cell cycle control and deregulation of Rho guanosine triphosphates (GTPases functioning in neuritogenesis. Tumors with MYCN amplification show a lower chromosome instability compared to MYCN single-copy NBs (P = .0008, dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives disruption of neuronal differentiation and reduction of cell adhesion process involved in tumor invasion and metastasis. Further validation studies are warranted to establish this as a risk stratification for patients.

Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002

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Eric K. Ring

2017-12-01

Full Text Available Despite advances in conventional chemotherapy, surgical techniques, and radiation, outcomes for patients with relapsed, refractory, or metastatic soft tissue sarcomas are dismal. Survivors often suffer from lasting morbidity from current treatments. New targeted therapies with less toxicity, such as those that harness the immune system, and immunocompetent murine sarcoma models to test these therapies are greatly needed. We characterized two new serendipitous murine models of undifferentiated sarcoma (SARC-28 and SARC-45 and tested their sensitivity to virotherapy with oncolytic herpes simplex virus 1 (HSV-1. Both models expressed high levels of the primary HSV entry molecule nectin-1 (CD111 and were susceptible to killing by interleukin-12 (IL-12 producing HSV-1 M002 in vitro and in vivo. M002 resulted in a significant intratumoral increase in effector CD4+ and CD8+ T cells and activated monocytes, and a decrease in myeloid-derived suppressor cells (MDSCs in immunocompetent mice. Compared to parent virus R3659 (no IL-12 production, M002 resulted in higher CD8:MDSC and CD8:T regulatory cell (Treg ratios, suggesting that M002 creates a more favorable immune tumor microenvironment. These data provide support for clinical trials targeting sarcomas with oncolytic HSV-1. These models provide an exciting opportunity to explore combination therapies for soft tissue sarcomas that rely on an intact immune system to reach full therapeutic potential.

Metastatic renal cell carcinoma management

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Flavio L. Heldwein

2009-06-01

Full Text Available PURPOSE: To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. MATERIAL AND METHODS: The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. RESULTS: Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. CONCLUSIONS: A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

Pre-metastatic niches

DEFF Research Database (Denmark)

Peinado, Héctor; Zhang, Haiying; Matei, Irina R.

2017-01-01

It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour......-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche....

Non- invasive in vivo analysis of a murine aortic graft using high resolution ultrasound microimaging

International Nuclear Information System (INIS)

Rowinska, Zuzanna; Zander, Simone; Zernecke, Alma; Jacobs, Michael; Langer, Stephan; Weber, Christian; Merx, Marc W.; Koeppel, Thomas A.

2012-01-01

Introduction: As yet, murine aortic grafts have merely been monitored histopathologically. The aim of our study was to examine how these grafts can be monitored in vivo and non-invasively by using high-resolution ultrasound microimaging to evaluate function and morphology. A further aim was to prove if this in vivo monitoring can be correlated to immunohistological data that indicates graft integrity. Methods: Murine infrarenal aortic isografts were orthotopically transplanted into 14 female mice (C57BL/6-Background) whereas a group of sham-operated animals (n = 10) served as controls. To assess the graft morphology and hemodynamics, we examined the mice over a post-operative period of 8 weeks with a sophisticated ultrasound system (Vevo 770, Visual Sonics). Results: The non-invasive graft monitoring was feasible in all transplanted mice. We could demonstrate a regular post-transplant graft function and morphology, such as anterior/posterior wall displacement and wall thickness. Mild alterations of anterior wall motion dynamics could only be observed at the site of distal graft anastomosis (8 weeks after grafting (transplant vs. sham mice: 0.02 mm ± 0.01 vs. 0.03 mm ± 0.01, p < 0.05). However, the integrity of the entire graft wall could be confirmed by histopathological evaluation of the grafts. Conclusions: With regard to graft patency, function and morphology, high resolution ultrasound microimaging has proven to be a valuable tool for longitudinal, non-invasive, in vivo graft monitoring in this murine aortic transplantation model. Consequently, this experimental animal model provides an excellent basis for molecular and pharmacological studies using genetically engineered mice.

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin.

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Jahnabi Roy

Full Text Available Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics.

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin.

Science.gov (United States)

Roy, Jahnabi; Wycislo, Kathryn L; Pondenis, Holly; Fan, Timothy M; Das, Aditi

2017-01-01

Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics.

Epidemiology and therapies for metastatic sarcoma

Science.gov (United States)

Amankwah, Ernest K; Conley, Anthony P; Reed, Damon R

2013-01-01

Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models. Metastatic sarcomas are excellent candidates for novel approaches with additional agents as they have demonstrated chemosensitivity and affect a portion of the population that is motivated toward curative therapy. In this paper, we provide an overview on the common sarcomas of childhood (rhabdomyosarcoma), adolescence, and young adults (osteosarcoma, Ewing sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor) and older adults (leiomyosarcoma, liposarcoma, and undifferentiated high grade sarcoma) in terms of the epidemiology, current therapy, promising therapeutic directions and outcome with a focus on metastatic disease. Potential advances in terms of promising therapy and biologic insights may lead to more effective and safer therapies; however, more clinical trials and research are needed for patients with metastatic sarcoma. PMID:23700373

Characteristics and Patterns of Metastatic Disease from Chordoma

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Victoria A. Young

2015-01-01

Full Text Available Chordoma is a rare, slow-growing malignant tumor arising from notochordal remnants. A retrospective review of patient records at two major referral centers was undertaken to assess the incidence, location, and prognostic factors of metastatic disease from chordoma. 219 patients with chordoma (1962–2009 were identified. 39 patients (17.8% developed metastatic disease, most frequently to lung (>50%. Median survival from the time of initial diagnosis was 130.4 months for patients who developed metastatic disease and 159.3 months for those who did not (P=0.05. Metastatic disease was most common in the youngest patients (P=0.07, and it was 2.5 times more frequent among patients with local recurrence (26.3% than in those without (10.8% (P=0.003. Patient survival with metastatic disease was highly variable, and it was dependent on both the location of the tumor primary and the site of metastasis. Metastasis to distal bone was the most rapid to develop and had the worst prognosis.

Differentiation of Metastatic and Non-Metastatic Mesenteric Lymph Nodes by Strain Elastography in Surgical Specimens

DEFF Research Database (Denmark)

Havre, R F; Leh, S M; Gilja, O H

2016-01-01

Purpose: To investigate if strain elastography could differentiate between metastatic and non-metastatic mesenteric lymph nodes ex-vivo. Materials and Methods: 90 mesenteric lymph nodes were examined shortly after resection from 25 patients including 17 patients with colorectal cancer and 8...... patients with Crohn's disease. Ultrasound-based strain elastography was performed with a linear probe. Tissue hardness in lymph nodes was assessed using visual scales and measuring the strain ratio. B-mode characteristics were also recorded. Pathological diagnosis with grading of fibrosis served...... non-metastatic nodes, but the difference was not significant (65.5 vs. 55.0, p = 0.055). There was no difference between lymph nodes in Crohn's and non-metastatic cancer specimens. The metastatic lymph nodes were significantly more fibrotic than the non-metastatic lymph nodes by the ordinal fibrosis...

Imaging of Spinal Metastatic Disease

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Lubdha M. Shah

2011-01-01

Full Text Available Metastases to the spine can involve the bone, epidural space, leptomeninges, and spinal cord. The spine is the third most common site for metastatic disease, following the lung and the liver. Approximately 60–70% of patients with systemic cancer will have spinal metastasis. Materials/Methods. This is a review of the imaging techniques and typical imaging appearances of spinal metastatic disease. Conclusions. Awareness of the different manifestations of spinal metastatic disease is essential as the spine is the most common site of osseous metastatic disease. Imaging modalities have complimentary roles in the evaluation of spinal metastatic disease. CT best delineates osseous integrity, while MRI is better at assessing soft tissue involvement. Physiologic properties, particularly in treated disease, can be evaluated with other imaging modalities such as FDG PET and advanced MRI sequences. Imaging plays a fundamental role in not only diagnosis but also treatment planning of spinal metastatic disease.

Topotecan-Vincristine-Doxorubicin in Stage 4 High-Risk Neuroblastoma Patients Failing to Achieve a Complete Metastatic Response to Rapid COJEC: A SIOPEN Study.

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Amoroso, Loredana; Erminio, Giovanni; Makin, Guy; Pearson, Andrew D J; Brock, Penelope; Valteau-Couanet, Dominique; Castel, Victoria; Pasquet, Marlène; Laureys, Genevieve; Thomas, Caroline; Luksch, Roberto; Ladenstein, Ruth; Haupt, Riccardo; Garaventa, Alberto

2018-01-01

Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([ 123 I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate. Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m 2 /day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m 2 , and doxorubicin, 45 mg/m 2 . Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%). TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors.

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Adalsteinsson, Viktor A; Ha, Gavin; Freeman, Samuel S; Choudhury, Atish D; Stover, Daniel G; Parsons, Heather A; Gydush, Gregory; Reed, Sarah C; Rotem, Denisse; Rhoades, Justin; Loginov, Denis; Livitz, Dimitri; Rosebrock, Daniel; Leshchiner, Ignaty; Kim, Jaegil; Stewart, Chip; Rosenberg, Mara; Francis, Joshua M; Zhang, Cheng-Zhong; Cohen, Ofir; Oh, Coyin; Ding, Huiming; Polak, Paz; Lloyd, Max; Mahmud, Sairah; Helvie, Karla; Merrill, Margaret S; Santiago, Rebecca A; O'Connor, Edward P; Jeong, Seong H; Leeson, Rachel; Barry, Rachel M; Kramkowski, Joseph F; Zhang, Zhenwei; Polacek, Laura; Lohr, Jens G; Schleicher, Molly; Lipscomb, Emily; Saltzman, Andrea; Oliver, Nelly M; Marini, Lori; Waks, Adrienne G; Harshman, Lauren C; Tolaney, Sara M; Van Allen, Eliezer M; Winer, Eric P; Lin, Nancy U; Nakabayashi, Mari; Taplin, Mary-Ellen; Johannessen, Cory M; Garraway, Levi A; Golub, Todd R; Boehm, Jesse S; Wagle, Nikhil; Getz, Gad; Love, J Christopher; Meyerson, Matthew

2017-11-06

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.

Tetrofosmin in metastatic breast cancer

International Nuclear Information System (INIS)

Berghammer, P.; Obwegeser, R.; Ulm, M.; Wiltschke, C.; Kubista, E.; Sinzinger, H.; Zielinski, C.

1997-01-01

% detection rate for extrahepatic metastases was found. It seems evident that tetrofosmin scintigraphy can effectively help detect metastatic disease in patients with breast cancer. Due to tetrofosmins hepatobiliary elimination pathway, the detection of liver metastases is impossible. Therefore, liver ultrasonography has to be used concomitantly in the staging process when tetrofosmin scintigraphy is used to detect metastatic lesions. Nevertheless, the low costs of tetrofosmin scintigraphy and its high correlation with CT/MRI scan suggest its use as a screening test for metastatic disease in the restaging process of cancer patients. (author)

High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review.

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Frank Peinemann

Full Text Available INTRODUCTION: Patients with metastatic rhabdomyosarcoma (RMS have a poor prognosis. The aim of this systematic review is to investigate whether high-dose chemotherapy (HDCT followed by autologous hematopoietic stem cell transplantation (HSCT in patients with metastatic RMS has additional benefit or harm compared to standard chemotherapy. METHODS: Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to February 2010. PubMed was searched in June 2010 for a last update. In addition to randomized and non-randomized controlled trials, case series and case reports were included to complement results from scant data. The primary outcome was overall survival. A meta-analysis was performed using the hazard ratio as primary effect measure, which was estimated from Cox proportional hazard models or from summary statistics of Kaplan Meier product-limit estimations. RESULTS: A total of 40 studies with 287 transplant patients with metastatic RMS (age range 0 to 32 years were included in the assessment. We identified 3 non-randomized controlled trials. The 3-year overall survival ranged from 22% to 53% in the transplant groups vs. 18% to 55% in the control groups. Meta-analysis on overall survival in controlled trials showed no difference between treatments. Result of meta-analysis of pooled individual survival data of case series and case reports, and results from uncontrolled studies with aggregate data were in the range of those from controlled data. The risk of bias was high in all studies due to methodological flaws. CONCLUSIONS: HDCT followed by autologous HSCT in patients with RMS remains an experimental treatment. At present, it does not appear justifiable to use this treatment except in appropriately designed controlled trials.

Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology.

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Walker, Steven M; Knight, Laura A; McCavigan, Andrena M; Logan, Gemma E; Berge, Viktor; Sherif, Amir; Pandha, Hardev; Warren, Anne Y; Davidson, Catherine; Uprichard, Adam; Blayney, Jaine K; Price, Bethanie; Jellema, Gera L; Steele, Christopher J; Svindland, Aud; McDade, Simon S; Eden, Christopher G; Foster, Chris; Mills, Ian G; Neal, David E; Mason, Malcolm D; Kay, Elaine W; Waugh, David J; Harkin, D Paul; Watson, R William; Clarke, Noel W; Kennedy, Richard D

2017-10-01

Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; pmolecular subgroup of primary prostate cancers with metastatic potential. The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

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Sustarsic, Elahu G. [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Department of Biological Sciences, Ohio University, Athens, OH (United States); Junnila, Riia K. [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Kopchick, John J., E-mail: kopchick@ohio.edu [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Department of Biological Sciences, Ohio University, Athens, OH (United States); Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH (United States)

2013-11-08

Highlights: •Most cancer types of the NCI60 have sub-sets of cell lines with high GHR expression. •GHR is highly expressed in melanoma cell lines. •GHR is elevated in advanced stage IV metastatic tumors vs. stage III. •GH treatment of metastatic melanoma cell lines alters growth and cell signaling. -- Abstract: Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute’s NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on

High-throughput genotyping in metastatic esophageal squamous cell carcinoma identifies phosphoinositide-3-kinase and BRAF mutations.

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Chi Hoon Maeng

Full Text Available Given the high incidence of metastatic esophageal squamous cell carcinoma, especially in Asia, we screened for the presence of somatic mutations using OncoMap platform with the aim of defining subsets of patients who may be potential candidate for targeted therapy.We analyzed 87 tissue specimens obtained from 80 patients who were pathologically confirmed with esophageal squamous cell carcinoma and received 5-fluoropyrimidine/platinum-based chemotherapy. OncoMap 4.0, a mass-spectrometry based assay, was used to interrogate 471 oncogenic mutations in 41 commonly mutated genes. Tumor specimens were prepared from primary cancer sites in 70 patients and from metastatic sites in 17 patients. In order to test the concordance between primary and metastatic sites from the patient for mutations, we analyzed 7 paired (primary-metastatic specimens. All specimens were formalin-fixed paraffin embedded tissues and tumor content was >70%.In total, we have detected 20 hotspot mutations out of 80 patients screened. The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L (N = 10, 11.5% followed by MLH1 V384D (N = 7, 8.0%, TP53 (R306, R175H and R273C (N = 3, 3.5%, BRAF V600E (N = 1, 1.2%, CTNNB1 D32N (N = 1, 1.2%, and EGFR P733L (N = 1, 1.2%. Distributions of somatic mutations were not different according to anatomic sites of esophageal cancer (cervical/upper, mid, lower. In addition, there was no difference in frequency of mutations between primary-metastasis paired samples.Our study led to the detection of potentially druggable mutations in esophageal SCC which may guide novel therapies in small subsets of esophageal cancer patients.

Metastatic and non-metastatic lymph nodes. Quantification and different distribution of iodine uptake assessed by dual-energy CT

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Rizzo, Stefania [European Institute of Oncology, Department of Radiology, Milan (Italy); Radice, Davide [Department of Epidemiology and Biostatistics, Milan (Italy); Femia, Marco; Vigorito, Raffaella [Universita di Milano, Department of Health Sciences, Milan (Italy); De Marco, Paolo; Origgi, Daniela [Medical Physics, European Institute of Oncology, Milan (Italy); Preda, Lorenzo [Division of Radiology, National Centre of Oncological Hadrontherapy (CNAO Foundation), Pavia (Italy); University of Pavia, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, Pavia (Italy); Barberis, Massimo [European Institute of Oncology, Department of Pathology, Milan (Italy); Mauri, Giovanni [European Institute of Oncology, Division of Interventional Radiology, Milan (Italy); Mauro, Alberto [GE Medical Systems Italia SpA, Milan (Italy); Bellomi, Massimo [European Institute of Oncology, Department of Radiology, Milan (Italy); Universita di Milano, Department of Oncology, Milan (Italy)

2018-02-15

To evaluate quantification of iodine uptake in metastatic and non-metastatic lymph nodes (LNs) by dual-energy CT (DECT) and to assess if the distribution of iodine within LNs at DECT correlates with the pathological structure. Ninety LNs from 37 patients (23 with lung and 14 with gynaecological malignancies) were retrospectively selected. Information of LNs sent for statistical analysis included Hounsfield units (HU) at different energy levels; decomposition material densities fat-iodine, iodine-fat, iodine-water, water-iodine. Statistical analysis included evaluation of interobserver variability, material decomposition densities and spatial HU distribution within LNs. Interobserver agreement was excellent. There was a significant difference in iodine-fat and iodine-water decompositions comparing metastatic and non-metastatic LNs (p < 0.001); fat-iodine and water-iodine did not show significant differences. HU distribution showed a significant gradient from centre to periphery within non-metastatic LNs that was significant up to 20-30% from the centre, whereas metastatic LNs showed a more homogeneous distribution of HU, with no significant gradient. DECT demonstrated a lower iodine uptake in metastatic compared to non-metastatic LNs. Moreover, the internal iodine distribution showed an evident gradient of iodine distribution from centre to periphery in non-metastatic LNs, and a more homogeneous distribution within metastatic LNs, which corresponded to the pathological structure. (orig.)

miR-200–containing extracellular vesicles promote breast cancer cell metastasis

Science.gov (United States)

Le, Minh T.N.; Hamar, Peter; Guo, Changying; Basar, Emre; Perdigão-Henriques, Ricardo; Balaj, Leonora; Lieberman, Judy

2014-01-01

Metastasis is associated with poor prognosis in breast cancer patients. Not all cancer cells within a tumor are capable of metastasizing. The microRNA-200 (miR-200) family, which regulates the mesenchymal-to-epithelial transition, is enriched in the serum of patients with metastatic cancers. Ectopic expression of miR-200 can confer metastatic ability to poorly metastatic tumor cells in some settings. Here, we investigated whether metastatic capability could be transferred between metastatic and nonmetastatic cancer cells via extracellular vesicles. miR-200 was secreted in extracellular vesicles from metastatic murine and human breast cancer cell lines, and miR-200 levels were increased in sera of mice bearing metastatic tumors. In culture, murine and human metastatic breast cancer cell extracellular vesicles transferred miR-200 microRNAs to nonmetastatic cells, altering gene expression and promoting mesenchymal-to-epithelial transition. In murine cancer and human xenograft models, miR-200–expressing tumors and extracellular vesicles from these tumors promoted metastasis of otherwise weakly metastatic cells either nearby or at distant sites and conferred to these cells the ability to colonize distant tissues in a miR-200–dependent manner. Together, our results demonstrate that metastatic capability can be transferred by the uptake of extracellular vesicles. PMID:25401471

High-dose estrogen as salvage hormonal therapy for highly refractory metastatic breast cancer: a retrospective chart review.

Science.gov (United States)

Mahtani, Reshma L; Stein, Alisha; Vogel, Charles L

2009-01-01

High-dose estrogens (HDEs) are an efficacious but widely overlooked treatment option for patients with metastatic breast cancer (MBC). This is due in part to the introduction of tamoxifen in the 1970s, which was proven to be equivalent in efficacy and associated with fewer adverse events (AEs). The aim of this study was to report our experience with the use of HDE in postmenopausal women with advanced breast cancer. Local institutional review board approval was obtained to conduct a retrospective chart review of patients with MBC treated with HDEs at the Boca Raton Comprehensive Cancer Center, Boca Raton, Florida, from 2001 through March 2009. Demographic information, response rates, and tolerability profiles were collected. Of the 426 patients with MBC identified, we found 26 patients with MBC who were prescribed HDEs as a treatment in any line of therapy for advanced breast cancer. The median age at the start of HDE therapy was 59 years (range, 42-92 years). Three of the 26 patients (11.5%) were human epidermal growth factor receptor 2-positive determined via fluorescent in situ hybridization analysis. With the exception of 1 patient who had received no prior systemic treatment for metastatic disease, all patients received multiple lines of treatment (both chemotherapy and hormonal treatments) in the advanced setting (median, 7 lines; range, 0-12) prior to the initiation of HDE. Five of 20 patients (25%) with measurable metastatic disease (visceral and/or soft tissue metastases) had objective antitumor responses defined as either a partial response (PR) or a complete response (CR). Four additional patients (20%) had prolonged stable disease (SD) for > or =6 months. Three of 6 patients (50%) with nonmeasurable metastatic disease (bone-only) had prolonged SD for > or =6 months. Clinical benefit rate (defined as CR + PR + SD > or =6 months) for all patients was 46% (12/26), with a median duration of 10 months. Overall median progression-free survival for the 26

Evaluation of dual energy spectral CT in differentiating metastatic from non-metastatic lymph nodes in rectal cancer: Initial experience

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Liu, Huanhuan [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Department of Radiology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine (China); Yan, Fuhua; Pan, Zilai; Lin, Xiaozhu; Luo, Xianfu; Shi, Cen [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Chen, Xiaoyan [Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Wang, Baisong [Department of Biomedical Statistics, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Zhang, Huan, E-mail: huanzhangy@126.com [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China)

2015-02-15

Highlights: • Colorectal cancer is the third most prevalent cancer and the status of the regional lymph nodes in rectal cancer is considered to be one of the most powerful prognostic factor in the absence of distant metastatic disease. Detecting LNs metastasis is still a challenging problem due to the presence of microscopic metastasis or inflammatory swelling of LNs. • We investigated the value of dual energy spectral CT in differentiating metastatic from non-metastatic lymph nodes in rectal cancer. Our study demonstrated that the quantitative normalized iodine concentration (nIC) could be useful for differentiating metastatic and non-metastatic lymph nodes. The combination of nIC in portal venous phase and conventional size criterion could improve the diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of rectal cancer. - Abstract: Objectives: To investigate the value of dual energy spectral CT (DEsCT) imaging in differentiating metastatic from non-metastatic lymph nodes in rectal cancer. Methods: Fifty-five patients with rectal cancer underwent the arterial phase (AP) and portal venous phase (PP) contrast-enhanced DEsCT imaging. The virtual monochromatic images and iodine-based material decomposition images derived from DEsCT imaging were interpreted for lymph nodes (LNs) measurement. The short axis diameter and the normalized iodine concentration (nIC) of metastatic and non-metastatic LNs were measured. The two-sample t test was used to compare the short axis diameters and nIC values of metastatic and non-metastatic LNs. ROC analysis was performed to assess the diagnostic performance. Results: One hundred and fifty two LNs including 92 non-metastatic LNs and 60 metastatic LNs were matched using the radiological-pathological correlation. The mean short axis diameter of metastatic LNs was significantly larger than that of the non-metastatic LNs (7.28 ± 2.28 mm vs. 4.90 ± 1.64 mm, P < 0.001). The mean n

Epidemiology and therapies for metastatic sarcoma

Directory of Open Access Journals (Sweden)

Amankwah EK

2013-05-01

Full Text Available Ernest K Amankwah,1 Anthony P Conley,2 Damon R Reed2 1Department of Cancer Epidemiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2Sarcoma Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Abstract: Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models. Metastatic sarcomas are excellent candidates for novel approaches with additional agents as they have demonstrated chemosensitivity and affect a portion of the population that is motivated toward curative therapy. In this paper, we provide an overview on the common sarcomas of childhood (rhabdomyosarcoma, adolescence, and young adults (osteosarcoma, Ewing sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor and older adults (leiomyosarcoma, liposarcoma, and undifferentiated high grade sarcoma in terms of the epidemiology, current therapy, promising therapeutic directions and outcome with a focus on metastatic disease. Potential advances in terms of promising therapy and biologic insights may lead to more effective and safer therapies; however, more clinical trials and research are needed for patients with metastatic sarcoma. Keywords: chemotherapy, pediatric sarcoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, synovial sarcoma

Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors.

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Dondossola, Eleonora; Dobroff, Andrey S; Marchiò, Serena; Cardó-Vila, Marina; Hosoya, Hitomi; Libutti, Steven K; Corti, Angelo; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

2016-02-23

Circulating cancer cells can putatively colonize distant organs to form metastases or to reinfiltrate primary tumors themselves through a process termed "tumor self-seeding." Here we exploit this biological attribute to deliver tumor necrosis factor alpha (TNF), a potent antitumor cytokine, directly to primary and metastatic tumors in a mechanism that we have defined as "tumor self-targeting." For this purpose, we genetically engineered mouse mammary adenocarcinoma (TSA), melanoma (B16-F10), and Lewis lung carcinoma cells to produce and release murine TNF. In a series of intervention trials, systemic administration of TNF-expressing tumor cells was associated with reduced growth of both primary tumors and metastatic colonies in immunocompetent mice. We show that these malignant cells home to tumors, locally release TNF, damage neovascular endothelium, and induce massive cancer cell apoptosis. We also demonstrate that such tumor-cell-mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents. In a clinical context, this unique paradigm represents a personalized approach to be translated into applications potentially using patient-derived circulating tumor cells as self-targeted vectors for drug delivery.

Ecotropic murine leukemia virus-induced fusion of murine cells

International Nuclear Information System (INIS)

Pinter, A.; Chen, T.; Lowy, A.; Cortez, N.G.; Silagi, S.

1986-01-01

Extensive fusion occurs upon cocultivation of murine fibroblasts producing ecotropic murine leukemia viruses (MuLVs) with a large variety of murine cell lines in the presence of the polyene antibiotic amphotericin B, the active component of the antifungal agent Fungizone. The resulting polykaryocytes contain nuclei from both infected and uninfected cells, as evidenced by autoradiographic labeling experiments in which one or the other parent cell type was separately labeled with [ 3 H]thymidine and fused with an unlabeled parent. This cell fusion specifically requires the presence of an ecotropic MuLV-producing parent and is not observed for cells producing xenotropic, amphotropic, or dualtropic viruses. Mouse cells infected with nonecotropic viruses retain their sensitivity toward fusion, whereas infection with ecotropic viruses abrogates the fusion of these cells upon cocultivation with other ecotropic MuLV-producing cells. Nonmurine cells lacking the ecotropic gp70 receptor are not fused under similar conditions. Fusion is effectively inhibited by monospecific antisera to gp70, but not by antisera to p15(E), and studies with monoclonal antibodies identify distinct amino- and carboxy-terminal gp70 regions which play a role in the fusion reaction. The enhanced fusion which occurs in the presence of amphotericin B provides a rapid and sensitive assay for the expression of ecotropic MuLVs and should facilitate further mechanistic studies of MuLV-induced fusion of murine cells

Highly efficient gene transfer using a retroviral vector into murine T cells for preclinical chimeric antigen receptor-expressing T cell therapy

International Nuclear Information System (INIS)

Kusabuka, Hotaka; Fujiwara, Kento; Tokunaga, Yusuke; Hirobe, Sachiko; Nakagawa, Shinsaku; Okada, Naoki

2016-01-01

Adoptive immunotherapy using chimeric antigen receptor-expressing T (CAR-T) cells has attracted attention as an efficacious strategy for cancer treatment. To prove the efficacy and safety of CAR-T cell therapy, the elucidation of immunological mechanisms underlying it in mice is required. Although a retroviral vector (Rv) is mainly used for the introduction of CAR to murine T cells, gene transduction efficiency is generally less than 50%. The low transduction efficiency causes poor precision in the functional analysis of CAR-T cells. We attempted to improve the Rv gene transduction protocol to more efficiently generate functional CAR-T cells by optimizing the period of pre-cultivation and antibody stimulation. In the improved protocol, gene transduction efficiency to murine T cells was more than 90%. In addition, almost all of the prepared murine T cells expressed CAR after puromycin selection. These CAR-T cells had antigen-specific cytotoxic activity and secreted multiple cytokines by antigen stimulation. We believe that our optimized gene transduction protocol for murine T cells contributes to the advancement of T cell biology and development of immunotherapy using genetically engineered T cells. - Highlights: • We established highly efficient gene transduction protocols for murine T cells. • CD8"+ CAR-T cells had antigen-specific cytotoxic activity. • CD4"+ CAR-T cells secreted multiple cytokines by antigen stimulation. • This finding can contribute to the development of T-cell biology and immunotherapy.

Highly efficient gene transfer using a retroviral vector into murine T cells for preclinical chimeric antigen receptor-expressing T cell therapy

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Kusabuka, Hotaka; Fujiwara, Kento; Tokunaga, Yusuke; Hirobe, Sachiko; Nakagawa, Shinsaku, E-mail: nakagawa@phs.osaka-u.ac.jp; Okada, Naoki, E-mail: okada@phs.osaka-u.ac.jp

2016-04-22

Adoptive immunotherapy using chimeric antigen receptor-expressing T (CAR-T) cells has attracted attention as an efficacious strategy for cancer treatment. To prove the efficacy and safety of CAR-T cell therapy, the elucidation of immunological mechanisms underlying it in mice is required. Although a retroviral vector (Rv) is mainly used for the introduction of CAR to murine T cells, gene transduction efficiency is generally less than 50%. The low transduction efficiency causes poor precision in the functional analysis of CAR-T cells. We attempted to improve the Rv gene transduction protocol to more efficiently generate functional CAR-T cells by optimizing the period of pre-cultivation and antibody stimulation. In the improved protocol, gene transduction efficiency to murine T cells was more than 90%. In addition, almost all of the prepared murine T cells expressed CAR after puromycin selection. These CAR-T cells had antigen-specific cytotoxic activity and secreted multiple cytokines by antigen stimulation. We believe that our optimized gene transduction protocol for murine T cells contributes to the advancement of T cell biology and development of immunotherapy using genetically engineered T cells. - Highlights: • We established highly efficient gene transduction protocols for murine T cells. • CD8{sup +} CAR-T cells had antigen-specific cytotoxic activity. • CD4{sup +} CAR-T cells secreted multiple cytokines by antigen stimulation. • This finding can contribute to the development of T-cell biology and immunotherapy.

Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks.

Science.gov (United States)

de Assis, Leonardo Vinícius Monteiro; Moraes, Maria Nathália; Magalhães-Marques, Keila Karoline; Kinker, Gabriela Sarti; da Silveira Cruz-Machado, Sanseray; Castrucci, Ana Maria de Lauro

2018-04-03

The biological clock has received increasing interest due to its key role in regulating body homeostasis in a time-dependent manner. Cancer development and progression has been linked to a disrupted molecular clock; however, in melanoma, the role of the biological clock is largely unknown. We investigated the effects of the tumor on its micro- (TME) and macro-environments (TMaE) in a non-metastatic melanoma model. C57BL/6J mice were inoculated with murine B16-F10 melanoma cells and 2 weeks later the animals were euthanized every 6 h during 24 h. The presence of a localized tumor significantly impaired the biological clock of tumor-adjacent skin and affected the oscillatory expression of genes involved in light- and thermo-reception, proliferation, melanogenesis, and DNA repair. The expression of tumor molecular clock was significantly reduced compared to healthy skin but still displayed an oscillatory profile. We were able to cluster the affected genes using a human database and distinguish between primary melanoma and healthy skin. The molecular clocks of lungs and liver (common sites of metastasis), and the suprachiasmatic nucleus (SCN) were significantly affected by tumor presence, leading to chronodisruption in each organ. Taken altogether, the presence of non-metastatic melanoma significantly impairs the organism's biological clocks. We suggest that the clock alterations found in TME and TMaE could impact development, progression, and metastasis of melanoma; thus, making the molecular clock an interesting pharmacological target.

Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks

Directory of Open Access Journals (Sweden)

Leonardo Vinícius Monteiro de Assis

2018-04-01

Full Text Available The biological clock has received increasing interest due to its key role in regulating body homeostasis in a time-dependent manner. Cancer development and progression has been linked to a disrupted molecular clock; however, in melanoma, the role of the biological clock is largely unknown. We investigated the effects of the tumor on its micro- (TME and macro-environments (TMaE in a non-metastatic melanoma model. C57BL/6J mice were inoculated with murine B16-F10 melanoma cells and 2 weeks later the animals were euthanized every 6 h during 24 h. The presence of a localized tumor significantly impaired the biological clock of tumor-adjacent skin and affected the oscillatory expression of genes involved in light- and thermo-reception, proliferation, melanogenesis, and DNA repair. The expression of tumor molecular clock was significantly reduced compared to healthy skin but still displayed an oscillatory profile. We were able to cluster the affected genes using a human database and distinguish between primary melanoma and healthy skin. The molecular clocks of lungs and liver (common sites of metastasis, and the suprachiasmatic nucleus (SCN were significantly affected by tumor presence, leading to chronodisruption in each organ. Taken altogether, the presence of non-metastatic melanoma significantly impairs the organism’s biological clocks. We suggest that the clock alterations found in TME and TMaE could impact development, progression, and metastasis of melanoma; thus, making the molecular clock an interesting pharmacological target.

Clearance of 131I-labeled murine monoclonal antibody from patients' blood by intravenous human anti-murine immunoglobulin antibody

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Stewart, J.S.; Sivolapenko, G.B.; Hird, V.; Davies, K.A.; Walport, M.; Ritter, M.A.; Epenetos, A.A.

1990-01-01

Five patients treated with intraperitoneal 131I-labeled mouse monoclonal antibody for ovarian cancer also received i.v. exogenous polyclonal human anti-murine immunoglobulin antibody. The pharmacokinetics of 131I-labeled monoclonal antibody in these patients were compared with those of 28 other patients receiving i.p.-radiolabeled monoclonal antibody for the first time without exogenous human anti-murine immunoglobulin, and who had no preexisting endogenous human anti-murine immunoglobulin antibody. Patients receiving i.v. human anti-murine immunoglobulin antibody demonstrated a rapid clearance of 131I-labeled monoclonal antibody from their circulation. The (mean) maximum 131I blood content was 11.4% of the injected activity in patients receiving human anti-murine immunoglobulin antibody compared to 23.3% in patients not given human anti-murine immunoglobulin antibody. Intravenous human anti-murine immunoglobulin antibody decreased the radiation dose to bone marrow (from 131I-labeled monoclonal antibody in the vascular compartment) 4-fold. Following the injection of human anti-murine immunoglobulin antibody, 131I-monoclonal/human anti-murine immunoglobulin antibody immune complexes were rapidly transported to the liver. Antibody dehalogenation in the liver was rapid, with 87% of the injected 131I excreted in 5 days. Despite the efficient hepatic uptake of immune complexes, dehalogenation of monoclonal antibody was so rapid that the radiation dose to liver parenchyma from circulating 131I was decreased 4-fold rather than increased. All patients developed endogenous human anti-murine immunoglobulin antibody 2 to 3 weeks after treatment

Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.

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Debbie Liao

2009-11-01

Full Text Available Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer.We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+ T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression.Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.

Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.

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Liao, Debbie; Luo, Yunping; Markowitz, Dorothy; Xiang, Rong; Reisfeld, Ralph A

2009-11-23

Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer. We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+) T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression. Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.

Hyper-IL-15 suppresses metastatic and autochthonous liver cancer by promoting tumour-specific CD8+ T cell responses.

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Cheng, Liang; Du, Xuexiang; Wang, Zheng; Ju, Jianqi; Jia, Mingming; Huang, Qibin; Xing, Qiao; Xu, Meng; Tan, Yi; Liu, Mingyue; Du, Peishuang; Su, Lishan; Wang, Shengdian

2014-12-01

Liver cancer has a very dismal prognosis due to lack of effective therapy. Here, we studied the therapeutic effects of hyper-interleukin15 (hyper-IL-15), which is composed of IL-15 and the sushi domain of the IL-15 receptor α chain, on metastatic and autochthonous liver cancers. Liver metastatic tumour models were established by intraportally injecting syngeneic mice with murine CT26 colon carcinoma cells or B16-OVA melanoma cells. Primary hepatocellular carcinoma (HCC) was induced by diethylnitrosamine (DEN). A hydrodynamics-based gene delivery method was used to achieve sustained hyper-IL-15 expression in the liver. Liver gene delivery of hyper-IL-15 robustly expanded CD8(+) T and NK cells, leading to a long-term (more than 40 days) accumulation of CD8(+) T cells in vivo, especially in the liver. Hyper-IL-15 treatment exerted remarkable therapeutic effects on well-established liver metastatic tumours and even on DEN-induced autochthonous HCC, and these effects were abolished by depletion of CD8(+) T cells but not NK cells. Hyper-IL-15 triggered IL-12 and interferon-γ production and reduced the expression of co-inhibitory molecules on dendritic cells in the liver. Adoptive transfer of T cell receptor (TCR) transgenic OT-1 cells showed that hyper-IL-15 preferentially expanded tumour-specific CD8(+) T cells and promoted their interferon-γ synthesis and cytotoxicity. Liver delivery of hyper-IL-15 provides an effective therapy against well-established metastatic and autochthonous liver cancers in mouse models by preferentially expanding tumour-specific CD8(+) T cells and promoting their anti-tumour effects. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

IL-12 Expressing oncolytic herpes simplex virus promotes anti-tumor activity and immunologic control of metastatic ovarian cancer in mice.

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Thomas, Eric D; Meza-Perez, Selene; Bevis, Kerri S; Randall, Troy D; Gillespie, G Yancey; Langford, Catherine; Alvarez, Ronald D

2016-10-27

Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; consequently there is a need for new therapeutic agents and innovative treatment paradigms for the treatment of ovarian cancer. Several studies have demonstrated that ovarian cancer is an immunogenic disease and immunotherapy represents a promising and novel approach that has not been completely evaluated in ovarian cancer. Our objective was to evaluate the anti-tumor activity of an oncolytic herpes simplex virus "armed" with murine interleukin-12 and its ability to elicit tumor-specific immune responses. We evaluated the ability of interleukin-12-expressing and control oncolytic herpes simplex virus to kill murine and human ovarian cancer cell lines in vitro. We also administered interleukin-12-expressing oncolytic herpes simplex virus to the peritoneal cavity of mice that had developed spontaneous, metastatic ovarian cancer and determined overall survival and tumor burden at 95 days. We used flow cytometry to quantify the tumor antigen-specific CD8 + T cell response in the omentum and peritoneal cavity. All ovarian cancer cell lines demonstrated susceptibility to oncolytic herpes simplex virus in vitro. Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus demonstrated a more robust tumor antigen-specific CD8 + T-cell immune response in the omentum (471.6 cells vs 33.1 cells; p = 0.02) and peritoneal cavity (962.3 cells vs 179.5 cells; p = 0.05). Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus were more likely to control ovarian cancer metastases (81.2 % vs 18.2 %; p = 0.008) and had a significantly longer overall survival (p = 0.02). Finally, five of 6 mice treated with interleukin-12-expressing oHSV had no evidence of metastatic tumor when euthanized at 6 months, compared to two of 4 mice treated with

High susceptibility of metastatic cells derived from human prostate and colon cancer cells to TRAIL and sensitization of TRAIL-insensitive primary cells to TRAIL by 4,5-dimethoxy-2-nitrobenzaldehyde

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Lee Jae-Won

2011-04-01

Full Text Available Abstract Background Tumor recurrence and metastasis develop as a result of tumors' acquisition of anti-apoptotic mechanisms and therefore, it is necessary to develop novel effective therapeutics against metastatic cancers. In this study, we showed the differential TRAIL responsiveness of human prostate adenocarcinoma PC3 and human colon carcinoma KM12 cells and their respective highly metastatic PC3-MM2 and KM12L4A sublines and investigated the mechanism underlying high susceptibility of human metastatic cancer cells to TRAIL. Results PC3-MM2 and KM12L4A cells with high level of c-Myc and DNA-PKcs were more susceptible to TRAIL than their poorly metastatic primary PC3 and KM12 cells, which was associated with down-regulation of c-FLIPL/S and Mcl-1 and up-regulation of the TRAIL receptor DR5 but not DR4 in both metastatic cells. Moreover, high susceptibility of these metastatic cells to TRAIL was resulted from TRAIL-induced potent activation of caspase-8, -9, and -3 in comparison with their primary cells, which led to cleavage and down-regulation of DNA-PKcs. Knockdown of c-Myc gene in TRAIL-treated PC3-MM2 cells prevented the increase of DR5 cell surface expression, caspase activation and DNA-PKcs cleavage and attenuated the apoptotic effects of TRAIL. Moreover, the suppression of DNA-PKcs level with siRNA in the cells induced the up-regulation of DR5 and active caspase-8, -9, and -3. We also found that 4,5-dimethoxy-2-nitrobenzaldehyde (DMNB, a specific inhibitor of DNA-PK, potentiated TRAIL-induced cytotoxicity and apoptosis in relatively TRAIL-insensitive PC3 and KM12 cells and therefore functioned as a TRAIL sensitizer. Conclusion This study showed the positive relationship between c-Myc expression in highly metastatic human prostate and colon cancer cells and susceptibility to TRAIL-induced apoptosis and therefore indicated that TRAIL might be used as an effective therapeutic modality for advanced metastatic cancers overexpressing c-Myc and

High salt intake does not exacerbate murine autoimmune thyroiditis

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Kolypetri, P; Randell, E; Van Vliet, B N; Carayanniotis, G

2014-01-01

Recent studies have shown that high salt (HS) intake exacerbates experimental autoimmune encephalomyelitis and have raised the possibility that a HS diet may comprise a risk factor for autoimmune diseases in general. In this report, we have examined whether a HS diet regimen could exacerbate murine autoimmune thyroiditis, including spontaneous autoimmune thyroiditis (SAT) in non-obese diabetic (NOD.H2h4) mice, experimental autoimmune thyroiditis (EAT) in C57BL/6J mice challenged with thyroglobulin (Tg) and EAT in CBA/J mice challenged with the Tg peptide (2549–2560). The physiological impact of HS intake was confirmed by enhanced water consumption and suppressed aldosterone levels in all strains. However, the HS treatment failed to significantly affect the incidence and severity of SAT or EAT or Tg-specific immunoglobulin (Ig)G levels, relative to control mice maintained on a normal salt diet. In three experimental models, these data demonstrate that HS intake does not exacerbate autoimmune thyroiditis, indicating that a HS diet is not a risk factor for all autoimmune diseases. PMID:24528002

High hydrostatic pressure processing of murine norovirus 1-contaminated oysters inhibits oral infection in STAT-1 -/- deficient female mice

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We have previously demonstrated that high pressure processing (HPP) is effective in preventing in vitro replication of murine norovirus strain 1 (MNV-1), a human norovirus surrogate, in a monocyte cell line following extraction from MNV-1-contaminated oysters. In the present study, the efficacy of ...

Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors.

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Lobos-González, Lorena; Silva, Verónica; Araya, Mariela; Restovic, Franko; Echenique, Javiera; Oliveira-Cruz, Luciana; Fitzpatrick, Christopher; Briones, Macarena; Villegas, Jaime; Villota, Claudio; Vidaurre, Soledad; Borgna, Vincenzo; Socias, Miguel; Valenzuela, Sebastián; Lopez, Constanza; Socias, Teresa; Varas, Manuel; Díaz, Jorge; Burzio, Luis O; Burzio, Verónica A

2016-09-06

We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.

Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor

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Gough, N.M.; Gearing, D.P.; King, J.A.; Willson, T.A.; Hilton, D.J.; Nicola, N.A.; Metcalf, D.

1988-01-01

A human homologue of the recently cloned murine leukemia-inhibitory factor (LIF) gene was isolated from a genomic library by using the marine cDNA as a hybridization probe. The nucleotide sequence of the human gene indicated that human LIF has 78% amino acid sequence identity with murine LIF, with no insertions or deletions, and that the region of the human gene encoding the mature protein has one intervening sequence. After oligonucleotide-mediated mutagenesis, the mature protein-coding region of the LIF gene was introduced into the yeast expression vector YEpsec1. Yeast cells transformed with the resulting recombinant could be induced with galactose to produce high levels of a factor that induced the differentiation of murine M1 leukemic cells in a manner analogous to murine LIF. This factor competed with 125 I-labeled native murine LIF for binding to specific cellular receptors on murine cells, compatible with a high degree of structural similarity between the murine and human factors

Group B streptococcal metastatic endophthalmitis.

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Nagelberg, H P; Petashnick, D E; To, K W; Woodcome, H A

1994-04-15

Reports of invasive Group B Streptococcus infection in adults with underlying medical conditions have been increasing. Ocular infection with this organism is unusual. Metastatic endophthalmitis in adults caused by this organism has been reported rarely and has only been associated with endocarditis. We encountered two cases of Group B streptococcal metastatic endophthalmitis in adults who did not have endocarditis. These cases reflect the increasing incidence of invasive Group B Streptococcus infection with its varying manifestations. Additionally, they emphasize the importance of considering this pathogen as a cause of metastatic endophthalmitis in adults with predisposing illnesses.

Treatment Outcomes in Non-Metastatic Prostate Cancer Patients With Ultra-High Prostate-Specific Antigen

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Tai, Patricia; Tonita, Jon; Woitas, Carla; Zhu Tong; Joseph, Kurian; Skarsgard, David

2012-01-01

Purpose: It is commonly believed that prostate cancer patients with very high prostate-specific antigen (PSA) levels are unlikely to benefit from definitive local treatment, and patients with very high PSA are often underrepresented in, or excluded from, randomized clinical trials. Consequently, little is known about their optimal treatment or prognosis. We performed a registry-based analysis of management and outcome in this population of patients. Methods and Materials: Our provincial Cancer Registry was used to identify all men who were diagnosed with prostate cancer from 1990 to 2001. A retrospective chart review provided information on stage, Gleason score, PSA at diagnosis, and treatment. In this study, ultra-high PSA was defined as PSA of ≥50 ng/ml. For a more complete perspective, treatment outcomes of patients with PSA of 20 to 49.9 ng/ml were also studied. Results: Of the 8378 men diagnosed with prostate cancer during this period, 6,449 had no known nodal or distant metastatic disease. The median follow-up of this group was 67.2 months (range, 0–192 months). A total of 1534 patients had PSA of ≥20 ng/ml. Among the 995 patients with PSA 20 to 49.9 ng/ml, 85 had radical prostatectomy (RP), and their 5- and 10-year cause-specific survivals (CSS) were 95% and 84%, respectively. The 497 patients treated with radiotherapy (RT) had 5- and 10-year CSS of 92% and 71%. For the 332 patients with PSA 50–99.9 ng/ml, RT was associated with 5- and 10-year CSS of 81% and 55%. For the 207 patients with PSA of ≥100 ng/ml, RT was associated with 5- and 10-year CSS of 80% and 54%. Conclusions: This is the largest series in the world on non metastatic cancer patients with ultra-high PSA at diagnosis. Even in the setting of a very high presenting PSA level, prostatectomy and radiotherapy are often associated with prolonged survival.

Increased metastatic potential of tumor cells in von Willebrand factor-deficient mice.

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Terraube, V; Pendu, R; Baruch, D; Gebbink, M F B G; Meyer, D; Lenting, P J; Denis, C V

2006-03-01

The key role played by von Willebrand factor (VWF) in platelet adhesion suggests a potential implication in various pathologies, where this process is involved. In cancer metastasis development, tumor cells interact with platelets and the vessel wall to extravasate from the circulation. As a potential mediator of platelet-tumor cell interactions, VWF could influence this early step of tumor spread and therefore play a role in cancer metastasis. To investigate whether VWF is involved in metastasis development. In a first step, we characterized the interaction between murine melanoma cells B16-BL6 and VWF in vitro. In a second step, an experimental metastasis model was used to compare the formation of pulmonary metastatic foci in C57BL/6 wild-type and VWF-null mice following the injection of B16-BL6 cells or Lewis lung carcinoma cells. In vitro adhesion assays revealed that VWF is able to promote a dose-dependent adhesion of B16-BL6 cells via its Arg-Gly-Asp (RGD) sequence. In the experimental metastasis model, we found a significant increase in the number of pulmonary metastatic foci in VWF-null mice compared with the wild-type mice, a phenotype that could be corrected by restoring VWF plasma levels. We also showed that increased survival of the tumor cells in the lungs during the first 24 h in the absence of VWF was the cause of this increased metastasis. These findings suggest that VWF plays a protective role against tumor cell dissemination in vivo. Underlying mechanisms remain to be investigated.

Exosomes from metastatic cancer cells transfer amoeboid phenotype to non-metastatic cells and increase endothelial permeability: their emerging role in tumor heterogeneity.

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Schillaci, Odessa; Fontana, Simona; Monteleone, Francesca; Taverna, Simona; Di Bella, Maria Antonietta; Di Vizio, Dolores; Alessandro, Riccardo

2017-07-05

The goal of this study was to understand if exosomes derived from high-metastatic cells may influence the behavior of less aggressive cancer cells and the properties of the endothelium. We found that metastatic colon cancer cells are able to transfer their amoeboid phenotype to isogenic primary cancer cells through exosomes, and that this morphological transition is associated with the acquisition of a more aggressive behavior. Moreover, exosomes from the metastatic line (SW620Exos) exhibited higher ability to cause endothelial hyperpermeability than exosomes from the non metastatic line (SW480Exos). SWATH-based quantitative proteomic analysis highlighted that SW620Exos are significantly enriched in cytoskeletal-associated proteins including proteins activating the RhoA/ROCK pathway, known to induce amoeboid properties and destabilization of endothelial junctions. In particular, thrombin was identified as a key mediator of the effects induced by SW620Exos in target cells, in which we also found a significant increase of RhoA activity. Overall, our results demonstrate that in a heterogeneous context exosomes released by aggressive sub-clones can contribute to accelerate tumor progression by spreading malignant properties that affect both the tumor cell plasticity and the endothelial cell behavior.

Intracardiac Metastatic Rhabdomyosarcoma

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Tae Ho Kim

2015-12-01

Full Text Available A 70-year-old man who visited Samsung Medical Center reported experiencing palpitation for 2 weeks. He had undergone excision of a mass in the right buttock due to rhabdomyosarcoma 7 years prior to this visit. Transesophageal echocardiography showed a pedunculated mass in the left ventricle, which was thought to be a vegetation of infective endocarditis, metastasis of the primary tumor, or thrombus. He underwent removal of the cardiac tumor, and the pathologic report was metastatic rhabdomyosarcoma. Thus, here, we report a rare case of metastatic rhabdomyosarcoma in the left ventricle.

Computed tomography scans of metastatic hepatic tumors

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Takemoto, Kazumasa; Fukuda, Haruyuki; Nemoto, Yutaka [Osaka City Univ. (Japan). Faculty of Medicine

1984-01-01

Computed tomography scans of 114 metastatic hepatic tumors were reviewed. Central low density was found in 82 cases (71.9%) and seems to be characteristic to metastatic hepatic tumors. Dynamic CT was performed on 34 cases, and 21 (61.8%) of these had ring enhancement at the arterial phase. Most of metastatic hepatic tumors could be differentiated from hepatocellular carcinoma. However, metastatic hepatic tumors from renal cell carcinoma, renal rhabdomyosarcoma, malignant melanoma and leiomyosarcoma could not be differentiated from hepatocellular carcinoma, even with use of dynamic study.

Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review

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Rachna Raman

2015-01-01

Full Text Available Localized renal cell carcinoma (RCC is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC.

Metastatic nasopharyngeal carcinoma: clinical study and therapeutic results of 95 cases

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Khanfir, A.; Frikha, M.; Ghorbel, A.; Drira, M.M.; Karray, H.; Daoud, J.

2006-01-01

Purpose. -- The objective of this retrospective study was to discuss the epidemio-clinical criteria and the therapeutic results of metastatic nasopharyngeal carcinoma. Patients and methods. - The current study concerned 95 patients with histologically proven nasopharyngeal carcinoma who were metastatic at diagnosis or who had developed late metastasis. We reviewed the epidemio-clinical records of all the patients. Patients were treated with chemotherapy (BEC regimen: bleomycin, epirubicin and cisplatin or PBF regimen: bleomycin, 5-fluorouracil and cisplatin) and radiotherapy of pauci metastatic localizations (single or double) or bone metastasis with high risk of compression or fracture ±associated with locoregional radiotherapy for patients who were metastatic at diagnosis. Response was assessed according to the WHO criteria. Overall survival was calculated according to the Kaplan-Meier method. A long-term disease-free survival was defined from 36 months. Results. - There were 34 patients who were metastatic at diagnosis and 61 patients who had developed late metastasis. The mean age was 41.5 years (sex-ratio: 3.1). Bone metastases were the most frequent (83%). Objective and complete response rates were respectively 75% and 70%, and 32% and 16% for BEC and PBF regimens. Twenty-five patients received radiotherapy for pauci metastatic localizations, among whom 19 patients who were metastatic at diagnosis received locoregional irradiation. The overall survival probability was of 15% for three years. Eleven patients were long survivors (extremes: 36 and 134 months). Conclusion. - Therapeutic results were comparable to those reported in other series using platin combination chemotherapy. Radiotherapy of metastasis yielded to long-term survival. (authors)

Pharmacokinetics of 111In-labeled anti-p97 monoclonal antibody in patients with metastatic malignant melanoma

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Rosenblum, M.G.; Murray, J.L.; Haynie, T.P.; Glenn, H.J.; Jahns, M.F.; Benjamin, R.S.; Frincke, J.M.; Carlo, D.J.; Hersh, E.M.

1985-01-01

Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at doses between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111 In by the bifunctional chelating agent diethyltriaminepentaacetic acid. Clearance of 111 In from plasma closely fit an open, one-compartment mathematical model (r2 greater than 0.90). The overall half-life of 111 In plasma was approximately 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111 In label approximated the total blood volume (7.8 +/- 0.7 liters) at the 1-mg dose and decreased to 3.0 +/- 0.14 liters at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody in plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111 In-labeled antibody pharmacokinetics. This suggests that the 111 In radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111 In label over 48 h was between 12 and 23% of the total administered dose and is assumed to represent 111 In-labeled chelate complex unattached to antibody. Analysis of the 111 In label in spleen, liver, heart, and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution

Hepatoma SK Hep-1 cells exhibit characteristics of oncogenic mesenchymal stem cells with highly metastatic capacity.

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Jong Ryeol Eun

Full Text Available SK Hep-1 cells (SK cells derived from a patient with liver adenocarcinoma have been considered a human hepatoma cell line with mesenchymal origin characteristics, however, SK cells do not express liver genes and exhibit liver function, thus, we hypothesized whether mesenchymal cells might contribute to human liver primary cancers. Here, we characterized SK cells and its tumourigenicity.We found that classical mesenchymal stem cell (MSC markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative. SK cells are capable of differentiate into adipocytes and osteoblasts as adipose-derived MSC (Ad-MSC and bone marrow-derived MSC (BM-MSC do. Importantly, a single SK cell exhibited a substantial tumourigenicity and metastatic capacity in immunodefficient mice. Metastasis not only occurred in circulating organs such as lung, liver, and kidneys, but also in muscle, outer abdomen, and skin. SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC. The xenograft cells from subcutaneous and metastatic tumors exhibited a similar tumourigenicity and metastatic capacity, and showed the same relatively homogenous population with MSC characteristics when compared to parental SK cells. SK cells could unlimitedly expand in vitro without losing MSC characteristics, its tumuorigenicity and metastatic capacity, indicating that SK cells are oncogenic MSC with enhanced self-renewal capacity. We believe that this is the first report that human MSC appear to be transformed into cancer stem cells (CSC, and that their derivatives also function as CSCs.Our findings demonstrate that SK cells represent a transformation mechanism of normal MSC into an enhanced self-renewal CSC with metastasis capacity, SK cells and their xenografts represent a same relative homogeneity of CSC with substantial metastatic capacity. Thus, it represents a novel mechanism of tumor initiation, development and

Attachment, invasion, chemotaxis, and proteinase expression of B16-BL6 melanoma cells exhibiting a low metastatic phenotype after exposure to dietary restriction of tyrosine and phenylalanine.

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Uhlenkott, C E; Huijzer, J C; Cardeiro, D J; Elstad, C A; Meadows, G G

1996-03-01

We previously reported that low levels of tyrosine (Tyr) and phenylalanine (Phe) alter the metastatic phenotype of B16-BL6 (BL6) murine melanoma and select for tumor cell populations with decreased lung colonizing ability. To more specifically characterize the effects of Tyr and Phe restriction on the malignant phenotype of BL6, we investigated in vitro attachment, invasion, proteinase expression, and chemotaxis of high and low metastatic BL6 variants. High metastatic variant cells were isolated from subcutaneous tumors of mice fed a nutritionally complete diet (ND cells) and low metastatic variant cells were isolated from mice fed a diet restricted in Tyr and Phe (LTP cells). Results indicate that attachment to reconstituted basement membrane (Matrigel) was significantly reduced in LTP cells as compared to ND cells. Attachment to collagen IV, laminin, and fibronectin were similar between the two variants. Invasion through Matrigel and growth factor-reduced Matrigel were significantly decreased in LTP cells as compared to ND cells. Zymography revealed the presence of M(r) 92,000 and M(r) 72,000 progelatinases, tissue plasminogen activator, and urokinase plasminogen activator in the conditioned medium of both variants; however, there were no differences in activity of these secreted proteinases between the two variants. Growth of the variants on growth factor-reduced Matrigel similarly induced expression of the M(r) 92,000 progelatinase. The variants exhibited similar chemotactic responses toward laminin. However, the chemotactic response toward fibronectin by LTP cells was significantly increased. MFR5, a monoclonal antibody which selectively blocks function of the alpha 5 chain of the alpha 5 beta 1 integrin, VLA-5, decreased the chemotactic response toward fibronectin of ND cells by 37%; the chemotactic response by LTP cells was reduced by 49%. This effect was specific for fibronectin-mediated chemotaxis since the chemotaxis toward laminin and invasion through

Cutaneous metastatic adenocarcinoma

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Joshi Arun

2001-01-01

Full Text Available A 5.5-year-old male presented with asymptomatic nodules and plaques on his scalp and pubic region of 2 months′ duration. He was having productive cough, haemoptysis, chest pain, anorexia and weight loss and receiving antitubercular treatment for these symptoms for last 3 months. Clinical diagnosis of cutaneous metastatic disease was made. Chest x-ray revealed multiple coin shaped shadows on both sides with pleural effusion. Routine investigations were normal except for anemia and hyperuricemia. Biopsy of skin nodules showed features of metastatic adenocarcinoma. Features and significance of cutaneous metastases are discussed.

Pleiotropic function of ezrin in human metastatic melanomas.

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Federici, Cristina; Brambilla, Daria; Lozupone, Francesco; Matarrese, Paola; de Milito, Angelo; Lugini, Luana; Iessi, Elisabetta; Cecchetti, Serena; Marino, Marialucia; Perdicchio, Maurizio; Logozzi, Mariantonia; Spada, Massimo; Malorni, Walter; Fais, Stefano

2009-06-15

The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors. Copyright 2008 UICC.

Malignant Mesothelioma Versus Metastatic Carcinoma of the Pleura: A CT Challenge

International Nuclear Information System (INIS)

Bakhshayesh Karam, Mehrdad; Karimi, Shirin; Mosadegh, Leila; Chaibakhsh, Samira

2016-01-01

most prevalent parameters among metastatic cases. CT scan is highly accurate in differentiating malignant pleural mesothelioma and metastatic pleural diseases. Pleural thickening and thickening of interlobar fissure lead us to the diagnosis of MPM and massive free pleural effusion is more commonly seen in metastatic pleural malignancy

Co-immunotherapy with interleukin-2 and taurolidine for progressive metastatic melanoma.

LENUS (Irish Health Repository)

O'Brien, G C

2012-02-03

BACKGROUND: Recombinant interleukin-2(rIL-2) therapy in metastatic melanoma is limited by toxicities, particularly vascular leak syndrome(VLS). Taurolidine potentiates the anti-neoplastic effects of IL-2 while reducing its associated endothelial cell dysfunction in experimental settings. We hypothesized that co-administration of rIL-2 with taurolidine could enhance tolerability without weakening effectiveness. METHODS: Eleven patients with progressive metastatic melanoma received high-dose rIL-2 with co-infusion of taurolidine. Patients were monitored for the development of toxicities and evidence of response. RESULTS: Ten patients tolerated twenty-nine courses of high-dose rIL-2 without dose-reduction. Most toxicities were low-grade. No patient developed VLS. Seven patients died from disease progression. Two had complete clinical and radiological responses to treatment. Two patients remain alive despite evidence of disease progression a mean of 17.5 months after diagnosing metastatic disease. CONCLUSION: Co-administration of taurolidine with high-dose rIL-2 in stage IV melanoma patients appears to greatly enhance the tolerability of this regime without diminishing its therapeutic value.

Endoscopic-radiological findings in metastatic obstructive jaundice

International Nuclear Information System (INIS)

Hoerder, U.; Heyder, N.; Riemann, J.F.

1983-01-01

Metastatic obstructive jaundice usually results from an occlusion of the common hepatic or bile duct. More rarely, the underlying cause is a disseminated intrahepatic infiltration that has led to the occlusion of the bile canaliculi. The endoscopic-radiological examination techniques usually permit a reliable differentiation between neoplasms originating primarily in the biliary tract, and ductal occlusions caused by metastatic disease. In addition to this, both ERC and PTC permit the placement of an internal or external biliary drain during one and the same procedure. ERC represents a highly suitable method for the follow-up monitoring or documentation of the therapeutic effect of biliary drainage, radiotherapy and/or polychemotherapy. With the aid of regular follow-up examinations, recurrent diesase can be detected early on, and appropriately treated. (orig.)

TH and DCX mRNAs in peripheral blood and bone marrow predict outcome in metastatic neuroblastoma patients.

Science.gov (United States)

Yáñez, Yania; Hervás, David; Grau, Elena; Oltra, Silvestre; Pérez, Gema; Palanca, Sarai; Bermúdez, Mar; Márquez, Catalina; Cañete, Adela; Castel, Victoria

2016-03-01

In metastatic neuroblastoma (NB) patients, accurate risk stratification and disease monitoring would reduce relapse probabilities. This study aims to evaluate the independent prognostic significance of detecting tyrosine hydroxylase (TH) and doublecortin (DCX) mRNAs by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral blood (PB) and bone marrow (BM) samples from metastatic NB patients. RT-qPCR was performed on PB and BM samples from metastatic NB patients at diagnosis, post-induction therapy and at the end of treatment for TH and DCX mRNAs detection. High levels of TH and DCX mRNAs when detected in PB and BM at diagnosis independently predicted worse outcome in a cohort of 162 metastatic NB. In the subgroup of high-risk metastatic NB, TH mRNA detected in PB remained as independent predictor of EFS and OS at diagnosis. After the induction therapy, high levels of TH mRNA in PB and DCX mRNA in BM independently predicted poor EFS and OS. Furthermore TH mRNA when detected in BM predicted worse EFS. TH mRNA in PB samples at the end of treatment is an independent predictor of worse outcome. TH and DCX mRNAs levels in PB and BM assessed by RT-qPCR should be considered in new pre-treatment risk stratification strategies to reliable estimate outcome differences in metastatic NB patients. In those high-risk metastatic NB, TH and DCX mRNA quantification could be used for the assessment of response to treatment and for early detection of progressive disease or relapses.

PALBOCICLIB IN COMBINATION WITH HORMONE THERAPY FOR LUMINAL HER2-NEGATIVE METASTATIC BREAST CANCER: NEW HIGHLY EFFECTIVE STRATEGY OF DRUG TREATMENT

Directory of Open Access Journals (Sweden)

E. V. Artamonova

2017-01-01

Full Text Available The review considers a new oral targeted drug palbociclib and its place in treatment of luminal (estrogen receptor-positive HER2– metastatic breast cancer. The results of randomized clinical trials have shown that inclusion of palbociclib in various hormone therapy regimens for treatment of HER2– metastatic breast cancer with expression of estrogen receptors allows to significantly improve clinical outcomes and increase survival, objective response rate and its duration, as well as clinical benefit rate (CBR. Addition of palbociclib to letrozole in the 1st line hormone therapy or to fulvestrant in patients with progression at/after previous endocrine therapy increased progression-free survival in all groups irrespective of clinical characteristics, tumor progression, or expression of molecular markers mediating development of hormone resistance. The main adverse events associated with palbociclib were neutropenia, leukopenia and thrombocytopenia, but overall hematological toxicity was manageable, and the therapy itself was safe. This strategy received a “breakthrough therapy designation” from the experts and combines proven effectiveness and satisfactory tolerability, allows to maintain high quality of life, and should be prescribed to patients with luminal HER2– metastatic breast cancer.

Metastatic Cancer

Science.gov (United States)

Metastatic cancer is cancer that spreads from its site of origin to another part of the body. Learn how cancer spreads, possible symptoms, common sites where cancer spreads, and how to find out about treatment options.

Working after a metastatic cancer diagnosis: Factors affecting employment in the metastatic setting from ECOG-ACRIN's Symptom Outcomes and Practice Patterns study.

Science.gov (United States)

Tevaarwerk, Amye J; Lee, Ju-Whei; Terhaar, Abigail; Sesto, Mary E; Smith, Mary Lou; Cleeland, Charles S; Fisch, Michael J

2016-02-01

Improved survival for individuals with metastatic cancer accentuates the importance of employment for cancer survivors. A better understanding of how metastatic cancer affects employment is a necessary step toward the development of tools for assisting survivors in this important realm. The ECOG-ACRIN Symptom Outcomes and Practice Patterns study was analyzed to investigate what factors were associated with the employment of 680 metastatic cancer patients. Univariate and multivariate logistic regression analyses were conducted to compare patients stably working with patients no longer working. There were 668 metastatic working-age participants in the analysis: 236 (35%) worked full- or part-time, whereas 302 (45%) had stopped working because of illness. Overall, 58% reported some change in employment due to illness. A better performance status and non-Hispanic white ethnicity/race were significantly associated with continuing to work despite a metastatic cancer diagnosis in the multivariate analysis. The disease type, time since metastatic diagnosis, number of metastatic sites, location of metastatic disease, and treatment status had no significant impact. Among the potentially modifiable factors, receiving hormonal treatment (if a viable option) and decreasing symptom interference were associated with continuing to work. A significant percentage of the metastatic patients remained employed; increased symptom burden was associated with a change to no longer working. Modifiable factors resulting in work interference should be minimized so that patients with metastatic disease may continue working if this is desired. Improvements in symptom control and strategies developed to help address workplace difficulties have promise for improving this aspect of survivorship. © 2015 American Cancer Society.

Importance of Metastatic Lymph Node Ratio in Non-Metastatic, Lymph Node-Invaded Colon Cancer: A Clinical Trial

Science.gov (United States)

Isik, Arda; Peker, Kemal; Firat, Deniz; Yilmaz, Bahri; Sayar, Ilyas; Idiz, Oguz; Cakir, Coskun; Demiryilmaz, Ismail; Yilmaz, Ismayil

2014-01-01

Background The aim of this study was to evaluate the prognostic importance of the metastatic lymph node ratio for stage III colon cancer patients and to find a cut-off value at which the overall survival and disease-free survival change. Material/Methods Patients with pathological stage III colon cancer were retrospectively evaluated for: age; preoperative values of Crp, Cea, Ca 19-9, and Afp; pathologic situation of vascular, perineural, lymphatic, and serosal involvement; and metastatic lymph node ratio values were calculated. Results The study included 58 stage III colon cancer patients: 20 (34.5%) females and 38 (65.5%) males were involved in the study. Multivariate analysis was applied to the following variables to evaluate significance for overall survival and disease-free survival: age, Crp, Cea, perineural invasion, and metastatic lymph node ratio. The metastatic lymph node ratio (<0.25 or ≥0.25) is the only independent variable significant for overall and disease-free survival. Conclusions Metastatic lymph node ratio is an ideal prognostic marker for stage III colon cancer patients, and 0.25 is the cut-off value for prognosis. PMID:25087904

Cost-Effectiveness Analysis of Regorafenib for Metastatic Colorectal Cancer.

Science.gov (United States)

Goldstein, Daniel A; Ahmad, Bilal B; Chen, Qiushi; Ayer, Turgay; Howard, David H; Lipscomb, Joseph; El-Rayes, Bassel F; Flowers, Christopher R

2015-11-10

Regorafenib is a standard-care option for treatment-refractory metastatic colorectal cancer that increases median overall survival by 6 weeks compared with placebo. Given this small incremental clinical benefit, we evaluated the cost-effectiveness of regorafenib in the third-line setting for patients with metastatic colorectal cancer from the US payer perspective. We developed a Markov model to compare the cost and effectiveness of regorafenib with those of placebo in the third-line treatment of metastatic colorectal cancer. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2014. Model robustness was addressed in univariable and probabilistic sensitivity analyses. Regorafenib provided an additional 0.04 QALYs (0.13 life-years) at a cost of $40,000, resulting in an incremental cost-effectiveness ratio of $900,000 per QALY. The incremental cost-effectiveness ratio for regorafenib was > $550,000 per QALY in all of our univariable and probabilistic sensitivity analyses. Regorafenib provides minimal incremental benefit at high incremental cost per QALY in the third-line management of metastatic colorectal cancer. The cost-effectiveness of regorafenib could be improved by the use of value-based pricing. © 2015 by American Society of Clinical Oncology.

Enzalutamide for patients with metastatic castration-resistant prostate cancer

Science.gov (United States)

Ramadan, Wijdan H; Kabbara, Wissam K; Al Basiouni Al Masri, Hiba S

2015-01-01

Objective To review and evaluate current literature on the US Food and Drug Administration (FDA)-approved drug enzalutamide (XTANDI®) in metastatic castration-resistant prostate cancer. Data sources Literature search was done through PubMed using the terms enzalutamide, MDV3100, abiraterone, and castration-resistant prostate cancer. Data from FDA product labels were also used. Study selection and data extraction Recent and relevant studies were included in the review. Collected clinical trials were screened and evaluated. Data synthesis Enzalutamide is an androgen receptor (AR) inhibitor with high selectivity and affinity to the AR. It was approved by the FDA to treat metastatic castration-resistant prostate cancer in patients previously treated with docetaxel, after a Phase III trial (AFFIRM) that showed a 4.8-month survival benefit in this population. Recently, the FDA expanded the approval of enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) who did not receive chemotherapy. Moreover, enzalutamide is shown to be associated with an acceptable safety profile. Conclusion Enzalutamide has been shown to be both safe and effective in improving overall survival in metastatic castration-resistant prostate cancer postchemotherapy with docetaxel and as a first line treatment before initiation of chemotherapy. However, additional studies and head-to-head trials are needed. PMID:25945058

Asiatic acid attenuates malignancy of human metastatic ovarian ...

African Journals Online (AJOL)

vimetin, N-cad and. ZEB1/2) were suppressed, indicating the EMT process was significantly suppressed by AA treatment at the concentration of 10 μM. DISCUSSION. As a highly metastatic disease, patients with a stage III/IV ovarian cancer ...

Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

Energy Technology Data Exchange (ETDEWEB)

Blanchard, Miran [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Shim, Kevin G. [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Department of Immunology, Mayo Clinic, Rochester, Minnesota (United States); Grams, Michael P. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Rajani, Karishma; Diaz, Rosa M. [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Furutani, Keith M. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Thompson, Jill [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Olivier, Kenneth R.; Park, Sean S. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Markovic, Svetomir N. [Department of Immunology, Mayo Clinic, Rochester, Minnesota (United States); Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Pandha, Hardev [The Postgraduate Medical School, University of Surrey, Guildford (United Kingdom); Melcher, Alan [Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds (United Kingdom); Harrington, Kevin [Targeted Therapy Laboratory, The Institute of Cancer Research, London (United Kingdom); Zaidi, Shane [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Targeted Therapy Laboratory, The Institute of Cancer Research, London (United Kingdom); Vile, Richard, E-mail: vile.richard@mayo.edu [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Department of Immunology, Mayo Clinic, Rochester, Minnesota (United States); Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds (United Kingdom)

2015-11-01

Purpose: The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials: We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results: Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions: We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary

Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

International Nuclear Information System (INIS)

Blanchard, Miran; Shim, Kevin G.; Grams, Michael P.; Rajani, Karishma; Diaz, Rosa M.; Furutani, Keith M.; Thompson, Jill; Olivier, Kenneth R.; Park, Sean S.; Markovic, Svetomir N.; Pandha, Hardev; Melcher, Alan; Harrington, Kevin; Zaidi, Shane; Vile, Richard

2015-01-01

Purpose: The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials: We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results: Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions: We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary

Carboplatin AUC 10 for IGCCCG good prognosis metastatic seminoma.

Science.gov (United States)

Tookman, Laura; Rashid, Sukaina; Matakidou, Athena; Phillips, Melissa; Wilson, Peter; Ansell, Wendy; Jamal-Hanjani, Mariam; Chowdhury, Simon; Harland, Stephen; Sarwar, Naveed; Oliver, Timothy; Powles, Thomas; Shamash, Jonathan

2013-06-01

Metastatic seminoma is a highly curable disease. Standard treatment comprises of combination chemotherapy. The short- and long-term toxicities of this treatment are increasingly recognised and the possibility of over treatment in such a curable disease should be considered. We have therefore assessed the use of single agent carboplatin at a dose of AUC 10 in patients with good prognosis metastatic seminoma. Patients with good prognosis metastatic seminoma treated with carboplatin (AUC 10) were identified at our institution and affiliated institutions. Treatment was three weekly for a total of three or four cycles. Outcome and toxicities were analysed. With a median follow-up of 36 months, 61 patients in total were treated with carboplatin AUC 10, all good prognosis by the IGCCCG criteria. Forty-eight percent had stage IIA/IIB disease and 52% had greater than stage IIB disease. Thirty-one patients (51%) had a complete response following treatment. Three-year survival was 96.3% with a three-year progression free survival of 93.2%. The main treatment toxicity was haematological with 46% having grade 3, 24% having grade 4 neutropenia and 54% experiencing grade 3/4 thrombocytopenia. There were no treatment related deaths. Single agent carboplatin at a dose of AUC 10 is an effective treatment for good prognosis metastatic seminoma. The outcome compares favourably to previously published outcomes of combination chemotherapy. Although haematological toxicity is a concern, single agent carboplatin treatment for good prognosis metastatic seminoma could be considered a treatment option and is associated with less toxicity than combination regimens currently used.

Molecular characterization of murine models of squamous carcinomas of preclinical application; Caracterización molecular de modelos múridos de carcinomas escamosos de aplicación preclínica

Energy Technology Data Exchange (ETDEWEB)

Bornachea Gomez, O.; Berdugo Zamora, A.

2015-07-01

The epidermis is a stratified epithelium affected by numerous pathologies, including cancer, being the tumors originated in this tissue more than half of the epithelial tumors diagnosed every year. Animal models are an essential tool for cancer research, as they provide information to understand how a homologous gene may cause or contribute to the disease in humans. The p53 CE and Rb CE; p53 CE murine models develop undifferentiated epidermal tumors with high metastatic potential that show a strong transcriptional similarity to many human tumors with poor prognosis. Numerous studies have associated the p53 tumor suppressor with deregulation of microRNAs involved in the epithelial-mesenchymal transition (EMT) and metastasis processes. Furthermore, tumors in p53 EC models show an early repression of p63 whose predominant isoform in keratinocytes of the basal layer is Np63. Our results indicate that miR21 helps to provide metastatic capacity to p53-deficient mouse skin tumors. The increased expression of miR21 correlates with active signaling pathways that can be inhibited pharmacologically. Moreover, miR21 expression is elevated in human metastatic lung tumors with poor prognosis. Besides, we also show that ?Np63? expression in p53-deficient cells partially reduces the metastatic behavior, most probably through the modulation microRNAs and transcription factors involved in the EMT process. These facts point to p53-deficient epidermal animal models as excellent candidates for preclinical analysis of human metastatic tumors characterized by TP53 alterations. Finally we developed a model in which the three members of the retinoblastoma family are ablated in the basal cells of stratified epithelia in a tamoxifen inducible manner: Rb1F/F ; Rbl2F/F;Rbl1-/-;K14CreErT2 (TKO). Previously our laboratory had shown that, in the absence of pRb, malignant conversion occurred when p53 is lost. At high doses of tamoxifen these animals show early lethality. When we adjust the dose

Effect of two tumors (metastatic and non-metastatic) on tissue distribution of Ga-67 citrate in the rat

International Nuclear Information System (INIS)

Durakovic, A.

1985-01-01

The effect of metastatic and non-metastatic mammary adenocarcinoma on tissue distribution of Ga-67 citrate in Fischer female rats was studied. The homogenate (0.1 ml) of each tumor was injected subcutaneously in separate groups of rats and the animals were studied from day 2-30 after tumor homogenate implantation. All animals were injected with 30 μCi of Ga-67 citrate and sacrificed by halothane anethesia 48 hours later. Tissue samples of blood, lung, heart, liver, spleen, kidney, adrenal, stomach, small and large intestine, ovaries, and lymph nodes (popliteal, lumbar, and mediastinal) were obtained and counted in a gamma well counter. The control group consisted of four animals and tumor bearing groups of seven to eight animals at each time. Ga-67 uptake was increased in the liver (24 days) and in the popliteal lymph nodes on days 7, 10, and 18 in the metastatic tumor group (P<0.05). This probably represents Ga-67 uptake in the metastatic deposits in these organs. No difference was observed in non-metastatic tumor group

Metastatic papillary craniopharyngioma: case study and study of tumor angiogenesis.

Science.gov (United States)

Elmaci, Lhan; Kurtkaya-Yapicier, Ozlem; Ekinci, Gazanfer; Sav, Aydin; Pamir, M. Necmettin; Vidal, Sergio; Kovacs, Kalman; Scheithauer, Bernd W.

2002-01-01

We report a case of suprasellar papillary craniopharyngioma metastatic to the temporoparietal region 2 years after its initial resection. The literature documents examples of craniopharyngioma recurrences along the surgical tract, as well as remote ipsi- and contralateral metastases via cerebrospinal fluid seeding. Ours is the second report of a craniopharyngioma of papillary type to exhibit metastatic behavior. The tumor spread opposite the side of craniotomy. Although a rare occurrence, it confirms the limited capacity of histologically benign craniopharyngiomas to undergo meningeal seeding, likely the result of surgical manipulation. Immunohistochemical demonstration of increased microvascular density and vascular endothelial growth factor expression, as well as a high vascular endothelial growth receptor (VEGFR2) signal by in situ hybridization, suggests that tumor vascularity facilitated angiogenesis and may have been involved in the establishment and growth of the metastatic deposit. PMID:11916504

Mitochondrial ASncmtRNA-1 and ASncmtRNA-2 as potent targets to inhibit tumor growth and metastasis in the RenCa murine renal adenocarcinoma model.

Science.gov (United States)

Borgna, Vincenzo; Villegas, Jaime; Burzio, Verónica A; Belmar, Sebastián; Araya, Mariela; Jeldes, Emanuel; Lobos-González, Lorena; Silva, Verónica; Villota, Claudio; Oliveira-Cruz, Luciana; Lopez, Constanza; Socias, Teresa; Castillo, Octavio; Burzio, Luis O

2017-07-04

Knockdown of antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptosis in several human and mouse tumor cell lines, but not normal cells, suggesting this approach for a selective therapy against different types of cancer. Here we show that in vitro knockdown of murine ASncmtRNAs induces apoptotic death of mouse renal adenocarcinoma RenCa cells, but not normal murine kidney epithelial cells. In a syngeneic subcutaneous RenCa model, treatment delayed and even reversed tumor growth. Since the subcutaneous model does not reflect the natural microenviroment of renal cancer, we used an orthotopic model of RenCa cells inoculated under the renal capsule. These studies showed inhibition of tumor growth and metastasis. Direct metastasis assessment by tail vein injection of RenCa cells also showed a drastic reduction in lung metastatic nodules. In vivo treatment reduces survivin, N-cadherin and P-cadherin levels, providing a molecular basis for metastasis inhibition. In consequence, the treatment significantly enhanced mouse survival in these models. Our results suggest that the ASncmtRNAs could be potent and selective targets for therapy against human renal cell carcinoma.

The proximal first exon architecture of the murine ghrelin gene is highly similar to its human orthologue

Directory of Open Access Journals (Sweden)

Seim Inge

2009-05-01

Full Text Available Abstract Background The murine ghrelin gene (Ghrl, originally sequenced from stomach tissue, contains five exons and a single transcription start site in a short, 19 bp first exon (exon 0. We recently isolated several novel first exons of the human ghrelin gene and found evidence of a complex transcriptional repertoire. In this report, we examined the 5' exons of the murine ghrelin orthologue in a range of tissues using 5' RACE. Findings 5' RACE revealed two transcription start sites (TSSs in exon 0 and four TSSs in intron 0, which correspond to 5' extensions of exon 1. Using quantitative, real-time RT-PCR (qRT-PCR, we demonstrated that extended exon 1 containing Ghrl transcripts are largely confined to the spleen, adrenal gland, stomach, and skin. Conclusion We demonstrate that multiple transcription start sites are present in exon 0 and an extended exon 1 of the murine ghrelin gene, similar to the proximal first exon organisation of its human orthologue. The identification of several transcription start sites in intron 0 of mouse ghrelin (resulting in an extension of exon 1 raises the possibility that developmental-, cell- and tissue-specific Ghrl mRNA species are created by employing alternative promoters and further studies of the murine ghrelin gene are warranted.

Metastatic hidradenocarcinoma: Surgery and chemotherapy.

Science.gov (United States)

Amel, Trabelsi; Olfa, Gharbi; Faten, Hammedi; Makrem, Hochlef; Slim, Ben Ahmed; Moncef, Mokni

2009-12-01

Hidradenocarcinoma is a rare carcinoma of high malignant potential. It most metastasizes to regional lymph nodes and distant viscera. We report a case of 52-year-old woman who presented with an invasive hidradenocarcinoma of the finger, treated with surgical excision. The patient presented with skin and lymph node metastases four years after, treated by chemotherapy. Hidradenocarcinoma is an aggressive tumor. It seems important to use adjuvant therapies particularly for recurrent and metastatic forms.

Distant metastatic retinoblastoma without central nervous system involvement

Directory of Open Access Journals (Sweden)

Mohammad Javed Ali

2013-01-01

Full Text Available Retinoblastoma is the most common intraocular malignancy in children, with a reported incidence ranging from 1 in 15,000 to 1 in 18,000 live births. Metastatic retinoblastoma is rare in developed countries, with a reported range from 4.8% in the United States to 5.8% in the United Kingdom. However, the frequency reported from developing countries varies from 9 to 11% at presentation. The mortality is very high owing to late presentations, delayed diagnosis compounded by socio-economic factors. The management of metastatic retinoblastoma is evolving, but it is still a challenge in pediatric oncology. We present a case of an extensive skeletal metastasis that initially presented as a massive orbital retinoblastoma.

Benzofuroxan derivatives N-Br and N-I induce intrinsic apoptosis in melanoma cells by regulating AKT/BIM signaling and display anti metastatic activity in vivo

International Nuclear Information System (INIS)

Farias, C. F.; Massaoka, M. H.; Girola, N.; Azevedo, R. A.; Ferreira, A. K.; Jorge, S. D.; Tavares, L. C.; Figueiredo, C. R.; Travassos, L. R.

2015-01-01

Malignant melanoma is an aggressive type of skin cancer, and despite recent advances in treatment, the survival rate of the metastatic form remains low. Nifuroxazide analogues are drugs based on the substitution of the nitrofuran group by benzofuroxan, in view of the pharmacophore similarity of the nitro group, improving bioavailability, with higher intrinsic activity and less toxicity. Benzofuroxan activity involves the intracellular production of free-radical species. In the present work, we evaluated the antitumor effects of different benzofuroxan derivatives in a murine melanoma model. B16F10-Nex2 melanoma cells were used to investigate the antitumor effects of Benzofuroxan derivatives in vitro and in a syngeneic melanoma model in C57Bl/6 mice. Cytotoxicity, morphological changes and reactive oxygen species (ROS) were assessed by a diphenyltetrasolium reagent, optical and fluorescence microscopy, respectively. Annexin-V binding and mitochondrial integrity were analyzed by flow cytometry. Western blotting and colorimetry identified cell signaling proteins. Benzofuroxan N-Br and N-I derivatives were active against murine and human tumor cell lines, exerting significant protection against metastatic melanoma in a syngeneic model. N-Br and N-I induce apoptosis in melanoma cells, evidenced by specific morphological changes, DNA condensation and degradation, and phosphatidylserine translocation in the plasma membrane. The intrinsic mitochondrial pathway in B16F10-Nex2 cells is suggested owing to reduced outer membrane potential in mitochondria, followed by caspase −9, −3 activation and cleavage of PARP. The cytotoxicity of N-Br and N-I in B16F10-Nex2 cells is mediated by the generation of ROS, inhibited by pre-incubation of the cells with N-acetylcysteine (NAC). The induction of ROS by N-Br and N-I resulted in the inhibition of AKT activation, an important molecule related to tumor cell survival, followed by upregulation of BIM. We conclude that N-Br and N-I are

Benzofuroxan derivatives N-Br and N-I induce intrinsic apoptosis in melanoma cells by regulating AKT/BIM signaling and display anti metastatic activity in vivo.

Science.gov (United States)

Farias, C F; Massaoka, M H; Girola, N; Azevedo, R A; Ferreira, A K; Jorge, S D; Tavares, L C; Figueiredo, C R; Travassos, L R

2015-10-27

Malignant melanoma is an aggressive type of skin cancer, and despite recent advances in treatment, the survival rate of the metastatic form remains low. Nifuroxazide analogues are drugs based on the substitution of the nitrofuran group by benzofuroxan, in view of the pharmacophore similarity of the nitro group, improving bioavailability, with higher intrinsic activity and less toxicity. Benzofuroxan activity involves the intracellular production of free-radical species. In the present work, we evaluated the antitumor effects of different benzofuroxan derivatives in a murine melanoma model. B16F10-Nex2 melanoma cells were used to investigate the antitumor effects of Benzofuroxan derivatives in vitro and in a syngeneic melanoma model in C57Bl/6 mice. Cytotoxicity, morphological changes and reactive oxygen species (ROS) were assessed by a diphenyltetrasolium reagent, optical and fluorescence microscopy, respectively. Annexin-V binding and mitochondrial integrity were analyzed by flow cytometry. Western blotting and colorimetry identified cell signaling proteins. Benzofuroxan N-Br and N-I derivatives were active against murine and human tumor cell lines, exerting significant protection against metastatic melanoma in a syngeneic model. N-Br and N-I induce apoptosis in melanoma cells, evidenced by specific morphological changes, DNA condensation and degradation, and phosphatidylserine translocation in the plasma membrane. The intrinsic mitochondrial pathway in B16F10-Nex2 cells is suggested owing to reduced outer membrane potential in mitochondria, followed by caspase -9, -3 activation and cleavage of PARP. The cytotoxicity of N-Br and N-I in B16F10-Nex2 cells is mediated by the generation of ROS, inhibited by pre-incubation of the cells with N-acetylcysteine (NAC). The induction of ROS by N-Br and N-I resulted in the inhibition of AKT activation, an important molecule related to tumor cell survival, followed by upregulation of BIM. We conclude that N-Br and N-I are

Working after a metastatic cancer diagnosis: factors affecting employment in the metastatic setting from ECOG’s Symptom Outcomes and Practice Patterns (SOAPP) study

Science.gov (United States)

Tevaarwerk, Amye; Lee, Ju-Whei; Terhaar, Abigail; Sesto, Mary; Smith, Mary Lou; Cleeland, Charles; Fisch, Michael

2015-01-01

Background Improved survival for individuals with metastatic cancer accentuates the importance of employment for cancer survivors. Better understanding of how metastatic cancer affects employment is a necessary step towards the development of tools to assist survivors in this important realm. Methods We analyzed the Eastern Cooperative Oncology Group’s “Symptom Outcomes and Practice Patterns (SOAPP)” study to investigate what factors were associated with employment of 680 metastatic cancer patients. Univariable and multivariable logistic regression analyses were conducted to compare patients stably working (Group A) to patients no longer working (Group B). Results There were 668 metastatic working-age participants in our analysis; 236 (35%) worked full or part-time while 302 (45%) stopped working due to illness. Overall, 58% reported some change in employment due to illness. Better performance status and non-Hispanic White ethnicity/race were significantly associated with continuing to work despite a metastatic cancer diagnosis on multivariable analysis. Disease type, time since metastatic diagnosis, number of metastatic sites, location of metastatic disease, and treatment status had no significant impact. Among the potentially modifiable factors, receiving hormonal treatment (if a viable option) and decreasing symptom interference were associated with continuing to work. Conclusions A significant percentage of metastatic patients remain employed; symptom burden was associated with change to no longer working. Modifiable factors resulting in work interference should be minimized so that patients with metastatic disease may continue working, if desired. Improvements in symptom control and strategies developed to help address work place difficulties have promise to improve this aspect of survivorship. PMID:26687819

Metastatic myxoid liposarcomas: imaging and histopathologic findings

International Nuclear Information System (INIS)

Sheah, Kenneth; Ouellette, Hugue A.; Torriani, Martin; Kattapuram, Susan; Bredella, Miriam A.; Nielsen, G.P.

2008-01-01

The objective was to describe the imaging and histopathologic characteristics of metastatic myxoid liposarcomas. This retrospective study was approved by the institutional review board and complied with HIPAA guidelines. The study group comprised 12 patients with metastatic myxoid liposarcoma who underwent MRI, CT, or FDG-PET. The location and imaging characteristics of the metastatic lesions were recorded, and the histopathology of all metastatic lesions was reviewed. There were 23 histologically proven metastases in 12 patients. Based on imaging criteria, there were 41 metastases. The mean time from the diagnosis of primary tumor to the first metastasis was 4.4 years. Sixty-seven percent of patients had bone and soft tissue metastases, 33% had pulmonary metastases, 33% had liver metastases, 25% had intra-abdominal, and 16% retroperitoneal metastases. CT demonstrated well-defined lobulated masses with soft tissue attenuation in all cases, without macroscopic fat component. In cases of osseous metastases, CT showed mixed lytic and sclerotic foci, with bone destruction in advanced cases. MRI demonstrated fluid-like signal intensity with mild heterogeneous enhancement in cases of soft tissue metastases. In osseous metastases, MRI showed avid heterogeneous enhancement. FDG-PET showed no significant FDG uptake for all metastases. MRI was the most useful imaging modality for osseous and soft tissue metastases. Myxoid liposarcomas are soft tissue sarcomas, with a high prevalence of extrapulmonary metastases. The bones and soft tissues were the most common site of involvement, followed by the lungs and liver. MRI was the most sensitive modality in the detection of osseous and soft tissue metastases, and is the recommended modality for the diagnosis and follow-up of bone and soft tissue involvement. (orig.)

The Ezrin Metastatic Phenotype Is Associated with the Initiation of Protein Translation

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Joseph W. Briggs

2012-04-01

Full Text Available We previously associated the cytoskeleton linker protein, Ezrin, with the metastatic phenotype of pediatric sarcomas, including osteosarcoma and rhabdomyosarcoma. These studies have suggested that Ezrin contributes to the survival of cancer cells after their arrival at secondary metastatic locations. To better understand this role in metastasis, we undertook two noncandidate analyses of Ezrin function including a microarray subtraction of high-and low-Ezrin-expressing cells and a proteomic approach to identify proteins that bound the N-terminus of Ezrin in tumor lysates. Functional analyses of these data led to a novel and unifying hypothesis that Ezrin contributes to the efficiency of metastasis through regulation of protein translation. In support of this hypothesis, we found Ezrin to be part of the ribonucleoprotein complex to facilitate the expression of complex messenger RNA in cells and to bind with poly A binding protein 1 (PABP1; PABPC1. The relevance of these findings was supported by our identification of Ezrin and components of the translational machinery in pseudopodia of highly metastatic cells during the process of cell invasion. Finally, two small molecule inhibitors recently shown to inhibit the Ezrin metastatic phenotype disrupted the Ezrin/PABP1 association. Taken together, these results provide a novel mechanistic basis by which Ezrin may contribute to metastasis.

Outcomes of colon resection in patients with metastatic colon cancer.

Science.gov (United States)

Moghadamyeghaneh, Zhobin; Hanna, Mark H; Hwang, Grace; Mills, Steven; Pigazzi, Alessio; Stamos, Michael J; Carmichael, Joseph C

2016-08-01

Patients with advanced colorectal cancer have a high incidence of postoperative complications. We sought to identify outcomes of patients who underwent resection for colon cancer by cancer stage. The National Surgical Quality Improvement Program database was used to evaluate all patients who underwent colon resection with a diagnosis of colon cancer from 2012 to 2014. Multivariate logistic regression analysis was performed to investigate patient outcomes by cancer stage. A total of 7,786 colon cancer patients who underwent colon resection were identified. Of these, 10.8% had metastasis at the time of operation. Patients with metastatic disease had significantly increased risks of perioperative morbidity (adjusted odds ratio [AOR]: 1.44, P = .01) and mortality (AOR: 3.72, P = .01). Patients with metastatic disease were significantly younger (AOR: .99, P colon cancer have metastatic disease. Postoperative morbidity and mortality are significantly higher than in patients with localized disease. Published by Elsevier Inc.

Derivatives of Dictyostelium differentiation-inducing factors inhibit lysophosphatidic acid–stimulated migration of murine osteosarcoma LM8 cells

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Kubohara, Yuzuru, E-mail: ykuboha@juntendo.ac.jp [Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512 (Japan); Department of Health Science, Juntendo University Graduate School of Health and Sports Science, Inzai 270-1695 (Japan); Komachi, Mayumi [Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512 (Japan); Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8511 (Japan); Homma, Yoshimi [Department of Biomolecular Science, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295 (Japan); Kikuchi, Haruhisa; Oshima, Yoshiteru [Laboratory of Natural Product Chemistry, Tohoku University Graduate School of Pharmaceutical Sciences, Aoba-yama, Aoba-ku, Sendai 980-8578 (Japan)

2015-08-07

Osteosarcoma is a common metastatic bone cancer that predominantly develops in children and adolescents. Metastatic osteosarcoma remains associated with a poor prognosis; therefore, more effective anti-metastatic drugs are needed. Differentiation-inducing factor-1 (DIF-1), −2, and −3 are novel lead anti-tumor agents that were originally isolated from the cellular slime mold Dictyostelium discoideum. Here we investigated the effects of a panel of DIF derivatives on lysophosphatidic acid (LPA)-induced migration of mouse osteosarcoma LM8 cells by using a Boyden chamber assay. Some DIF derivatives such as Br-DIF-1, DIF-3(+2), and Bu-DIF-3 (5–20 μM) dose-dependently suppressed LPA-induced cell migration with associated IC{sub 50} values of 5.5, 4.6, and 4.2 μM, respectively. On the other hand, the IC{sub 50} values of Br-DIF-1, DIF-3(+2), and Bu-DIF-3 versus cell proliferation were 18.5, 7.2, and 2.0 μM, respectively, in LM8 cells, and >20, 14.8, and 4.3 μM, respectively, in mouse 3T3-L1 fibroblasts (non-transformed). Together, our results demonstrate that Br-DIF-1 in particular may be a valuable tool for the analysis of cancer cell migration, and that DIF derivatives such as DIF-3(+2) and Bu-DIF-3 are promising lead anti-tumor agents for the development of therapies that suppress osteosarcoma cell proliferation, migration, and metastasis. - Highlights: • LPA induces cell migration (invasion) in murine osteosarcoma LM8 cells. • DIFs are novel lead anti-tumor agents found in Dictyostelium discoideum. • We examined the effects of DIF derivatives on LPA-induced LM8 cell migration in vitro. • Some of the DIF derivatives inhibited LPA-induced LM8 cell migration.

CD147 and matrix-metalloproteinase-2 expression in metastatic and non-metastatic uveal melanomas.

Science.gov (United States)

Lüke, Julia; Vukoja, Vlatka; Brandenbusch, Tim; Nassar, Khaled; Rohrbach, Jens Martin; Grisanti, Salvatore; Lüke, Matthias; Tura, Aysegül

2016-06-03

Extracellular matrix remodelling regulated by matrix-metalloproteinase (MMP) inducer (CD147) is a crucial process during tumor cell invasion and regulation of blood supply. In this study, we evaluated the correlation of CD147 and MMP-2 expression with major prognostic factors for uveal melanoma and the development of metastasis. The expression of CD147 and MMP-2 was analyzed in 49 samples of uveal melanomas. Triple immunofluorescence stainings using markers against glial cells (GFAP), endothelial cells (CD34) and macrophages (CD68) were performed to further analyse the exact localisation of CD147 and MMP-2 positivity. In 28 cases clinical metastatic disease were found. The remaining 21 cases showed no signs of metastatic disease for an average follow-up of 10 years. Correlation analysis (Pearson correlation) was performed to analyse the association of CD147 and MMP-2 expression with known prognostic factors, vasculogenic mimicry (VM), the mature vasculature (von Willebrand Factor) and tumor induced angiogenesis (by means of Endoglin expression). CD147 and MMP-2 were expressed in 47 (96.0 %) of the uveal melanomas. CD147 up-regulation was significantly correlated with a higher MMP-2 expression. The overall expression analysis revealed no significant difference in the metastatic (p = 0.777) and non-metastatic subgroup (p = 0.585). No correlation of CD147 expression and any system of blood supply was evident. In the non-metastatic sub-group a significant correlation of clustered CD147 positive cells with largest basal diameter (p = 0.039), height (p = 0.047) and TNM-stage (p = 0.013) was evident. These data may indicate that CD147 regulates MMP-2 expression in uveal melanoma cells.

Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells

Energy Technology Data Exchange (ETDEWEB)

Husmann, Knut, E-mail: khusmann@research.balgrist.ch [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland); Ducommun, Pascal [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland); Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich (Switzerland); Sabile, Adam A.; Pedersen, Else-Marie; Born, Walter; Fuchs, Bruno [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland)

2015-09-04

The poor outcome of osteosarcoma (OS), particularly in patients with metastatic disease and a five-year survival rate of only 20%, asks for more effective therapeutic strategies targeting malignancy-promoting mechanisms. Dysregulation of C-MET, its ligand hepatocyte growth factor (HGF) and the fusion oncogene product TPR-MET, first identified in human MNNG-HOS OS cells, have been described as cancer-causing factors in human cancers. Here, the expression of these molecules at the mRNA and the protein level and of HGF-stimulated signaling and downregulation of C-MET was compared in the parental low metastatic HOS and MG63 cell lines and the respective highly metastatic MNNG-HOS and 143B and the MG63-M6 and MG63-M8 sublines. Interestingly, expression of TPR-MET was only observed in MNNG-HOS cells. HGF stimulated the phosphorylation of Akt and Erk1/2 in all cell lines investigated, but phospho-Stat3 remained at basal levels. Downregulation of HGF-stimulated Akt and Erk1/2 phosphorylation was much faster in the HGF expressing MG63-M8 cells than in HOS cells. Degradation of HGF-activated C-MET occurred predominantly through the proteasomal and to a lesser extent the lysosomal pathway in the cell lines investigated. Thus, HGF-stimulated Akt and Erk1/2 signaling as well as proteasomal degradation of HGF activated C-MET are potential therapeutic targets in OS. - Highlights: • Expression of TPR-MET was only observed in MNNG-HOS cells. • HGF stimulated the phosphorylation of Akt and Erk1/2 but not of Stat3 in osteosarcoma cell lines. • Degradation of HGF-activated C-MET occurred predominantly through the proteasomal pathway.

Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model

International Nuclear Information System (INIS)

Marques, Ines J; Bagowski, Christoph P; Weiss, Frank Ulrich; Vlecken, Danielle H; Nitsche, Claudia; Bakkers, Jeroen; Lagendijk, Anne K; Partecke, Lars Ivo; Heidecke, Claus-Dieter; Lerch, Markus M

2009-01-01

Aberrant regulation of cell migration drives progression of many diseases, including cancer cell invasion and metastasis formation. Analysis of tumour invasion and metastasis in living organisms to date is cumbersome and involves difficult and time consuming investigative techniques. For primary human tumours we establish here a simple, fast, sensitive and cost-effective in vivo model to analyse tumour invasion and metastatic behaviour. We fluorescently labelled small explants from gastrointestinal human tumours and investigated their metastatic behaviour after transplantation into zebrafish embryos and larvae. The transparency of the zebrafish embryos allows to follow invasion, migration and micrometastasis formation in real-time. High resolution imaging was achieved through laser scanning confocal microscopy of live zebrafish. In the transparent zebrafish embryos invasion, circulation of tumour cells in blood vessels, migration and micrometastasis formation can be followed in real-time. Xenografts of primary human tumours showed invasiveness and micrometastasis formation within 24 hours after transplantation, which was absent when non-tumour tissue was implanted. Furthermore, primary human tumour cells, when organotopically implanted in the zebrafish liver, demonstrated invasiveness and metastatic behaviour, whereas primary control cells remained in the liver. Pancreatic tumour cells showed no metastatic behaviour when injected into cloche mutant embryos, which lack a functional vasculature. Our results show that the zebrafish is a useful in vivo animal model for rapid analysis of invasion and metastatic behaviour of primary human tumour specimen

Imported rickettsioses : think of murine typhus

NARCIS (Netherlands)

van der Kleij, FGH; Gansevoort, RT; Kreeftenberg, HG

Murine typhus is a disease still prevalent in many parts of the world. Because the incidence in the US and Europe has declined rapidly, physicians in these continents have become unfamiliar with the clinical picture. Murine typhus is associated with significant morbidity and fatalities do occur,

Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells

Science.gov (United States)

Mansur, Nuzhat; Raziul Hasan, Mohammad; Kim, Young-tae; Iqbal, Samir M.

2017-09-01

Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

Concepts for treatment of micrometastases developed in murine systems

International Nuclear Information System (INIS)

Schabel, F.M. Jr.

1976-01-01

Current knowledge of tumor cell population growth kinetics indicates that the growth fraction (viable tumor cells undergoing active cell replication) is inversely related to population size. Tumor cells in micrometastases should, therefore, be more sensitive to anticancer drugs active against anabolizing cells than are tumor cells in the larger, grossly apparent primary tumor from which they were derived. This indicates the probability that micrometastases will be effectively responsive to more drugs than is the primary and clinically apparent tumor from which they came. Studies with at least four metastatic and uniformly fatal murine solid tumors (lung, breast, colon, and melanoma) have demonstrated significantly improved cure rates with drug treatment following surgical removal of the grossly apparent primary tumor than can be obtained with either surgery or drug treatment when used alone. Further, both disease staging and drug dosage have been shown to influence cure rates of combined-modality treatment. With several mouse tumors, a significantly smaller number of viable tumor cells can establish lethal tumors in the presence of radiation-inactivated tumor cells than in their absence. This suggests that small numbers of residual viable tumor cells in radiation-treated tumor sites may be a greater threat to clinical cure than smaller tumor cell populations remaining in situ after surgery

Thoracoabdominal actinomycosis mimicking metastatic disease: case report

International Nuclear Information System (INIS)

Ros, L.H.; Villacampa, V.M.; Torres, G.M.; Ros, P.R.

1999-01-01

Actinomycosis is a chronic suppurative infection with bacteria of the Actinomycetaceae family, characterized by the formation of abundant granular tissue and multiple abscesses. It is a rare entity, and clinical and radiological findings are similar to those in other inflammatory and in neoplastic processes. Actinomycosis should be considered in the differential diagnosis in high-risk patients with predisposing factors, such as alcoholism, poor oral hygiene, maxillofacial trauma, tuberculosis, chronic obstructive pulmonary disease, steroid ingestion or immunodeficiency, and in patients in whom the disease history does not correlate with widespread metastatic involvement. Early diagnosis is important, to prevent disease progression and unnecessary surgery, since the response to drug treatment is very good. We present a case of diffuse actinomycosis involving multiple organs (liver, kidneys, colon, and lungs) that simulated metastatic disease on radiography and computed tomography (CT). (author)

Thoracoabdominal actinomycosis mimicking metastatic disease: case report

Energy Technology Data Exchange (ETDEWEB)

Ros, L.H.; Villacampa, V.M. [Hospital Miguel Servet, Dept. of Radiology, Zaragoza (Spain); Torres, G.M. [Univ. of Florida, Dept. of Radiology, Gainesville, Florida (United States); Ros, P.R. [Harvard Medical School, Brigham and Women' s Hospital, Dept. of Radiology, Boston, Massachusetts (United States)

1999-12-01

Actinomycosis is a chronic suppurative infection with bacteria of the Actinomycetaceae family, characterized by the formation of abundant granular tissue and multiple abscesses. It is a rare entity, and clinical and radiological findings are similar to those in other inflammatory and in neoplastic processes. Actinomycosis should be considered in the differential diagnosis in high-risk patients with predisposing factors, such as alcoholism, poor oral hygiene, maxillofacial trauma, tuberculosis, chronic obstructive pulmonary disease, steroid ingestion or immunodeficiency, and in patients in whom the disease history does not correlate with widespread metastatic involvement. Early diagnosis is important, to prevent disease progression and unnecessary surgery, since the response to drug treatment is very good. We present a case of diffuse actinomycosis involving multiple organs (liver, kidneys, colon, and lungs) that simulated metastatic disease on radiography and computed tomography (CT). (author)

Trastuzumab and survival of patients with metastatic breast cancer.

Science.gov (United States)

Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

2017-08-01

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without

Early radiation effects in highly apoptotic murine lymphoma xenografts monitored by 31P magnetic resonance spectroscopy

International Nuclear Information System (INIS)

Sakurai, Hideyuki; Mitsuhashi, Norio; Murata, Osamu; Kitamoto, Yoshizumi; Saito, Yoshihiro; Hasegawa, Masatoshi; Akimoto, Tetsuo; Takahashi, Takeo; Nasu, Sachiko; Niibe, Hideo

1998-01-01

Purpose: Phosphorus-31 magnetic resonance spectra ( 31 P-MRS) were obtained from highly apoptotic murine lymphoma xenografts before and up to 24 hr following graded doses of radiation ranging from 2 to 30 Gy. Radiation-induced apoptosis was also estimated up to 24 hr by scoring apoptotic cells in tumor tissue. Methods and Materials: Highly apoptotic murine lymphoma cells, EL4, were subcutaneously transplanted into C57/BL mice. At 7 days after transplantation, radiation was given to the tumor with a single dose at 3, 10, and 30 Gy. The β-ATP/Pi, PME/Pi, and β-ATP/PME values were calculated from the peak area of each spectrum. Radiation-induced apoptosis was scored with counting apoptotic cells on hematoxylin and eosin stained specimens (%apoptosis). Results: The values of % apoptosis 4, 8, and 24 hr after radiation were 21.8, 19.6, and 4.6% at 3 Gy, 35.1, 25.6, and 14.8% at 10 Gy, 38.4, 38.0, and 30.6% at 30 Gy, respectively (cf. 4.4% in control). There was no correlation between early change in β-ATP/Pi and % apoptosis at 4 hr after radiation when most of the apoptosis occurred. An early decrease in PME/Pi was observed at 4 hr after radiation dose at 30 Gy. For each dose, the values of β-ATP/Pi 24 hr after radiation were inversely related to radiation dose. Conclusion: The increase in β-ATP/Pi observed by 31 P-MRS was linked to the degree of histological recovery from radiation-induced apoptosis

Metastatic tonsillar squamous cell carcinoma masquerading as a pancreatic cystic tumor and diagnosed by EUS-guided FNA.

Science.gov (United States)

Glass, Ryan; Andrawes, Sherif A; Hamele-Bena, Diane; Tong, Guo-Xia

2017-11-01

Metastatic carcinoma to the pancreas is uncommon and head and neck squamous carcinoma metastatic to the pancreas is extremely rare. Metastatic squamous cell carcinoma to the pancreas presents a unique diagnostic challenge: in addition to mimicking the rare primary squamous cell carcinoma of the pancreas based on cytologic, histologic, and immunohistochemical features, it may be mistaken for a cystic neoplasm of the pancreas because of its high predilection for cystic degeneration in metastatic sites. Herein, we report a case of tonsillar squamous cell carcinoma with a cystic pancreatic metastasis diagnosed by ultrasound-guided fine needle aspiration biopsy (EUS-FNA). This represents a third reported case of metastatic squamous cell carcinoma to the pancreas from the head and neck region. Metastatic squamous cell carcinoma should be considered in the differential diagnosis of EUS-FNA during evaluation of pancreatic cystic lesion. © 2017 Wiley Periodicals, Inc.

High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer

DEFF Research Database (Denmark)

Alves, Carla Maria Lourenco; Elias, Daniel; Lyng, Maria B

2016-01-01

expression impaired fulvestrant-resistant cell growth and induced apoptosis. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma protein phosphorylation. High CDK6 levels in metastatic samples from two independent cohorts of breast cancer...

Quantitative Method of Measuring Metastatic Activity

Science.gov (United States)

Morrison, Dennis R. (Inventor)

1999-01-01

The metastatic potential of tumors can be evaluated by the quantitative detection of urokinase and DNA. The cell sample selected for examination is analyzed for the presence of high levels of urokinase and abnormal DNA using analytical flow cytometry and digital image analysis. Other factors such as membrane associated uroldnase, increased DNA synthesis rates and certain receptors can be used in the method for detection of potentially invasive tumors.

Metastatic Patterns of Myxoid/Round Cell Liposarcoma: A Review of a 25-Year Experience

Directory of Open Access Journals (Sweden)

Naofumi Asano

2012-01-01

Full Text Available Myxoid/round cell liposarcoma (MRCL, unlike other soft tissue sarcomas, has been associated with unusual pattern of metastasis to extrapulmonary sites. In an attempt to elucidate the clinical features of MRCL with metastatic lesions, 58 cases, from the medical database of Keio University Hospital were used for the evaluation. 47 patients (81% had no metastases, whereas 11 patients (11% had metastases during their clinical course. Among the 11 patients with metastatic lesions, 8 patients (73% had extrapulmonary metastases and 3 patients (27% had pulmonary metastases. Patients were further divided into three groups; without metastasis, with extrapulmonary metastasis, and with pulmonary metastasis. When the metastatic patterns were stratified according to tumor size, there was statistical significance between the three groups (P=0.028. The 8 cases with extrapulmonary metastases were all larger than 10 cm. Similarly, histological grading had a significant impact on metastatic patterns (P=0.027. 3 cases with pulmonary metastatic lesions were all diagnosed as high grade. In conclusion, large size and low histological grade were significantly associated with extrapulmonary metastasis.

Immunotherapy of distant metastatic disease

DEFF Research Database (Denmark)

Schadendorf, D; Algarra, S M; Bastholt, L

2009-01-01

Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated with signif......Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated...

Metastatic cervical lymphadenopathy from uterine leiomyosarcoma with good local response to radiotherapy and chemotherapy

International Nuclear Information System (INIS)

Oh, Yoon Kyeong; Park, Hee Chul; Kee, Keun Hong; Jeon, Ho Jong; Park, You Hwan; Chung, Choon Hai

2000-01-01

The metastasis of uterine leiomyosarcoma to the neck node has not been reported previously and the radiotherapy has been rarely used for the metastatic lesion of the other sites. We report a case of neck metastasis from a uterine leiomyosarcoma, which developed 10 months after surgery and postoperative pelvic radiotherapy. It also involved the parapharyngeal space, adjacent spine, and spinal canal. The metastatic neck mass was inoperable, and was treated by neck radiotherapy (6,000 cGy) and chemotherapy including taxol and carboplatin. The mass has regressed progressively to a nearly impalpable state. She has never developed spinal cord compression syndrome, and has maintained good swallowing for eight months since the neck radiotherapy and chemotherapy. Since the extensive metastatic neck mass showed good local response to high dose radiotherapy and chemotherapy, both treatments may be considered for an unresectable metastatic leiomyosarcoma

Adoptive cell transfer in the treatment of metastatic melanoma

DEFF Research Database (Denmark)

Straten, Per thor; Becker, Jürgen C

2009-01-01

Adoptive cell therapy (ACT) for metastatic cancer is the focus of considerable research effort. Rosenberg's laboratory demonstrated a 50% response rate in stage IV melanoma patients treated with in vitro expanded tumor-infiltrating lymphocytes (TILs) and high-dose IL-2 administered after...

Multiple urinary bladder masses from metastatic prostate adenocarcinoma

Directory of Open Access Journals (Sweden)

Richard Choo

2010-12-01

Full Text Available We present an unusual case of metastatic prostate adenocarcinoma that manifested with multiple exophytic intravesical masses, mimicking a multifocal primary bladder tumor. Biopsy with immunohistochemical analysis confirmed metastatic prostate adenocarcinoma. The patient was treated palliatively with external beam radiotherapy to prevent possible symptoms from local tumor progression. This case illustrates that when a patient with known prostate cancer presents with multifocal bladder tumors, the possibility of metastatic prostate cancer should be considered.

Theranostics Targeting Metastatic Breast Cancer

Science.gov (United States)

2017-10-01

AWARD NUMBER: W81XWH-15-1-0390 TITLE: Theranostics Targeting Metastatic Breast Cancer PRINCIPAL INVESTIGATOR: Zheng Li CONTRACTING ORGANIZATION...Breast Cancer 5b. GRANT NUMBER W81XWH-15-1-0390 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Zheng Li 5e. TASK NUMBER 5f. WORK UNIT...14 Theranostics Targeting Metastatic Breast  Cancer   A. Introduction (1paragraph) The overall goal of this proposal is to prepare TrkC

Radiological, pathological and DNA remission in recurrent metastatic nasopharyngeal carcinoma

Directory of Open Access Journals (Sweden)

Chan Anthony TC

2006-10-01

Full Text Available Abstract Background Circulating plasma Epstein Barr Virus DNA (EBV-DNA is a sensitive and specific marker of nasopharyngeal carcinoma (NPC. The mainstay of treatment of metastatic NPC is systemic chemotherapy and resection for solitary metastasis. Despite high response rate to chemotherapy, complete remission is uncommonly seen. Case Presentation We report a case of recurrent metastatic NPC in a 43-year-old man, who achieved complete remission three times with chemotherapy and surgery. Serial plasma EBV-DNA levels were measured during the course of disease. The patient had three episodes of recurrences of NPC manifested as distant metastasis. Both time, rise in the plasma EBV-DNA level preceded detection of recurrences by imaging. Following systemic chemotherapy, he achieved complete remission each time, of which was confirmed by 18-flourodeoxyglucose positron emission tomography and hepatectomy pathology. The plasma EBV-DNA level dropped to zero copy/ml at the time of each remission. Conclusion This case highlights the high chemosensitivity of NPC by illustrating a rare occurrence of complete response of metastatic NPC to chemotherapy. This case also underscores the usefulness of EBV-DNA as a useful tool in monitoring NPC by its ability to detect early recurrence and excellent correlation with treatment response.

Three-dimensional in vivo imaging of the murine liver: a micro-computed tomography-based anatomical study.

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Teresa Fiebig

Full Text Available Various murine models are currently used to study acute and chronic pathological processes of the liver, and the efficacy of novel therapeutic regimens. The increasing availability of high-resolution small animal imaging modalities presents researchers with the opportunity to precisely identify and describe pathological processes of the liver. To meet the demands, the objective of this study was to provide a three-dimensional illustration of the macroscopic anatomical location of the murine liver lobes and hepatic vessels using small animal imaging modalities. We analysed micro-CT images of the murine liver by integrating additional information from the published literature to develop comprehensive illustrations of the macroscopic anatomical features of the murine liver and hepatic vasculature. As a result, we provide updated three-dimensional illustrations of the macroscopic anatomy of the murine liver and hepatic vessels using micro-CT. The information presented here provides researchers working in the field of experimental liver disease with a comprehensive, easily accessable overview of the macroscopic anatomy of the murine liver.

Radiation therapy for metastatic spinal tumors

International Nuclear Information System (INIS)

Kida, Akio; Fukuda, Haruyuki; Taniguchi, Shuji; Sakai, Kazuaki

2000-01-01

The results of radiation therapy for metastatic spinal tumors were evaluated in terms of pain relief, improvement of neurological impairment, and survival. Between 1986 and 1995, 52 symptomatic patients with metastatic spinal tumors treated with radiation therapy were evaluated. The patients all received irradiation of megavoltage energy. Therapeutic efficacy was evaluated in terms of pain relief and improvement of neurological impairment. Pain relief was observed in 29 (61.7%) of 47 patients with pain. Therapy was effective for 17 (70.8%) of 24 patients without neurological impairment, and efficacy was detected in 12 (52.2%) of 23 patients with neurological impairment. Improvement of neurological symptoms was obtained in seven (25.0%) of 28 patients with neurological impairment. Radiation therapy was effective for pain relief in patients with metastatic spinal tumors. In patients with neurological impairment, less pain relief was observed than in those without impairment. Improvement of neurological impairment was restricted, but radiation therapy was thought to be effective in some cases in the early stage of neurological deterioration. Radiation therapy for metastatic spinal tumors contraindicated for surgery was considered effective for improvement of patients' activities of daily living. (author)

Tumor-infiltrating lymphocytes for the treatment of metastatic cancer

DEFF Research Database (Denmark)

Geukes Foppen, M H; Donia, M; Svane, I M

2015-01-01

five years, treatment with immunotherapy (anti CTLA-4, anti PD-1, or the combination of these antibodies) has shown very promising results and was able to improve survival in patients with metastatic melanoma. Adoptive cell therapy using tumor-infiltrating lymphocytes is yet another, but highly...

A Unique Case of Diffuse Metastatic Neuroendocrine Cancer with Subcutaneous Nodules on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computer Assisted Tomography

International Nuclear Information System (INIS)

Johnston, Mickaila J.; Sachedina, Archana; McDonald, James E.

2015-01-01

Neuroendocrine tumors (NETs) account for 8–10% of cases of carcinomas of unknown primary. Most of these cases are poorly differentiated with metastatic disease at the time of diagnosis. However, cutaneous metastatic presentation is rare. We present an interesting case of a 74-year-old woman presenting with cutaneous metastatic involvement from high grade poorly differentiated NET of unknown origin. She was referred to us with a diagnosis of lymphoma. 18 F-fluorodeoxyglucose positron emission tomography/computer assisted tomography imaging at our institution offered a differential diagnosis, including neuroendocrine cancer. Repeat skin lesion biopsy demonstrated “non-Merkel cell” carcinoma, favoring metastatic high-grade neuroendocrine carcinoma

Directed evolution and targeted mutagenesis to murinize Listeria monocytogenes Internalin A for enhanced infectivity in the murine oral infection model

LENUS (Irish Health Repository)

Monk, Ian R

2010-12-13

Abstract Background Internalin A (InlA) is a critical virulence factor which mediates the initiation of Listeria monocytogenes infection by the oral route in permissive hosts. The interaction of InlA with the host cell ligand E-cadherin efficiently stimulates L. monocytogenes entry into human enterocytes, but has only a limited interaction with murine cells. Results We have created a surface display library of randomly mutated InlA in a non-invasive heterologous host Lactococcus lactis in order to create and screen novel variants of this invasion factor. After sequential passage through a murine cell line (CT-26), multiple clones with enhanced invasion characteristics were identified. Competitive index experiments were conducted in mice using selected mutations introduced into L. monocytogenes EGD-e background. A novel single amino acid change was identified which enhanced virulence by the oral route in the murine model and will form the basis of further engineering approaches. As a control a previously described EGD-InlAm murinized strain was also re-created as part of this study with minor modifications and designated EGD-e InlA m*. The strain was created using a procedure that minimizes the likelihood of secondary mutations and incorporates Listeria-optimized codons encoding the altered amino acids. L. monocytogenes EGD-e InlA m* yielded consistently higher level murine infections by the oral route when compared to EGD-e, but did not display the two-fold increased invasion into a human cell line that was previously described for the EGD-InlAm strain. Conclusions We have used both site-directed mutagenesis and directed evolution to create variants of InlA which may inform future structure-function analyses of this protein. During the course of the study we engineered a murinized strain of L. monocytogenes EGD-e which shows reproducibly higher infectivity in the intragastric murine infection model than the wild type, but does not display enhanced entry into human

Directed evolution and targeted mutagenesis to murinize listeria monocytogenes internalin A for enhanced infectivity in the murine oral infection model

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Hill Colin

2010-12-01

Full Text Available Abstract Background Internalin A (InlA is a critical virulence factor which mediates the initiation of Listeria monocytogenes infection by the oral route in permissive hosts. The interaction of InlA with the host cell ligand E-cadherin efficiently stimulates L. monocytogenes entry into human enterocytes, but has only a limited interaction with murine cells. Results We have created a surface display library of randomly mutated InlA in a non-invasive heterologous host Lactococcus lactis in order to create and screen novel variants of this invasion factor. After sequential passage through a murine cell line (CT-26, multiple clones with enhanced invasion characteristics were identified. Competitive index experiments were conducted in mice using selected mutations introduced into L. monocytogenes EGD-e background. A novel single amino acid change was identified which enhanced virulence by the oral route in the murine model and will form the basis of further engineering approaches. As a control a previously described EGD-InlAm murinized strain was also re-created as part of this study with minor modifications and designated EGD-e InlAm*. The strain was created using a procedure that minimizes the likelihood of secondary mutations and incorporates Listeria-optimized codons encoding the altered amino acids. L. monocytogenes EGD-e InlAm* yielded consistently higher level murine infections by the oral route when compared to EGD-e, but did not display the two-fold increased invasion into a human cell line that was previously described for the EGD-InlAm strain. Conclusions We have used both site-directed mutagenesis and directed evolution to create variants of InlA which may inform future structure-function analyses of this protein. During the course of the study we engineered a murinized strain of L. monocytogenes EGD-e which shows reproducibly higher infectivity in the intragastric murine infection model than the wild type, but does not display enhanced

Characterization of the binding of radioiodinated hybrid recombinant IFN-alpha A/D to murine and human lymphoid cell lines

International Nuclear Information System (INIS)

Faltynek, C.R.; Princler, G.L.; Schwabe, M.; Shata, M.T.; Lewis, G.K.; Kamin-Lewis, R.M.

1990-01-01

The hybrid recombinant human interferon (IFN) rIFN-alpha A/D was radioiodinated. Specific binding of [125I]rIFN-alpha A/D was observed with both human and murine cell lines. The binding of [125I]rIFN-alpha A/D to human Daudi cells had similar characteristics to the previously described binding of [125I]rIFN-alpha A or -alpha 2. The following lines of evidence demonstrated that [125I]rIFN-alpha A/D bound with high affinity to the same receptor on murine cells as murine IFN-alpha and -beta: (i) the binding of [125I]rIFN-alpha A/D to murine LBRM cells was inhibited to a similar extent by natural murine IFN-alpha, natural murine IFN-beta, and rIFN-A/D; (ii) the Kd (approximately 2 X 10(-10) M) obtained from both competition experiments and saturation binding experiments with [125I]rIFN-alpha A/D was comparable to the previously reported Kd for the binding of natural murine IFN-alpha and -beta to other murine cell lines; (iii) the size of the cross-linked [125I]rIFN-alpha A/D receptor complex formed on murine LBRM cells was similar to the previously reported cross-linked complex formed after binding radioiodinated natural murine IFN-beta to other murine cell lines. Due to the current lack of readily available recombinant murine IFN-alpha or -beta for radiolabeling and the previously demonstrated biological activity of rIFN-alpha A/D on murine cells, [125I]rIFN-alpha A/D should prove to be a useful reagent for further studies of murine IFN receptors

REPORT OF SEVEN CASES OF METASTATIC TUMOURS

African Journals Online (AJOL)

Major Adebayo

Metastatic lesions may mimic odontogenic infections and other disease conditions in the oral cavity in presentation leading to late diagnosis by the unwary clinician. In Nigeria, reports on jaw tumours from metastasis elsewhere are quite scarce. This report presents a series of histologically verified metastatic tumours to the ...

Urothelial-Type adenocarcinoma of the prostate mimicking metastatic colorectal adenocarcinoma

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Brian P. Adley

2006-12-01

Full Text Available Adenocarcinoma arising in urinary bladder or prostatic urethra is uncommon. When they occur, the tumor can be mistaken for metastatic lesions, especially from the colon. Here we report the fifth case of a primary urothelial-type adenocarcinoma arising in the prostate which showed enteric differentiation. The patient was a 55 year-old male whose prostatic needle core biopsy showed a high grade adenocarcinoma which was initially thought to be metastatic colon cancer. A follow-up colonoscopy was unremarkable. Subsequent prostatectomy revealed a high grade adenocarcinoma which was positive for cytokeratins 7 and 20, carcinoembryonic antigen, CDX2, and high molecular weight cytokeratin, and negative for prostate specific antigen, prostate specific acid phosphatase and AMACR. A diagnosis of urothelial-type adenocarcinoma of the prostate was rendered. We review the literature regarding this entity, and discuss the differential diagnosis, emphasizing utility of immunohistochemistry in making the diagnosis. Finally, we speculate on the behavior of these rare tumors.

Characteristic findings of computed tomography in cerebral metastatic malignant melanomas

International Nuclear Information System (INIS)

Kukita, Chikashige; Nose, Tadao; Nakagawa, Kunio; Tomono, Yuji; Enomoto, Takao; Hashikawa, Masanori; Egashira, Taihei; Maki, Yutaka

1986-01-01

Four cases with metastatic cerebral melanoma were studied by means of computed tomography (CT). Two cases were male, and the other two were female, with an average age of 55 years. Their primary lesions were on the chest wall in two cases, around the calcaneus in one, and around the genitalia in one. All cases died within 6 months after the metastatic brain lesions were found. Necropsies were carried out in two cases. CT revealed high-density areas in all cases, and contrast studies showed an enhancement of the lesions, as has previously been reported. On the other hand, autopsied cases revealed neither fresh nor old intratumoral bleedings such as a scattered focus of hemosiderin. These findings suggest that the high-density tumoral shadows in CT are probably not intratumoral bleedings due to a bleeding tendency of the tumors, as some authors have previously supposed. We mentioned some other factors contributing to the high density of the melanoma on computed tomograms. (author)

Ultrasonic imaging of metastatic carcinoma in thyroid gland

International Nuclear Information System (INIS)

Bai Ling; Yang Tao; Tang Ying; Mao Jingning; Chen Wei; Wang Wei

2008-01-01

Objectives: To explore the ultrasonic findings of metastatic thyroid carcinoma and to evaluate the diagnostic value of the ultrasonic imaging for patients with metastatic thyroid neoplasm. Methods: The ultrasonic imaging characteristics of ten patients who were diagnosed with metastatic thyroid carcinoma were retrospectively analyzed. In all the cases, fine-needle aspiration cytology (FNAC) of the thyroid was performed during the clinical diagnosis. Results: The ultrasonic images of the ten patients fell into four types: multiple nodules in the thyroid, single nodule in the thyroid, diffuse calcification and heterogeneous echo. Seven cases showed speckled calcific foci. Abnormal blood flow signal was found in 9 cases. Conclusion: The ultrasonic findings of metastatic carcinoma in the thyroid gland are various and non-specific. Color Doppler ultrasound may provide ample evidence. The diagnosis depends on FNAC. (authors)

PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma.

Science.gov (United States)

Gaiser, Maria Rita; Bongiorno, Michelle; Brownell, Isaac

2018-04-01

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that lacks durable responses to traditional chemotherapy. Areas covered: After MCC was shown to be an immunogenic tumor, small trials revealed high objective response rates to PD-1/PD-L1 checkpoint inhibitors. The JAVELIN Merkel 200 (NCT02155647) trial tested the use of avelumab, a human IgG1 monoclonal antibody against PD-L1, in metastatic MCC. Avelumab recently became the first approved drug for metastatic MCC. Expert commentary: By conducting broad phase I studies assessing the safety of avelumab and a small phase II study demonstrating efficacy in this rare orphan tumor type, avelumab gained accelerated approval for the treatment of metastatic MCC. Additional studies are needed to determine how the antibody-dependent cellular cytotoxicity (ADCC) competent Fc region of avelumab contributes to disease control. Remaining questions: Longer follow-up will determine the durability of checkpoint blockade in controlling metastatic MCC. Additional studies will assess the utility and safety of adjuvant checkpoint blockade in patients with excised MCC. How to increase response rates by combining PD-1/PD-L1 blockade with other treatment approaches needs to be explored. In addition, treatment options for MCC patients who fail or do not respond to avelumab need to be identified.

Outcomes of Adolescent and Adult Patients with Lung Metastatic Osteosarcoma and Comparison of Synchronous and Metachronous Lung Metastatic Groups.

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Ayse Gok Durnali

Full Text Available Osteosarcomas with lung metastases are rather heterogenous group. We aimed to evaluate the clinicopathological characteristics and outcomes of osteosarcoma patients with lung metastases and to compare the synchronous and metachronous lung metastatic groups. A total of 93 adolescent and adult patients with lung metastatic osteosarcoma, from March 1995 to July 2011, in a single center, were included. Sixty-five patients (69.9% were male. The median age was 19 years (range, 14-74. Thirty-nine patients (41.9% had synchronous lung metastases (Group A and 54 patients (58.1% had metachronous lung metastases (Group B. The 5-year and 10-year post-lung metastases overall survival (PLM-OS was 17% and 15%, respectively. In multivariate analysis for PLM-OS, time to lung metastases (p = 0.010, number of metastatic pulmonary nodules (p = 0.020, presence of pulmonary metastasectomy (p = 0.007 and presence of chemotherapy for lung metastases (p< 0.001 were found to be independent prognostic factors. The median PLM-OS of Group A and Group B was 16 months and 9 months, respectively. In Group B, the median PLM-OS of the patients who developed lung metastases within 12 months was 6 months, whereas that of the patients who developed lung metastases later was 16 months. Time to lung metastases, number and laterality of metastatic pulmonary nodules, chemotherapy for lung metastatic disease and pulmonary metastasectomy were independent prognostic factors for patients with lung metastatic osteosarcoma. The best PLM-OS was in the subgroup of patients treated both surgery and chemotherapy. The prognosis of the patients who developed lung metastases within 12 months after diagnosis was worst.

Metastatic breast disease from cutaneous malignant melanoma.

Science.gov (United States)

Moschetta, Marco; Telegrafo, Michele; Lucarelli, Nicola Maria; Martino, Gianluigi; Rella, Leonarda; Stabile Ianora, Amato Antonio; Angelelli, Giuseppe

2014-01-01

Malignant melanoma is one of the most rapidly increasing cancer in the world. Breast metastases from melanoma are uncommon but could reflect a widespread disease. We report a case of malignant widespread melanoma presenting with bilateral breast nodules in a 39 year-old pre-menopausal Caucasian woman with an history of cutaneous melanoma of the trunk. Breast clinical examination revealed the presence of a hard and mobile lump located on the left breast. Ultrasound detected two bilateral nodules corresponding to oval opacities with well-defined edges and without calcifications or architectural distortion on mammography. Fine needle aspiration cytology performed on both breast nodules confirmed that the breast lesions were metastases from primary cutaneous malignant melanoma. A total-body CT examination detected brain, lung and abdominal lymph nodes metastases. The breast represents an uncommon site of metastatic disease from extra-mammary tumors. Imaging features of breast metastases from melanoma usually do not allow a differential diagnosis with breast primary tumors. Breast metastases may be asymptomatic or palpable as dense and well-circumscribed nodules. Breast metastases indicate a widespread disease and should lead to avoid aggressive surgical procedures because of the poor prognosis of patients affected by metastatic melanoma. The detection of bilateral breast metastases from melanoma is highly suggestive of metastatic multi-organ disease and could be useful to address the therapeutic approach. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Feature genes in metastatic breast cancer identified by MetaDE and SVM classifier methods.

Science.gov (United States)

Tuo, Youlin; An, Ning; Zhang, Ming

2018-03-01

The aim of the present study was to investigate the feature genes in metastatic breast cancer samples. A total of 5 expression profiles of metastatic breast cancer samples were downloaded from the Gene Expression Omnibus database, which were then analyzed using the MetaQC and MetaDE packages in R language. The feature genes between metastasis and non‑metastasis samples were screened under the threshold of PSVM) classifier training and verification. The accuracy of the SVM classifier was then evaluated using another independent dataset from The Cancer Genome Atlas database. Finally, function and pathway enrichment analyses for genes in the SVM classifier were performed. A total of 541 feature genes were identified between metastatic and non‑metastatic samples. The top 10 genes with the highest betweenness centrality values in the PPI network of feature genes were Nuclear RNA Export Factor 1, cyclin‑dependent kinase 2 (CDK2), myelocytomatosis proto‑oncogene protein (MYC), Cullin 5, SHC Adaptor Protein 1, Clathrin heavy chain, Nucleolin, WD repeat domain 1, proteasome 26S subunit non‑ATPase 2 and telomeric repeat binding factor 2. The cyclin‑dependent kinase inhibitor 1A (CDKN1A), E2F transcription factor 1 (E2F1), and MYC interacted with CDK2. The SVM classifier constructed by the top 30 feature genes was able to distinguish metastatic samples from non‑metastatic samples [correct rate, specificity, positive predictive value and negative predictive value >0.89; sensitivity >0.84; area under the receiver operating characteristic curve (AUROC) >0.96]. The verification of the SVM classifier in an independent dataset (35 metastatic samples and 143 non‑metastatic samples) revealed an accuracy of 94.38% and AUROC of 0.958. Cell cycle associated functions and pathways were the most significant terms of the 30 feature genes. A SVM classifier was constructed to assess the possibility of breast cancer metastasis, which presented high accuracy in several

Combined endoscopic and laparoscopic approach for palliative resection of metastatic melanoma of the stomach

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Pritchard SA

2006-03-01

Full Text Available Abstract Background Metastatic tumours of the stomach present a clinical dilemma for the surgeon. Palliative surgical resection can alleviate symptoms and prolong survival in selected patients. However, previous studies have used open methods of surgical resection with potentially high morbidity and mortality. We describe the use of laparoscopic wedge resection of the stomach for palliative resection of metastatic melanoma to highlight the benefits of this technique. Case presentation A 58 year old male was investigated for iron deficiency anaemia while under treatment for pulmonary metastatic malignant melanoma. An upper gastrointestinal endoscopy revealed a 5 cm diameter ulcer on the anterior wall of the stomach, biopsies from the ulcer confirmed metastatic melanoma. Laparoscopic wedge resection of the stomach lesion was performed without complication. Conclusion Laparoscopic approach has many benefits and is useful for the palliative resection of rare tumours of the stomach in order to preserve the quality of life. Its use should be considered in selected patients.

Metastatic pulmonary calcification: high-resolution computed tomography findings in 23 cases

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Luciana Camara Belém

Full Text Available Abstract Objective: The aim of this study was to evaluate the high-resolution computed tomography (HRCT findings in patients diagnosed with metastatic pulmonary calcification (MPC. Materials and Methods: We retrospectively reviewed the HRCT findings from 23 cases of MPC [14 men, 9 women; mean age, 54.3 (range, 26-89 years]. The patients were examined between 2000 and 2014 in nine tertiary hospitals in Brazil, Chile, and Canada. Diagnoses were established by histopathologic study in 18 patients and clinical-radiological correlation in 5 patients. Two chest radiologists analyzed the images and reached decisions by consensus. Results: The predominant HRCT findings were centrilobular ground-glass nodules (n = 14; 60.9%, consolidation with high attenuation (n = 10; 43.5%, small dense nodules (n = 9; 39.1%, peripheral reticular opacities associated with small calcified nodules (n = 5; 21.7%, and ground-glass opacities without centrilobular ground-glass nodular opacity (n = 5; 21.7%. Vascular calcification within the chest wall was found in four cases and pleural effusion was observed in five cases. The abnormalities were bilateral in 21 cases. Conclusion: MPC manifested with three main patterns on HRCT, most commonly centrilobular ground-glass nodules, often containing calcifications, followed by dense consolidation and small solid nodules, most of which were calcified. We also described another pattern of peripheral reticular opacities associated with small calcified nodules. These findings should suggest the diagnosis of MPC in the setting of hypercalcemia.

Metastatic pulmonary calcification: high-resolution computed tomography findings in 23 cases

Energy Technology Data Exchange (ETDEWEB)

Belem, Luciana Camara; Souza, Carolina A.; Souza Junior, Arthur Soares; Escuissato, Dante Luiz; Hochhegger, Bruno; Nobre, Luiz Felipe; Rodrigues, Rosana Souza; Gomes, Antonio Carlos Portugal; Silva, Claudio S.; Guimaraes, Marcos Duarte; Zanetti, Glaucia; Marchiori, Edson, E-mail: edmarchiori@gmail.com [Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ (Brazil); Ottawa Hospital Research Institute, University of Ottawa, (Canada); Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), SP (Brazil); Ultra X, Sao Jose do Rio Preto, SP (Brazil); Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil); Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA), Porto Alegre, RS (Brazil); Universidade Federal de Santa Catarina (UFSC), Florianopolis, SC (Brazil). Hospital Universitario

2017-07-15

Objective: The aim of this study was to evaluate the high-resolution computed tomography (HRCT) findings in patients diagnosed with metastatic pulmonary calcification (MPC). Materials and Methods: We retrospectively reviewed the HRCT findings from 23 cases of MPC [14 men, 9 women; mean age, 54.3 (range, 26-89) years]. The patients were examined between 2000 and 2014 in nine tertiary hospitals in Brazil, Chile, and Canada. Diagnoses were established by histopathologic study in 18 patients and clinical-radiological correlation in 5 patients. Two chest radiologists analyzed the images and reached decisions by consensus. Results: The predominant HRCT findings were centrilobular ground-glass nodules (n = 14; 60.9%), consolidation with high attenuation (n = 10; 43.5%), small dense nodules (n = 9; 39.1%), peripheral reticular opacities associated with small calcified nodules (n = 5; 21.7%), and ground-glass opacities without centrilobular ground-glass nodular opacity (n = 5; 21.7%). Vascular calcification within the chest wall was found in four cases and pleural effusion was observed in five cases. The abnormalities were bilateral in 21 cases. Conclusion: MPC manifested with three main patterns on HRCT, most commonly centrilobular ground-glass nodules, often containing calcifications, followed by dense consolidation and small solid nodules, most of which were calcified. We also described another pattern of peripheral reticular opacities associated with small calcified nodules. These findings should suggest the diagnosis of MPC in the setting of hypercalcemia. (author)

Metastatic pulmonary calcification: high-resolution computed tomography findings in 23 cases

International Nuclear Information System (INIS)

Belem, Luciana Camara; Souza, Carolina A.; Souza Junior, Arthur Soares; Escuissato, Dante Luiz; Hochhegger, Bruno; Nobre, Luiz Felipe; Rodrigues, Rosana Souza; Gomes, Antonio Carlos Portugal; Silva, Claudio S.; Guimaraes, Marcos Duarte; Zanetti, Glaucia; Marchiori, Edson; Ottawa Hospital Research Institute, University of Ottawa,; Faculdade de Medicina de Sao Jose do Rio Preto; Ultra X, Sao Jose do Rio Preto, SP; Universidade Federal do Parana; Universidade Federal de Ciencias da Saude de Porto Alegre; Universidade Federal de Santa Catarina

2017-01-01

Objective: The aim of this study was to evaluate the high-resolution computed tomography (HRCT) findings in patients diagnosed with metastatic pulmonary calcification (MPC). Materials and Methods: We retrospectively reviewed the HRCT findings from 23 cases of MPC [14 men, 9 women; mean age, 54.3 (range, 26-89) years]. The patients were examined between 2000 and 2014 in nine tertiary hospitals in Brazil, Chile, and Canada. Diagnoses were established by histopathologic study in 18 patients and clinical-radiological correlation in 5 patients. Two chest radiologists analyzed the images and reached decisions by consensus. Results: The predominant HRCT findings were centrilobular ground-glass nodules (n = 14; 60.9%), consolidation with high attenuation (n = 10; 43.5%), small dense nodules (n = 9; 39.1%), peripheral reticular opacities associated with small calcified nodules (n = 5; 21.7%), and ground-glass opacities without centrilobular ground-glass nodular opacity (n = 5; 21.7%). Vascular calcification within the chest wall was found in four cases and pleural effusion was observed in five cases. The abnormalities were bilateral in 21 cases. Conclusion: MPC manifested with three main patterns on HRCT, most commonly centrilobular ground-glass nodules, often containing calcifications, followed by dense consolidation and small solid nodules, most of which were calcified. We also described another pattern of peripheral reticular opacities associated with small calcified nodules. These findings should suggest the diagnosis of MPC in the setting of hypercalcemia. (author)

Combined high-intensity local treatment and systemic therapy in metastatic head and neck squamous cell carcinoma: An analysis of the National Cancer Data Base.

Science.gov (United States)

Zumsteg, Zachary S; Luu, Michael; Yoshida, Emi J; Kim, Sungjin; Tighiouart, Mourad; David, John M; Shiao, Stephen L; Mita, Alain C; Scher, Kevin S; Sherman, Eric J; Lee, Nancy Y; Ho, Allen S

2017-12-01

There is increasing evidence that primary tumor ablation can improve survival for some cancer patients with distant metastases. This may be particularly applicable to head and neck squamous cell carcinoma (HNSCC) because of its tropism for locoregional progression. This study included patients with metastatic HNSCC undergoing systemic therapy identified in the National Cancer Data Base. High-intensity local treatment was defined as radiation doses ≥ 60 Gy or oncologic resection of the primary tumor. Multivariate Cox regression, propensity score matching, landmark analysis, and subgroup analysis were performed to account for imbalances in covariates, including adjustments for the number and location of metastatic sites in the subset of patients with this information available. In all, 3269 patients were included (median follow-up, 51.5 months). Patients undergoing systemic therapy with local treatment had improved survival in comparison with patients receiving systemic therapy alone in propensity score-matched cohorts (2-year overall survival, 34.2% vs 20.6%; P treatment, whereas those receiving lower-intensity local treatment had survival similar to that of patients receiving systemic therapy without local treatment. The impact of high-intensity local therapy was time-dependent, with a stronger impact within the first 6 months after the diagnosis (adjusted hazard ratio [AHR], 0.255; 95% confidence interval [CI], 0.210-0.309; P treatment warrants prospective evaluation for select patients with metastatic HNSCC. Cancer 2017;123:4583-4593. © 2017 American Cancer Society. © 2017 American Cancer Society.

Reacquisition of E-cadherin expression in metastatic deposits of signet-ring cell carcinoma of the upper gastrointestinal system: a potential anchor for metastatic deposition.

Science.gov (United States)

Ma, Yihong R; Siegal, Gene P; Wei, Shi

2017-06-01

To examine the expression of E-cadherin in paired primary and metastatic signet-ring cell carcinomas (SRCC) of various organ systems in order to explore the potential role of the molecule in metastatic dissemination of this unique tumour type. Thirty-seven consecutive cases of SRCC from various organs with paired primary and metastatic tumorous tissue available were retrieved. The intensity of membranous E-cadherin expression was semiquantitatively scored on a scale of 0-3+. Reduced E-cadherin expression was a distinct feature of primary SRCC and was observed in 78% of primary tumours. Interestingly, the E-cadherin reduction was less frequently seen in metastatic SRCC when compared with their primary counterparts, and was only found in 57% of tumours in lymph node metastases or at distant sites of relapse. Furthermore, the mean score of E-cadherin expression of primary SRCC was significantly lower than that of their metastatic counterparts (2.3 vs 1.8; p=0.008). When divided by organ systems, the reacquisition of E-cadherin expression in the metastatic deposits was most remarkable in the SRCC of upper gastrointestinal tract origin (2.3 vs 1.4; p=0.003), whereas no significant difference was observed in other organ systems. While the reduction of E-cadherin in primary SRCC supports its pivotal role in epithelial-mesenchymal transition, a process crucial in tumour progression and metastatic dissemination, the re-expression of this molecule in metastatic SRCC cells implies a reversal to their epithelial phenotype (thus mesenchymal-epithelial transition) which, in turn, theoretically helps tumour cells to anchor and form cohesive metastatic deposits. 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/.

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

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Z.K. Tuong

2018-06-01

Full Text Available Currently available vaccines prevent HPV infection and development of HPV-associated malignancies, but do not cure existing HPV infections and dysplastic lesions. Persistence of infection(s in immunocompetent patients may reflect induction of local immunosuppressive mechanisms by HPV, providing a target for therapeutic intervention. We have proposed that a mouse, expressing HPV16 E7 oncoprotein under a Keratin 14 promoter (K14E7 mice, and which develops epithelial hyperplasia, may assist with understanding local immune suppression mechanisms that support persistence of HPV oncogene-induced epithelial hyperplasia. K14E7 skin grafts recruit immune cells from immunocompetent hosts, but consistently fail to be rejected. Here, we review the literature on HPV-associated local immunoregulation, and compare the findings with published observations on the K14E7 transgenic murine model, including comparison of the transcriptome of human HPV-infected pre-malignancies with that of murine K14E7 transgenic skin. We argue from the similarity of i the literature findings and ii the transcriptome profiles that murine K14E7 transgenic skin recapitulates the cellular and secreted protein profiles of high-grade HPV-associated lesions in human subjects. We propose that the K14E7 mouse may be an appropriate model to further study the immunoregulatory effects of HPV E7 expression, and can facilitate development and testing of therapeutic vaccines.

Sequential use of indium-111 labeled monoclonal antibodies 96.5 and ZME-018 does not increase detection sensitivity for metastatic melanoma

International Nuclear Information System (INIS)

Frontiera, M.; Murray, J.L.; Lamki, L.

1989-01-01

Two indium-111 labeled anti-melanoma murine monoclonal antibodies (MAb), 96.5 and ZME-018, each recognizing separate antigens on melanoma cells, were administered intravenously to 17 patients with melanoma in a sequential fashion to determine whether: (1) additional tumor sites could be imaged with the combination compared to a single Mab; (2) the first MAb influenced the biodistribution and tumor localization of the second; and (3) significantly toxicity occurred with the combination. Patients were randomized to receive either 96.5, followed by ZME-018, ZME-018 followed by 96.5, or each MAb followed by itself (controls). Infusions of the second MAb occurred 10 days after the first infusion. Gamma camera images were obtained 72 hours after each antibody infusion. There were 139 known metastatic sites of which 72 lesions were localized by either MAb for an overall sensitivity of 52%. The detection rate was higher when lesions only greater than 1.5 cm were considered. Imaging results were independent of MAb administration sequence. When ZME-018 was given as the first infusion, when ZME-018 was given as a second infusion (p = NS). However, mean sensitivities using 96.5 as the first or second infusion were 48% and 66% respectively (p = NS). There was not a significant number of sites detected by MAb 2 that were missed by MAb 1. Human anti-murine antibody (HAMA) response occurred in seven of eight patients studied; two patients who experienced toxicity had levels of HAMA greater than 2000 ng/ml. We conclude that the use of these two murine anti-melanoma monoclonal antibodies given in sequential fashion did not significantly change the imaging sensitivity from that seen with each individual antibody

High levels of circulating VEGFR2+ Bone marrow-derived progenitor cells correlate with metastatic disease in patients with pediatric solid malignancies.

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Taylor, Melissa; Rössler, Jochen; Geoerger, Birgit; Laplanche, Agnès; Hartmann, Olivier; Vassal, Gilles; Farace, Françoise

2009-07-15

Pediatric solid malignancies display important angiogenic potential, and blocking tumor angiogenesis represents a new therapeutic approach for these patients. Recent studies have evidenced rare circulating cells with endothelial features contributing to tumor neovascularization and have shown the pivotal role of bone marrow-derived (BMD) progenitor cells in metastatic disease progression. We measured these cells in patients with pediatric solid malignancies as a prerequisite to clinical trials with antiangiogenic therapy. Peripheral blood was drawn from 45 patients with localized (n = 23) or metastatic (n = 22) disease, and 20 healthy subjects. Subsets of circulating vascular endothelial growth factor receptor (VEGFR)2+-BMD progenitor cells, defined as CD45-CD34+VEGFR2(KDR)+7AAD- and CD45(dim)CD34+VEGFR2+7AAD- events, were measured in progenitor-enriched fractions by flow cytometry. Mature circulating endothelial cells (CEC) were measured in whole blood as CD31+CD146+CD45-7AAD- viable events. Data were correlated with VEGF and sVEGFR2 plasma levels. The CD45-CD34+VEGFR2(KDR)+7AAD- subset represented <0.003% of circulating BMD progenitor cells (< or =0.05 cells/mL). However, the median level (range) of the CD45(dim)CD34+VEGFR2+7AAD- subset was higher in patients compared with healthy subjects, 1.5% (0%-10.3%) versus 0.3% (0%-1.6%) of circulating BMD progenitors (P < 0.0001), and differed significantly between patients with localized and metastatic disease, 0.7% (0%-8.6%) versus 2.9% (0.6%-10.3%) of circulating BMD progenitors (P < 0.001). Median CEC value was 7 cells/mL (0-152 cells/mL) and similar in all groups. Unlike VEGFR2+-BMD progenitors, neither CECs, VEGF, or sVEGFR2 plasma levels correlated with disease status. High levels of circulating VEGFR2+-BMD progenitor cells correlated with metastatic disease. Our study provides novel insights for angiogenesis mechanisms in pediatric solid malignancies for which antiangiogenic targeting of VEGFR2+-BMD progenitors

Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer

International Nuclear Information System (INIS)

Forero-Torres, Andres; Infante, Jeffrey R; Waterhouse, David; Wong, Lucas; Vickers, Selwyn; Arrowsmith, Edward; He, Aiwu Ruth; Hart, Lowell; Trent, David; Wade, James; Jin, Xiaoping; Wang, Qiang; Austin, TaShara; Rosen, Michael; Beckman, Robert; Roemeling, Reinhard von; Greenberg, Jonathan; Saleh, Mansoor

2013-01-01

Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m 2 once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3–64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2–5.4 months). Median OS was 8.2 months (95% CI, 5.1–9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer

Unforeseen clonal evolution of tumor cell population in recurrent and metastatic dermatofibrosarcoma protuberans.

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Ensel Oh

Full Text Available Dermatofibrosarcoma protuberans (DFSP is a very rare soft tissue sarcoma, generally of low-grade malignancy. DFSP is locally aggressive with a high recurrence rate, but metastasis occurs rarely. To investigate the mechanism of metastasis in DFSP, we analyzed the whole exome sequencing data of serial tumor samples obtained from a patient who had a 10-year history of recurrent and metastatic DFSP. Tracking various genomic alterations, namely somatic mutations, copy number variations, and chromosomal rearrangements, we observed a dramatic change in tumor cell population during the occurrence of metastasis in this DFSP case. The new subclone that emerged in metastatic DFSP harbored a completely different set of somatic mutations and new focal amplifications, which had not been observed in the primary clone before metastasis. The COL1A1-PDGFB fusion, characteristic of DFSP, was found in all of the serial samples. Moreover, the break position on the fusion gene was identical in all samples. Based on these observations, we suggest a clonal evolution model to explain the mechanism underlying metastasis in DFSP and identified several candidate target genes responsible for metastatic DFSP by utilizing The Cancer Genome Atlas database. This is the first study to observe clonal evolution in metastatic DFSP and provide insight for a possible therapeutic strategy for imatinib-resistant or metastatic DFSP.

Metastatic neoplasms of the central nervous system

International Nuclear Information System (INIS)

Fenner, W.R.

1990-01-01

Metastatic neoplasms to the central nervous system are often encountered in the practice of surgical neuropathology. It is not uncommon for patients with systemic malignancies to present to medical attention because of symptoms from a brain metastasis and for the tissue samples procured from these lesions to represent the first tissue available to study a malignancy from an unknown primary. In general surgical pathology, the evaluation of a metastatic neoplasm of unknown primary is a very complicated process, requiring knowledge of numerous different tumor types, reagents, and staining patterns. The past few years, however, have seen a remarkable refinement in the immunohistochemical tools at our disposal that now empower neuropathologists to take an active role in defining the relatively limited subset of neoplasms that commonly metastasize to the central nervous system. This information can direct imaging studies to find the primary tumor in a patient with an unknown primary, clarify the likely primary site of origin in patients who have small tumors in multiple sites without an obvious primary lesion, or establish lesions as late metastases of remote malignancies. Furthermore, specific treatments can begin and additional invasive procedures may be prevented if the neuropathologic evaluation of metastatic neoplasms provides information beyond the traditional diagnosis of ''metastatic neoplasm.'' In this review, differential cytokeratins, adjuvant markers, and organ-specific antibodies are described and the immunohistochemical signatures of metastatic neoplasms that are commonly seen by neuropathologists are discussed

Enzalutamide in metastatic prostate cancer before chemotherapy

DEFF Research Database (Denmark)

Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana E

2014-01-01

BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have...... the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas...... skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P

Cediranib for Metastatic Alveolar Soft Part Sarcoma

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Kummar, Shivaani; Allen, Deborah; Monks, Anne; Polley, Eric C.; Hose, Curtis D.; Ivy, S. Percy; Turkbey, Ismail B.; Lawrence, Scott; Kinders, Robert J.; Choyke, Peter; Simon, Richard; Steinberg, Seth M.; Doroshow, James H.; Helman, Lee

2013-01-01

Purpose Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). Patients and Methods We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging. Results Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. Conclusion In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib. PMID:23630200

MC148 encoded by human molluscum contagiosum poxvirus is an antagonist for human but not murine CCR8

DEFF Research Database (Denmark)

Lüttichau, H R; Gerstoft, J; Schwartz, T W

2001-01-01

The viral CC chemokines MC148, encoded by the poxvirus molluscum contagiosum, and viral macrophage inflammatory protein (vMIP)-I and vMIP-II, encoded by human herpesvirus 8, were probed on the murine CC receptor (CCR) 8 in parallel with human CCR8. In calcium mobilization assays, vMIP-I acted...... as a high-affinity agonist, whereas vMIP-II acted as a low-affinity antagonist on the murine CCR8 as well as the human CCR8. MC148 was found to bind and block responses through the human CCR8 with high affinity, but surprisingly MC148 was unable to bind and block responses through the murine CCR8. Because...

uPAR Targeted Radionuclide Therapy with 177Lu-DOTA-AE105 Inhibits Dissemination of Metastatic Prostate Cancer

DEFF Research Database (Denmark)

Persson, Morten; Juhl, Karina; Rasmussen, Palle

2014-01-01

The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect...... of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific...... value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted 177Lu groups (p

The effects of high dose and highly fractionated radiation on distraction osteogenesis in the murine mandible

International Nuclear Information System (INIS)

Monson, Laura A; Cavaliere, Christi M; Deshpande, Sagar S; Ayzengart, Alexander L; Buchman, Steven R

2012-01-01

The ability of irradiated tissue to support bony growth remains poorly defined, although there are anecdotal cases reported showing mixed results for the use of mandibular distraction osteogenesis after radiation for head and neck cancer. Many of these reports lack objective measures that would allow adequate analysis of outcomes or efficacy. The purpose of this experiment was to utilize a rat model of mandibular distraction osteogenesis after high dose and highly fractionated radiation therapy and to evaluate and quantify distracted bone formation under these conditions. Male Sprague–Dawley rats underwent 12 fractions of external beam radiation (48 Gray) of the left mandible. Following a two week recovery period, an external frame distractor was applied and gradual distraction of the mandible was performed. Tissue was harvested after a twenty-eight day consolidation period. Gross, radiologic and histological evaluations were undertaken. Those animals subjected to pre-operative radiation showed severe attenuation of bone formation including bone atrophy, incomplete bridging of the distraction gap, and gross bony defects or non-union. Although physical lengthening was achieved, the irradiated bone consistently demonstrated marked damaging effects on the normal process of distraction osteogenesis. This murine model has provided reliable evidence of the injurious effects of high dose radiation on bone repair and regeneration in distraction osteogenesis utilizing accurate and reproducible metrics. These results can now be used to assist in the development of therapies directed at mitigating the adverse consequences of radiation on the regeneration of bone and to optimize distraction osteogenesis so it can be successfully applied to post-oncologic reconstruction

Metastatic breast carcinoma uncovered in an otherwise unremarkable “random colon biopsy”

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Mike Black

2016-06-01

Full Text Available Breast cancer is one of the most devastating cancers afflicting women, being a main cause of cancer related death. Approximately 50% of these patients have developed regional or distant metastases at the time of diagnosis; hence, an early diagnosis and surgery with indicated neoadjuvant therapy are crucial in eradicating this disease and improving patient survival. A significant percentage of patients, even after initial satisfactory tumor removal, still face the threat of metastatic diseases which could plague a wide spectrum of body sites such as bones, lungs, central nervous system, liver and gastrointestinal tract (mostly upper gastrointestinal locations. Colonic and anorectal involvement by metastatic breast cancer has been less frequently reported in disseminated diseases. Typically, metastatic disease presents as a mass, enteric stenosis, or obstruction. Rare cases, however, may not form an endoscopically or radiologically recognizable lesion, and thus could be overlooked. Here we report a unique case of random colon biopsies in a patient presenting with epigastric pain, whose stomach biopsy showed Helicobacter pylori-associated chronic active gastritis. No colonoscopic lesion was present; however, microscopic examination of the “random biopsy” revealed scattered single and small clusters of tumor cells involving the lamina propria of the colonic mucosa, morphologically and immunophenotypically consistent with metastatic disease from breast carcinoma. The clinical presentation and histopathology of the case were reviewed and compared with limited cases reported in the literature. We conclude that high levels of suspicion and alertness are essential to identify occult microscopic gastrointestinal metastatic breast cancer in the absence of a grossly appreciable lesion.

Surgical Management of Advanced and Metastatic Renal Cell Carcinoma: A Multidisciplinary Approach

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Brian M. Shinder

2017-05-01

Full Text Available The past decade has seen a rapid proliferation in the number and types of systemic therapies available for renal cell carcinoma. However, surgery remains an integral component of the therapeutic armamentarium for advanced and metastatic kidney cancer. Cytoreductive surgery followed by adjuvant cytokine-based immunotherapy (predominantly high-dose interleukin 2 has largely given way to systemic-targeted therapies. Metastasectomy also has a role in carefully selected patients. Additionally, neoadjuvant systemic therapy may increase the feasibility of resecting the primary tumor, which may be beneficial for patients with locally advanced or metastatic disease. Several prospective trials examining the role of adjuvant therapy are underway. Lastly, the first immune checkpoint inhibitor was approved for metastatic renal cell carcinoma (mRCC in 2015, providing a new treatment mechanism and new opportunities for combining systemic therapy with surgery. This review discusses current and historical literature regarding the surgical management of patients with advanced and mRCC and explores approaches for optimizing patient selection.

A method for high efficiency YAC lipofection into murine embryonic stem cells.

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Lee, J T; Jaenisch, R

1996-01-01

We describe a modified protocol for introducing yeast artificial chromosomes (YACs) into murine embryonic stem (ES) cells by lipofection. With a decreased DNA:cell ratio, increased concentration of condensing agents and altered culture conditions, this protocol reduces the requirement for YAC DNA to a few micrograms, improves the recovery of neomycin-resistant ES colonies and increases the yield of clones containing both flanking vector markers and insert. These modifications enable generation of sufficient 'intact' transgenic clones for biological analysis with a single experiment. PMID:9016681

Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice.

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Araújo, Wedson F; Naves, Marcelo A; Ravanini, Juliana N; Schor, Nestor; Teixeira, Vicente P C

2015-09-01

Renal cell carcinoma (RCC) is the most frequent type of cancer among renal neoplasms in adults and responds poorly to radiotherapy and chemotherapy. There is evidence that blockade of the renin-angiotensin system (RAS) might have antineoplastic effects. The aim of this study was to investigate the effects of RAS blockade on RCC in a murine model. Murine renal cancer cells (Renca) were injected (1 × 10(5)) into the subcapsular space of the left kidney of BALB/c mice (8 wk of age). The animals were divided into 4 groups: a control group (no treatment), angiotensin-receptor blockers group (losartan 100mg/kg/d), angiotensin-converting enzyme inhibitor group (captopril 10mg/kg/d), and angiotensin-receptor blockers +angiotensin-converting enzyme inhibitor group (losartan 100mg/kg/d +captopril 10mg/kg/d). The animals received the drugs by gavage for 21 days after inoculation, beginning 2 days before tumor induction, and were then euthanized. After killing the animals, the kidneys and lungs were removed, weighed, and processed for histopathological and immunohistochemical analyses. Angiogenesis and vascular microvessels were assessed with the antibodies anti-vascular endothelial growth factor and anti-CD34. Angiotensin II-inoculated animals developed renal tumors. Treated animals presented smaller tumors, regardless of the therapeutic regimen, and far fewer lung metastases in both quantity and dimension compared with the controls. The expression of vascular endothelial growth factor and CD34 were significantly decreased in renal tumors of treated animals compared with the controls. Our findings suggest that blockade of RAS decreases tumor proliferation and metastatic capacity of RCC in this experimental model. Copyright © 2015 Elsevier Inc. All rights reserved.

A novel murine model for evaluating bovine papillomavirus prophylactics/therapeutics for equine sarcoid-like tumours.

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Bogaert, Lies; Woodham, Andrew W; Da Silva, Diane M; Martens, Ann; Meyer, Evelyne; Kast, W Martin

2015-09-01

Equine sarcoids are highly recurrent bovine papillomavirus (BPV)-induced fibroblastic neoplasms that are the most common skin tumours in horses. In order to facilitate the study of potential equine sarcoid prophylactics or therapeutics, which can be a slow and costly process in equines, a murine model for BPV-1 protein-expressing equine sarcoid-like tumours was developed in mice through stable transfection of BPV-1 E5 and E6 in a murine fibroblast tumour cell line (K-BALB). Like equine sarcoids, these murine tumour cells (BPV-KB) were of fibroblast origin, were tumorigenic and expressed BPV-1 proteins. As an initial investigation of the preclinical potential of this tumour model for equine sarcoids prophylactics, mice were immunized with BPV-1 E5E6 Venezuelan equine encephalitis virus replicon particles, prior to BPV-KB challenge, which resulted in an increased tumour-free period compared with controls, indicating that the BPV-KB murine model may be a valuable preclinical alternative to equine clinical trials.

Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer

NARCIS (Netherlands)

Witjes, J.A.; Lebret, T.; Comperat, E.M.; Cowan, N.C.; Santis, M. de; Bruins, H.M.; Hernandez, V.; Espinos, E.L.; Dunn, J.; Rouanne, M.; Neuzillet, Y.; Veskimae, E.; Heijden, A.G. van der; Gakis, G.; Ribal, M.J.

2017-01-01

CONTEXT: Invasive bladder cancer is a frequently occurring disease with a high mortality rate despite optimal treatment. The European Association of Urology (EAU) Muscle-invasive and Metastatic Bladder Cancer (MIBC) Guidelines are updated yearly and provides information to optimise diagnosis,

Metastatic breast carcinoma in the mandible presenting as a periodontal abscess: a case report.

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Poulias, Evmenios; Melakopoulos, Ioannis; Tosios, Konstantinos

2011-07-01

Tumors can metastasize to the oral cavity and affect the jaws, soft tissue and salivary glands. Oral cavity metastases are considered rare and represent approximately 1% of all oral malignancies. Because of their rarity and atypical clinical and radiographic appearance, metastatic lesions are considered a diagnostic challenge. The purpose of this report is to present a rare case of a metastatic breast carcinoma mimicking a periodontal abscess in the mandible. A 55-year-old Caucasian woman was referred to our clinic for evaluation of bisphosphonate-induced jaw osteonecrosis. She had undergone modified radical mastectomy with axillary lymph node dissection for invasive ductal carcinoma of the left breast. Her clinical examination showed diffuse swelling and a periodontal pocket of 6 mm exhibiting suppuration in the posterior right mandible. Moreover, paresthesia of the lower right lip and chin was noted. There were no significant radiographic findings other than alveolar bone loss due to her periodontal disease. Although the lesion resembled a periodontal abscess, metastatic carcinoma of the breast was suspected on the basis of the patient's medical history. The area was biopsied, and histological analysis confirmed the final diagnosis of metastatic breast carcinoma. The general dentist or dental specialist should maintain a high level of suspicion while evaluating patients with a history of cancer. Paresthesias of the lower lip and the chin should be considered ominous signs of metastatic disease. This case highlights the importance of the value of a detailed medical history and thorough clinical examination for the early detection of metastatic tumors in the oral cavity.

Comparison of the Mismatch Repair System between Primary and Metastatic Colorectal Cancers Using Immunohistochemistry

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Jiyoon Jung

2017-03-01

Full Text Available Background Colorectal cancer (CRC is one of the most common malignancies worldwide. Approximately 10%–15% of the CRC cases have defective DNA mismatch repair (MMR genes. Although the high level of microsatellite instability status is a predictor of favorable outcome in primary CRC, little is known about its frequency and importance in secondary CRC. Immunohistochemical staining (IHC for MMR proteins (e.g., MLH1, MSH2, MSH6, and PMS2 has emerged as a useful technique to complement polymerase chain reaction (PCR analyses. Methods In this study, comparison between the MMR system of primary CRCs and paired liver and lung metastatic lesions was done using IHC and the correlation with clinical outcomes was also examined. Results Based on IHC, 7/61 primary tumors (11.4% showed deficient MMR systems, while 13/61 secondary tumors (21.3% showed deficiencies. In total, 44 cases showed proficient expression in both the primary and metastatic lesions. Three cases showed deficiencies in both the primary and paired metastatic lesions. In 10 cases, proficient expression was found only in the primary lesions, and not in the corresponding metastatic lesions. In four cases, proficient expression was detected in the secondary tumor, but not in the primary tumor. Conclusions Although each IHC result and the likely defective genes were not exactly matched between the primary and the metastatic tumors, identical results for primary and metastatic lesions were obtained in 77% of the cases (47/61. These data are in agreement with the previous microsatellite detection studies that used PCR and IHC.

Relationship between intrinsic radiation sensitivity and metastatic potential

International Nuclear Information System (INIS)

Lewis, Anne M.; Mei, Su; Doty, Jay; Chen Yi; Pardo, Francisco S.

1996-01-01

Purpose: Prior studies emphasized genetic modulation of tumorigenicity, and experimental metastatic potential in cells transfected with oncogenes. Whether the intrinsic radiation sensitivity of cells might correlate with parallel changes in metastatic potential is unknown. Methods and Materials: Rat embryo cells (REC) were transfected with the following oncogenes, and where appropriate, with corresponding selection markers: pCMV neopEJ6.6ras, pEJ6.6ras/v-myc, pE1a, and pEJ6-.6ras/E1a. Individual transfectant clones and corresponding pooled cellular populations were propagated in selective medium. In vitro cellular radiation sensitivity was determined via clonogenic assays, a minimum of three, by standard techniques and individual SF 2 and MID parameters determined. Tumorigenicity was defined as the number of tumors forming following the injection of 1 x 10 5 - 1 x 10 6 cells into the axillary pouch of three different strains of immune-deficient mice. Animals were killed once resultant tumors reached a maximum size of 1.5-2.0 cm in maximum diameter. For determination of experimental metastatic potential, between 1 x 10 5 -1 x 10 6 cells were injected into the tail veins of litter-matched sibling mice in parallel to the tumorigenicity studies. Results: Radiobiologic studies indicate similar levels of radiation sensitivity among REC, mock-transfected REC, E1a, and combined E1a/ras transfectants. pEJ6.6ras, and combined ras/myc transfected pooled cellular populations demonstrated increases in radiation resistance when compared to the pooled radiobiologic data from untransfected and mock-transfected corresponding pooled cellular populations (p 2 , MID). Rat embryo cells, E1a, and mock-transfectants were relatively radiation sensitive and nontumorigenic. pE1a/ras was tumorigenic but demonstrated relatively low experimental metastatic potential. Ras, and ras/myc transfectants, demonstrated similar levels of experimental metastatic potential on lung colonization assays

Gene expression profiles in primary pancreatic tumors and metastatic lesions of Ela-c-myc transgenic mice

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Liao Dezhong J

2008-01-01

Full Text Available Abstract Background Pancreatic carcinoma usually is a fatal disease with no cure, mainly due to its invasion and metastasis prior to diagnosis. We analyzed the gene expression profiles of paired primary pancreatic tumors and metastatic lesions from Ela-c-myc transgenic mice in order to identify genes that may be involved in the pancreatic cancer progression. Differentially expressed selected genes were verified by semi-quantitative and quantitative RT-PCR. To further evaluate the relevance of some of the selected differentially expressed genes, we investigated their expression pattern in human pancreatic cancer cell lines with high and low metastatic potentials. Results Data indicate that genes involved in posttranscriptional regulation were a major functional category of upregulated genes in both primary pancreatic tumors (PT and liver metastatic lesions (LM compared to normal pancreas (NP. In particular, differential expression for splicing factors, RNA binding/pre-mRNA processing factors and spliceosome related genes were observed, indicating that RNA processing and editing related events may play critical roles in pancreatic tumor development and progression. High expression of insulin growth factor binding protein-1 (Igfbp1 and Serine proteinase inhibitor A1 (Serpina1, and low levels or absence of Wt1 gene expression were exclusive to liver metastatic lesion samples. Conclusion We identified Igfbp1, Serpina1 and Wt1 genes that are likely to be clinically useful biomarkers for prognostic or therapeutic purposes in metastatic pancreatic cancer, particularly in pancreatic cancer where c-Myc is overexpressed.

Gene expression profiles in primary pancreatic tumors and metastatic lesions of Ela-c-myc transgenic mice.

Science.gov (United States)

Thakur, Archana; Bollig, Aliccia; Wu, Jiusheng; Liao, Dezhong J

2008-01-24

Pancreatic carcinoma usually is a fatal disease with no cure, mainly due to its invasion and metastasis prior to diagnosis. We analyzed the gene expression profiles of paired primary pancreatic tumors and metastatic lesions from Ela-c-myc transgenic mice in order to identify genes that may be involved in the pancreatic cancer progression. Differentially expressed selected genes were verified by semi-quantitative and quantitative RT-PCR. To further evaluate the relevance of some of the selected differentially expressed genes, we investigated their expression pattern in human pancreatic cancer cell lines with high and low metastatic potentials. Data indicate that genes involved in posttranscriptional regulation were a major functional category of upregulated genes in both primary pancreatic tumors (PT) and liver metastatic lesions (LM) compared to normal pancreas (NP). In particular, differential expression for splicing factors, RNA binding/pre-mRNA processing factors and spliceosome related genes were observed, indicating that RNA processing and editing related events may play critical roles in pancreatic tumor development and progression. High expression of insulin growth factor binding protein-1 (Igfbp1) and Serine proteinase inhibitor A1 (Serpina1), and low levels or absence of Wt1 gene expression were exclusive to liver metastatic lesion samples. We identified Igfbp1, Serpina1 and Wt1 genes that are likely to be clinically useful biomarkers for prognostic or therapeutic purposes in metastatic pancreatic cancer, particularly in pancreatic cancer where c-Myc is overexpressed.

TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells.

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Bartucci, M; Dattilo, R; Moriconi, C; Pagliuca, A; Mottolese, M; Federici, G; Benedetto, A Di; Todaro, M; Stassi, G; Sperati, F; Amabile, M I; Pilozzi, E; Patrizii, M; Biffoni, M; Maugeri-Saccà, M; Piccolo, S; De Maria, R

2015-02-05

Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.

Micro-computed tomography derived anisotropy detects tumor provoked deviations in bone in an orthotopic osteosarcoma murine model.

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Heather A Cole

Full Text Available Radiographic imaging plays a crucial role in the diagnosis of osteosarcoma. Currently, computed-tomography (CT is used to measure tumor-induced osteolysis as a marker for tumor growth by monitoring the bone fractional volume. As most tumors primarily induce osteolysis, lower bone fractional volume has been found to correlate with tumor aggressiveness. However, osteosarcoma is an exception as it induces osteolysis and produces mineralized osteoid simultaneously. Given that competent bone is highly anisotropic (systematic variance in its architectural order renders its physical properties dependent on direction of load and that tumor induced osteolysis and osteogenesis are structurally disorganized relative to competent bone, we hypothesized that μCT-derived measures of anisotropy could be used to qualitatively and quantitatively detect osteosarcoma provoked deviations in bone, both osteolysis and osteogenesis, in vivo. We tested this hypothesis in a murine model of osteosarcoma cells orthotopically injected into the tibia. We demonstrate that, in addition to bone fractional volume, μCT-derived measure of anisotropy is a complete and accurate method to monitor osteosarcoma-induced osteolysis. Additionally, we found that unlike bone fractional volume, anisotropy could also detect tumor-induced osteogenesis. These findings suggest that monitoring tumor-induced changes in the structural property isotropy of the invaded bone may represent a novel means of diagnosing primary and metastatic bone tumors.

Prognostic impact of carcinoembryonic antigen (CEA) on patients with metastatic pancreatic cancer: A retrospective cohort study.

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Imaoka, Hiroshi; Mizuno, Nobumasa; Hara, Kazuo; Hijioka, Susumu; Tajika, Masahiro; Tanaka, Tsutomu; Ishihara, Makoto; Hirayama, Yutaka; Hieda, Nobuhiro; Yoshida, Tsukasa; Okuno, Nozomi; Shimizu, Yasuhiro; Niwa, Yasumasa; Yamao, Kenji

2016-01-01

Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers, and its level is increased in 30-60% of patients with pancreatic cancer (PC). However, little is known about the implications of CEA as a prognostic marker in metastatic PC. The purpose of this study was to examine the usefulness of CEA levels as a prognostic marker in patients with metastatic PC. We conducted a retrospective cohort study using data from a computerized database. A total of 433 patients with metastatic disease were analyzed. Median overall survival (OS) was significantly shorter for patients with high CEA (>5 ng/ml) than with normal CEA (≤5 ng/ml) (6.8 vs. 10.3 months, respectively; p CEA level was an independent predictive factor for OS (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.45-2.26). In the high CEA group, OS in patients treated with combination chemotherapy was similar to that with single-agent chemotherapy (median, 7.1 vs. 6.8 months; HR for OS, 0.99; 95% CI, 0.71-1.40). The present results show that CEA level is an independent prognostic factor in patients with metastatic PC. A combination chemotherapy regimen may offer modest survival benefit in patients with high CEA. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Development and characterization of antiserum to murine granulocyte-macrophage colony-stimulating factor

International Nuclear Information System (INIS)

Mochizuki, D.Y.; Eisenman, J.R.; Conlon, P.J.; Park, L.S.; Urdal, D.L.

1986-01-01

The expression in yeast of a cDNA clone encoding murine granulocyte-macrophage colony-stimulating factor (GM-CSF) has made possible the purification of large quantities of this recombinant protein. Rabbits immunized with pure recombinant GM-CSF generated antibodies that were shown to be specific for both recombinant GM-CSF and GM-CSF isolated from natural sources. Other lymphokines, including IL 1β, IL 2, IL 3, and recombinant human GM-CSF did not react with the antiserum. The antiserum together with recombinant GM-CSF that had been radiolabeled with 125 I to high specific activity, formed the foundation for a rapid, sensitive, and quantitative radioimmunoassay specific for murine GM-CSF. Furthermore, the antiserum was found to inhibit the biologic activities of GM-CSF as measured in both a bone marrow proliferation assay and a colony assay, and thus should prove to be a useful reagent for dissecting the complex growth factor activities involved in murine hematopoiesis

Xenogeneic murine tyrosinase DNA vaccine for malignant melanoma of the digit of dogs.

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Manley, C A; Leibman, N F; Wolchok, J D; Rivière, I C; Bartido, S; Craft, D M; Bergman, P J

2011-01-01

Malignant melanoma of dogs is a highly aggressive neoplasm and is the 2nd most common digit tumor. Metastatic disease is a common sequela for which few effective treatment options exist. Studies show that xenogeneic tyrosinase DNA vaccination yields immune responses and prolongation of survival in dogs with oral malignant melanoma. Describe clinical findings and tumor characteristics of a cohort of dogs with digit malignant melanoma, and evaluate the prognostic utility of a proposed staging system. Determine if a novel xenogeneic DNA vaccine is safe and potentially effective for treatment of dogs with digit melanoma. Fifty-eight dogs with digit malignant melanoma treated at the Animal Medical Center between 2004 and 2007. Retrospective, medical records review of dogs with digit melanoma treated with xenogeneic DNA vaccine. Overall median survival time (MST) for dogs treated with loco-regional control and xenogeneic DNA vaccine was 476 days with a 1-year survival rate of 63%. MST for dogs presenting with metastasis was 105 days versus 533 days for dogs presenting without metastasis (P dogs in the latter group were alive at 2 and 3 years. A proposed staging system proved prognostic with stages I-IV dogs surviving >952, >1,093, 321, and 76 days, respectively. The xenogeneic murine tyrosinase DNA vaccine was safe and appears effective when used in conjunction with local and regional disease control. The proposed staging system was prognostic in this study and future studies might benefit from utilizing this staging system. Copyright © 2010 by the American College of Veterinary Internal Medicine.

Avelumab: A Review in Metastatic Merkel Cell Carcinoma.

Science.gov (United States)

Shirley, Matt

2018-05-24

Avelumab (Bavencio ® ) is a fully human IgG1 monoclonal antibody that is directed against programmed cell death ligand 1 (PD-L1). Avelumab functions as an immune checkpoint inhibitor and has recently been approved in the USA, the EU and Japan for the treatment of metastatic Merkel cell carcinoma (MCC). It is thus the first therapeutic agent specifically approved for use in this indication, and is approved for use independent of line of treatment. Approval for avelumab in metastatic MCC was based on the two-part, single-arm, phase II trial, JAVELIN Merkel 200. In Part A of the study, confirmed objective responses were observed in approximately one-third of patients with chemotherapy-refractory metastatic MCC treated with avelumab. The responses were observed early and appeared to be durable, with an estimated 74% of responses having a duration ≥ 12 months. Furthermore, interim results from a separate cohort of patients (Part B) indicate an objective response rate for avelumab of > 60% in patients who were chemotherapy-naïve in the metastatic disease setting. Avelumab is associated with a risk of immune-related adverse events but, overall, has an acceptable and manageable safety and tolerability profile. In conclusion, currently available data suggest that avelumab presents a clinically beneficial new treatment option for metastatic MCC, a rare but aggressive cancer associated with a poor prognosis.

Spontaneous regression of metastatic Merkel cell carcinoma.

LENUS (Irish Health Repository)

Hassan, S J

2010-01-01

Merkel cell carcinoma is a rare aggressive neuroendocrine carcinoma of the skin predominantly affecting elderly Caucasians. It has a high rate of local recurrence and regional lymph node metastases. It is associated with a poor prognosis. Complete spontaneous regression of Merkel cell carcinoma has been reported but is a poorly understood phenomenon. Here we present a case of complete spontaneous regression of metastatic Merkel cell carcinoma demonstrating a markedly different pattern of events from those previously published.

A high-resolution anatomical ontology of the developing murine genitourinary tract

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Little, Melissa H.; Brennan, Jane; Georgas, Kylie; Davies, Jamie A.; Davidson, Duncan R.; Baldock, Richard A.; Beverdam, Annemiek; Bertram, John F.; Capel, Blanche; Chiu, Han Sheng; Clements, Dave; Cullen-McEwen, Luise; Fleming, Jean; Gilbert, Thierry; Houghton, Derek; Kaufman, Matt H.; Kleymenova, Elena; Koopman, Peter A.; Lewis, Alfor G.; McMahon, Andrew P.; Mendelsohn, Cathy L.; Mitchell, Eleanor K.; Rumballe, Bree A.; Sweeney, Derina E.; Valerius, M. Todd; Yamada, Gen; Yang, Yiya; Yu., Jing

2007-01-01

Cataloguing gene expression during development of the genitourinary tract will increase our understanding not only of this process but also of congenital defects and disease affecting this organ system. We have developed a high-resolution ontology with which to describe the subcompartments of the developing murine genitourinary tract. This ontology incorporates what can be defined histologically and begins to encompass other structures and cell types already identified at the molecular level. The ontology is being used to annotate in situ hybridisation data generated as part of the Genitourinary Development Molecular Anatomy Project (GUDMAP), a publicly available data resource on gene and protein expression during genitourinary development. The GUDMAP ontology encompasses Theiler stage (TS) 17 to 27 of development as well as the sexually mature adult. It has been written as a partonomic, text-based, hierarchical ontology that, for the embryological stages, has been developed as a high-resolution expansion of the existing Edinburgh Mouse Atlas Project (EMAP) ontology. It also includes group terms for well-characterised structural and/or functional units comprising several sub-structures, such as the nephron and juxtaglomerular complex. Each term has been assigned a unique identification number. Synonyms have been used to improve the success of query searching and maintain wherever possible existing EMAP terms relating to this organ system. We describe here the principles and structure of the ontology and provide representative diagrammatic, histological, and whole mount and section RNA in situ hybridisation images to clarify the terms used within the ontology. Visual examples of how terms appear in different specimen types are also provided. PMID:17452023

Gamma-knife radiosurgery for metastatic brain tumors from primary lung cancer

International Nuclear Information System (INIS)

Uchiyama, Bine; Satoh, Ken; Saijo, Yasuo

1998-01-01

Forty patients with metastatic brain tumors from primary lung cancer underwent radiosurgery (γ-knife). We retrospectively compared their prior treatment history, number of metastatic foci, and performance status, to evaluate the effects of, and indications for, γ-knife therapy. After both the primary and the metastatic tumors were controlled, performance status could be used as an index in the choice of γ-knife therapy. Our results demonstrate that repeated γ-knife radiosurgeries prolonged survival time. Gamma-knife radiosurgery improves quality of life and prognosis of patients with metastatic brain tumors. (author)

Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process

International Nuclear Information System (INIS)

Chandran, Uma R; Ma, Changqing; Dhir, Rajiv; Bisceglia, Michelle; Lyons-Weiler, Maureen; Liang, Wenjing; Michalopoulos, George; Becich, Michael; Monzon, Federico A

2007-01-01

Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Understanding the differences in the biology of metastatic and organ confined primary tumors is essential for developing new prognostic markers and therapeutic targets. Using Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors. The metastatic samples are highly heterogenous in expression; however, differential expression analysis shows that 415 genes are upregulated and 364 genes are downregulated at least 2 fold in every patient with metastasis. The expression profile of metastatic samples reveals changes in expression of a unique set of genes representing both the androgen ablation related pathways and other metastasis related gene networks such as cell adhesion, bone remodelling and cell cycle. The differentially expressed genes include metabolic enzymes, transcription factors such as Forkhead Box M1 (FoxM1) and cell adhesion molecules such as Osteopontin (SPP1). We hypothesize that these genes have a role in the biology of metastatic disease and that they represent potential therapeutic targets for prostate cancer

Metabolic Plasticity of Metastatic Breast Cancer Cells: Adaptation to Changes in the Microenvironment

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Rui V. Simões

2015-08-01

Full Text Available Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of 13C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells, leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1 provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2 lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism.

Control of Metastatic Progression by microRNA Regulatory Networks

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Pencheva, Nora; Tavazoie, Sohail F.

2015-01-01

Aberrant microRNA (miRNA) expression is a defining feature of human malignancy. Specific miRNAs have been identified as promoters or suppressors of metastatic progression. These miRNAs control metastasis through divergent or convergent regulation of metastatic gene pathways. Some miRNA regulatory networks govern cell-autonomous cancer phenotypes, while others modulate the cell-extrinsic composition of the metastatic microenvironment. The use of small RNAs as probes into the molecular and cellular underpinnings of metastasis holds promise for the identification of candidate genes for potential therapeutic intervention. PMID:23728460

Epidermotropic metastatic melanoma with perilesional depigmentation in an Indian male

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Bhavana Doshi

2013-01-01

Full Text Available Melanoma is a rare form of cutaneous malignancy encountered in the dark skin population. Epidermotropic metastatic melanoma is a rare form of cutaneous metastatic melanoma which can mimic primary melanoma on histopathology. Hence its differentiation is of immense prognostic importance. The occurrence of rim of depigmentation around the primary cutaneous melanoma has previously been reported to portend a bad prognosis. The occurrence of vitiligo like lesions in patients with metastatic melanoma in comparison has a better prognosis. However the occurrence of depigmentation around the secondaries is rare and its importance is not well known. Hence we wish to report a case of epidermotropic metastatic melanoma with perilesional depigmentation in a 78 year old Indian male.

WITHDRAWN: Systemic treatments for metastatic cutaneous melanoma.

Science.gov (United States)

Crosby, Tom; Fish, Reg; Coles, Bernadette; Mason, Malcolm

2018-02-07

Systemic therapies for metastatic cutaneous melanoma, the most aggressive of all skin cancers, remain disappointing. Few lasting remissions are achieved and the therapeutic aim remains one of palliation.Many agents are used alone or in combination with varying degrees of toxicity and cost. It is unclear whether evidence exists to support these complex regimens over best supportive care / placebo. To review the benefits from the use of systemic therapies in metastatic cutaneous melanoma compared to best supportive care/placebo, and to establish whether a 'standard' therapy exists which is superior to other treatments. Randomised controlled trials were identified from the MEDLINE, EMBASE and CCTR/CENTRAL databases. References, conference proceedings, and Science Citation Index/Scisearch were also used to locate trials. Cancer registries and trialists were also contacted. Randomised controlled trials of adults with histologically proven metastatic cutaneous melanoma in which systemic anti-cancer therapy was compared with placebo or supportive care. Study selection was performed by two independent reviewers. Data extraction forms were used for studies which appeared to meet the selection criteria and, where appropriate, full text articles were retrieved and reviewed independently. No randomised controlled trials were found comparing a systemic therapy with placebo or best supportive care in metastatic cutaneous melanoma. There is no evidence from randomised controlled clinical trials to show superiority of systemic therapy over best supportive care / placebo in the treatment of malignant cutaneous melanoma.Given that patients with metastatic melanoma frequently receive systemic therapy, it is our pragmatic view that a future systematic review could compare any systemic treatment, or combination of treatments, to single agent dacarbazine.

Anatomy and Histology of the Human and Murine Prostate.

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Ittmann, Michael

2018-05-01

The human and murine prostate glands have similar functional roles in the generation of seminal fluid to assist in reproduction. There are significant differences in the anatomy and histology of murine and human prostate and knowledge of the normal anatomy and histology of the murine prostate is essential to interpreting changes in genetically engineered mouse models. In this review, the normal anatomy and histology of both human and mouse prostate will be described. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Differentiating metastatic from nonmetastatic lymph nodes in cervical cancer patients using monoexponential, biexponential, and stretched exponential diffusion-weighted MR imaging

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Wu, Qingxia; Wang, Meiyun; Shi, Dapeng [Radiological Department of Henan Provincial People' s Hospital, Zhengzhou, Henan (China); Zheng, Dandan [GE Healthcare, MR Research China, Beijing (China); Shi, Ligang [Pathological Department of Henan Provincial People' s Hospital, Zhengzhou, Henan (China); Liu, Mingbo [Radiotherapeutical Department of Henan Provincial People' s Hospital, Zhengzhou, Henan (China)

2017-12-15

To determine the diagnostic value of monoexponential, biexponential and stretched exponential models for identifying lymph nodes (LNs) in patients with cervical cancer. Fifty female patients with cervical cancer underwent preoperative magnetic resonance imaging. The diffusion parameters of the LNs were calculated by fitting the values to monoexponential, biexponential and stretched exponential models and were compared between the metastatic and non-metastatic LN groups. A total of 157 LNs with high signal intensity on multi-b-value DWI were detected, 41 of which were pathologically shown to be metastatic. Metastatic LNs presented with higher pure water diffusion (D) values, lower perfusion fraction (f) values, higher diffusion heterogeneity (α) values, higher short diameter (Size-S), long diameter (Size-L) and short long diameter ratio (S/L Ratio) than non-metastatic LNs (P<0.05). The Size-S of LNs exhibited the highest diagnostic value, with an area under the curve of 0.844. Compared with the size parameters, the diffusion parameters derived from multi-b-value diffusion-weighted imaging cannot reliably discriminate metastatic from non-metastatic LNs in daily clinical routine due to limited sensitivity and specificity. (orig.)

Decline in peripheral blood NKG2D+CD3+CD56+ NKT cells in metastatic colorectal cancer patients.

Science.gov (United States)

Gharagozloo, M; Rezaei, A; Kalantari, H; Bahador, A; Hassannejad, N; Maracy, M; Nouri, N; Sedghi, M; Ghazanfari, H; Bayat, B

2018-01-01

Colorectal cancer (CRC) is one of the main causes of cancer deaths in the world. This cancer can be divided into non-metastatic and metastatic CRC stages. CD3+CD56+ NKT cell subsets are a minor T cell subset in peripheral blood and conduct the killing of tumor cells in direct manner. Little is obvious about levels and surface markers of these cells such as NKG2D in different cancers, especially in CRC. We included 15 non-metastatic (low-grade), 11 non-metastatic (high-grade), 10 metastatic colorectal cancer patients and 18 healthy controls. The percentages of CD3+CD56+ NKT cells and NKG2D+CD56+ NKT cells from samples were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs) of samples. We found that there was a significantly lower number of NKG2D+CD3+CD56+ cells in peripheral blood of patients with metastatic colorectal cancer compared with normal controls (77.53 ± 5.79 % vs 90.74 ± 9.84 %; pNKT cells was significantly lower in patients with metastatic colorectal cancer compared to healthy controls strengthens the hypothesis that NKT cells can play a substantial role in the protection against human colorectal cancer, and this opens up avenues for novel studies about elucidating the other aspects of tumor surveillance in CRC progression and immunotherapy (Tab. 2, Fig. 2, Ref. 46).

Metastatic breast carcinoma in the mandible presenting as a periodontal abscess: a case report

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Tosios Konstantinos

2011-07-01

Full Text Available Abstract Introduction Tumors can metastasize to the oral cavity and affect the jaws, soft tissue and salivary glands. Oral cavity metastases are considered rare and represent approximately 1% of all oral malignancies. Because of their rarity and atypical clinical and radiographic appearance, metastatic lesions are considered a diagnostic challenge. The purpose of this report is to present a rare case of a metastatic breast carcinoma mimicking a periodontal abscess in the mandible. Case presentation A 55-year-old Caucasian woman was referred to our clinic for evaluation of bisphosphonate-induced jaw osteonecrosis. She had undergone modified radical mastectomy with axillary lymph node dissection for invasive ductal carcinoma of the left breast. Her clinical examination showed diffuse swelling and a periodontal pocket of 6 mm exhibiting suppuration in the posterior right mandible. Moreover, paresthesia of the lower right lip and chin was noted. There were no significant radiographic findings other than alveolar bone loss due to her periodontal disease. Although the lesion resembled a periodontal abscess, metastatic carcinoma of the breast was suspected on the basis of the patient's medical history. The area was biopsied, and histological analysis confirmed the final diagnosis of metastatic breast carcinoma. Conclusion The general dentist or dental specialist should maintain a high level of suspicion while evaluating patients with a history of cancer. Paresthesias of the lower lip and the chin should be considered ominous signs of metastatic disease. This case highlights the importance of the value of a detailed medical history and thorough clinical examination for the early detection of metastatic tumors in the oral cavity.

Transitional Cell Carcinoma of the Upper Ureter Metastatic to the Thoracic Spine Presenting as a Spinal Cord Compression

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J. O. Larkin

2008-01-01

Full Text Available We performed a left nephroureterectomy for a gentleman with transitional cell carcinoma of the upper ureter. Histological analysis revealed it to be a T1 lesion, but to be highly mitotically active. The gentleman defaulted on adjuvant therapy and defaulted on follow-up. He represented with symptoms of acute spinal cord compression and magnetic resonance imaging demonstrated a lesion at T6/7. Neurosurgical resection of the lesion showed it to be a metastatic deposit from the ureteric primary. Despite surgical debulking and subsequent radiotherapy to the lesion, the patient died secondary to metastatic complications. This case report is of interest to the surgeon as it demonstrates both the high metastatic potential of upper tract carcinomas and educates the surgeon on the presentation of acute spinal cord compression.

Integrative Genome Comparison of Primary and Metastatic Melanomas

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Feng, Bin; Nazarian, Rosalynn M.; Bosenberg, Marcus; Wu, Min; Scott, Kenneth L.; Kwong, Lawrence N.; Xiao, Yonghong; Cordon-Cardo, Carlos; Granter, Scott R.; Ramaswamy, Sridhar; Golub, Todd; Duncan, Lyn M.; Wagner, Stephan N.; Brennan, Cameron; Chin, Lynda

2010-01-01

A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes. PMID:20520718

Detecting Metastatic Bladder Cancer Using (18)F-Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography.

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Öztürk, Hakan

2015-10-01

The purpose of this study was to retrospectively investigate the contribution of (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography ((18)F-FDG-PET/CT) to detection of metastatic bladder cancer. The present study included 79 patients (69 men and 10 women) undergoing (18)F-FDG-PET/CT upon suspicion of metastatic bladder cancer between July 2007 and April 2013. The mean age was 66.1 years with a standard deviation of 10.7 years (range, 21 to 85 years). Patients were required to fast for 6 hours prior to scanning, and whole-body PET scanning from the skull base to the upper thighs was performed approximately 1 hour after intravenous injection of 555 MBq of (18)F-FDG. Whole body CT scanning was performed in the cranio-caudal direction. FDG-PET images were reconstructed using CT data for attenuation correction. Suspicious recurrent or metastatic lesions were confirmed by histopathology or clinical follow-up. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of (18)F-FDG-PET/CT were 89%, 78%, 90%, 75%, and 86%, respectively. (18)F-FDG-PET/CT can detect metastases with high sensitivity and positive predictive values in patients with metastatic bladder carcinoma.

Metastatic melanoma of mesentery

International Nuclear Information System (INIS)

Shamim, M. S.; Ali, S.A.; Shirazi, B.; Shamim, M.

2004-01-01

A case of malignant melanoma metastatic to small bowel mesentery in an old female is reported. Her primary malignant melanoma of nasal mucosa was already treated. She presented with intestinal obstruction, underwent surgical excision of the tumour and was tumour-free postoperatively. (author)

Dose-effect relationship of apoptosis induced by fission-neutron in murine thymocytes

International Nuclear Information System (INIS)

Yuan Bin; Li Liang; Xue Wencheng; Sun Jianmin; Wang Baoqin

2000-01-01

Objective: To investigate the effectiveness of high LET fission-neutron to induce apoptosis in murine thymocytes and to compare it with that of low LET 60 Co γ-ray. Methods: Apoptosis induction was studied qualitatively by light and transmission electron microscopy and DNA gel electrophoresis,also quantitatively by flow cytometry(FCM) and diphenylamine (DPA)methods. Results: DNA ladders of murine thymocytes were detectable, the typical apoptosis of thymocytes could be observed morphologically by means of light and electron microscopy at 6 h after fission-neutron irradiation with doses ranging from 0.5 to 5.0 Gy, meanwhile the percentages of apoptosis increased with increasing doses. After exposure to γ-rays with doses ranging from 1.0 to 30 Gy, the experimental results were similar to those from neutron radiation. The incidence of apoptosis peaked at about 20 Gy, the percentages did not increase further when doses increased. Conclusion: Apoptosis of murine thymocytes can be induced when mice are exposed to either fission-neutron (0.5-5.0 Gy) or to γ-ray (1-30 Gy). Although the relationship between apoptosis and radiation doses is similar, the percentage of apoptosis induced by neutron irradiation is higher than that induced by γ-irradiation. The RBE values of fission-neutron for inducing apoptosis murine thymocytes are 2.09 (by FCM method) and 2.37 (by DPA method), respectively. These results also suggest that fission-neutron-induced murine immune tissue is more severe than that induced by γ-rays at several hours post-irradiation and this might be the basis for heavy damage to immune tissues induced by fission-neutron-irradiation in later period

Characterization of an immunodominant cancer-specific O-glycopeptide epitope in murine podoplanin (OTS8)

DEFF Research Database (Denmark)

Steentoft, Catharina; Schjoldager, Katrine T; Cló, Emiliano

2010-01-01

antibody 237, developed to a spontaneous murine fibrosarcoma, was shown to be directed to murine podoplanin (OTS8) with truncated Tn O-glycans. Our understanding of such cancer-specific auto-antibodies to truncated glycoforms of glycoproteins is limited. Here we have investigated immunogenicity...... of a chemoenzymatically produced Tn-glycopeptide derived from the putative murine podoplanin O-glycopeptide epitope. We found that the Tn O-glycopeptide was highly immunogenic in mice and produced a Tn-glycoform specific response with no reactivity against unglycosylated peptides or the O-glycopeptide with extended O......-glycan (STn and T glycoforms). The immunodominant epitope was strictly dependent on the peptide sequence, required Tn at a specific single Thr residue (Thr(77)), and antibodies to the epitope were not found in naive mice. We further tested a Tn O-glycopeptide library derived from human podoplanin...

Monitoring treatment response and metastatic relapse in advanced bladder cancer by liquid biopsy analysis

DEFF Research Database (Denmark)

Birkenkamp-Demtröder, Karin; Christensen, Emil; Nordentoft, Iver Kristiansen

2017-01-01

of circulating tumour DNA (ctDNA) in plasma and urine to detect metastatic relapse after cystectomy and measure treatment efficacy. We exome sequenced tumour and germline DNA from patients with muscle-invasive bladder cancer and monitored ctDNA in 370 liquid biopsies throughout the disease courses by 84......DNA detection in plasma and diagnosis of relapse was 101 d after cystectomy (range 0-932 d). Early detection of metastatic relapse and treatment response using liquid biopsies represents a novel, highly sensitive tool for monitoring patients, supporting clinicians, and guiding treatment decisions. PATIENT...

Preclinical Efficacy of [V4Q5]dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer.

Science.gov (United States)

Garona, Juan; Sobol, Natasha T; Pifano, Marina; Segatori, Valeria I; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

2018-06-01

Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4Q5]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of AVPR2 present in endothelial and tumor cells, [V4Q5]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V4Q5]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V4Q5]dDAVP, both in vitro and in vivo. In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained i.v. treatment with [V4Q5]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V4Q5]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC50 1.08 µM) and addition to 5-FU resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. The present preclinical study establishes for the first time the efficacy of [V4Q5]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.

Predicting survival of de novo metastatic breast cancer in Asian women: systematic review and validation study.

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Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G M; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M

2014-01-01

In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48-0.53) to 0.63 (95% CI, 0.60-0.66). The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making.

Predicting survival of de novo metastatic breast cancer in Asian women: systematic review and validation study.

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Hui Miao

Full Text Available BACKGROUND: In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. MATERIALS AND METHODS: We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic. RESULTS: We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48-0.53 to 0.63 (95% CI, 0.60-0.66. CONCLUSION: The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making.

A mouse model of pulmonary metastasis from spontaneous osteosarcoma monitored in vivo by Luciferase imaging.

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Silvia Miretti

Full Text Available BACKGROUND: Osteosarcoma (OSA is lethal when metastatic after chemotherapy and/or surgical treatment. Thus animal models are necessary to study the OSA metastatic spread and to validate novel therapies able to control the systemic disease. We report the development of a syngeneic (Balb/c murine OSA model, using a cell line derived from a spontaneous murine tumor. METHODOLOGY: The tumorigenic and metastatic ability of OSA cell lines were assayed after orthotopic injection in mice distal femur. Expression profiling was carried out to characterize the parental and metastatic cell lines. Cells from metastases were propagated and engineered to express Luciferase, in order to follow metastases in vivo. PRINCIPAL FINDINGS: Luciferase bioluminescence allowed to monitor the primary tumor growth and revealed the appearance of spontaneous pulmonary metastases. In vivo assays showed that metastasis is a stable property of metastatic OSA cell lines after both propagation in culture and luciferase trasduction. When compared to parental cell line, both unmodified and genetically marked metastatic cells, showed comparable and stable differential expression of the enpp4, pfn2 and prkcd genes, already associated to the metastatic phenotype in human cancer. CONCLUSIONS: This OSA animal model faithfully recapitulates some of the most important features of the human malignancy, such as lung metastatization. Moreover, the non-invasive imaging allows monitoring the tumor progression in living mice. A great asset of this model is the metastatic phenotype, which is a stable property, not modifiable after genetic manipulation.

Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer.

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Cha, Yongjun; Kim, Kyung-Ju; Han, Sae-Won; Rhee, Ye Young; Bae, Jeong Mo; Wen, Xianyu; Cho, Nam-Yun; Lee, Dae-Won; Lee, Kyung-Hun; Kim, Tae-Yong; Oh, Do-Youn; Im, Seock-Ah; Bang, Yung-Jue; Jeong, Seung-Yong; Park, Kyu Joo; Kang, Gyeong Hoon; Kim, Tae-You

2016-07-12

The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1-4), and negative (0). A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22-80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (PCIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (PCIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (PCIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy.

Associations between primary tumor RAS, BRAF and PIK3CA mutation status and metastatic site in patients with chemo-resistant metastatic colorectal cancer

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Christensen, Troels Dreier; Palshof, Jesper Andreas; Larsen, Finn Ole

2018-01-01

investigated the association between RAS (KRAS or NRAS), BRAF, PIK3CA mutations and metastatic pattern in patients with metastatic (m) CRC. MATERIAL AND METHODS: This study reviewed Danish biobank and database of patients with mCRC who received cetuximab and irinotecan, independent of RAS mutation status...

Hand-foot syndrome in a patient with metastatic lung adenocarcinoma induced by high-dose icotinib: A case report and review of the literature.

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Zheng, Yulong; Fang, Weijia; Xu, Nong

2012-12-01

Icotinib is a new oral epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). The most frequent side-effects of icotinib include rash and diarrhea. Hand-foot syndrome (HFS) induced by EGFR-TKI is rare. The present study describes, for the first time, HFS induced by high-dose icotinib in a 65-year old female with metastatic lung adenocarcinoma. The patient developed HFS during the first week of icotinib treatment with characteristic clinical presentation. HFS regressed after icotinib dose-reduction was initiated. HFS may occur with icotinib, especially when administered in high doses.

Half-body irradiation in the treatment of metastatic prostatic carcinoma

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Rowland, C.G.; Bullimore, J.A.; Smith, P.J.B.; Roberts, J.B.M.

1981-01-01

High dose radiation therapy given as a single fraction to the upper and lower halves of the body gives effective palliation for metastatic solid tumours. This treatment modality appears to be particularly effective in tumours which may have a slow doubling time such as carcinoma of the prostate. Fifty-two patients with metastatic carcinoma of the prostate involving the skeletal system have received half-body irradiation (8 MeV X-rays at a dose rate of about 100 cGy/min). All had prior treatment with additive hormones or orchiectomy and the majority had received localised irradiation and/or chemotherapy. Significant immediate pain relief was achieved in 42 out of 52 patients (80%). This pain relief was maintained until death in 29 out of 43 patients (67%). Pain relief in responders appears to occur within 24 to 48 h of treatment. (author)

SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer

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Perk, T; Bradshaw, T; Harmon, S; Perlman, S; Liu, G; Jeraj, R [University of Wisconsin, Madison, WI (United States)

2015-06-15

Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40high (N>100) numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.

Correction of murine mucopolysaccharidosis VII by a human. beta. -glucuronidase transgene

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Kyle, J.W.; Vogler, C.; Hoffmann, J.W.; Sly, W.S. (St. Louis Univ. School of Medicine, MO (USA)); Birkenmeier, E.H.; Gwynn, B. (Jackson Laboratory, Bar Harbor, ME (USA))

1990-05-01

The authors recently described a murine model for mucopolysaccharidosis VII in mice that have an inherited deficiency of {beta}-glucuronidase. Affected mice, of genotype gus{sup mps}/gus{sup mps}, present clinical manifestations similar to those of humans with mucopolysaccharidosis VII (Sly syndrome) and are shown here to have secondary elevations of other lysosomal enzymes. The mucopolysaccharidosis VII phenotype in both species includes dwarfism, skeletal deformities, and premature death. Lysosome storage is visualized within enlarged vesicles and correlates biochemically with accumulation of undegraded and partially degraded glycosaminoglycans. In this report they describe the consequences of introducing the human {beta}-glucuronidase gene, GUSB, into gus{sup mps}/gus{sup mps} mice that produce virtually no murine {beta}-glucuronidase. Transgenic mice homozygous for the mucopolysaccharidosis VII mutation expressed high levels of human {beta}-glucuronidase activity in all tissues examined and were phenotypically normal. Biochemically, both the intralysosomal storage of glycosaminoglycans and the secondary elevation of other acid hydrolases were corrected. These findings demonstrate that the GUSB transgene is expressed in gus{sup mps}/gus{sup mps} mice and that human {beta}-glucuronidase corrects the murine mucopolysaccharidosis storage disease.

Metastatic neuroblastoma presenting as refusal to use the left upper extremity in a six-year-old girl

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Casey Grover

2014-12-01

Full Text Available Neuroblastoma is the most common extracranial neoplasm in children, commonly presenting at an advanced stage. Despite the high prevalence of metastatic disease with neuroblastoma, metastases to the central nervous system are rare and predominantly involve the spinal cord. We present a case of neuroblastoma with metastases to the brain presenting as refusal to move the left arm. The lesion initially appeared to be both a subdural and epidural hematoma on computed tomography of the head, but upon magnetic resonance imaging, was found to represent metastatic neuroblastoma. In pediatric patients with systemic symptoms and neurologic deficits, metastatic disease, such as neuroblastoma, should be included in the differential diagnosis and appropriate imaging should be obtained.

Utility and limitation of radiosurgery for metastatic brain tumors

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Kagawa, Kota; Kiya, Katsuzo; Satoh, Hideki; Mizoue, Tatsuya; Matsushige, Toshinori; Araki, Hayato; Akimitsu, Tomohide

2003-01-01

The purpose of this study was to evaluate the utility and limitations of radiosurgery for metastatic brain lesions, and to compare the clinical results of stereotactic radiosurgery (SRS) with those of whole-brain radiation therapy (WBRT) in 45 patients with metastatic brain tumors. The patients were divided into two groups: the SRS group (22 patients) and the WBRT group (23 patients). Mean survival was not significantly different between the two groups. However, in patients with 6 or more lesions, both survival time and recurrence-free time in the SRS group were inferior to those in the WBRT group. The main complication in the SRS group was perifocal edema, while dementia was seen in the WBRT group. The bedridden period was longer in the WBRT group than in the SRS group. Death caused by brain lesions was rare in both groups. From these results, SRS preserves high quality of life longer than WBRT, but SRS should be cautiously used in patients with 6 or more lesions. (author)

Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion

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Cai, Kun; Mulatz, Kirk; Ard, Ryan; Nguyen, Thanh; Gee, Stephen H

2014-01-01

Unraveling the signaling pathways responsible for the establishment of a metastatic phenotype in carcinoma cells is critically important for understanding the pathology of cancer. The acquisition of cell motility is a key property of metastatic tumor cells and is a prerequisite for invasion. Rho GTPases regulate actin cytoskeleton reorganization and the cellular responses required for cell motility and invasion. Diacylglycerol kinase ζ (DGKζ), an enzyme that phosphorylates diacylglycerol to yield phosphatidic acid, regulates the activity of the Rho GTPases Rac1 and RhoA. DGKζ mRNA is highly expressed in several different colon cancer cell lines, as well as in colon cancer tissue relative to normal colonic epithelium, and thus may contribute to the metastatic process. To investigate potential roles of DGKζ in cancer metastasis, a cellular, isogenic model of human colorectal cancer metastatic transition was used. DGKζ protein levels, Rac1 and RhoA activity, and PAK phosphorylation were measured in the non-metastatic SW480 adenocarcinoma cell line and its highly metastatic variant, the SW620 line. The effect of DGKζ silencing on Rho GTPase activity and invasion through Matrigel-coated Transwell inserts was studied in SW620 cells. Invasiveness was also measured in PC-3 prostate cancer and MDA-MB-231 breast cancer cells depleted of DGKζ. DGKζ protein levels were elevated approximately 3-fold in SW620 cells compared to SW480 cells. There was a concomitant increase in active Rac1 in SW620 cells, as well as substantial increases in the expression and phosphorylation of the Rac1 effector PAK1. Similarly, RhoA activity and expression were increased in SW620 cells. Knockdown of DGKζ expression in SW620 cells by shRNA-mediated silencing significantly reduced Rac1 and RhoA activity and attenuated the invasiveness of SW620 cells in vitro. DGKζ silencing in highly metastatic MDA-MB-231 breast cancer cells and PC-3 prostate cancer cells also significantly attenuated

Stereotactic irradiation for metastatic brain tumor

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Nomura, Ryutaro

2017-01-01

First, this paper reviewed the latest findings of stereotactic irradiation (STI) for metastatic brain tumors. Then, it described the results of randomized controlled trials for single or a few (2-4) metastasis in the following comparison tests: (1) comparison between whole brain radiotherapy (WBRT) alone group and (WBRT + STI) group, (2) comparison between STI alone group and (STI + WBRT) group, (3) comparison between STI alone group and (tumorectomy + WBRT) group, (4) comparison between (STI + WBRT) group and (tumorectomy + WBRT) group, and (5) between (tumorectomy + WBRT) group and (tumorectomy + STI) group. Among these, STI alone without WBRT has obtained a certain consensus. Against multiple metastatic brain tumors of 5 or more, when considering cognitive impairment and QOL loss by adding WBRT, it is general consensus that STI alone may be sufficient. At the authors' institution, cyber knife (CK) was introduced in 2008 and nearly 300 stereotactic radiotherapy for metastatic brain tumors have been performed annually. By adopting a robot arm and development of a lesion tracking system, the positional correction against the deviation of the bone margin of the skull is guaranteed in real time to ensure accuracy during irradiation, and hypofractionated stereotactic irradiation becomes easier. (A.O.)

Targeted destruction of murine macrophage cells with bioconjugated gold nanorods

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Pissuwan, Dakrong; Valenzuela, Stella M.; Killingsworth, Murray C.; Xu, Xiaoda; Cortie, Michael B.

2007-12-01

Gold nanorods manifest a readily tunable longitudinal plasmon resonance with light and consequently have potential for use in photothermal therapeutics. Recent work by others has shown how gold nanoshells and rods can be used to target cancer cells, which can then be destroyed using relatively high power laser radiation (˜1×105 to 1×1010 W/m2). Here we extend this concept to demonstrate how gold nanorods can be modified to bind to target macrophage cells, and show that high intensity laser radiation is not necessary, with even 5×102 W/m2 being sufficient, provided that a total fluence of ˜30 J/cm2 is delivered. We used the murine cell line RAW 264.7 and the monoclonal antibody CD11b, raised against murine macrophages, as our model system and a 5 mW solid state diode laser as our energy source. Exposure of the cells labeled with gold nanorods to a laser fluence of 30 J/cm2 resulted in 81% cell death compared to only 0.9% in the control, non-labeled cells.

Colon carcinoma metastatic to the thyroid gland

International Nuclear Information System (INIS)

Lester, J.W. Jr.; Carter, M.P.; Berens, S.V.; Long, R.F.; Caplan, G.E.

1986-01-01

Metastatic carcinoma to the thyroid gland rarely is encountered in clinical practice; however, autopsy series have shown that it is not a rare occurrence. A case of adenocarcinoma of the colon with metastases to the thyroid is reported. A review of the literature reveals that melanoma, breast, renal, and lung carcinomas are the most frequent tumors to metastasize to the thyroid. Metastatic disease must be considered in the differential diagnosis of cold nodules on radionuclide thyroid scans, particularly in patients with a known primary

Metastatic melanoma masquerading as a furuncle

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Imran Aslam

2017-10-01

Full Text Available Melanoma metastasizes to the skin in about 10-17% of patients. Although there are reports of metastatic melanoma masquerading as panniculitis and erysipelas, it is very uncommon for it to present as an inflammatory skin lesion. When malignant melanoma cells invade the superficial dermal lymphatic vessels it can result in erythema, edema and induration of the overlying skin. This presentation can be problematic for clinicians if they do not suspect melanoma and choose not to biopsy the lesion. We report a case of an elderly man with a history of invasive melanoma who presented with a furuncle-like lesion that was found to be in-transit metastatic melanoma.

Radiation therapy of a metastatic tumour of the orbit caused by prostatic carcinoma

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Daniel, F.; Langmann, G.; Faulborn, J.; Poschauko, J.

1994-01-01

We report a case of metastatic carcinoma to the apex of the orbit in a 66-year old patient. Orbital metastasis occurred while the patient suffered from another metastatic activity especially in his bony structures. The orbital tumour caused rapid visual impairment because of compression of the optic nerve. The metastasis was treated by radiation therapy. With CT-scan, electrophysiological examination, visual field examination, and visual function we demonstrate the regression of the tumour. One year after therapy the tumor was no longer detectable. Visual function had recovered and visual fields were normally. Radiation therapy prolonged high quality life for our patient due to preservation of visual function. (authors)

Local bone pain and osseous scintigraphic findings in patients with metastatic bone tumor

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Imaeda, Takeyoshi; Iinuma, Gen; Hirota, Keiichi; Inoue, Akemi; Sone, Yasuhiro; Seki, Matsuzo; Suzuki, Masao; Doi, Hidetaka

1988-01-01

Local bone pain and osseous scintigraphic findings were evaluated in patients with cancer of the lung, breast or prostate. (1) In 77-92% out of the patients with local pain, metastatic bone lesions were detected. (2) The sacrum and scapulae were the frequent sites of pain as estimated from the metastatic bone lesions. On the other hand, the incidence of pain was low in the ribs, cervical vertebrae, skull and femurs. (3) When calculated by the weight of red bone marrow, the most likely sites for bone metastases consisted of the scapulae, clavicles, sternum, humeri, ribs and cervical vertebrae, somewhat different from previous reports. Those bones involved were all proximate to the heart. (4) Extensive bone metastases were already detected in more than 50% of patients who complain of pain in the metastatic bone lesion. On the other hand, extensive bone metastases occurred in less than 6% of patients who didn't complain of pain. (5) The appearance of pain in the metastatic bone lesion was earlier in only 3% and was later in 71% than the detection of abnormal radioisotope accumulation on scintigram. (6) Majority of the patients with pain in the metastatic bone lesion showed a high degree of abnormal radioisotope accumulation which measured more than 5 cm in diameter on scintigram. On the other hand, the abnormal radioisotope accumulation in most of patients without pain was mild and mostly measured less than 5 cm in diameter. (7) The positive rate of bone metastasis amounted to 29% by plain X-ray and 41% by local bone pain as compaired to positive bone scintigram. (author)

Local bone pain and osseous scintigraphic findings in patients with metastatic bone tumor

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Imaeda, Takeyoshi; Iinuma, Gen; Hirota, Keiichi; Inoue, Akemi; Sone, Yasuhiro; Seki, Matsuzo; Suzuki, Masao; Doi, Hidetaka

1988-12-01

Local bone pain and osseous scintigraphic findings were evaluated in patients with cancer of the lung, breast or prostate. (1) In 77-92% out of the patients with local pain, metastatic bone lesions were detected. (2) The sacrum and scapulae were the frequent sites of pain as estimated from the metastatic bone lesions. On the other hand, the incidence of pain was low in the ribs, cervical vertebrae, skull and femurs. (3) When calculated by the weight of red bone marrow, the most likely sites for bone metastases consisted of the scapulae, clavicles, sternum, humeri, ribs and cervical vertebrae, somewhat different from previous reports. Those bones involved were all proximate to the heart. (4) Extensive bone metastases were already detected in more than 50% of patients who complain of pain in the metastatic bone lesion. On the other hand, extensive bone metastases occurred in less than 6% of patients who didn't complain of pain. (5) The appearance of pain in the metastatic bone lesion was earlier in only 3% and was later in 71% than the detection of abnormal radioisotope accumulation on scintigram. (6) Majority of the patients with pain in the metastatic bone lesion showed a high degree of abnormal radioisotope accumulation which measured more than 5 cm in diameter on scintigram. On the other hand, the abnormal radioisotope accumulation in most of patients without pain was mild and mostly measured less than 5 cm in diameter. (7) The positive rate of bone metastasis amounted to 29% by plain X-ray and 41% by local bone pain as compaired to positive bone scintigram.

Absence of hypoxanthine:guanine phosphoribosyltransferase activity in murine Dunn osteosarcoma

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Abelson, H.T.; Gorka, C.

1983-01-01

The transplantable murine Dunn osteosarcoma has no detectable hypoxanthine:guanine phosphoribosyltransferase (EC 2.4.2.8) activity. This was established from the tumors directly and from tissue culture cell lines derived from the tumor using a variety of assays: e.g., no [3H]hypoxanthine uptake into tumor or tissue culture cells, no conversion of [3H]hypoxanthine to [3H]IMP by cell extracts from tumors or tissue culture cells, no growth of tissue culture cells in hypoxanthine:aminopterin:thymidine medium, and normal growth of these cells in 10 microM 6-mercaptopurine. Ten human osteosarcomas have been assayed, and two have no apparent hypoxanthine:guanine phosphoribosyltransferase enzyme activity. After high-dose methotrexate treatment in vivo, murine tumors could be selectively killed and normal tissues could be spared by using a rescue regimen of hypoxanthine-thymidine-allopurinol

Fatal Gastrointestinal Hemorrhage in a Young Boy with Newly Diagnosed Metastatic Medulloblastoma on High Dose Dexamethasone

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Victor Wong

2014-01-01

Full Text Available A 10-year-old boy with newly diagnosed metastatic medulloblastoma was placed on high dose dexamethasone and ranitidine prior to surgery. The child underwent subtotal resection and was discharged 5 days postoperatively with an uneventful hospital course on a tapering dose of dexamethasone and ranitidine. Over the next 2 days the patient complained of mild abdominal distension with flatulence, without pain, vomiting, or dysmotility. On follow-up in clinic 5 days after discharge, he had normal vital signs when he suddenly became pale and had loss of consciousness. Emergent computerized tomography of the head showed no acute hemorrhage and complete blood count revealed hemoglobin of 4.2 gm/dL. In spite of maximum resuscitation with copious blood products the patient died. Autopsy revealed evidence of duodenal perforation with intraluminal hemorrhage. This case demonstrates a rare fatal complication of high dose dexamethasone therapy even with concurrent gastrointestinal prophylactic therapy. We provide a review of the limited literature on steroid use in pediatric neurooncology with regard to gastrointestinal bleeding.

Metastatic Renal Cell Carcinoma to Jejunum: An Unusual Case Presentation

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Igor Medic

2017-07-01

Full Text Available The small intestine is a very uncommon and peculiar site for metastasis from renal cell carcinoma (RCC. We present a clinical presentation of insidious and unusual development of a jejunal metastasis while having stable disease in a remainder of metastatic sites, in a patient undergoing immunotherapy with nivolumab. Due to the extreme rarity of metastatic renal cell carcinoma to the lumen of the small bowel, it is easy to overlook and misdiagnose symptoms of this pathologic entity, particularly when the remainder of metastatic disease responds well to ongoing therapy.

Tumor progression: analysis of the instability of the metastatic phenotype, sensitivity to radiation and chemotherapy

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Welch, D.R.

1984-01-01

The major complications for tumor therapy are 1) tumor spread (metastasis); 2) the mixed nature of tumors (heterogeneity); and 3) the capacity of tumors to evolve (progress). To study these tumor characteristics, the rat 13762NF mammary adenocarcinoma was cloned and studied for metastatic properties and sensitivities to therapy (chemotherapy, radiation and hyperthermia). The cell clones were heterogeneous and no correlation between metastatic potential and therapeutic sensitivities was observed. Further, these phenotypes were unstable during pasage in vitro; yet, the changes were clone dependent and reproducible using different cryoprotected cell stocks. To understand the phenotypic instability, subclones were isolated from low and high passage cell clones. The results demonstrated that 1) tumor cells are heterogeneous for multiple phenotypes; 2) tumor cells are unstable for multiple phenotypes; 3) the magnitude, direction and time of occurrence of phenotypic drift is clone dependent; 4) the sensitivity of cell clones to ionizing radiation (γ or heat) and chemotherapy agents is independent of their metastatic potential; 5) shifts in metastatic potential and sensitivity to therapy may occur simultaneously but are not linked; and 6) tumor cells independently diverge to form several subpopulations with unique phenotypic profiles

MET Activation and Physical Dynamics of the Metastatic Process: The Paradigm of Cancers of Unknown Primary Origin

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Giulia M. Stella

2017-10-01

Full Text Available The molecular and cellular mechanisms which drive metastatic spread are the topic of constant debate and scientific research due to the potential implications for cancer patients' prognosis. In addition to genetics and environmental factors, mechanics of single cells and physical interaction with the surrounding environment play relevant role in defining invasive phenotype. Reconstructing the physical properties of metastatic clones may help to clarify still open issues in disease progression as well as to lead to new diagnostic and therapeutic approaches. In this perspective cancer of unknown primary origin (CUP identify the ideal model to study physical interactions and forces involved in the metastatic process. We have previously demonstrated that MET oncogene is mutated with unexpected high frequency in CUPs. We here analyze and discuss how the MET activation by somatic mutation may affect physical properties in giving rise to such a highly malignant syndrome, as that defined by CUP.

Paclitaxel and doxorubicin in metastatic breast cancer

DEFF Research Database (Denmark)

Gehl, J; Boesgaard, M; Paaske, T

1996-01-01

For the past decades the anthracyclines have been regarded as among the most active drugs for the treatment of metastatic breast cancer. However, the 5-year survival rate in patients with stage IV breast cancer continues to be below 20%, and new active drugs and drug combinations clearly must...... be explored. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been demonstrated to be highly effective in treating patients with advanced breast cancer, including those with anthracycline-resistant breast cancer, a fact that has led to efforts to combine paclitaxel and anthracyclines...

Effects of the murine skull in optoacoustic brain microscopy.

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Kneipp, Moritz; Turner, Jake; Estrada, Héctor; Rebling, Johannes; Shoham, Shy; Razansky, Daniel

2016-01-01

Despite the great promise behind the recent introduction of optoacoustic technology into the arsenal of small-animal neuroimaging methods, a variety of acoustic and light-related effects introduced by adult murine skull severely compromise the performance of optoacoustics in transcranial imaging. As a result, high-resolution noninvasive optoacoustic microscopy studies are still limited to a thin layer of pial microvasculature, which can be effectively resolved by tight focusing of the excitation light. We examined a range of distortions introduced by an adult murine skull in transcranial optoacoustic imaging under both acoustically- and optically-determined resolution scenarios. It is shown that strong low-pass filtering characteristics of the skull may significantly deteriorate the achievable spatial resolution in deep brain imaging where no light focusing is possible. While only brain vasculature with a diameter larger than 60 µm was effectively resolved via transcranial measurements with acoustic resolution, significant improvements are seen through cranial windows and thinned skull experiments. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Clinicopathologic factors associated with de novo metastatic breast cancer.

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

2016-12-01

While breast cancers with distant metastasis at presentation (de novo metastasis) harbor significantly inferior clinical outcomes, there have been limited studies analyzing the clinicopathologic characteristics in this subset of patients. In this study, we analyzed 6126 breast cancers diagnosed between 1998 and 2013 to identify factors associated with de novo metastatic breast cancer. When compared to patients without metastasis at presentation, race, histologic grade, estrogen/progesterone receptor (ER/PR) and HER2 statuses were significantly associated with de novo metastasis in the entire cohort, whereas age, histologic grade, PR and HER2 status were the significant parameters in the subset of patients with locally advanced breast cancer (Stage IIB/III). The patients with de novo metastatic breast cancer had a significant older mean age and a lower proportion of HER2-positive tumors when compared to those with metastatic recurrence. Further, the HER2-rich subtype demonstrated a drastically higher incidence of de novo metastasis when compared to the luminal and triple-negative breast cancers in the entire cohort [odds ratio (OR)=5.68 and 2.27, respectively] and in the patients with locally advanced disease (OR=4.02 and 2.12, respectively), whereas no significant difference was seen between de novo metastatic cancers and those with metastatic recurrence. Moreover, the luminal and HER2-rich subtypes showed bone-seeking (OR=1.92) and liver-homing (OR=2.99) characteristics, respectively, for the sites of de novo metastasis, while the latter was not observed in those with metastatic recurrence. Our data suggest that an algorithm incorporating clinicopathologic factors, especially histologic grade and receptor profile, remains of significant benefit during decision making in newly diagnosed breast cancer in the pursuit of precision medicine. Copyright © 2016 Elsevier GmbH. All rights reserved.

Esophageal Large-Cell Neuroendocrine Carcinoma with Inconsistent Response to Treatment in the Primary and Metastatic Lesions

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Takashi Tomiyama

2018-05-01

Full Text Available Esophageal large-cell neuroendocrine carcinoma (NEC is a rare malignant tumor that is characterized by high-grade malignancy and a poor prognosis. However, the rarity of esophageal NEC has prevented the development of an established treatment, and no reports have described a discrepancy in the effectiveness of cisplatin plus irinotecan between primary and metastatic lesions. A 43-year-old Japanese man was referred to our hospital with refractory epigastralgia. A previous gastrointestinal endoscopy had revealed a 50-mm type 2 tumor in the abdominal esophagus. The pathological findings indicated poorly differentiated squamous cell carcinoma. Contrast-enhanced computed tomography revealed a metastatic liver tumor. One cycle of fluorouracil and cisplatin was not effective, and endoscopy was repeatedly performed. The pathological findings indicated a large-cell malignant tumor with tumor cells that were positive for CD56, synaptophysin, and Ki-67 (> 80%. Based on a diagnosis of esophageal large-cell NEC with a metastatic liver tumor, the patient received cisplatin plus irinotecan biweekly. After 4 months, computed tomography revealed marked shrinkage of the metastatic tumor, but the patient complained of dysphagia. Endoscopy revealed enlargement of the primary tumor, which was then treated using radiotherapy plus fluorouracil and cisplatin. The primary tumor subsequently shrank, and the patient’s symptoms were relieved, but the metastatic tumor grew. Thus, chemoradiotherapy could be an option for managing a primary esophageal large-cell NEC that does not respond to chemotherapy alone. However, the possibility of an inconsistent response to therapy in primary and metastatic lesions should be considered.

Murine Models of Gastric Corpus PreneoplasiaSummary

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Christine P. Petersen

2017-01-01

Full Text Available Intestinal-type gastric adenocarcinoma evolves in a field of pre-existing metaplasia. Over the past 20 years, a number of murine models have been developed to address aspects of the physiology and pathophysiology of metaplasia induction. Although none of these models has achieved true recapitulation of the induction of adenocarcinoma, they have led to important insights into the factors that influence the induction and progression of metaplasia. Here, we review the pathologic definitions relevant to alterations in gastric corpus lineages and classification of metaplasia by specific lineage markers. In addition, we review present murine models of the induction and progression of spasmolytic polypeptide (TFF2–expressing metaplasia, the predominant metaplastic lineage observed in murine models. These models provide a basis for the development of a broader understanding of the physiological and pathophysiological roles of metaplasia in the stomach. Keywords: SPEM, Intestinal Metaplasia, Gastric Cancer, TFF2, Chief Cell, Hyperplasia

Molecular alterations as target for therapy in metastatic osteosarcoma: a review of literature

NARCIS (Netherlands)

Posthuma de Boer, J.; Witlox, M.A.; Kaspers, G.J.L.; van Royen, B.J.

2011-01-01

Treating metastatic osteosarcoma (OS) remains a challenge in oncology. Current treatment strategies target the primary tumour rather than metastases and have a limited efficacy in the treatment of metastatic disease. Metastatic cells have specific features that render them less sensitive to therapy

Reinfusion of autologous lymphocytes with granulocyte-macrophage colony-stimulating factor induces rapid recovery of CD4+ and CD8+ T cells after high-dose chemotherapy for metastatic breast cancer

NARCIS (Netherlands)

de Gast, G. C.; Vyth-Dreese, F. A.; Nooijen, W.; van den Bogaard, C. J. C.; Sein, J.; Holtkamp, M. M. J.; Linthorst, G. A. M.; Baars, J. W.; Schornagel, J. H.; Rodenhuis, S.

2002-01-01

PURPOSE: Repeated high-dose chemotherapy (HDCT) followed by peripheral-blood progenitor cell (PBPC) transplantation can induce a complete remission in patients with metastatic breast cancer sensitive to standard chemotherapy (CT), but the majority of patients relapse within 1 to 2 years. The immune

Murine Typhus: An Important Consideration for the Nonspecific Febrile Illness

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Gurjot Basra

2012-01-01

Full Text Available Murine typhus is a widely distributed flea-borne infection caused by Rickettsia typhi. Symptoms of murine typhus are nonspecific and mimic a variety of other infectious diseases. We herein report a case of murine typhus in an area where the broad use of DDT in the mid-20th century has now made it a rare disease. The patient described presented with headache, fever, and a faint macular rash. Initial laboratory studies revealed a slight transaminase elevation. Further questioning revealed exposure to opossums, prompting the consideration of murine typhus as a diagnosis. Although typhus group antibodies were not present during the patient’s acute illness, empiric therapy with doxycycline was initiated, and the patient defervesced. One month after convalescence, the patient returned to clinic with serum that contained typhus group antibodies with an IgG titer of 1 : 1024. Murine typhus is an important consideration during the workup of a patient with a nonspecific febrile illness. Exposure to reservoir hosts and the flea vector place humans at risk for this disease. Clinician recognition of this entity is required for diagnosis and effective therapy.

Tumor ocular metastásico Metastatic ocular tumor

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Martha G Domínguez Expósito

2004-06-01

Full Text Available El carcinoma metastásico del ojo es considerado la neoplasia maligna que más frecuente se encuentra de forma intraocular. Solo cerca del 10 % de las personas que tienen una o más lesiones metastásicas intraoculares son detectadas clínicamente antes de la muerte. A menudo, el carcinoma metastásico ocular es diagnosticado por el oftalmólogo ante la presencia de síntomas oculares. Las lesiones están localizadas con preferencia en coroides. Nos motivo a realizar la presentación de este caso la presencia de lesiones intraoculares múltiples tumorales metastásicos en un paciente cuyo síntoma de presentación fue la disminución de la agudeza visualThe eye metastatic carcinoma is considered the most frequently found intraocular malignant neoplasia. Only 10 % of the persons with one or more metastatic intraocular injuries are clinically detected before death. The metastatic ocular carcinoma is often diagnosed by the ophthalmologist in the presence of ocular symptoms. The injuries are preferably located in the choroid. The appearance of multiple metastatic intraaocular tumoral injuries in a patient whose chief complaint was the reduction of visual acuity motivated us to presente this case

The glycomic effect of N-acetylglucosaminyltransferase III overexpression in metastatic melanoma cells. GnT-III modifies highly branched N-glycans.

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Link-Lenczowski, Paweł; Bubka, Monika; Balog, Crina I A; Koeleman, Carolien A M; Butters, Terry D; Wuhrer, Manfred; Lityńska, Anna

2018-04-01

N-acetylglucosaminyltransferase III (GnT-III) is known to catalyze N-glycan "bisection" and thereby modulate the formation of highly branched complex structures within the Golgi apparatus. While active, it inhibits the action of other GlcNAc transferases such as GnT-IV and GnT-V. Moreover, GnT-III is considered as an inhibitor of the metastatic potential of cancer cells both in vitro and in vivo. However, the effects of GnT-III may be more diverse and depend on the cellular context. We describe the detailed glycomic analysis of the effect of GnT-III overexpression in WM266-4-GnT-III metastatic melanoma cells. We used MALDI-TOF and ESI-ion-trap-MS/MS together with HILIC-HPLC of 2-AA labeled N-glycans to study the N-glycome of membrane-attached and secreted proteins. We found that the overexpression of GnT-III in melanoma leads to the modification of a broad range of N-glycan types by the introduction of the "bisecting" GlcNAc residue with highly branched complex structures among them. The presence of these unusual complex N-glycans resulted in stronger interactions of cellular glycoproteins with the PHA-L. Based on the data presented here we conclude that elevated activity of GnT-III in cancer cells does not necessarily lead to a total abrogation of the formation of highly branched glycans. In addition, the modification of pre-existing N-glycans by the introduction of "bisecting" GlcNAc can modulate their capacity to interact with carbohydrate-binding proteins such as plant lectins. Our results suggest further studies on the biological function of "bisected" oligosaccharides in cancer cell biology and their interactions with carbohydrate-binding proteins.

Representability of metastatic bone lesions in magnification radiography

International Nuclear Information System (INIS)

Togawa, Takashi

1981-01-01

Magnification radiography, bone scintigraphy, and normal roentgenography were performed on patients with malignant tumors to detect their bone metastases, and from the results obtained, these diagnostic procedures were evaluated for the detectability and representability of metastatic bone lesions. Bone scan and normal roentgenography were performed on 90 metastatic bone lesions in 37 patients, and magnification radiography was done on 14 bone lesions noted in 10 of the 37 and another with benign osseous change. Among the three, bone scintigraphy was best, and magnification radiography and normal roentgenography did not differ significantly in detectability. In magnification radiography, some metastatic bone lesions were represented more clearly than by normal roentgeography, but some were not. As regards the representability of the ribs, magnification radiography was very useful. One case of bone destruction was detected by magnification radiography, but not by normal roentgenography. (author)

Vertebral compression fractures after spine irradiation using conventional fractionation in patients with metastatic colorectal cancer

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Ree, Woo Joong; Kim, Kyung Hwan; Chang, Jee Suk; Kim, Hyun Ju; Choi, Seo Hee; Koom, Woong Sub [Dept.of Radiation Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul (Korea, Republic of)

2014-12-15

To evaluate the risk of vertebral compression fracture (VCF) after conventional radiotherapy (RT) for colorectal cancer (CRC) with spine metastasis and to identify risk factors for VCF in metastatic and non-metastatic irradiated spines. We retrospectively reviewed 68 spinal segments in 16 patients who received conventional RT between 2009 and 2012. Fracture was defined as a newly developed VCF or progression of an existing fracture. The target volume included all metastatic spinal segments and one additional non-metastatic vertebra adjacent to the tumor-involved spines. The median follow-up was 7.8 months. Among all 68 spinal segments, there were six fracture events (8.8%) including three new VCFs and three fracture progressions. Observed VCF rates in vertebral segments with prior irradiation or pre-existing compression fracture were 30.0% and 75.0% respectively, compared with 5.2% and 4.7% for segments without prior irradiation or pre-existing compression fracture, respectively (both p < 0.05). The 1-year fracture-free probability was 87.8% (95% CI, 78.2-97.4). On multivariate analysis, prior irradiation (HR, 7.30; 95% CI, 1.31-40.86) and pre-existing compression fracture (HR, 18.45; 95% CI, 3.42-99.52) were independent risk factors for VCF. The incidence of VCF following conventional RT to the spine is not particularly high, regardless of metastatic tumor involvement. Spines that received irradiation and/or have pre-existing compression fracture before RT have an increased risk of VCF and require close observation.

Flexibility damps macromolecular crowding effects on protein folding dynamics: Application to the murine prion protein (121-231)

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Bergasa-Caceres, Fernando; Rabitz, Herschel A.

2014-01-01

A model of protein folding kinetics is applied to study the combined effects of protein flexibility and macromolecular crowding on protein folding rate and stability. It is found that the increase in stability and folding rate promoted by macromolecular crowding is damped for proteins with highly flexible native structures. The model is applied to the folding dynamics of the murine prion protein (121-231). It is found that the high flexibility of the native isoform of the murine prion protein (121-231) reduces the effects of macromolecular crowding on its folding dynamics. The relevance of these findings for the pathogenic mechanism are discussed.

A Unique Case of Muscle Invasive Metastatic Breast Cancer Mimicking Myositis

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2017-06-28

TYPE 08/ 03/20 17 Publ ication/Journal 4. TITLE AND SUBTITLE A unique case of muscle-invasive metastatic breast cancer mimicking myositis 6...Rev. 8/98) Prescnbed by ANSI Std Z39. 18 Adobe Profes11on11 7.0 Title: A Unique Case of M uscle-Invasive Metastatic Breast Cancer M imicking...an 84-year-old female who presented with neck swelling and upper airway obstruction due to metastatic breast cancer invading the sternocleidomastoid

Expressions of topoisomerase IIα and BCRP in metastatic cells are associated with overall survival in small cell lung cancer patients.

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Rijavec, Matija; Silar, Mira; Triller, Nadja; Kern, Izidor; Cegovnik, Urška; Košnik, Mitja; Korošec, Peter

2011-09-01

The aim of this study was to investigate the mRNA expression levels of multidrug resistance-associated proteins in chemo-naïve metastatic lung cancer cells and to determine the correlation with response to chemotherapy and overall survival. Metastatic cells were obtained by transbronchial fine needle aspiration biopsy of enlarged mediastinal lymph nodes in 14 patients with small cell lung cancer (SCLC) and 7 patients with non-small cell lung cancer (NSCLC). After cytological confirmation of lung cancer type, total RNA was extracted from biopsy samples and reverse transcribed to cDNA, and real-time PCR for the genes of interest [P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance protein (LRP) and topoisomerase IIα (TOPIIα)], was performed. We observed significantly decreased expression of BCRP and significantly increased expression of TOPIIα in metastatic SCLC cells compared to NSCLC. Furthermore, in SCLC high topoisomerase IIα and low BCRP expression levels positively correlated with longer overall survival. Our results showed higher expression levels of BCRP as well as lower levels of topoisomerase IIα in chemo-naïve metastatic cells in NSCLC than in SCLC. These results correlate with previous observations that metastatic SCLC cells at the beginning of chemotherapy are potentially more sensitive to chemotherapeutic agents while in metastatic NSCLC cells resistance is usually inherent. We also showed that altered levels of topoisomerase IIα and BCRP in SCLC are important factors that contribute to resistance to chemotherapeutics that interfere with the enzyme and/or DNA and are highly associated with overall survival.

Breast Angiosarcoma Metastatic to the Ovary

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Frederico F. Souza

2009-01-01

Full Text Available Ovarian masses are common findings in general gynecological practice. Approximately 5%–10% of ovarian malignancies are diagnosed as metastatic tumors. Primary angiosarcoma can arise anywhere in the body and when it arises in the breast, it usually affects women in their 3rd and 4th decades and accounts for one in 1700–2300 cases of primary breast cancer. Although unusual, breast angiosarcomas tend to metastasize hematogenously rather than lymphogenously, have high rates of local recurrence, that often develop metastases soon after treatment, and have a dismal prognosis. We present a case of a solitary ovarian metastasis from angiosarcoma of the breast.

Craniospinal irradiation with concurrent temozolomide for primary metastatic pediatric high-grade or diffuse intrinsic pontine gliomas. A first report from the GPOH-HIT-HGG Study Group

International Nuclear Information System (INIS)

Mueller, K.; Schlamann, A.; Pietschmann, S.; Kortmann, R.D.; Guckenberger, M.; Warmuth-Metz, M.; Glueck, A.; Wawer, A.; Kramm, C.; Bueren, A.O. von

2014-01-01

High-grade (HGG) and diffuse intrinsic pontine gliomas (DIPG) with primary metastatic spread are extremely rare and have a dismal prognosis. Analogous to simultaneous radiochemotherapy in non-metastatic HGG and DIPG, concurrent craniospinal irradiation (CSI) and metronomic temozolomide (metroTMZ) may represent a reasonable therapeutic approach. However, the antitumor efficacy and toxicity of this treatment still have to be investigated. Between March 2007 and December 2012, six children with primary metastatic HGG (n=4) or DIPG (n=2) received CSI and concurrent metroTMZ based on individual treatment recommendations and, in some cases, within the HIT-HGG 2007 multicenter trial. Outcome and treatment-related toxicities were evaluated. All patients received irradiation to the entire craniospinal axis (35.2 Gy, n=5; 36 Gy, n=1:) and 5 received a local boost to macroscopic tumor deposits. Simultaneously, metroTMZ (75 mg/m 2 /day, n=5; 60 mg/m 2 /day, n=1) was administered. Additionally, 1 patient received nimotuzumab once per week. Within a median follow-up of 10.0 months (range 6.5-18.7 months), all patients experienced disease progression and 5 patients died. Median progression-free survival was 4.0±0.8 months (range 2.4-10.7 months) and median overall survival was 7.6±3.5 months (range 4.0-17.6 months). Acute myelosuppression most severely limited application of this aggressive treatment strategy. Severe hematotoxicities (= grade 3) occurred in all patients and metroTMZ had to be interrupted or discontinued in 4 out of 6 cases. Concurrent CSI and metroTMZ might represent a feasible treatment approach for primary metastatic HGG and DIPG. On the basis of our experience, severe but manageable acute hematotoxicity has to be expected. An international effort is warranted to reassess the efficacy and toxicity of this approach within a prospective study. (orig.)

Craniospinal irradiation with concurrent temozolomide for primary metastatic pediatric high-grade or diffuse intrinsic pontine gliomas. A first report from the GPOH-HIT-HGG Study Group

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Mueller, K.; Schlamann, A.; Pietschmann, S.; Kortmann, R.D. [University Medical Center Leipzig, Department of Radiation Oncology, Leipzig (Germany); Guckenberger, M. [University Medical Center Wuerzburg, Department of Radiation Oncology, Wuerzburg (Germany); Warmuth-Metz, M. [University Medical Center Wuerzburg, Department of Neuroradiology, Wuerzburg (Germany); Glueck, A. [Clinic for Radiation Oncology Schwabing, Muenchen (Germany); Wawer, A. [University Medical Center Muenchen Schwabing, Department of Pediatric Hematology and Oncology, Muenchen (Germany); Kramm, C.; Bueren, A.O. von [University Medical Center Goettingen, Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Goettingen (Germany)

2014-04-15

High-grade (HGG) and diffuse intrinsic pontine gliomas (DIPG) with primary metastatic spread are extremely rare and have a dismal prognosis. Analogous to simultaneous radiochemotherapy in non-metastatic HGG and DIPG, concurrent craniospinal irradiation (CSI) and metronomic temozolomide (metroTMZ) may represent a reasonable therapeutic approach. However, the antitumor efficacy and toxicity of this treatment still have to be investigated. Between March 2007 and December 2012, six children with primary metastatic HGG (n=4) or DIPG (n=2) received CSI and concurrent metroTMZ based on individual treatment recommendations and, in some cases, within the HIT-HGG 2007 multicenter trial. Outcome and treatment-related toxicities were evaluated. All patients received irradiation to the entire craniospinal axis (35.2 Gy, n=5; 36 Gy, n=1:) and 5 received a local boost to macroscopic tumor deposits. Simultaneously, metroTMZ (75 mg/m{sup 2}/day, n=5; 60 mg/m{sup 2}/day, n=1) was administered. Additionally, 1 patient received nimotuzumab once per week. Within a median follow-up of 10.0 months (range 6.5-18.7 months), all patients experienced disease progression and 5 patients died. Median progression-free survival was 4.0±0.8 months (range 2.4-10.7 months) and median overall survival was 7.6±3.5 months (range 4.0-17.6 months). Acute myelosuppression most severely limited application of this aggressive treatment strategy. Severe hematotoxicities (= grade 3) occurred in all patients and metroTMZ had to be interrupted or discontinued in 4 out of 6 cases. Concurrent CSI and metroTMZ might represent a feasible treatment approach for primary metastatic HGG and DIPG. On the basis of our experience, severe but manageable acute hematotoxicity has to be expected. An international effort is warranted to reassess the efficacy and toxicity of this approach within a prospective study. (orig.)

Merkel Cell Carcinoma Metastatic to Pleural Fluid: A Case Report

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Ye-Young Rhee

2018-05-01

Full Text Available Merkel cell carcinoma (MCC is a rare aggressive neuroendocrine carcinoma of the skin that shows locoregional or distant metastasis. Metastasis of MCC to body cavity effusion is extremely rare; only three cases have been reported so far. Metastatic MCC in effusion cytology shows small blue round cells with fine stippled chromatin like other small blue round cell tumors such as small cell lung carcinoma or lymphoma. The diagnosis of metastatic MCC can grant patients good chances at recently advanced therapeutic options. Here, we present a case of metastatic MCC to pleural effusion with characteristic single file-like pattern.

Merkel Cell Carcinoma Metastatic to Pleural Fluid: A Case Report.

Science.gov (United States)

Rhee, Ye-Young; Kim, Soo Hee; Kim, Eun Kyung; Kim, Se Hoon

2018-05-01

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine carcinoma of the skin that shows locoregional or distant metastasis. Metastasis of MCC to body cavity effusion is extremely rare; only three cases have been reported so far. Metastatic MCC in effusion cytology shows small blue round cells with fine stippled chromatin like other small blue round cell tumors such as small cell lung carcinoma or lymphoma. The diagnosis of metastatic MCC can grant patients good chances at recently advanced therapeutic options. Here, we present a case of metastatic MCC to pleural effusion with characteristic single file-like pattern.

Biological markers as predictors of radiosensitivity in syngeneic murine tumors

International Nuclear Information System (INIS)

Chang, Sei Kyung; Shin, Hyun Soo; Seong, Jin Sil; Kim, Sung Hee

2006-01-01

We investigated whether a relationship exists between tumor control dose 50 (TCD 50 ) or tumor growth delay (TGD) and radiation induced apoptosis (RIA) in syngeneic murine tumors. Also we investigated the biological markers that can predict radiosensitivity in murine tumor system through analysis of relationship between TCD 50 , TGD, RIA and constitutive expression levels of the genetic products regulating RIA. Syngeneic murine tumors such as ovarian adenocarcinoma, mammary carcinoma, squamous cell carcinoma, fibrosarcoma, hepatocarcinoma were used in this study. C3H/HeJ mice were bred and maintained in our specific pathogen free mouse colony and were 8 ∼ 12 weeks old when used for the experiments. The tumors, growing in the right hind legs of mice, were analyzed for TCD 50 , TGD, and RIA at 8 mm in diameter. The tumors were also analyzed for the constitutive expression levels of p53, p21 WAF1/CIP1 , BAX, Bcl-2, Bcl-x L , Bcl-x S , and p34. Correlation analysis was performed whether the level of RIA were correlated with TCD 50 or TGD, and the constitutive expression levels of genetic products regulating RIA were correlated with TCD 50 , TGD, RIA. The level of RIA showed a significant positive correlation (R = 0.922, ρ = 0.026) with TGD, and showed a trend to correlation (R = -0.848), marginally significant correlation with TCD 50 (ρ = 0.070). It indicates that tumors that respond to radiation with high percentage of apoptosis were more radiosensitive. The constitutive expression levels of p21 WAF1/CIP1 and p34 showed a significant correlation either with TCD 50 (R = 0.893, ρ = 0.041 and R = 0.904, ρ = 0.035) or with TGD (R = -0.922, ρ 0.026 and R = -0.890, ρ = 0.043). The tumors with high constitutive expression levels of p21 WAF1/CIP1 or p34 were less radiosensitive than those with low expression. Radiosensitivity may be predicted with the level of RIA in murine tumors. The constitutive expression levels of p21 WAF1/CIP1 or p34 can be used as biological

Biological markers as predictors of radiosensitivity in syngeneic murine tumors

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Chang, Sei Kyung; Shin, Hyun Soo [Bundang CHA General Hospital, Seongnam (Korea, Republic of); Seong, Jin Sil; Kim, Sung Hee [Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (Korea, Republic of)

2006-06-15

We investigated whether a relationship exists between tumor control dose 50 (TCD{sub 50}) or tumor growth delay (TGD) and radiation induced apoptosis (RIA) in syngeneic murine tumors. Also we investigated the biological markers that can predict radiosensitivity in murine tumor system through analysis of relationship between TCD{sub 50}, TGD, RIA and constitutive expression levels of the genetic products regulating RIA. Syngeneic murine tumors such as ovarian adenocarcinoma, mammary carcinoma, squamous cell carcinoma, fibrosarcoma, hepatocarcinoma were used in this study. C3H/HeJ mice were bred and maintained in our specific pathogen free mouse colony and were 8 {approx} 12 weeks old when used for the experiments. The tumors, growing in the right hind legs of mice, were analyzed for TCD{sub 50}, TGD, and RIA at 8 mm in diameter. The tumors were also analyzed for the constitutive expression levels of p53, p21{sup WAF1/CIP1}, BAX, Bcl-2, Bcl-x{sub L}, Bcl-x{sub S}, and p34. Correlation analysis was performed whether the level of RIA were correlated with TCD{sub 50} or TGD, and the constitutive expression levels of genetic products regulating RIA were correlated with TCD{sub 50}, TGD, RIA. The level of RIA showed a significant positive correlation (R = 0.922, {rho} = 0.026) with TGD, and showed a trend to correlation (R = -0.848), marginally significant correlation with TCD{sub 50} ({rho} = 0.070). It indicates that tumors that respond to radiation with high percentage of apoptosis were more radiosensitive. The constitutive expression levels of p21{sup WAF1/CIP1} and p34 showed a significant correlation either with TCD{sub 50} (R = 0.893, {rho} = 0.041 and R = 0.904, {rho} = 0.035) or with TGD (R = -0.922, {rho} 0.026 and R = -0.890, {rho} = 0.043). The tumors with high constitutive expression levels of p21{sup WAF1/CIP1} or p34 were less radiosensitive than those with low expression. Radiosensitivity may be predicted with the level of RIA in murine tumors. The

Metastatic Basal Cell Carcinoma Accompanying Gorlin Syndrome

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Yeliz Bilir

2014-01-01

Full Text Available Gorlin-Goltz syndrome or basal cell nevus syndrome is an autosomal dominant syndrome characterized by skeletal anomalies, numerous cysts observed in the jaw, and multiple basal cell carcinoma of the skin, which may be accompanied by falx cerebri calcification. Basal cell carcinoma is the most commonly skin tumor with slow clinical course and low metastatic potential. Its concomitance with Gorlin syndrome, resulting from a mutation in a tumor suppressor gene, may substantially change morbidity and mortality. A 66-year-old male patient with a history of recurrent basal cell carcinoma was presented with exophthalmus in the left eye and the lesions localized in the left lateral orbita and left zygomatic area. His physical examination revealed hearing loss, gapped teeth, highly arched palate, and frontal prominence. Left orbital mass, cystic masses at frontal and ethmoidal sinuses, and multiple pulmonary nodules were detected at CT scans. Basal cell carcinoma was diagnosed from biopsy of ethmoid sinus. Based on the clinical and typical radiological characteristics (falx cerebri calcification, bifid costa, and odontogenic cysts, the patient was diagnosed with metastatic skin basal cell carcinoma accompanied by Gorlin syndrome. Our case is a basal cell carcinoma with aggressive course accompanying a rarely seen syndrome.

Hand-foot syndrome in a patient with metastatic lung adenocarcinoma induced by high-dose icotinib: A case report and review of the literature

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ZHENG, YULONG; FANG, WEIJIA; XU, NONG

2012-01-01

Icotinib is a new oral epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). The most frequent side-effects of icotinib include rash and diarrhea. Hand-foot syndrome (HFS) induced by EGFR-TKI is rare. The present study describes, for the first time, HFS induced by high-dose icotinib in a 65-year old female with metastatic lung adenocarcinoma. The patient developed HFS during the first week of icotinib treatment with characteristic clinical presentation. HFS regressed after icotinib do...

Alpha Particle Therapy in Metastatic Prostate Cancer

International Nuclear Information System (INIS)

O’Sullivan, Joe

2013-01-01

Metastatic castrate resistant prostate cancer (CRPC) is a leading cause of cancer mortality among men in western countries. Although nearly 85% of patients present with localised disease, up to 40% will eventually develop metastatic disease during the course of illness. Of men dying from prostate cancer, more than 90% have bone metastases many with no other significant metastatic sites. Symptoms related to bone metastases and skeletal related events (SREs) account for the major cause of morbidity in these patients. Bone-seeking radionuclides have been used in the treatment of prostate cancer bone metastases for many years. The first bone seeking radionuclide drug approved by the FDA was Strontium-89. Other agents have also been used including Samarium-153 EDTMP, Rhenium-186 (-188)-HEDP. These radionuclides are all emit shortrange therapeutic beta radiation with bone marrow as the dose limiting toxicity. There is strong clinical trial evidence of benefit for these radionuclides in reducing pain in advanced prostate cancer; however, none of the drugs has been shown to improve survival, albeit none of the clinical trials were powered to detect differences in survival

Sorafenib for Metastatic Thyroid Cancer

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A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

Topical Apigenin Alleviates Cutaneous Inflammation in Murine Models

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Mao-Qiang Man

2012-01-01

Full Text Available Herbal medicines have been used in preventing and treating skin disorders for centuries. It has been demonstrated that systemic administration of chrysanthemum extract exhibits anti-inflammatory properties. However, whether topical applications of apigenin, a constituent of chrysanthemum extract, influence cutaneous inflammation is still unclear. In the present study, we first tested whether topical applications of apigenin alleviate cutaneous inflammation in murine models of acute dermatitis. The murine models of acute allergic contact dermatitis and acute irritant contact dermatitis were established by topical application of oxazolone and phorbol 12-myristate 13-acetate (TPA, respectively. Inflammation was assessed in both dermatitis models by measuring ear thickness. Additionally, the effect of apigenin on stratum corneum function in a murine subacute allergic contact dermatitis model was assessed with an MPA5 physiology monitor. Our results demonstrate that topical applications of apigenin exhibit therapeutic effects in both acute irritant contact dermatitis and allergic contact dermatitis models. Moreover, in comparison with the vehicle treatment, topical apigenin treatment significantly reduced transepidermal water loss, lowered skin surface pH, and increased stratum corneum hydration in a subacute murine allergic contact dermatitis model. Together, these results suggest that topical application of apigenin could provide an alternative regimen for the treatment of dermatitis.

Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families.

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Ching-Ni Jenny Njauw

Full Text Available BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome.To characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds.Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059. Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003. Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs. Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition.Germline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome, which could be a useful clinical marker for constitutive BAP1 inactivation.

Impact of sentinel lymphadenectomy on survival in a murine model of melanoma.

Science.gov (United States)

Rebhun, Robert B; Lazar, Alexander J F; Fidler, Isaiah J; Gershenwald, Jeffrey E

2008-01-01

Lymphatic mapping and sentinel lymph node biopsy-also termed sentinel lymphadenectomy (SL)-has become a standard of care for patients with primary invasive cutaneous melanoma. This technique has been shown to provide accurate information about the disease status of the regional lymph node basins at risk for metastasis, provide prognostic information, and provide durable regional lymph node control. The potential survival benefit afforded to patients undergoing SL is controversial. Central to this controversy is whether metastasis to regional lymph nodes occurs independent of or prior to widespread hematogenous dissemination. A related area of uncertainty is whether tumor cells residing within regional lymph nodes have increased metastatic potential. We have used a murine model of primary invasive cutaneous melanoma based on injection of B16-BL6 melanoma cells into the pinna to address two questions: (1) does SL plus wide excision of the primary tumor result in a survival advantage over wide excision alone; and (2) do melanoma cells growing within lymph nodes produce a higher incidence of hematogenous metastases than do cells growing at the primary tumor site? We found that SL significantly improved the survival of mice with small primary tumors. We found no difference in the incidence of lung metastases produced by B16-BL6 melanoma cells growing exclusively within regional lymph nodes and cells growing within the pinna.

Metastatic tumor of the pancreas: helical CT findings

International Nuclear Information System (INIS)

Lee, Soon Jin; Lee, Won Jae; Lim, Hyo Keun; Kim, Seung Hoon; Kim, Kyeong Ah; Choi, Sang Hee; Jang, Hyun Jung; Lee, Ji Yeon

2000-01-01

To analyze the helical computed tomographic (CT) findings of distant metastatic tumors to the pancreas and to determine the differential points between these and primary pamcreatic carcinomas. We sruveyed 22 patients with metastatic tumor of the pancreas, proven on the basis of clinical and pathological findings. Seventeen patients were men, and five were women, and their ages ranged between 36 and 83 years. Their primary conditions were lung cancer (n=3D15), rectal cancer (n=3D2), melanoma of the foot, chondrosarcoma of the sacrum, cervical cancer, leiomyosarcoma of the uterus, and extragonadal choriocarcinoma of the mediastinum. We retrospectively reviewed the abdominal helical CT findings, analysing the number, location, size and attenuation of masses, as well as secondary change, which included dilatation of the pancreatic and biliary ducts and invasion of peripancreatic tissue or vessels. We also evaluated the differential findings of primary pancreatic cancer. Sixteen patients had a solitary focal mass, while in five, two masses were present. Among the 22 patients, low-density nodular masses were present in 21; in the other, in whom multiple metastasis from chondrosarcoma had occurred, there was dense calcification. The size of metastatic masses varied, ranging from 0.6 to 6 cm in diameter. The pancreatic duct proximal to the mass was dilated in ten cases, while the bile duct was dilated in six. The metastatic masses masses demonstrated no peripancreatic or vascular invasion, though they showed a discrete margin and contour bulging. Single metastasis to the pancreas was most common, and metastatic masses had a discrete margin, with contour bulging. There was no peripancreatic or vascular invasion. If the metastasis involved a single low-attenuated mass, however, with pancreatic or biliary dilatation, it was difficult to differentiate this from primary pancreatic cancer. (author)

Salvage Lenvatinib Therapy in Metastatic Anaplastic Thyroid Cancer.

Science.gov (United States)

Iñiguez-Ariza, Nicole M; Ryder, Mabel M; Hilger, Crystal R; Bible, Keith C

2017-07-01

Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required

Chest radiographic findings of tsutsugamushi disease and murine typhus in Chunchon

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Kim, Heung Chul; Han, Tae Giun; Jang, Won Ho; Hwang, Woo Chul; Park, Man Soo; Lee, Myoung Gu; Kim, Yoon Won [School of Medicine, Hallym University, Chuncheon (Korea, Republic of); Park, Choong Ki [College of Medicine, Hanyang University, Guri (Korea, Republic of)

1995-06-15

To evaluate the chest radiographic findings of rickettsial disease including murine typhus and tsutsugamushi disease in Chunchon. Chest radiographic films of 81 cases diagnosed as rickettsial disease(55 cases of tsutsugamushi disease, 26 cases of murine typhus) by immunofluorescence test were retrospectively analyzed. Main serotypes of Rickettsia tsutsugamushi were Gilliam and Karp. Incidence rate of tsutsugamushi disease was 2.1 times greater than that of murine typhus. Chest radiographs were abnormal in 63.6% of tsutsugamushi disease, and in 30.8% of murine typhus. Radiographic findings were Kerly's B line, reticulonodular densities, hilar enlargement, pleural effusion, and splenomegaly in both entities, but pulmonary consolidation was only found in tsutsugamushi disease. The patients with the abnormal radiographic findings were statistically well correlated with cardiomegaly ({rho} < 0.01) and azygos engorgement ({rho} < 0.05), as compared to the patients with normal radiographic findings. Radiographic findings of both murine typhus and tsutsugamushi disease were interstitial pattern. But the chest radiographs in patients with tsutsugamushi disease showed more severe pattern with higher rate of abnormality.

Chest radiographic findings of tsutsugamushi disease and murine typhus in Chunchon

International Nuclear Information System (INIS)

Kim, Heung Chul; Han, Tae Giun; Jang, Won Ho; Hwang, Woo Chul; Park, Man Soo; Lee, Myoung Gu; Kim, Yoon Won; Park, Choong Ki

1995-01-01

To evaluate the chest radiographic findings of rickettsial disease including murine typhus and tsutsugamushi disease in Chunchon. Chest radiographic films of 81 cases diagnosed as rickettsial disease(55 cases of tsutsugamushi disease, 26 cases of murine typhus) by immunofluorescence test were retrospectively analyzed. Main serotypes of Rickettsia tsutsugamushi were Gilliam and Karp. Incidence rate of tsutsugamushi disease was 2.1 times greater than that of murine typhus. Chest radiographs were abnormal in 63.6% of tsutsugamushi disease, and in 30.8% of murine typhus. Radiographic findings were Kerly's B line, reticulonodular densities, hilar enlargement, pleural effusion, and splenomegaly in both entities, but pulmonary consolidation was only found in tsutsugamushi disease. The patients with the abnormal radiographic findings were statistically well correlated with cardiomegaly (ρ < 0.01) and azygos engorgement (ρ < 0.05), as compared to the patients with normal radiographic findings. Radiographic findings of both murine typhus and tsutsugamushi disease were interstitial pattern. But the chest radiographs in patients with tsutsugamushi disease showed more severe pattern with higher rate of abnormality

Chest radiographic findings of tsutsugamushi disease and murine typhus in Chunchon

Energy Technology Data Exchange (ETDEWEB)

Kim, Heung Chul; Han, Tae Giun; Jang, Won Ho; Hwang, Woo Chul; Park, Man Soo; Lee, Myoung Gu; Kim, Yoon Won [School of Medicine, Hallym University, Chuncheon (Korea, Republic of); Park, Choong Ki [College of Medicine, Hanyang University, Guri (Korea, Republic of)

1995-06-15

To evaluate the chest radiographic findings of rickettsial disease including murine typhus and tsutsugamushi disease in Chunchon. Chest radiographic films of 81 cases diagnosed as rickettsial disease(55 cases of tsutsugamushi disease, 26 cases of murine typhus) by immunofluorescence test were retrospectively analyzed. Main serotypes of Rickettsia tsutsugamushi were Gilliam and Karp. Incidence rate of tsutsugamushi disease was 2.1 times greater than that of murine typhus. Chest radiographs were abnormal in 63.6% of tsutsugamushi disease, and in 30.8% of murine typhus. Radiographic findings were Kerly's B line, reticulonodular densities, hilar enlargement, pleural effusion, and splenomegaly in both entities, but pulmonary consolidation was only found in tsutsugamushi disease. The patients with the abnormal radiographic findings were statistically well correlated with cardiomegaly ({rho} < 0.01) and azygos engorgement ({rho} < 0.05), as compared to the patients with normal radiographic findings. Radiographic findings of both murine typhus and tsutsugamushi disease were interstitial pattern. But the chest radiographs in patients with tsutsugamushi disease showed more severe pattern with higher rate of abnormality.

Analysis of cardiomyocyte movement in the developing murine heart

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Hashimoto, Hisayuki [Department of Cardiology, Keio University School of Medicine, Tokyo (Japan); Yuasa, Shinsuke, E-mail: yuasa@a8.keio.jp [Department of Cardiology, Keio University School of Medicine, Tokyo (Japan); Tabata, Hidenori [Department of Anatomy, Keio University School of Medicine, Tokyo (Japan); Tohyama, Shugo; Seki, Tomohisa; Egashira, Toru; Hayashiji, Nozomi; Hattori, Fumiyuki; Kusumoto, Dai; Kunitomi, Akira; Takei, Makoto; Kashimura, Shin; Yozu, Gakuto; Shimojima, Masaya; Motoda, Chikaaki; Muraoka, Naoto [Department of Cardiology, Keio University School of Medicine, Tokyo (Japan); Nakajima, Kazunori [Department of Anatomy, Keio University School of Medicine, Tokyo (Japan); Sakaue-Sawano, Asako; Miyawaki, Atsushi [Life Function and Dynamics, ERATO, JST, 2-1 Hirosawa, Wako-city, Saitama 351-0198 (Japan); Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-city, Saitama 351-0198 (Japan); Fukuda, Keiichi [Department of Cardiology, Keio University School of Medicine, Tokyo (Japan)

2015-09-04

The precise assemblage of several types of cardiac precursors controls heart organogenesis. The cardiac precursors show dynamic movement during early development and then form the complicated heart structure. However, cardiomyocyte movements inside the newly organized mammalian heart remain unclear. We previously established the method of ex vivo time-lapse imaging of the murine heart to study cardiomyocyte behavior by using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system, which can effectively label individual G1, S/G2/M, and G1/S-transition phase nuclei in living cardiomyocytes as red, green, and yellow, respectively. Global analysis of gene expression in Fucci green positive ventricular cardiomyocytes confirmed that cell cycle regulatory genes expressed in G1/S, S, G2/M, and M phase transitions were upregulated. Interestingly, pathway analysis revealed that many genes related to the cell cycle were significantly upregulated in the Fucci green positive ventricular cardiomyocytes, while only a small number of genes related to cell motility were upregulated. Time-lapse imaging showed that murine proliferating cardiomyocytes did not exhibit dynamic movement inside the heart, but stayed on site after entering the cell cycle. - Highlights: • We directly visualized cardiomyocyte movement inside the developing murine heart. • Cell cycle related genes were upregulated in the proliferating cardiomyocytes. • Time-lapse imaging revealed that proliferating murine cardiomyocytes stayed in place. • Murine ventricular cardiomyocytes proliferate on site during development.

High-fat diet determines the composition of the murine gut microbiome independently of obesity.

Science.gov (United States)

Hildebrandt, Marie A; Hoffmann, Christian; Sherrill-Mix, Scott A; Keilbaugh, Sue A; Hamady, Micah; Chen, Ying-Yu; Knight, Rob; Ahima, Rexford S; Bushman, Frederic; Wu, Gary D

2009-11-01

The composition of the gut microbiome is affected by host phenotype, genotype, immune function, and diet. Here, we used the phenotype of RELMbeta knockout (KO) mice to assess the influence of these factors. Both wild-type and RELMbeta KO mice were lean on a standard chow diet, but, upon switching to a high-fat diet, wild-type mice became obese, whereas RELMbeta KO mice remained comparatively lean. To investigate the influence of diet, genotype, and obesity on microbiome composition, we used deep sequencing to characterize 25,790 16S rDNA sequences from uncultured bacterial communities from both genotypes on both diets. We found large alterations associated with switching to the high-fat diet, including a decrease in Bacteroidetes and an increase in both Firmicutes and Proteobacteria. This was seen for both genotypes (ie, in the presence and absence of obesity), indicating that the high-fat diet itself, and not the obese state, mainly accounted for the observed changes in the gut microbiota. The RELMbeta genotype also modestly influenced microbiome composition independently of diet. Metagenomic analysis of 537,604 sequence reads documented extensive changes in gene content because of a high-fat diet, including an increase in transporters and 2-component sensor responders as well as a general decrease in metabolic genes. Unexpectedly, we found a substantial amount of murine DNA in our samples that increased in proportion on a high-fat diet. These results demonstrate the importance of diet as a determinant of gut microbiome composition and suggest the need to control for dietary variation when evaluating the composition of the human gut microbiome.

Changes in cytoskeletal dynamics and nonlinear rheology with metastatic ability in cancer cell lines

International Nuclear Information System (INIS)

Coughlin, Mark F; Fredberg, Jeffrey J

2013-01-01

Metastatic outcome is impacted by the biophysical state of the primary tumor cell. To determine if changes in cancer cell biophysical properties facilitate metastasis, we quantified cytoskeletal biophysics in well-characterized human skin, bladder, prostate and kidney cell line pairs that differ in metastatic ability. Using magnetic twisting cytometry with optical detection, cytoskeletal dynamics was observed through spontaneous motion of surface bound marker beads and nonlinear rheology was characterized through large amplitude forced oscillations of probe beads. Measurements of cytoskeletal dynamics and nonlinear rheology differed between strongly and weakly metastatic cells. However, no set of biophysical parameters changed systematically with metastatic ability across all cell lines. Compared to their weakly metastatic counterparts, the strongly metastatic kidney cancer cells exhibited both increased cytoskeletal dynamics and stiffness at large deformation which are thought to facilitate the process of vascular invasion. (paper)

Ixabepilone: a new chemotherapeutic option for refractory metastatic breast cancer

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Shannon Puhalla

2008-09-01

Full Text Available Shannon Puhalla, Adam BrufskyUPMC Magee-Womens Cancer Program, University of Pittsburgh, Pittsburgh, Pennsylvania, USAAbstract: Taxane therapy is commonly used in the treatment of metastatic breast cancer. However, most patients will eventually become refractory to these agents. Ixabepilone is a newly approved chemotherapeutic agent for the treatment of metastatic breast cancer. Although it targets microtubules similarly to docetaxel and paclitaxel, ixabepilone has activity in patients that are refractory to taxanes. This review summarizes the pharmacology of ixapebilone and clinical trials with the drug both as a single agent and in combination. Data were obtained using searches of PubMed and abstracts of the annual meetings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium from 1995 to 2008. Ixapebilone is a semi-synthetic analog of epothilone B that acts to induce apoptosis of cancer cells via the stabilization of microtubules. Phase I clinical trials have employed various dosing schedules ranging from daily to weekly to 3-weekly. Dose-limiting toxicites included neuropathy and neutropenia. Responses were seen in a variety of tumor types. Phase II studies verified activity in taxane-refractory metastatic breast cancer. The FDA has approved ixabepilone for use as monotherapy and in combination with capecitabine for the treatment of metastatic breast cancer. Ixabepilone is an efficacious option for patients with refractory metastatic breast cancer. The safety profile is similar to that of taxanes, with neuropathy and neutropenia being dose-limiting. Studies are ongoing with the use of both iv and oral formulations and in combination with other chemotherapeutic and biologic agents.Keywords: ixabepilone, epothilone, metastatic breast cancer, taxane-refractory

Regorafenib Induces Apoptosis and Inhibits Metastatic Potential of Human Bladder Carcinoma Cells.

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Hsu, Fei-Ting; Sun, Cho-Chin; Wu, Chia-Hsing; Lee, Yen-Ju; Chiang, Chih-Hung; Wang, Wei-Shu

2017-09-01

The aim of the present study was to verify the effects of regorafenib on apoptosis and metastatic potential in TSGH 8301 human bladder carcinoma cells in vitro. Cells were treated with different concentration of regorafenib for different periods of time. Effects of regorafenib on cell viability, apoptosis pathways, metastatic potential, and expression of metastatic and anti-apoptotic proteins were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, flow cytometry, cell migration and invasion assay, and western blotting. We found regorafenib significantly reduced cell viability, cell migration and invasion, and expression of metastatic and anti-apoptotic proteins. In addition, regorafenib significantly induced accumulation of sub-G 1 phase cells, loss of mitochondrial membrane potential, and expression of active caspase-3 and caspase-8. These results show that regorafenib not only induces apoptosis, but also inhibits metastatic potential in bladder cancer TSGH 8301 cells in vitro. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Icotinib plus gemcitabine for metastatic pancreatic cancer: a case report.

Science.gov (United States)

Zhao, Jing; Shen, Hong; Hu, Han-Guang; Huang, Jian-Jin

2015-03-21

A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative.

MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

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Brian Shuch

2015-01-01

Full Text Available Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1. MET expression weakly correlated between primary and matched metastatic sites (R=0.5 and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39. Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

Metastatic skeletal leiomyomatosis (leiomyomatosis ossea)

International Nuclear Information System (INIS)

Pimentel, Jose Raimundo; De Almeida, Ana Luzia Brito; Aymore, Ierece Lins; Pinto, Edna Pottes; Osthoff, Laura; Smith, Julius

2002-01-01

We present a unique case of metastatic leiomyomatosis to the skeleton. The very extensive involvement of the axial and peripheral skeleton with ''ring'' lesions and associated cyclical premenstrual pain eventually led to the correct diagnosis and total relief with hormonal therapy. (orig.)

DMPD: The actions of bacterial DNA on murine macrophages. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 10534106 The actions of bacterial DNA on murine macrophages. Sester DP, Stacey KJ, ... Show The actions of bacterial DNA on murine macrophages. PubmedID 10534106 Title The actions of bacterial DNA on murine macrophage

Targeted destruction of murine macrophage cells with bioconjugated gold nanorods

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Pissuwan, Dakrong [University of Technology Sydney, Institute for Nanoscale Technology (Australia); Valenzuela, Stella M. [University of Technology Sydney, Department of Medical and Molecular Biosciences (Australia)], E-mail: stella.valenzuela@uts.edu.au; Killingsworth, Murray C. [Sydney South West Pathology Service (Australia)], E-mail: murray.killingsworth@swsahs.nsw.gov.au; Xu, Xiaoda; Cortie, Michael B. [University of Technology Sydney, Institute for Nanoscale Technology (Australia)], E-mail: michael.cortie@uts.edu.au

2007-12-15

Gold nanorods manifest a readily tunable longitudinal plasmon resonance with light and consequently have potential for use in photothermal therapeutics. Recent work by others has shown how gold nanoshells and rods can be used to target cancer cells, which can then be destroyed using relatively high power laser radiation ({approx}1x10{sup 5} to 1x10{sup 10} W/m{sup 2}). Here we extend this concept to demonstrate how gold nanorods can be modified to bind to target macrophage cells, and show that high intensity laser radiation is not necessary, with even 5x10{sup 2} W/m{sup 2} being sufficient, provided that a total fluence of {approx}30 J/cm{sup 2} is delivered. We used the murine cell line RAW 264.7 and the monoclonal antibody CD11b, raised against murine macrophages, as our model system and a 5 mW solid state diode laser as our energy source. Exposure of the cells labeled with gold nanorods to a laser fluence of 30 J/cm{sup 2} resulted in 81% cell death compared to only 0.9% in the control, non-labeled cells.

Targeted destruction of murine macrophage cells with bioconjugated gold nanorods

International Nuclear Information System (INIS)

Pissuwan, Dakrong; Valenzuela, Stella M.; Killingsworth, Murray C.; Xu, Xiaoda; Cortie, Michael B.

2007-01-01

Gold nanorods manifest a readily tunable longitudinal plasmon resonance with light and consequently have potential for use in photothermal therapeutics. Recent work by others has shown how gold nanoshells and rods can be used to target cancer cells, which can then be destroyed using relatively high power laser radiation (∼1x10 5 to 1x10 10 W/m 2 ). Here we extend this concept to demonstrate how gold nanorods can be modified to bind to target macrophage cells, and show that high intensity laser radiation is not necessary, with even 5x10 2 W/m 2 being sufficient, provided that a total fluence of ∼30 J/cm 2 is delivered. We used the murine cell line RAW 264.7 and the monoclonal antibody CD11b, raised against murine macrophages, as our model system and a 5 mW solid state diode laser as our energy source. Exposure of the cells labeled with gold nanorods to a laser fluence of 30 J/cm 2 resulted in 81% cell death compared to only 0.9% in the control, non-labeled cells

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

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R Rangarao

2018-01-01

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

Increased Expression and Aberrant Localization of Mucin 13 in Metastatic Colon Cancer

Science.gov (United States)

Gupta, Brij K.; Maher, Diane M.; Ebeling, Mara C.; Sundram, Vasudha; Koch, Michael D.; Lynch, Douglas W.; Bohlmeyer, Teresa; Watanabe, Akira; Aburatani, Hiroyuki; Puumala, Susan E.; Jaggi, Meena

2012-01-01

MUC13 is a newly identified transmembrane mucin. Although MUC13 is known to be overexpressed in ovarian and gastric cancers, limited information is available regarding the expression of MUC13 in metastatic colon cancer. Herein, we investigated the expression profile of MUC13 in colon cancer using a novel anti-MUC13 monoclonal antibody (MAb, clone ppz0020) by immunohistochemical (IHC) analysis. A cohort of colon cancer samples and tissue microarrays containing adjacent normal, non-metastatic colon cancer, metastatic colon cancer, and liver metastasis tissues was used in this study to investigate the expression pattern of MUC13. IHC analysis revealed significantly higher (pcolon cancer samples compared with faint or very low expression in adjacent normal tissues. Interestingly, metastatic colon cancer and liver metastasis tissue samples demonstrated significantly (pcolon cancer and adjacent normal colon samples. Moreover, cytoplasmic and nuclear MUC13 expression correlated with larger and poorly differentiated tumors. Four of six tested colon cancer cell lines also expressed MUC13 at RNA and protein levels. These studies demonstrate a significant increase in MUC13 expression in metastatic colon cancer and suggest a correlation between aberrant MUC13 localization (cytoplasmic and nuclear expression) and metastatic colon cancer. PMID:22914648

A novel combination treatment of armed oncolytic adenovirus expressing IL-12 and GM-CSF with radiotherapy in murine hepatocarcinoma

International Nuclear Information System (INIS)

Kim, Wonwoo; Seong, Jinsil; Oh, Hae-Jin; Koom, Woong-Sub; Choi, Kyung-Joo; Yun, Chae-Ok

2011-01-01

In this study, a novel combination treatment of armed oncolytic adenovirus expressing interleukin 12 (IL-12) and granulocyte-macrophage colony-stimulating factor (GM-CSF) with radiation was investigated for antitumor and antimetastatic effect in a murine hepatic cancer (HCa-I) model. Tumor bearing syngeneic mice were treated with radiation, armed oncolytic virus Ad-ΔE1Bmt7 (dB7) expressing both IL-12 and GM-CSF (armed dB7), or a combination of both. The adenovirus was administered by intratumoral injection 1 x 10 8 plaque forming units (PFU) per tumor in 50 μl of phosphate buffered saline (PBS) four times every other day. Tumor response to treatment was determined by a tumor growth delay assay. Metastatic potential was evaluated by a lung metastasis model. To understand the underlying mechanism, the level of apoptosis was examined as well as the change in microvessel density and expression of immunological markers: CD4+, CD8+ and Cd11c. The combination of armed dB7 and radiation resulted in significant growth delay of murine hepatic cancer, HCa-1, with an enhancement factor of 4.3. The combination treatment also resulted in significant suppression of lung metastasis. Increase of apoptosis level as well as decrease of microvessel density was shown in the combination treatment, suggesting an underlying mechanism for the enhancement of antitumor effect. Expression of immunological markers: CD4+, CD8+ and Cd11c also increased in the combination treatment. This study showed that a novel combination treatment of radiotherapy with armed oncolytic adenovirus expressing IL-12 and GM-CSF was effective in suppressing primary tumor growth. (author)

The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer

Science.gov (United States)

Magnani, Luca; Patten, Darren K.; Nguyen, Van T.M.; Hong, Sung-Pil; Steel, Jennifer H.; Patel, Naina; Lombardo, Ylenia; Faronato, Monica; Gomes, Ana R.; Woodley, Laura; Page, Karen; Guttery, David; Primrose, Lindsay; Garcia, Daniel Fernandez; Shaw, Jacqui; Viola, Patrizia; Green, Andrew; Nolan, Christopher; Ellis, Ian O.; Rakha, Emad A.; Shousha, Sami; Lam, Eric W.-F.; Győrffy, Balázs; Lupien, Mathieu; Coombes, R. Charles

2015-01-01

Over 30% of ERα breast cancer patients develop relapses and progress to metastatic disease despite treatment with endocrine therapies. The pioneer factor PBX1 translates epigenetic cues and mediates estrogen induced ERα binding. Here we demonstrate that PBX1 plays a central role in regulating the ERα transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ERα genes highly expressed in aggressive breast tumours. Retrospective stratification of luminal patients using PBX1 protein levels in primary cancer further demonstrates that elevated PBX1 protein levels correlate with earlier metastatic progression. In agreement, PBX1 protein levels are significantly upregulated during metastatic progression in ERα-positive breast cancer patients. Finally we reveal that PBX1 upregulation in aggressive tumours is partly mediated by genomic amplification of the PBX1 locus. Correspondingly, ERα-positive breast cancer patients carrying PBX1 amplification are characterized by poor survival. Notably, we demonstrate that PBX1 amplification can be identified in tumor derived-circulating free DNA of ERα-positive metastatic patients. Metastatic patients with PBX1 amplification are also characterized by shorter relapse-free survival. Our data identifies PBX1 amplification as a functional hallmark of aggressive ERα-positive breast cancers. Mechanistically, PBX1 amplification impinges on several critical pathways associated with aggressive ERα-positive breast cancer. PMID:26215677

Volume measurement variability in three-dimensional high-frequency ultrasound images of murine liver metastases

International Nuclear Information System (INIS)

Wirtzfeld, L A; Graham, K C; Groom, A C; MacDonald, I C; Chambers, A F; Fenster, A; Lacefield, J C

2006-01-01

The identification and quantification of tumour volume measurement variability is imperative for proper study design of longitudinal non-invasive imaging of pre-clinical mouse models of cancer. Measurement variability will dictate the minimum detectable volume change, which in turn influences the scheduling of imaging sessions and the interpretation of observed changes in tumour volume. In this paper, variability is quantified for tumour volume measurements from 3D high-frequency ultrasound images of murine liver metastases. Experimental B16F1 liver metastases were analysed in different size ranges including less than 1 mm 3 , 1-4 mm 3 , 4-8 mm 3 and 8-70 mm 3 . The intra- and inter-observer repeatability was high over a large range of tumour volumes, but the coefficients of variation (COV) varied over the volume ranges. The minimum and maximum intra-observer COV were 4% and 14% for the 1-4 mm 3 and 3 tumours, respectively. For tumour volumes measured by segmenting parallel planes, the maximum inter-slice distance that maintained acceptable measurement variability increased from 100 to 600 μm as tumour volume increased. Comparison of free breathing versus ventilated animals demonstrated that respiratory motion did not significantly change the measured volume. These results enable design of more efficient imaging studies by using the measured variability to estimate the time required to observe a significant change in tumour volume

Co-expression of putative stemness and epithelial-to-mesenchymal transition markers on single circulating tumour cells from patients with early and metastatic breast cancer.

Science.gov (United States)

Papadaki, Maria A; Kallergi, Galatea; Zafeiriou, Zafeiris; Manouras, Lefteris; Theodoropoulos, Panayiotis A; Mavroudis, Dimitris; Georgoulias, Vassilis; Agelaki, Sofia

2014-09-03

The detection of circulating tumor cells (CTCs) in peripheral blood (PB) of patients with breast cancer predicts poor clinical outcome. Cancer cells with stemness and epithelial-to-mesenchymal transition (EMT) features display enhanced malignant and metastatic potential. A new methodology was developed in order to investigate the co-expression of a stemness and an EMT marker (ALDH1 and TWIST, respectively) on single CTCs of patients with early and metastatic breast cancer. Triple immunofluorescence using anti-pancytokeratin (A45-B/B3), anti-ALDH1 and anti-TWIST antibodies was performed in cytospins prepared from hepatocellular carcinoma HepG2 cells and SKBR-3, MCF-7 and MDA.MB.231 breast cancer cell lines. Evaluation of ALDH1 expression levels (high, low or absent) and TWIST subcellular localization (nuclear, cytoplasmic or absent) was performed using the ARIOL system. Cytospins prepared from peripheral blood of patients with early (n = 80) and metastatic (n = 50) breast cancer were analyzed for CTC detection (based on pan-cytokeratin expression and cytomorphological criteria) and characterized according to ALDH1 and TWIST. CTCs were detected in 13 (16%) and 25 (50%) patients with early and metastatic disease, respectively. High ALDH1 expression (ALDH1high) and nuclear TWIST localization (TWISTnuc) on CTCs was confirmed in more patients with metastatic than early breast cancer (80% vs. 30.8%, respectively; p = 0.009). In early disease, ALDH1low/neg CTCs (p = 0.006) and TWISTcyt/neg CTCs (p = 0.040) were mainly observed. Regarding co-expression of these markers, ALDH1high/TWISTnuc CTCs were more frequently evident in the metastatic setting (76% vs. 15.4% of patients, p = 0.001; 61.5% vs. 12.9% of total CTCs), whereas in early disease ALDH1low/neg/TWISTcyt/neg CTCs were mainly detected (61.5% vs. 20% of patients, p = 0.078; 41.9% vs. 7.7% of total CTCs). A new assay is provided for the evaluation of ALDH1 and TWIST co-expression at the

Effect of a high-fat diet and alcohol on cutaneous repair: A systematic review of murine experimental models.

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Daiane Figueiredo Rosa

Full Text Available Chronic alcohol intake associated with an inappropriate diet can cause lesions in multiple organs and tissues and complicate the tissue repair process. In a systematic review, we analyzed the relevance of alcohol and high fat consumption to cutaneous and repair, compared the main methodologies used and the most important parameters tested. Preclinical investigations with murine models were assessed to analyze whether the current evidence support clinical trials.The studies were selected from MEDLINE/PubMed and Scopus databases, according to Fig 1. All 15 identified articles had their data extracted. The reporting bias was investigated according to the ARRIVE (Animal Research: Reporting of in Vivo Experiments strategy.In general, animals offered a high-fat diet and alcohol showed decreased cutaneous wound closure, delayed skin contraction, chronic inflammation and incomplete re-epithelialization.In further studies, standardized experimental design is needed to establish comparable study groups and advance the overall knowledge background, facilitating data translatability from animal models to human clinical conditions.

Diagnosis the metastatic sentinel node with Tc-99m-MIBI

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Georgiev-Predic, M.; Predic, P.; Karner, I.; Dodig, D.

2002-01-01

Aim: The purpose of this study was to analyse the occurrence of visualisation malignancy of sentinel node during preoperative lymphoscintigraphy in breast cancer. To precisely diagnose the metastatic sentinel node is very difficult. Material and Methods:Preoperative lymphoscintigraphy was performed in 47 patients with breast cancer after injection of Tc-99m-MIBI. We injected 20-40 MBq Tc-99m-MIBI peritumoral. Anterior and prone lateral planar images were obtained 2h, 4h, 6h and 20h after injection. The uptake were in region of sentinel node calculed. The sentinel node was intraoperatively identified and histologically analysed. Results: In 27 patients with intraoperatively detected metastatic sentinel node was in 25 patients increased uptake in sentinel node on scintigrams after 20h detected. In 20 patients with intraoperatively non detected metastatic sentinel node was in 19 patients increased uptake on scintigrams ower 2h-6h detected. Conclusion: The results indicated that is lymphoscintigraphy with Tc-99m-MIBI is a new method for detection the preoperatively metastatic sentinel node

Fournier gangrene as a manifestation of undiagnosed metastatic perforated colorectal cancer.

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Chan, Cyrus C; Williams, Mallory

2013-01-01

Abstract Fournier gangrene is a necrotizing soft tissue infection involving the perineum. We present a case of Fournier gangrene as the clinical presentation of perforated metastatic rectal cancer. The patient is a 78-year-old man in a nursing home who presented to our institution with necrosis and ischemia of the scrotum. After wide debridement of necrotic tissue and bilateral orchiectomy, computed tomography was carried out to investigate abnormal findings seen on his chest X-ray, which revealed multiple pulmonary metastases as well as a mass highly suspicious for a perforated rectal mass. Once stable, a diverting colostomy and biopsies of the rectal mass were performed, confirming the presence of a metastatic, poorly differentiated rectal adenocarcinoma. Albeit an unusual etiology of Fournier gangrene, this case highlights the rare but important causes of this deadly condition and teaches us to be cognizant of the variations in the presentation of colorectal cancer.

Identification of 42 Genes Linked to Stage II Colorectal Cancer Metastatic Relapse

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Rabeah A. Al-Temaimi

2016-04-01

Full Text Available Colorectal cancer (CRC is one of the leading causes of cancer mortality. Metastasis remains the primary cause of CRC death. Predicting the possibility of metastatic relapse in early-stage CRC is of paramount importance to target therapy for patients who really need it and spare those with low-potential of metastasis. Ninety-six stage II CRC cases were stratified using high-resolution array comparative genomic hybridization (aCGH data based on a predictive survival algorithm and supervised clustering. All genes included within the resultant copy number aberrations were each interrogated independently at mRNA level using CRC expression datasets available from public repositories, which included 1820 colon cancers, and 167 normal colon tissues. Reduced mRNA expression driven by copy number losses and increased expression driven by copy number gains revealed 42 altered transcripts (29 reduced and 13 increased transcripts associated with metastatic relapse, short disease-free or overall survival, and/or epithelial to mesenchymal transition (EMT. Resultant genes were classified based on gene ontology (GO, which identified four functional enrichment groups involved in growth regulation, genomic integrity, metabolism, and signal transduction pathways. The identified 42 genes may be useful for predicting metastatic relapse in stage II CRC. Further studies are necessary to validate these findings.

Quantitative method of measuring cancer cell urokinase and metastatic potential

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Morrison, Dennis R. (Inventor)

1993-01-01

The metastatic potential of tumors can be evaluated by the quantitative detection of urokinase and DNA. The cell sample selected for examination is analyzed for the presence of high levels of urokinase and abnormal DNA using analytical flow cytometry and digital image analysis. Other factors such as membrane associated urokinase, increased DNA synthesis rates and certain receptors can be used in the method for detection of potentially invasive tumors.

Metastatic skeletal leiomyomatosis (leiomyomatosis ossea)

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Pimentel, Jose Raimundo [Radiologic Clinic Felippe Mattoso, Rio de Janeiro (Brazil); De Almeida, Ana Luzia Brito; Aymore, Ierece Lins [Claudio Lemos Surgical Pathology Laboratory, Rio de Janeiro (Brazil); Pinto, Edna Pottes [Edna Pottes Pinto Clinic, Rio de Janeiro (Brazil); Osthoff, Laura [Basilio Clinic, Rio de Janeiro (Brazil); Smith, Julius [National Cancer Institute (INCA), Rio de Janeiro (Brazil)

2002-01-01

We present a unique case of metastatic leiomyomatosis to the skeleton. The very extensive involvement of the axial and peripheral skeleton with ''ring'' lesions and associated cyclical premenstrual pain eventually led to the correct diagnosis and total relief with hormonal therapy. (orig.)

Second-line systemic therapy for metastatic colorectal cancer.

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Mocellin, Simone; Baretta, Zora; Roqué I Figuls, Marta; Solà, Ivan; Martin-Richard, Marta; Hallum, Sara; Bonfill Cosp, Xavier

2017-01-27

. modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate-quality evidence); 3. irinotecan-based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence).With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens.We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available). Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.

PET-CT in the evaluation of metastatic breast cancer

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Sullivan, A.M.; Fulham, M.J.

2005-01-01

A 44-year-old woman underwent two PET-CT scans for the evaluation of metastatic breast cancer. A radical left mastectomy with axillary dissection (1 of 43 nodes positive) followed by chemotherapy, was performed in 1998. She represented in October 2003 with a left supraclavicular fossa mass. This was confirmed to be recurrent breast cancer on FNAB. She was considered for a radical neck dissection and the surgeon requested a PET scan. Other imaging at this time included a normal bone scan and CT brain. CT neck/chest/abdomen/pelvis showed soft tissue thickening in the left lower neck. The PET-CT scan showed multiple glucose avid lesions in the sternum, mediastinum and neck lymph nodes as well as a small lesion in the proximal left femur consistent with extensive metastatic disease. Surgery was cancelled and Femara chemotherapy commenced. Femara was stopped in March 2004 and the patient began alternative therapies. In October 2004 she presented to her surgeon with new back and chest pain. CT of the neck/chest/abdomen/pelvis showed a soft tissue mass in the upper sternum and a lymph node at the base of the neck highly suspicious for metastatic disease. There were also 2 suspicious lung nodules and a lesion in the proximal left femur reported as an osteoid osteoma. Wholebody PET-CT scans were performed on a Siemens LSO Biograph, 60mins after the injection of 350Mbq of Fl 8-Fag, with arms at the patient's side and head in the field-of-view. On both occasions the patient had to pay for the scan. On the 2004 PET-CT scan, the CT brain revealed multiple hyperdense lesions consistent with hemorrhagic metastases. In addition, there were innumerable glucose avid foci involving viscera, nodes and skeleton consistent with disseminated disease. Our case illustrates: (i) the value of PET in the management of metastatic breast cancer; (ii) the improved accuracy of PET-CT in delineating sites of disease; (iii) the issues of head movement in PET-CT and. (iv) the problem with lack of

m-RNA mammaglobin expression in metastatic breast cancer patient at Medan city, Indonesia

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Rimbun, S.; Siregar, Y.

2018-03-01

Breast cancer is the most common causes of women’s death in the world. Metastatic spread presents a major clinical problem in about 30% of the patients. The study aims to investigate the clinical reliability of mammaglobin mRNA as a marker of circulating cancer cells in breast cancer patients. The positivity of blood was analyzed in relation to clinical and pathological characteristics. This study was on 29 breast cancer patients (13 metastatic, 16 non- metastatic patients), where28 were invasive intraductal carcinoma type and 1 was invasive lobular carcinoma type. Breast cancer patients were according to the histologic grade into grade I (7 patients),grade II (6 patients) and grade III (15 patients). All individuals included in this study were subjected to detection of mammaglobin m-RNA of circulating tumor cells in peripheral blood using RT-PCR technique. Positivity for mammaglobin in blood samples was in 38% of patients with metastatic but not in the non-metastatic patients. The presence of mammaglobin correlated with metastatic tumor (P = 0.011). Mammaglobin overexpression in breast tissue was significantly positive in low-grade tumors (I and II).

Use of I-131 labeled, murine Fab against a high molecular weight antigen of human melanoma: Preliminary experience

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Larson, S.M.; Carrasquillo, J.A.; McGuffin, R.W.

1985-01-01

High molecular-weight antigen (HMWA) is tumor-associated proteoglycan of human malignant melanoma. I-131 labeled Fab fragments of these specific antibodies were used for preliminary feasibility studies for radioimmunodetection and therapy of human subjects who had inoperable metastatic melanoma. Ten patients received tracer doses of I-131 (anti-HMWA) Fab. All patients (8/8) who had melanoma lesions greater than 1 cm by correlative diagnosis methods had one or more lesions that had localization to tumor of the radiolabelled Fab. In all, 17 of 23 (74%) documented metastases were seen. Two patients who had avid uptake received potentially radiotherapeutic doses. For both of these patients, whole imaging studies showed that the localization of the high dose I-131 Fab was predominantly in tumor. On whole body images, the anti-Fab HMWA appears to be more tumor selective than Fab preparations that target the p97 antigen for melanoma, and there is less uptake in liver

Technetium-99m labeled monoclonal antibodies in the detection of metastatic melanoma

International Nuclear Information System (INIS)

Serafini, A.N.; Kotler, J.; Feun, L.; Dewanjee, M.; Robinson, D.; Salk, D.; Sfakianakis, G.; Abrams, P.; Savaraj, N.; Goodwin, D.

1989-01-01

Twenty-six stage II/III malignant melanoma patients with 321 measurable metastatic lesions were imaged using Fab fragments of an IgG murine monoclonal antibody labeled specifically with 10-30 mCi Tc-99m with a bi-functional chelating method (NeoRx, Seattle, WA). There were no side effects or adverse reactions. Immunoscintigraphy demonstrated 66.6% of lesions larger than 1 cm and 92.5% of lesions larger than 3 cm. Most frequently detected metastases were in lymph nodes, subcutaneous areas, and bone. Of lesions less than 1 cm, 23.6% were detected if superficial cutaneous lesions were excluded. The smallest detectable lesion was 4 mm. Twenty-one additional clinically unsuspected sites were visualized in 12 of the 26 patients studied. Of these, 56% were confirmed as metastasis by other tests. There were apparent nonspecific localizations owing to other causes, including fracture, varicosities, skin abscess and pneumonitis. Increased experience in image analysis facilitates correct interpretation of these localizations. This study demonstrates that imaging with Tc-99m labeled antibody fragments detects melanoma lesions in organs routinely surveyed and in other areas not routinely assessed by other imaging techniques. The procedure is readily performed and safe. The principal advantage of the test is its ability to survey the entire body and all organs with a single test. Its principal limitation, in common with other diagnostic imaging procedures, is its poor sensitivity for detecting lesions less than 1 cm

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia.

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Greco, Stephanie H; Tomkötter, Lena; Vahle, Anne-Kristin; Rokosh, Rae; Avanzi, Antonina; Mahmood, Syed Kashif; Deutsch, Michael; Alothman, Sara; Alqunaibit, Dalia; Ochi, Atsuo; Zambirinis, Constantinos; Mohaimin, Tasnima; Rendon, Mauricio; Levie, Elliot; Pansari, Mridul; Torres-Hernandez, Alejandro; Daley, Donnele; Barilla, Rocky; Pachter, H Leon; Tippens, Daniel; Malik, Hassan; Boutajangout, Allal; Wisniewski, Thomas; Miller, George

2015-01-01

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia.

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Stephanie H Greco

Full Text Available Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

Science.gov (United States)

Rokosh, Rae; Avanzi, Antonina; Mahmood, Syed Kashif; Deutsch, Michael; Alothman, Sara; Alqunaibit, Dalia; Ochi, Atsuo; Zambirinis, Constantinos; Mohaimin, Tasnima; Rendon, Mauricio; Levie, Elliot; Pansari, Mridul; Torres-Hernandez, Alejandro; Daley, Donnele; Barilla, Rocky; Pachter, H. Leon; Tippens, Daniel; Malik, Hassan; Boutajangout, Allal; Wisniewski, Thomas; Miller, George

2015-01-01

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival. PMID:26172047

Medical image of the week: metastatic testicular cancer

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Debo M

2014-06-01

Full Text Available A 30 year-old man with metastatic embryonal testicular cancer was admitted to the hospital with severe abdominal pain. A contrast enhanced CT of the abdomen demonstrated large metastatic burden throughout the liver and the left adrenal gland (Figures 1 and 2. The mass arising from the left adrenal gland caused significant mass effect. The left kidney was compressed, though without hydronephrosis, and the spleen was displaced laterally. Renal and hepatic functions were preserved. His pain was controlled with opioids and oral steroids with significant improvement.

Reproducibility analysis of the stability and treatment of vertebral metastatic lesions

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Raphael de Rezende Pratali

2014-09-01

Full Text Available OBJECTIVES: To investigate the reproducibility among spine surgeons in defining the treatment of vertebral metastatic lesions, taking into account the mechanical stability of injuries. METHODS: Twenty cases of isolated vertebral metastatic lesions were presented to ten experts. Their opinion was then asked about the stability of the lesion, as well as their treatment option. RESULTS: The interobserver Kappa coefficient obtained both for stability analysis as to the decision of the treatment was poor (0.334 and 0.248, respectively. CONCLUSIONS: Poor interobserver reproducibility was observed in deciding the treatment of vertebral metastatic lesions when considering the stability of the lesions.

Targeted biomarker profiling of matched primary and metastatic estrogen receptor positive breast cancers.

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Erica B Schleifman

Full Text Available Patients with newly diagnosed, early stage estrogen receptor positive (ER+ breast cancer often show disease free survival in excess of five years following surgery and systemic adjuvant therapy. An important question is whether diagnostic tumor tissue from the primary lesion offers an accurate molecular portrait of the cancer post recurrence and thus may be used for predictive diagnostic purposes for patients with relapsed, metastatic disease. As the class I phosphatidylinositol 3' kinase (PI3K pathway is frequently activated in ER+ breast cancer and has been linked to acquired resistance to hormonal therapy, we hypothesized pathway status could evolve over time and treatment. Biomarker analyses were conducted on matched, asynchronous primary and metastatic tumors from 77 patients with ER+ breast cancer. We examined whether PIK3CA and AKT1 alterations or PTEN and Ki67 levels showed differences between primary and metastatic samples. We also sought to look more broadly at gene expression markers reflective of proliferation, molecular subtype, and key receptors and signaling pathways using an mRNA analysis platform developed on the Fluidigm BioMark™ microfluidics system to measure the relative expression of 90 breast cancer related genes in formalin-fixed paraffin-embedded (FFPE tissue. Application of this panel of biomarker assays to matched tumor pairs showed a high concordance between primary and metastatic tissue, with generally few changes in mutation status, proliferative markers, or gene expression between matched samples. The collection of assays described here has been optimized for FFPE tissue and may have utility in exploratory analyses to identify patient subsets responsive to targeted therapies.

The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer.

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Angela M Poff

Full Text Available INTRODUCTION: Abnormal cancer metabolism creates a glycolytic-dependency which can be exploited by lowering glucose availability to the tumor. The ketogenic diet (KD is a low carbohydrate, high fat diet which decreases blood glucose and elevates blood ketones and has been shown to slow cancer progression in animals and humans. Abnormal tumor vasculature creates hypoxic pockets which promote cancer progression and further increase the glycolytic-dependency of cancers. Hyperbaric oxygen therapy (HBO₂T saturates tumors with oxygen, reversing the cancer promoting effects of tumor hypoxia. Since these non-toxic therapies exploit overlapping metabolic deficiencies of cancer, we tested their combined effects on cancer progression in a natural model of metastatic disease. METHODS: We used the firefly luciferase-tagged VM-M3 mouse model of metastatic cancer to compare tumor progression and survival in mice fed standard or KD ad libitum with or without HBO₂T (2.5 ATM absolute, 90 min, 3x/week. Tumor growth was monitored by in vivo bioluminescent imaging. RESULTS: KD alone significantly decreased blood glucose, slowed tumor growth, and increased mean survival time by 56.7% in mice with systemic metastatic cancer. While HBO₂T alone did not influence cancer progression, combining the KD with HBO₂T elicited a significant decrease in blood glucose, tumor growth rate, and 77.9% increase in mean survival time compared to controls. CONCLUSIONS: KD and HBO₂T produce significant anti-cancer effects when combined in a natural model of systemic metastatic cancer. Our evidence suggests that these therapies should be further investigated as potential non-toxic treatments or adjuvant therapies to standard care for patients with systemic metastatic disease.

A case of metastatic follicular thyroid carcinoma complicated with Graves' disease after total thyroidectomy.

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Aoyama, Mariko; Takizawa, Hiromitsu; Tsuboi, Mitsuhiro; Nakagawa, Yasushi; Tangoku, Akira

2017-12-28

Thyroid cancer and Graves' disease may present simultaneously in one patient. The incidence of the development of hyperthyroidism from metastatic differentiated thyroid carcinoma is rare. We herein report a case of metastatic follicular carcinoma complicated with Graves' disease after total thyroidectomy. A 57-year-old woman underwent right hemithyroidectomy for follicular carcinoma. Metastatic lesions appeared in the lungs and skull two years after the first surgery, and remnant thyroidectomy was performed for radioactive iodine-131 (RAI) therapy, during which the TSH receptor antibody (TRAb) was found to be negative. The patient was treated with RAI therapy four times for four years and was receiving levothyroxine suppressive therapy. Although radioiodine uptake was observed in the lesions after the fourth course of RAI therapy, metastatic lesions had progressed. Four years after the second surgery, she had heart palpitations and tremors. Laboratory data revealed hyperthyroidism and positive TRAb. She was diagnosed with Graves' disease and received a fifth course of RAI therapy. 131I scintigraphy after RAI therapy showed strong radioiodine uptake in the metastatic lesions. As a result, the sizes and numbers of metastatic lesions decreased, and thyroid function improved. Metastatic lesions produced thyroid hormone and caused hyperthyroidism. RAI therapy was effective for Graves' disease and thyroid carcinoma.

Living Well? Strategies Used by Women Living With Metastatic Breast Cancer.

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Lewis, Sophie; Willis, Karen; Yee, Jasmine; Kilbreath, Sharon

2016-07-01

Metastatic breast cancer is a disease of changing status-once an imminent death sentence, now a chronic (albeit incurable) disease. Medical intervention advances mean women with metastatic breast cancer now have symptoms alleviated and, potentially, life extended. Living with this disease, however, requires more than a medical approach to symptoms. We were interested to know whether women manage, and if so, how, to "live well" with metastatic cancer. We conducted interviews with 18 women. Women differed in the approaches they used. Most common was the attempt to reestablish a sense of normality in their lives. However, a second group reevaluated and reprioritized their lives; and a third group was restricted in their capacity to live well because of symptoms. The findings provide the foundation for future research exploring normalization of experiences of metastatic cancer, and other chronic illnesses, where people are living with knowledge that they have contracted time. © The Author(s) 2015.

Ocular melanoma metastatic to skin: the value of HMB-45 staining.

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Schwartz, Robert A; Kist, Joseph M; Thomas, Isabelle; Fernández, Geover; Cruz, Manuel A; Koziorynska, Ewa I; Lambert, W Clark

2004-06-01

Cutaneous metastatic disease is an important finding that may represent the first sign of systemic cancer, or, if already known, that may change tumor staging and thus dramatically altered therapeutic plans. Although cutaneous metastases are relatively frequent in patients with cutaneous melanoma, they are less so from ocular melanoma. To demonstrate the value of HMB-45, staining in the detection of ocular melanoma metastatic to skin. The immunohistochemical stain HMB-45 a monoclonal antibody directed against intact human melanoma cells, was employed on a skin biopsy specimen from a cutaneous tumor. HMB-45 staining was positive in the atypical hyperchromatic cells of the deep dermis. HMB-45 may be of value in the detection of ocular melanoma metastatic to skin. Cutaneous metastatic disease is a somewhat common and extremely important diagnosis. Although cutaneous metastases from cutaneous melanoma are relatively frequent, those from ocular melanomas are less so. Use of histochemical staining, especially the HMB-45 stain, allows confirmation of the diagnosis.

Effect of cordycepin (3'-deoxyadenosine) on hematogenic lung metastatic model mice.

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Nakamura, Kazuki; Konoha, Keiko; Yoshikawa, Noriko; Yamaguchi, Yu; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru

2005-01-01

We investigated the anti-metastatic effect of cordycepin (3'-deoxyadenosine) on a hematogenic metastatic mouse model which was intravenously injected with B16-BL6 melanoma cells. A 3-hour exposure to various concentrations of cordycepin (0.3, 1 and 3 microg/ml) dose-dependently reduced the number of nodules formed in lung at 15 days after the tumor injection. To elucidate the mechanism of this anti-metastatic effect, we examined the effect of cordycepin on the invasiveness of B16-BL6 cells using a chemo-invasion chamber in vitro. The B16-BL6 cells pretreated with cordycepin (3 microg/ml) for 3 hours showed a significant decrease in invasiveness. Under the same conditions, however, cordycepin did not influence the growth curve of B16-BL6 cells at concentrations up to 3 microg/ml. These results suggest that cordycepin exerts an anti-metastatic action, in part, by inhibiting the invasiveness of mouse melanoma cells.

Health related quality of life assessment in metastatic disease of the spine: a systematic review.

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Street, John; Berven, Sigurd; Fisher, Charles; Ryken, Timothy

2009-10-15

Systematic literature review. To examine the available literature on health related quality of life (HRQOL) assessment in metastatic disease of the spine and identify the optimal functional outcome scales to be used in developing a disease-specific tool. There is a lack of consensus in the use of HRQOL measures in patients with metastatic spine disease. A systematic review was conducted using MEDLINE, EMBASE, the Science Citation Index (ISI), the Cumulative Index to Nursing and Allied Health Literature, the PsycINFO, the Allied and Complementary Medicine (AMED), Cochrane Reviews and Global Health databases for clinical studies addressing metastatic spine disease from 1966 through 2008. The validity of outcome tools was established by linkage analysis with the International Classification of Functioning Disability and Health (ICF). One hundred forty-one clinical studies met inclusion criteria including 10,347 patients. Only 5 moderate grade and 1 high grade study were identified. Thirty- four studies used a patient self-assessment instrument to assess health status. None of the instruments were validated for metastatic spine patients. The most commonly used Pi-by-no tools were SF-36, SIP 5, and the ADL. None of the studies defined health related quality of life (HRQOL) or justified the choice of instrument. The most commonly used cancer-specific tools were ECOG, EORTC QCQ-C30, and EUROQOL 5D. Based on frequency of citation and on correlation with the International Classification of Functioning Disability and Health, the ECOG and SF36 were judged as most valid and reliable. A systematic review of the available evidence suggests that valid and reliable health related quality of life measures exist for the assessment of oncology patients; however, a disease-specific tool for metastatic spine disease awaits development. Until such time as a disease-specific tool is available, we recommend that the ECOG and SF-36 be considered for use in studies addressing the outcome

High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features.

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Achkar, Tala; Arjunan, Ananth; Wang, Hong; Saul, Melissa; Davar, Diwakar; Appleman, Leonard J; Friedland, David; Parikh, Rahul A

2017-01-01

High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12-20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10-15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2. Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan-Meier method. Disease characteristics were evaluated for significance using the Fischer's exact test and Wilcoxon rank sum test. Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0-21.3). Median OS was 30.5 months (95% CI 13.3-57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3-35.3). In patients who received second-line therapy, median PFS was 7.9 months (95% CI 2.4-10.2). In

Benzimidazole as Novel Therapy for Hormone-Refractory Metastatic Prostate Cancer

Science.gov (United States)

2011-05-01

8 4 INTRODUCTION The focus of this project is to evaluate the anti-tumor effects of benzimidazoles as a...potential anti-metastatic prostate cancer therapy. We identified benzimidazoles , a class of anti-parasitic drug, in a drug screening process for...preferential anti-tumor activity on metastatic prostate cancer cells. We have data indicate that benzimidazoles have potent anti-tumor activities

Characterization of the melanoma brain metastatic niche in mice and humans

International Nuclear Information System (INIS)

Amit, Moran; Laider-Trejo, Leonor; Shalom, Vardit; Shabtay-Orbach, Ayelet; Krelin, Yakov; Gil, Ziv

2013-01-01

Brain metastases occur in 15% of patients with melanoma and are associated with a dismal prognosis. Here, we investigate the architectural phenotype and stromal reaction of melanoma brain metastasis in mice and humans. A syngeneic, green fluorescence protein (GFP)-expressing murine B16-F1 melanoma clone was introduced via intracardiac injection, and was examined in vivo in comparison with human specimens. Immunofluorescence analyses of the brain metastases revealed that F4/80 + macrophages/microglia were most abundant at the tumor front, but rare in its core, where they were found only around blood vessels (P = 0.01). Similar pattern of infiltration was found in CD3 + T cells (P < 0.01). Infiltrating T cells were prominently CD4 + compared with CD8 + T cells (P < 0.001). Blood vessels (CD31 + ) were less abundant at the tumor front than in its center (12 ± 1 vs. 4 ± 0.6 vessels per high-power field [HPF], P < 0.001). In contrast, there were few vessels at the tumor front, but their diameter was significantly larger at the front (8236 μm 2 vs. 4617 μm 2 average cross-sectional area, P < 0.005). This is the first comparative analysis of melanoma brain metastases showing similar stromal reaction in murine models and human specimens. Our results validate the utility of this murine model of melanoma brain metastases for investigating the mechanism of the human disease

Periostin is identified as a putative metastatic marker in breast cancer-derived exosomes.

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Vardaki, Ioulia; Ceder, Sophia; Rutishauser, Dorothea; Baltatzis, George; Foukakis, Theodoros; Panaretakis, Theocharis

2016-11-15

Breast cancer (BrCa) is the most frequent cancer type in women and a leading cause of cancer related deaths in the world. Despite the decrease in mortality due to better diagnostics and palliative care, there is a lack of prognostic markers of metastasis. Recently, the exploitation of liquid biopsies and in particular of the extracellular vesicles has shown promise in the identification of such prognostic markers. In this study we compared the proteomic content of exosomes derived from metastatic and non-metastatic human (MCF7 and MDA-MB-231) and mouse (67NR and 4T1) cell lines. We found significant differences not only in the amount of secreted exosomes but most importantly in the protein content of exosomes secreted from metastatic versus non-metastatic ones. We identified periostin as a protein that is enriched in exosomes secreted by metastatic cells and validated its presence in a pilot cohort of breast cancer patient samples with localized disease or lymph node (LN) metastasis.

Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

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Amelia Kellar

2015-01-01

Full Text Available Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer.

Thyrotoxicosis associated with distant metastatic follicular carcinoma of the thyroid

International Nuclear Information System (INIS)

Bowden, W.D.; Jones, R.E.

1986-01-01

In a man with metastatic follicular carcinoma of the thyroid, thyrotoxicosis developed after total thyroidectomy and was successfully treated with antithyroid medications. Treatment with radioactive iodine decreased the size of the distant metastasis and eventually diminished thyroid hormone production. Follicular carcinoma complicated by hyperthyroidism requires vigorous control of the hypermetabolic state. Treatment with radioactive iodine can effectively reduce metabolic complications and tumor bulk, and yields a remission rate as high as 33%

Sputum cytology of a metastatic postradiation sarcoma

International Nuclear Information System (INIS)

Tanaka, Toshio; Murakami, Itsuko; Awai, Seiji; Ogura, Yasuko; Morishita, Yumiko

1981-01-01

A female patient who died of apparent postradiation sarcoma in the inguinal region after irradiating a metastatic squamous cell carcinoma of the same site was reported. For approximately 20 months, the patient had received a total of 6,600 and 9,600 Roentgen to the right para-aortic and inguinal areas, respectively. About 10 years later, she developed a sarcoma, namely a malignant fibrous histiocytoma. Sputum cytology demonstrated numerous giant cells with bizarre nuclei; subsequent chest films also presented apparent metastatic tumor shadows. The cellular characteristics and also rather low incidence of detection of nonepithelial malignant tumor by sputum cytology were briefly discussed, and ways of enhancing cytodiagnostic accuracy were proposed. (author)

Metastatic cancer of unknown primary in 21 dogs.

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Rossi, F; Aresu, L; Vignoli, M; Buracco, P; Bettini, G; Ferro, S; Gattino, F; Ghiani, F; Costantino, R; Ressel, L; Bellei, E; Marconato, L

2015-03-01

The aim of this retrospective study was to describe clinical features, treatment and outcome of 21 dogs with metastatic cancer of unknown primary (MCUP), a biopsy-proven malignancy being diagnosed at a metastatic stage, in which the anatomical origin of the primary tumour cannot be detected. All dogs underwent total-body computed tomography. Signalment, type and duration of clinical signs, metastasis site, pathology results, treatment and outcome were recorded. Carcinoma was the most common diagnosis (57.1%), followed by sarcoma, melanoma and mast cell tumour. The median number of disease sites per dog was 2, with bones, lymph nodes, lungs and spleen being the most frequent metastatic locations. The median survival for all dogs was 30 days. Overall, a primary site was not identified in 20 (95.2%) dogs. MCUP encompasses a variety of different pathologic entities and harbours a poor prognosis. © 2013 Blackwell Publishing Ltd.

Metastatic Renal Cell Carcinoma to the Pancreas: A Review.

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Cheng, Shaun Kian Hong; Chuah, Khoon Leong

2016-06-01

The pancreas is an unusual site for tumor metastasis, accounting for only 2% to 5% of all malignancies affecting the pancreas. The more common metastases affecting the pancreas include renal cell carcinomas, melanomas, colorectal carcinomas, breast carcinomas, and sarcomas. Although pancreatic involvement by nonrenal malignancies indicates widespread systemic disease, metastatic renal cell carcinoma to the pancreas often represents an isolated event and is thus amenable to surgical resection, which is associated with long-term survival. As such, it is important to accurately diagnose pancreatic involvement by metastatic renal cell carcinoma on histology, especially given that renal cell carcinoma metastasis may manifest more than a decade after its initial presentation and diagnosis. In this review, we discuss the clinicopathologic findings of isolated renal cell carcinoma metastases of the pancreas, with special emphasis on separating metastatic renal cell carcinoma and its various differential diagnoses in the pancreas.

The carcinoembryonic antigen IgV-like N domain plays a critical role in the implantation of metastatic tumor cells.

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Abdul-Wahid, Aws; Huang, Eric H-B; Cydzik, Marzena; Bolewska-Pedyczak, Eleonora; Gariépy, Jean

2014-03-01

The human carcinoembryonic antigen (CEA) is a cell adhesion molecule involved in both homotypic and heterotypic interactions. The aberrant overexpression of CEA on adenocarcinoma cells correlates with their increased metastatic potential. Yet, the mechanism(s) by which its adhesive properties can lead to the implantation of circulating tumor cells and expansion of metastatic foci remains to be established. In this study, we demonstrate that the IgV-like N terminal domain of CEA directly participates in the implantation of cancer cells through its homotypic and heterotypic binding properties. Specifically, we determined that the recombinant N terminal domain of CEA directly binds to fibronectin (Fn) with a dissociation constant in the nanomolar range (K(D) 16 ± 3 nM) and interacts with itself (K(D) 100 ± 17 nM) and more tightly to the IgC-like A(3) domain (K(D) 18 ± 3 nM). Disruption of these molecular associations through the addition of antibodies specific to the CEA N or A(3)B(3) domains, or by adding soluble recombinant forms of the CEA N, A(3) or A(3)B(3) domains or a peptide corresponding to residues 108-115 of CEA resulted in the inhibition of CEA-mediated intercellular aggregation and adherence events in vitro. Finally, pretreating CEA-expressing murine colonic carcinoma cells (MC38.CEA) with rCEA N, A3 or A(3)B(3) modules blocked their implantation and the establishment of tumor foci in vivo. Together, these results suggest a new mechanistic insight into how the CEA IgV-like N domain participates in cellular events that can have a macroscopic impact in terms of cancer progression and metastasis. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Role of capecitabine in treating metastatic colorectal cancer in Chinese patients

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Wang F

2014-04-01

Full Text Available Feng Wang,* Feng-Hua Wang,* Long Bai, Rui-Hua XuDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China *These authors contributed equally to this workAbstract: The China Food and Drug Administration approved the use of capecitabine in patients with metastatic colorectal cancer (mCRC in 2004. This paper reviews the available information of capecitabine in Chinese patients with mCRC, focusing on its effectiveness and safety against mCRC. Identification of all eligible studies was made by searching the PubMed and Wanfang database from 2000 to 2013. Published data examining various aspects of clinical response and tolerability with capecitabine alone or in combination with other chemotherapeutic or biological agents for first- and second-line mCRC were examined. Capecitabine and its combination displayed high efficacy in Chinese patients with mCRC. Toxicities are generally manageable, and elderly patients can tolerate capecitabine well.Keywords: capecitabine, metastatic colorectal cancer, Chinese

The key role of extracellular vesicles in the metastatic process.

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Zhao, Hongyun; Achreja, Abhinav; Iessi, Elisabetta; Logozzi, Mariantonia; Mizzoni, Davide; Di Raimo, Rossella; Nagrath, Deepak; Fais, Stefano

2018-01-01

Extracellular vesicles (EVs), including exosomes, have a key role in the paracrine communication between organs and compartments. EVs shuttle virtually all types of biomolecules such as proteins, lipids, nucleic acids, metabolites and even pharmacological compounds. Their ability to transfer their biomolecular cargo into target cells enables EVs to play a key role in intercellular communication that can regulate cellular functions such as proliferation, apoptosis and migration. This has led to the emergence of EVs as a key player in tumor growth and metastasis through the formation of "tumor niches" in target organs. Recent data have also been shown that EVs may transform the microenvironment of primary tumors thus favoring the selection of cancer cells with a metastatic behavior. The release of EVs from resident non-malignant cells may contribute to the metastatic processes as well. However, cancer EVs may induce malignant transformation in resident mesenchymal stem cells, suggesting that the metastatic process is not exclusively due to circulating tumor cells. In this review, we outline and discuss evidence-based roles of EVs in actively regulating multiple steps of the metastatic process and how we can leverage EVs to impair metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

Should Aggressive Surgical Local Control Be Attempted in All Patients with Metastatic or Pelvic Ewing's Sarcoma?

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Thorpe, Steven W.; Weiss, Kurt R.; Goodman, Mark A.; Heyl, Alma E.; McGough, Richard L.

2012-01-01

In previous reports, patients with Ewing's sarcoma received radiation therapy (XRT) for definitive local control because metastatic disease and pelvic location were thought to preclude aggressive local treatment. We sought to determine if single-site metastatic disease should be treated differently from multicentric-metastatic disease. We also wanted to reinvestigate the impact of XRT, pelvic location, and local recurrence on outcomes. Our results demonstrated a significant difference in overall survival (OS) between patients with either localized disease or a single-metastatic site and patients with multicentric-metastatic disease (P = 0.004). Local control was also found to be an independent predictor of outcomes as demonstrated by a significant difference in OS between those with and without local recurrence (P = 0.001). Axial and pelvic location did not predict a decreased OS. Based on these results, we concluded that pelvic location and the diagnosis of metastatic disease at diagnosis should not preclude aggressive local control, except in cases of multicentric-metastatic disease. PMID:22550427

Efficient inhibition of murine breast cancer growth and metastasis by gene transferred mouse survivin Thr34→Ala mutant

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Chen li-Juan

2008-09-01

Full Text Available Abstract Background Metastasis in breast cancer is a vital concern in treatment because most women with primary breast cancer have micrometastases to distant sites at diagnosis. As a member of the inhibitor of apoptosis protein (IAP family, survivin has been proposed as an attractive target for new anticancer interventions. In this study, we investigated the role of the plasmid encoding the phosphorylation-defective mouse survivin threonine 34→alanine mutant (Msurvivin T34A plasmid in suppressing both murine primary breast carcinomas and pulmonary metastases. Methods In vitro study, induction of apoptosis by Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol was examined by PI staining fluorescence microscopy and flow cytometric analysis. The anti-tumor and anti-metastases activity of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol was evaluated in female BALB/c mice bearing 4T1 s.c. tumors. Mice were treated twice weekly with i.v. administration of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol, PORF-9 null plasmid complexed with cationic liposome (DOTAP/Chol, 0.9% NaCl solution for 4 weeks. Tumor volume was observed. After sacrificed, tumor net weight was measured and Lung metastatic nodules of each group were counted. Assessment of apoptotic cells by TUNEL assay was conducted in tumor tissue. Microvessel density within tumor tissue was determined by CD31 immunohistochemistry. Alginate-encapsulated tumor cells test was conducted to evaluate the effect on angiogenesis. By experiment of cytotoxicity T lymphocytes, we test whether Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol can induce specific cell immune response. Results Administration of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol resulted in significant inhibition in the growth and metastases of 4T1 tumor model. These anti-tumor and anti-metastases responses were associated with

Metastatic urachal carcinoma in bronchial brush cytology

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Fatima Zahra Aly

2013-01-01

Full Text Available Urachal carcinoma is rare comprising less than 1% of all bladder carcinomas. Metastases of urachal carcinoma have been reported to meninges, brain, ovary, lung, and maxilla. Cytologic features of metastatic urachal carcinoma have not been previously reported. We present a case of metastatic urachal adenocarcinoma in bronchial brushings and review the use of immunohistochemistry in its diagnosis. A 47-year-old female was seen initially in 2007 with adenocarcinoma of the bladder dome for which she underwent partial cystectomy. She presented in 2011 with a left lung mass and mediastinal adenopathy. Bronchoscopy showed an endobronchial lesion from which brushings were obtained. These showed numerous groups of columnar cells with medium sized nuclei and abundant cytoplasm. The cells were positive for CK20 and CDX2 and negative for CK7. The cytomorphological findings were similar to those in the previous resection specimen and concurrent biopsy. This is the first case report of bronchial brushings containing metastatic urachal carcinoma. No specific immunohistochemical profile is available for its diagnosis. The consideration of a second primary was a distinct possibility in this case due to the lapse of time from primary resection, absence of local disease, and lack of regional metastases.

Mechanisms of buffer therapy resistance.

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Bailey, Kate M; Wojtkowiak, Jonathan W; Cornnell, Heather H; Ribeiro, Maria C; Balagurunathan, Yoganand; Hashim, Arig Ibrahim; Gillies, Robert J

2014-04-01

Many studies have shown that the acidity of solid tumors contributes to local invasion and metastasis. Oral pH buffers can specifically neutralize the acidic pH of tumors and reduce the incidence of local invasion and metastatic formation in multiple murine models. However, this effect is not universal as we have previously observed that metastasis is not inhibited by buffers in some tumor models, regardless of buffer used. B16-F10 (murine melanoma), LL/2 (murine lung) and HCT116 (human colon) tumors are resistant to treatment with lysine buffer therapy, whereas metastasis is potently inhibited by lysine buffers in MDA-MB-231 (human breast) and PC3M (human prostate) tumors. In the current work, we confirmed that sensitive cells utilized a pH-dependent mechanism for successful metastasis supported by a highly glycolytic phenotype that acidifies the local tumor microenvironment resulting in morphological changes. In contrast, buffer-resistant cell lines exhibited a pH-independent metastatic mechanism involving constitutive secretion of matrix degrading proteases without elevated glycolysis. These results have identified two distinct mechanisms of experimental metastasis, one of which is pH-dependent (buffer therapy sensitive cells) and one which is pH-independent (buffer therapy resistant cells). Further characterization of these models has potential for therapeutic benefit. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

L1-mediated retrotransposition of murine B1 and B2 SINEs recapitulated in cultured cells.

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Dewannieux, Marie; Heidmann, Thierry

2005-06-03

SINEs are short interspersed nucleotide elements with transpositional activity, present at a high copy number (up to a million) in mammalian genomes. They are 80-400 bp long, non-coding sequences which derive either from the 7SL RNA (e.g. human Alus, murine B1s) or tRNA (e.g. murine B2s) polymerase III-driven genes. We have previously demonstrated that Alus very efficiently divert the enzymatic machinery of the autonomous L1 LINE (long interspersed nucleotide element) retrotransposons to transpose at a high rate. Here we show, using an ex vivo assay for transposition, that both B1 and B2 SINEs can be mobilized by murine LINEs, with the hallmarks of a bona fide retrotransposition process, including target site duplications of varying lengths and integrations into A-rich sequences. Despite different phylogenetic origins, transposition of the tRNA-derived B2 sequences is as efficient as that of the human Alus, whereas that of B1s is 20-100-fold lower despite a similar high copy number of these elements in the mouse genome. We provide evidence, via an appropriate nucleotide substitution within the B1 sequence in a domain essential for its intracellular targeting, that the current B1 SINEs are not optimal for transposition, a feature most probably selected for the host sake in the course of evolution.

Automated extraction of metastatic liver cancer regions from abdominal contrast CT images

International Nuclear Information System (INIS)

Yamakawa, Junki; Matsubara, Hiroaki; Kimura, Shouta; Hasegawa, Junichi; Shinozaki, Kenji; Nawano, Shigeru

2010-01-01

In this paper, automated extraction of metastatic liver cancer regions from abdominal contrast X-ray CT images is investigated. Because even in Japan, cases of metastatic liver cancers are increased due to recent Europeanization and/or Americanization of Japanese eating habits, development of a system for computer aided diagnosis of them is strongly expected. Our automated extraction procedure consists of following four steps; liver region extraction, density transformation for enhancement of cancer regions, segmentation for obtaining candidate cancer regions, and reduction of false positives by shape feature. Parameter values used in each step of the procedure are decided based on density and shape features of typical metastatic liver cancers. In experiments using practical 20 cases of metastatic liver tumors, it is shown that 56% of true cancers can be detected successfully from CT images by the proposed procedure. (author)

Costal chondrosarcoma requiring differential diagnosis from metastatic tumor.

Science.gov (United States)

Matsuoka, Katsunari; Ueda, Mitsuhiro; Miyamoto, Yoshihiro

2017-02-01

Although chondrosarcoma is a common malignant bone tumor, cases arising in the rib are relatively rare. We experienced a case of chondrosarcoma arising in the right 10th rib during follow-up after lung cancer surgery. Although the finding of an osteolytic mass suggested a metastatic bone tumor, 18F-fluorodeoxyglucose positron-emission tomography demonstrated low fluorodeoxyglucose uptake, and a primary bone tumor was suspected. The bone tumor was resected and diagnosed as chondrosarcoma. Four years after resection, there has been no recurrence or metastasis. Positron-emission tomography was useful for differential diagnosis between a chondrosarcoma and a metastatic bone tumor.

Hyperfunctioning metastatic follicular thyroid carcinoma in Pendred's syndrome

International Nuclear Information System (INIS)

Abs, R.; Verhelst, J.; Schoofs, E.; De Somer, E.

1991-01-01

A 66-year-old woman with Pendred's syndrome underwent a partial thyroidectomy when she was 17 years old. At the age of 52 years, she had a second thyroid operation because of hyperthyroidism due to a toxic multinodular goiter with a mediastinal extension consisting of several separate nodules. Five years later a hyperfunctioning metastatic follicular carcinoma was diagnosed histologically. After treatment with radioactive iodine, the patient was well. To the authors' knowledge, this is the first description of a metastatic follicular thyroid carcinoma in Pendred's syndrome and the first report of hyperthyroidism occurring after malignant degeneration of a dyshormonogenetic goiter

From scratch: developing a hepatic resection service for metastatic colorectal cancer.

Science.gov (United States)

Wylie, Neil; Hider, Phillip; Armstrong, Delwyn; Rajkomar, Kheman; Srinivasa, Sanket; Rodgers, Michael; Brown, Anna; Koea, Jonathan

2018-05-01

Waitemata District Health Board has New Zealand's largest catchment and busiest colorectal unit. The upper gastrointestinal unit was established in 2005, in part to provide a hepatic resection service for patients with colorectal carcinoma metastatic to the liver. The aim of this investigation was to report on quality indicators for the hepatic resection of colorectal carcinoma in the development of a regional resection service. Prospectively collected data on patients undergoing hepatic resection for colorectal carcinoma between 2005 and 2014 was reviewed and correlated with costing data and national hepatic resection rates. A total of 123 patients underwent 138 hepatic resections for metastatic colorectal cancer with a median hospital stay of 8 days (range 4-37 days), a zero 30-day mortality and a median cost of NZ$21 374 for minor hepatectomy and NZ$43 133 for major hepatectomy. Actuarial 5-year disease-free survival was 44%, with 28 patients alive and disease free at 5 years post-resection. Median overall survival was not reached. Review of national hepatic resection rates indicate that Waitemata District Health Board performs one sixth of all hepatic resections in New Zealand and that this treatment modality may be underutilized in the management of patients with metastatic colorectal cancer. A regional hepatic resection centre for colorectal metastases can be established in areas of population need and can provide a high-quality, cost-effective service. © 2016 Royal Australasian College of Surgeons.

Radiosurgery for metastatic disease at the craniocervical junction.

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Tuchman, Alexander; Yu, Cheng; Chang, Eric L; Kim, Paul E; Rusch, Mairead C; Apuzzo, Michael L J

2014-12-01

Metastatic disease of the craniovertebral junction (CVJ) can cause pain, cranial nerve deficits, occipitocervical instability, or brainstem/spinal cord compression if left untreated. Many patients with metastasis in this region have a high burden of systemic disease and short life expectancy, making them poor candidates for aggressive surgical resections and fusion procedures. Traditionally, symptom palliation and local disease control in these patients has been achieved through conventional radiation therapy. Stereotactic radiosurgery (SRS) has the advantage of precisely delivering radiation to a target in fewer fractions. To our knowledge, we report the results of the largest series of patients with CVJ metastasis treated with stereotactic radiosurgery. We performed a retrospective review of 9 consecutive patients with 10 tumors of the CVJ treated with SRS at the Keck Medical Center of the University of Southern California. Two tumors were treated with Gamma Knife, whereas the other 8 received CyberKnife. The median marginal dose was 20 Gy (16-24 Gy) over 1-5 fractions. Point maximal dose to the brainstem or spinal cord ranged between 8 and 18.9 Gy. Median survival was 4 months (1-51 months). Five of six patients presenting with pain had at least partial symptom resolution. No patient went on to require surgical decompression or fusion, and there were no complications directly related to SRS. In well-selected patients, SRS for metastatic lesions of the CVJ has a low risk for complications or treatment failure, while achieving a high rate of palliation of pain symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

Addison's disease as a presentation of metastatic malignant melanoma.

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Srinivasan, B; Patel, M; Ethunandan, M; Ilankovan, V

2016-01-01

Melanoma accounts for 5% of all skin cancers. The risk of metastasis is related to the thickness of the tumour, and can affect local, regional and distant sites. Adrenal metastasis from melanoma of the head and neck is uncommon and often asymptomatic. Addison's disease as a presentation of metastatic melanoma is extremely rare and we are unaware of previous reports in the world literature. We report a case of a patient with metastatic melanoma presenting with signs and symptoms of Addison's disease.

Metastatic melanoma after 23 years of primary ocular melanoma.

LENUS (Irish Health Repository)

Karde, Supriya Ramesh

2016-11-23

We describe a case of 52-year-old man who presented with an episode of tonic-clonic seizures. He had right ocular melanoma 23 years ago with subsequent enucleation which was the standard treatment at that time. CT scans of the brain and of the thorax-abdomen-pelvis revealed widespread metastatic lesions in the brain, lung and liver. Further investigations including bronchoscopy with cytopathology uncovered that the metastatic disease was a recurrence of ocular melanoma. He received palliative radiotherapy and died 6 months later. Ocular melanoma is often associated with fulminant metastatic disease after a period of dormancy. Thus, despite successful treatment of the localised disease at initial presentation, an effort is needed for optimal long-term follow-up plan in order to improve survival in case of recurrence.

Metastatic spreading and growth of rhabdomyosarcoma in exposure to hyperglycemia, hyperthermia and ionizing radiation

International Nuclear Information System (INIS)

Ul'yanenko, S.E.; Salamatina, N.A.; Dedenkov, A.N.

1985-01-01

Under the effect of local UHF-hyperthermia, short-term hyperglycemia and ionizing radiation on metastasing strain of rhabdomysarcoma an increase in metastatic spreading or stimulated growth of primary tumor are not noticed. Otherwise, it is stated that hyperglycemia and hyperthermia thrice-used prevent from metastatic spreading of the tumor. Ionizing radiation decelerates both tumor growth and to a least extent its metastatic spreading

Comparison of vectorial ion transport in primary murine airway and human sinonasal air-liquid interface cultures, models for studies of cystic fibrosis, and other airway diseases.

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Zhang, Shaoyan; Fortenberry, James A; Cohen, Noam A; Sorscher, Eric J; Woodworth, Bradford A

2009-01-01

The purpose of this study was to compare vectorial ion transport within murine trachea, murine nasal septa, and human sinonasal cultured epithelium. Our hypothesis is that murine septal epithelium, rather than trachea, will more closely mimic the electrophysiology properties of human sinonasal epithelium. Epithelium from murine trachea, murine septa, and human sinonasal tissue were cultured at an air-liquid interface to confluence and full differentiation. A limited number of homozygous dF508 epithelia were also cultured. Monolayers were mounted in modified Ussing chambers to investigate pharmacologic manipulation of ion transport. The change in forskolin-stimulated current (delta-I(SC), expressed as micro-A/cm(2)) in murine septal (n = 19; 16.84 +/- 2.09) and human sinonasal (n = 18; 12.15 +/- 1.93) cultures was significantly increased over murine tracheal cultures (n = 15; 6.75 +/- 1.35; p = 0.035 and 0.0005, respectively). Forskolin-stimulated I(SC) was inhibited by the specific cystic fibrosis transmembrane regulator (CFTR) inhibitor INH-172 (5 microM). No forskolin-stimulated I(SC) was shown in cultures of dF508 homozygous murine septal epithelium (n = 3). Murine septal I(SC) was largely inhibited by amiloride (12.03 +/- 0.66), whereas human sinonasal cultures had a very limited response (0.70 +/- 0.47; p < 0.0001). The contribution of CFTR to stimulated chloride current as measured by INH-172 was highly significantly different between all groups (murine septa, 19.51 +/- 1.28; human sinonasal, 11.12 +/- 1.58; murine trachea, 4.85 +/- 0.49; p < 0.0001). Human sinonasal and murine septal epithelial cultures represent a useful model for studying CFTR activity and may provide significant advantages over lower airway tissues for investigating upper and lower respiratory pathophysiology.

Total Thyroidectomy for Thyroid Cancer Followed by Thyroid Storm due to Thyrotropin Receptor Antibody Stimulation of Metastatic Thyroid Tissue

DEFF Research Database (Denmark)

Folkestad, Lars; Brandt, Frans; Brix, Thomas

2017-01-01

BACKGROUND: Graves disease (GD) is an autoimmune condition characterized by the presence of antibodies against the thyrotropin receptor (TRAB), which stimulate the thyroid gland to produce excess thyroid hormone. Theoretically, TRAB could stimulate highly differentiated thyroid cancer tissue and...... treatment continued until after the fourth RAI dose. Hypothyroidism did not occur until following the fifth RAI treatment. SUMMARY AND CONCLUSIONS: We present a patient initially diagnosed with thyrotoxicosis and subsequently with metastatic follicular variant of papillary thyroid cancer. It is suggested...... that TRAB stimulated the highly differentiated extrathyroidal metastatic thyroid tissue to produce excessive amounts of thyroid hormone, delayed diagnosis, and potential aggravation of the course of thyroid cancer....

Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients

Science.gov (United States)

Tsai, Wen-Sy; Chen, Jinn-Shiun; Shao, Hung-Jen; Wu, Jen-Chia; Lai-Ming, Jr.; Lu, Si-Hong; Hung, Tsung-Fu; Chiu, Yen-Chi; You, Jeng-Fu; Hsieh, Pao-Shiu; Yeh, Chien-Yuh; Hung, Hsin-Yuan; Chiang, Sum-Fu; Lin, Geng-Ping; Tang, Reiping; Chang, Ying-Chih

2016-04-01

Enumeration of circulating tumor cells (CTCs) has been proven as a prognostic marker for metastatic colorectal cancer (m-CRC) patients. However, the currently available techniques for capturing and enumerating CTCs lack of required sensitivity to be applicable as a prognostic marker for non-metastatic patients as CTCs are even more rare. We have developed a microfluidic device utilizing antibody-conjugated non-fouling coating to eliminate nonspecific binding and to promote the multivalent binding of target cells. We then established the correlation of CTC counts and neoplasm progression through applying this platform to capture and enumerate CTCs in 2 mL of peripheral blood from healthy (n = 27), benign (n = 21), non-metastatic (n = 95), and m-CRC (n = 15) patients. The results showed that the CTC counts progressed from 0, 1, 5, to 36. Importantly, after 2-year follow-up on the non-metastatic CRC patients, we found that those who had ≥5 CTCs were 8 times more likely to develop distant metastasis within one year after curable surgery than those who had marker for the non-metastatic CRC patients who are at high risk of early recurrence.

Mechanism of infectivity of a murine leukemia virus in adult mice

International Nuclear Information System (INIS)

Levy, R.L.; Barrington, M.H.; Lerner, R.A.; Dixon, F.J.

1976-01-01

Infection of adult BALB/c mice with murine leukemia virus (MuLV) induces typical thymic lymphomas. Expression of virus was measured by using a radioimmunoassay for murine P-30, a virion core protein. Nineteen days after injection of MuLV-S into adult mice, there were 0.3μg P-30/ml of serum. X-irradiation permitted the early expression of high levels of viremia, when given before or after MuLV-S administration, and it also hastened the development of lymphomas. Seventeen to 21 days after injection of MuLV-S into x-irradiated (600 rads) adult mice, there were 2.7 μg of P-30/ml of serum. The virus produced by infected adult mice was infectious and oncogenic when given to newborn mice. Several lines of evidence are presented that suggest the mechanism by which x-irradiation permits early expession of virion proteins and lymphomas is not immunosuppression

Merkel cell carcinoma metastatic to the small bowel mesentery

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Guang-Yu Yang

2011-03-01

Full Text Available Merkel cell carcinoma (MCC is an uncommon cutaneous malignant tumor that presents as a rapidly growing skin nodule on sun-exposed areas of the body. MCC is aggressive with regional nodal and distant metastases to the skin, lung, and bones. There have been no reports of metastatic MCC to the mesentery and 6 reports describing metastasis to the small intestine. We present a case of metastatic MCC to the mesentery with infiltration to the small bowel, 8 years after original tumor resection. This is the 5th metastasis and it encased the small bowel resulting in a hair-pin loop contributing to the unusual clinical presentation. Although MCC metastatic to the bowel is uncommon, it is not rare. It is important to recognize the unusual manifestations of this disease as they are becoming more common in the future. Routine radiologic surveillance and thorough review of systems are important to patient follow-up.

Metastatic extrapleural malignant solitary fibrous tumor presenting with hypoglycemia (Doege–Potter syndrome

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Andrew J. Degnan, MD, MPhil

2017-03-01

Full Text Available We report a rare case of metastatic malignant solitary fibrous tumor (SFT that presented with hypoglycemia because of insulin growth factor-2 production. Initial workup included computed tomography imaging that revealed a large, partially necrotic liver mass, a hypervascular pancreatic head lesion, and 2 renal lesions. Following hepatic resection, pancreatic head resection and nephrectomy, all these lesions demonstrated pathological findings that were consistent with SFT. The patient also had a history of an intracranial mass that had been previously resected and treated with gamma knife therapy at an outside institution, which was found to also be SFT. Six months after initial pancreatic head resection, the patient developed a new lesion involving the pancreatic tail that was found to represent recurrent metastatic SFT. This case emphasizes the highly aggressive nature of extrapleural SFT, while rare, and the role of imaging in follow-up for disease recurrence.

Model of metastatic growth valuable for radionuclide therapy

International Nuclear Information System (INIS)

Bernhardt, Peter; Ahlman, Haakan; Forssell-Aronsson, Eva

2003-01-01

The aim was to make a Monte Carlo simulation approach to estimate the distribution of tumor sizes and to study the curative potential of three candidate radionuclides for radionuclide therapy: the high-energy electron emitter 90 Y, the medium-energy electron emitter 177 Lu and the low-energy electron emitter 103m Rh. A patient with hepatocellular carcinoma with recently published serial CT data on tumor growth in the liver was used. From these data the growth of the primary tumor, and the metastatis formation rate, were estimated. Assuming the same tumor growth of the primary and all metastases and the same metastatis formation rate from both primary and metastases the metastatic size distribution was simulated for various time points. Tumor cure of the metastatic size distribution was simulated for uniform activity distribution of three radionuclides; the high-energy electron emitter 90 Y, the mean-energy electron emitter 177 Lu and the low-energy electron emitter 103m Rh. The simulation of a tumor cure was performed for various time points and tumor-to-normal tissue activity concentrations, TNC. It was demonstrated that it is important to start therapy as early as possible after diagnosis. It was of crucial importance to use an optimal radionuclide for therapy. These simulations demonstrated that 90 Y was not suitable for systemic radionuclide therapy, due to the low absorbed fraction of the emitted electrons in small tumors ( 103m Rh was slightly better than 177 Lu. For high TNC values low-energy electron emitters, e.g., 103m Rh was the best choice for tumor cure. However, the short half-life of 103m Rh (56 min) might not be optimal for therapy. Therefore, other low-energy electron emitters, or alpha emitters, should be considered for systemic targeted therapy

Current Translational Research and Murine Models For Duchenne Muscular Dystrophy

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Rodrigues, Merryl; Echigoya, Yusuke; Fukada, So-ichiro; Yokota, Toshifumi

2016-01-01

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration. Mutations in the DMD gene result in the absence of dystrophin, a protein required for muscle strength and stability. Currently, there is no cure for DMD. Since murine models are relatively easy to genetically manipulate, cost effective, and easily reproducible due to their short generation time, they have helped to elucidate the pathobiology of dystrophin deficiency and to assess therapies for treating DMD. Recently, several murine models have been developed by our group and others to be more representative of the human DMD mutation types and phenotypes. For instance, mdx mice on a DBA/2 genetic background, developed by Fukada et al., have lower regenerative capacity and exhibit very severe phenotype. Cmah-deficient mdx mice display an accelerated disease onset and severe cardiac phenotype due to differences in glycosylation between humans and mice. Other novel murine models include mdx52, which harbors a deletion mutation in exon 52, a hot spot region in humans, and dystrophin/utrophin double-deficient (dko), which displays a severe dystrophic phenotype due the absence of utrophin, a dystrophin homolog. This paper reviews the pathological manifestations and recent therapeutic developments in murine models of DMD such as standard mdx (C57BL/10), mdx on C57BL/6 background (C57BL/6-mdx), mdx52, dystrophin/utrophin double-deficient (dko), mdxβgeo, Dmd-null, humanized DMD (hDMD), mdx on DBA/2 background (DBA/2-mdx), Cmah-mdx, and mdx/mTRKO murine models. PMID:27854202

Metastatic Mantle Cell Lymphoma to the Pituitary Gland: Case Report and Literature Review

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Arthur Wang

2016-01-01

Full Text Available We present an unusual case of a metastatic mantle cell lymphoma (MCL to the pituitary gland. The patient had a known history of MCL for which she previously received chemotherapy. She presented with new-onset diplopia and confusion, and reported a history of progressive vision blurriness associated with headache, nausea, and vomiting. MRI of the brain showed an enhancing lesion within the sella turcica involving the cavernous sinuses bilaterally, extending into Meckel's cave on the left, and abutting the optic nerves bilaterally. Following surgical excision, histopathology revealed the tumor to be a MCL. Metastatic pituitary tumors are rare and have been estimated to make up 1% of tumors discovered in the sellar region. The two most common secondary metastatic lesions to the sella are breast and lung carcinoma followed by prostate, renal cell, and gastrointestinal carcinoma. Metastatic lymphoma to the pituitary gland is especially rare and is estimated to constitute 0.5% of all metastatic tumors to the sella turcica. To our knowledge, this is the first reported case of MCL metastasizing to the pituitary gland.

Nivolumab-induced vitiligo in a metastatic melanoma patient: A case report.

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Edmondson, Lindsay A; Smith, Leticia V; Mallik, Alka

2017-12-01

The programmed-death-1 inhibitors selectively block programmed-death-1 interaction with its receptor, which restores active T-cell response directed at tumor cells, inducing an anti-tumor effect. This nonspecific activation of the immune system can also lead to a wide spectrum of side effects. Nivolumab has been used effectively to prolong survival in patients with metastatic melanoma and is recommended as a category 1 agent for systemic therapy in metastatic or unresectable melanoma per the National Comprehensive Cancer Network guidelines. We present a case of a 64-year-old woman who began nivolumab therapy for metastatic melanoma. After six doses of nivolumab therapy, the patient experienced generalized hypopigmentation on her face, chest, back, arms, and lower extremities. Although vitiligo has been reported in as many as 10.7% of patients undergoing nivolumab therapy in some clinical trials, we believe this is the first case to describe the progression of nivolumab-induced vitiligo in a metastatic melanoma patient. This case provides significant insight into the onset, symptoms, development, and treatment options for patients experiencing vitiligo as a result of nivolumab therapy.

Metastatic breast cancer to the liver with hepatoid features and Hep Par 1 antibody positive mimicking hepatocellular carcinoma.

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Affleck, Authur; Lyman, William B; Jacobs, W Carl; Livasy, Chad A; Martinie, John B; Iannitti, David A; Vrochides, Dionisios

2018-05-09

The hepatocyte paraffin 1 antibody (Hep Par 1) has a high positive predictive value for differentiating hepatocellular carcinoma from cholangiocarcinoma and metastatic carcinoma. 1 We report a case of metastatic breast cancer to the liver with hepatoid histology and strong positive staining for Hep Par 1 mimicking hepatocellular carcinoma. To our knowledge, primary breast carcinoma staining Hep Par 1 positive has not been reported in the setting of hepatic metastasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

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Klose, Johannes; Eissele, Jana; Volz, Claudia; Schmitt, Steffen; Ritter, Alina; Ying, Shen; Schmidt, Thomas; Heger, Ulrike; Schneider, Martin; Ulrich, Alexis

2016-01-01

The polyether antibiotic Salinomycin (Sal) is regarded as an inhibitor of cancer stem cells. Its effectiveness on human colorectal cancer (CRC) cells in vitro has been demonstrated before. The aim of this study was to establish a murine model to investigate the effectiveness of Sal in vivo. Furthermore, we investigated the impact of Sal on Wnt/β-catenin signaling in human CD133 + CRC cells. The two murine CRC cell lines MC38 and CT26 were used to analyze the impact of Sal on tumor cell proliferation, viability, migration, cell cycle progression and cell death in vitro. For in vivo studies, CT26 cells were injected into syngeneic BALB/c mice to initiate (i) subcutaneous, (ii) orthotopic, or (iii) metastatic CRC growth. Sal was administered daily, 5-Fluoruracil served as a control. For mechanistic studies, the CD133 + and CD133 - subpopulations of human CRC cells were separated by flow cytometry and separately exposed to increasing concentrations of Sal. The impact on Wnt/β-catenin signaling was determined by Western blotting and quantitative PCR. Sal markedly impaired tumor cell viability, proliferation and migration, and induced necrotic cell death in vitro. CRC growth in vivo was likewise inhibited upon Sal treatment. Interference with Wnt signaling and reduced expression of the Wnt target genes Fibronectin and Lgr5 indicates a novel molecular mechanism, mediating anti-tumoral effects of Sal in CRC. Sal effectively impairs CRC growth in vivo. Furthermore, Sal acts as an inhibitor of Wnt/β-catenin signaling. Thus, Salinomycin represents a promising candidate for clinical CRC treatment. The online version of this article (doi:10.1186/s12885-016-2879-8) contains supplementary material, which is available to authorized users

Diffuse metastatic infiltration of a carcinoma into skeletal muscle

International Nuclear Information System (INIS)

Hundt, W.; Braunschweig, R.; Reiser, M.

1999-01-01

Skeletal muscle is one of the most unusual sites of metastasis from any malignancy. We report a patient with rapidly progressive contractures due to metastatic infiltration of a carcinoma of unknown origin into the skeletal muscle. This 61-year-old man presented with a 1-month history of rapidly evolving, painful restriction of mobility of his right arm and his legs. Computed tomography showed diffuse metastatic nodules in all muscles, particularly in the hip abductors. Muscle biopsy revealed extensive infiltration of the muscle with carcinoma cells. (orig.)

Novel Inflammation-Based Prognostic Score for Predicting Survival in Patients with Metastatic Urothelial Carcinoma.

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Yu-Li Su

Full Text Available We developed a novel inflammation-based model (NPS, which consisted of a neutrophil to lymphocyte ratio (NLR and platelet count (PC, for assessing the prognostic role in patients with metastatic urothelial carcinoma (UC.We performed a retrospective analysis of patients with metastatic UC who underwent systemic chemotherapy between January 1997 and December 2014 in Kaohsiung Chang Gung Memorial Hospital. The defined cutoff values for the NLR and PC were 3.0 and 400 × 103/μL, respectively. Patients were scored 1 for either an elevated NLR or PC, and 0 otherwise. The NPS was calculated by summing the scores, ranging from 0 to 2. The primary endpoint was overall survival (OS by using Kaplan-Meier analysis. Multivariate Cox regression analysis was used to identify the independent prognostic factors for OS.In total, 256 metastatic UC patients were enrolled. Univariate analysis revealed that patients with either a high NLR or PC had a significantly shorter survival rate compared with those with a low NLR (P = .001 or PC (P < .0001. The median OS in patients with NPS 0, 1, and 2 was 19.0, 12.8, and 9.3 months, respectively (P < .0001. Multivariate analysis revealed that NPS, along with the histologic variant, liver metastasis, age, and white cell count, was an independent factor facilitating OS prediction (hazard ratio 1.64, 95% confidence interval 1.20-2.24, P = .002.The NLR and PC are independent prognostic factors for OS in patients with metastatic UC. The NPS model has excellent discriminant ability for OS.

Serial passaging of Candida albicans in systemic murine infection suggests that the wild type strain SC5314 is well adapted to the murine kidney.

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Anja Lüttich

Full Text Available The opportunistic fungal pathogen Candida albicans has a remarkable ability to adapt to unfavorable environments by different mechanisms, including microevolution. For example, a previous study has shown that passaging through the murine spleen can cause new phenotypic characteristics. Since the murine kidney is the main target organ in murine Candida sepsis and infection of the spleen differs from the kidney in several aspects, we tested whether C. albicans SC5314 could evolve to further adapt to infection and persistence within the kidney. Therefore, we performed a long-term serial passage experiment through the murine kidney of using a low infectious dose. We found that the overall virulence of the commonly used wild type strain SC5314 did not change after eight passages and that the isolated pools showed only very moderate changes of phenotypic traits on the population level. Nevertheless, the last passage showed a higher phenotypic variability and a few individual strains exhibited phenotypic alterations suggesting that microevolution has occurred. However, the majority of the tested single strains were phenotypically indistinguishable from SC5314. Thus, our findings indicate that characteristics of SC5314 which are important to establish and maintain kidney infection over a prolonged time are already well developed.

Curable Metastatic Colorectal Cancer

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Hochster, Howard S.

2010-01-01

Colon cancer, though already metastatic, may still be curable through multi-modality approaches, which require combined planning between medical and surgical oncologists. Retrospective surgical series have historically shown 5-year survival or “cures” for 30% to 50% of patients with solitary or a few resectable liver metastases. The role of adjuvant chemotherapy in this setting has been poorly defined. A recent European Organization for Research and Treatment of Cancer (EORTC) study randomize...

Effect of induced hyperglycemia on metastatic spreading in Lewis lung carcinoma

International Nuclear Information System (INIS)

Shmakova, N.L.; Fomenkova, T.E.; Fadeeva, T.A.

1991-01-01

The effect of induced hyperglycemia on the intensity of metastatic dissemination of Lewis lung carcinoma was investigated in experiments on mice. Neither long-, nor short-term hyperglycemia, induced at different phases of dissemination, influenced the intensity of metastatic spreading, primary tumor growth, the time of appearance of metastases, and the average life duration of tumor-bearing animals

Unusual metastatic localizations of differentiated thyroid carcinoma

International Nuclear Information System (INIS)

Ben Rais, N.; Ghfir, I.

2007-01-01

Full text: Introduction: The majority of thyroid cancers have a slow evolution, a more often loco-regional extension, and a good forecast. Remote metastases, when they exist, generally touch the osseous skeleton and/or pulmonary tissue. However, unusual metastatic localizations much more exceptional are possible. The authors report through these work five cases of atypical metastasis of differentiated thyroid carcinoma followed in Nuclear Medicine department of Ibn Sina hospital in Rabat under the directives of Professor N Ben Rais. Materials and methods: Our five patients had initially undergone a total thyroidectomy for differentiated thyroid carcinoma histologically confirmed. They had profited 4 weeks after the surgical gesture from a reference isotopic exploration (131 Iodine whole body scan and thyroglobulin dosage). The paraclinic assessment was supplemented by a computed tomography (CT). Results: Revealing symptomatology in the first 69 year old patient was dominated by blindness associated with an elective up-take of radioactive 131-Iodine on the level of hypophyseal gland extending to the sphenoid bone. The second 55 year old patient reported right basithoracic pains resisting to the usual antalgic treatment with a bulky mass driving back the kidney right to the bottom at CT with and important up-take 131-Iodine at whole body scan; a surrenalectomy was thus carried out with conservation of the kidney. The three other patients presented at the clinical examination dermohypodermic nodular lesions of various localizations whose anatomopathologic study had confirmed their thyroid metastatic origin. In the 5 patients the rate of thyroglobulin was considerably high. An activity of 3,7 GBq 131-Iodine was managed with the 5 patients. The evolution was marked, in the short run, at the first patient by a recovery partial of the sight, the disappearance of pain in the second patient and a remarkable reduction of thyroglobulin level for all our patients. Conclusion

Establishment of a method of murine obestatin RIA and its primary application

International Nuclear Information System (INIS)

Yan Guangtao Lin Ji; Hao Xiuhua; Xue Hui; Den Zihui; Di Dongdong

2009-01-01

Objective: To develop a method of murine obestatin RIA and study the role obestatin played in traumatic stress responses. Methods: New Zealand white rabbits were immunized with synthetic murine obestatin to obtain anti-serum, while chloramines-T method was used to iodinate obestatin antigen and a method of RIA for obestatin was established. A mouse sepsis model made with cecal ligation and puncture was established. Serum obestatin levels in the sacrificed models were determined with this method of RIA at 3h, 6h, 9h after the cecum puncture respectively (5 animals each time) as well as in 5 animals after sham operation. Results: Both the shape of standard curve and metrical results of the obestatin RIA were satisfactory. Serum obstatin levels at 6h after injury were significantly higher than those in animals with sham operation out the levels at 3h and 9h were not much different from those in sham operation animals. Meanwhile, the levels at 6h after injury expressed a trend to be significantly higher than that at 3h or 9h after injury. Conclusion: The established method for murine obestatin RIA is highly sensitive, simple and reliable, and it can be used to detect samples from rats and mice. Obestatin may be a traumatic stress factor participating in the modulation of homeostasis after sepsis. (authors)

Increased levels of circulating platelet-derived microparticles are associated with metastatic cutaneous melanoma.

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Moreau, Joséphine; Pelletier, Fabien; Biichle, Sabeha; Mourey, Guillaume; Puyraveau, Marc; Badet, Nicolas; Caubet, Matthieu; Laresche, Claire; Garnache-Ottou, Francine; Saas, Philippe; Seilles, Estelle; Aubin, François

2017-10-01

We investigated the plasma levels of PMPs in patients with 45 stage III and 45 stage IV melanoma. PMPs were characterised by flow cytometry and their thrombogenic activity. We also investigated the link between PMPs circulating levels and tumor burden. The circulating levels of PMPs were significantly higher in stage IV (8500 μL -1 ) than in patients with stage III (2041 μL -1 ) melanoma (P=.0001). We calculated a highly specific (93.3%) and predictive (91.7%) cut-off value (5311 μL -1 ) allowing the distinction between high-risk stage III and metastatic stage IV melanoma. The thrombogenic activity of PMPs was significantly higher in patients with stage IV melanoma (clotting time: 40.7 second vs 65 second, P=.0001). There was no significant association between the radiological tumoral syndrome and the plasma level of PMPs. Our data suggest the role of PMPs in metastatic progression of melanoma. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Novel immunotherapy approaches for metastatic urothelial and renal cell carcinoma

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Zhiying Shao

2016-10-01

Full Text Available The treatment of metastatic renal cell carcinoma (RCC and urothelial carcinoma (UC remains a major challenge. Past research has implicated the immune system in tumor surveillance of both malignancies, leading to the application of immunotherapy agents for both cancers. Among them, the most promising agents are the checkpoint blockade drugs, such as antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, programmed death receptor 1 (PD-1, and PD-1 ligand (PD-L1. In normal physiology, these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions, which is pivotal for maintaining self-tolerance. However, tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response, leading to disease progression and metastasis. Thus, there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC. To date, nivolumab (anti-PD-1 and atezolizumab (anti-PD-L1 have been approved for the treatment of metastatic RCC and UC, respectively. Despite these successes, challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach. In this report, we review existing data and research on immunotherapy in metastatic RCC and UC.

Metastatic Invasive Lobular Breast Cancer Presenting Clinically with Esophageal Dysphagia

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Lilit Karapetyan

2017-01-01

Full Text Available Background. Intra-abdominal metastases of invasive lobular breast cancer (ILBC may be insidious. We report a case of metastatic ILBC that presented with dysphagia within weeks of a negative mammogram and before the development of intra-abdominal symptoms. Case. A 70-year-old female developed esophageal dysphagia. She underwent EGD which showed a short segment of stricture of the distal esophagus without significant mucosal changes. Biopsy was unremarkable and patient underwent lower esophageal sphincter (LES dilation. Severe progressive dysphagia led to esophageal impaction and three LES dilatations. CT scan showed bilateral pleural effusions, more prominent on right side, and ascites. The pleural effusions were transudative. Repeat EGD with biopsy showed lymphocytic esophagitis, and she was started on swallowed fluticasone. Abdominal ultrasound with Doppler showed that the main portal vein had atypical turbulent flow that was felt to possibly be due to retroperitoneal process. The patient underwent diagnostic laparoscopy which revealed diffuse punctate lesions on the peritoneum. Pathology was consistent with metastatic ILBC. Conclusion. Dysphagia in the setting of peritoneal carcinomatosis from metastatic ILBC is a rare finding. The case highlights the importance of metastatic ILBC as a differential diagnosis for female patients with progressive dysphagia and associated ascites or pleural effusions.

MicroRNA expression analysis and Multiplex ligation-dependent probe amplification in metastatic and non-metastatic uveal melanoma

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Larsen, Ann-Cathrine; Holst, Line; Kaczkowski, Bogumil

2014-01-01

Purpose: To determine the association of microRNA expression and chromosomal changes with metastasis and survival in uveal melanoma (UM). Methods: Thirty-six patients with UM were selected based on the metastatic status, and clinicopathological data were collected. Multiplex ligation-dependent pr...

Metastatic hepatocellular carcinoma on the mandible: a case report

International Nuclear Information System (INIS)

Kim, Jin Soo; Kim, Jae Duk

2005-01-01

Hepatocellular carcinoma is one of the most common cancer worldwide, primarily affecting those in regions with a high prevalence of viral hepatitis. However, the metastasis of hepatocellular carcinoma to the oral cavity is a rare phenomenon. This report presents a case of metastatic hepatocellular carcinoma in the left mandibular angle and ramus region of a 62-year-old man. Panoramic radiograph revealed an ill-defined radiolucent lesion extending from the retained root of the mandibular left second molar into the ascending ramus. The lesion had irregular and ill-defined margins.

Diagnostic Approaches to Metastatic Hepatocellular Carcinoma of the Orbit.

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Geske, Michael J; Bloomer, Michele M; Kersten, Robert C; Vagefi, M Reza

Orbital metastasis of hepatocellular carcinoma is exceedingly rare and caries a grave prognosis. Three cases of metastatic orbital hepatocellular carcinoma in which the primary tumor was initially unknown and the diagnostic challenges encountered are presented. With hepatocellular carcinoma, open biopsy and palliative tumor debulking has an increased bleeding risk due to the highly vascular nature of the tumor and coagulopathy associated with chronic liver disease. As an alternative, fine needle aspiration biopsy should be considered for hepatocellular carcinoma with a readily accessible mass and the availability of an experienced cytopathologist.

microRNA-222 modulates liver fibrosis in a murine model of biliary atresia

Energy Technology Data Exchange (ETDEWEB)

Shen, Wen-jun; Dong, Rui; Chen, Gong, E-mail: chengongzlp@hotmail.com; Zheng, Shan

2014-03-28

Highlights: • The RRV infected group showed cholestasis, retardation and extrahepatic biliary atresia. • miR-222 was highly expressed, and PPP2R2A was inhibited in the murine biliary atresia model. • miR-222 profoundly modulated the process of fibrosis in the murine biliary atresia model. • miR-222 might represent a potential target for improving biliary atresia prognosis. - Abstract: microRNA-222 (miR-222) has been shown to initiate the activation of hepatic stellate cells, which plays an important role in the pathogenesis of liver fibrosis. The aim of our study was to evaluate the role of miR-22 in a mouse model of biliary atresia (BA) induced by Rhesus Rotavirus (RRV) infection. New-born Balb/c mice were randomized into control and RRV infected groups. The extrahepatic bile ducts were evaluated. The experimental group was divided into BA group and negative group based on histology. The expression of miR-222, protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), proliferating cell nuclear antigen (PCNA) and phospho-Akt were detected. We found that the experimental group showed signs of cholestasis, retardation and extrahepatic biliary atresia. No abnormalities were found in the control group. In the BA group, miR-222, PCNA and Akt were highly expressed, and PPP2R2A expression was significantly inhibited. Our findings suggest that miR-222 profoundly modulated the process of fibrosis in the murine BA model, which might represent a potential target for improving BA prognosis.

microRNA-222 modulates liver fibrosis in a murine model of biliary atresia

International Nuclear Information System (INIS)

Shen, Wen-jun; Dong, Rui; Chen, Gong; Zheng, Shan

2014-01-01

Highlights: • The RRV infected group showed cholestasis, retardation and extrahepatic biliary atresia. • miR-222 was highly expressed, and PPP2R2A was inhibited in the murine biliary atresia model. • miR-222 profoundly modulated the process of fibrosis in the murine biliary atresia model. • miR-222 might represent a potential target for improving biliary atresia prognosis. - Abstract: microRNA-222 (miR-222) has been shown to initiate the activation of hepatic stellate cells, which plays an important role in the pathogenesis of liver fibrosis. The aim of our study was to evaluate the role of miR-22 in a mouse model of biliary atresia (BA) induced by Rhesus Rotavirus (RRV) infection. New-born Balb/c mice were randomized into control and RRV infected groups. The extrahepatic bile ducts were evaluated. The experimental group was divided into BA group and negative group based on histology. The expression of miR-222, protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), proliferating cell nuclear antigen (PCNA) and phospho-Akt were detected. We found that the experimental group showed signs of cholestasis, retardation and extrahepatic biliary atresia. No abnormalities were found in the control group. In the BA group, miR-222, PCNA and Akt were highly expressed, and PPP2R2A expression was significantly inhibited. Our findings suggest that miR-222 profoundly modulated the process of fibrosis in the murine BA model, which might represent a potential target for improving BA prognosis

Metastatic Squamous Neck Cancer with Occult Primary Treatment (PDQ®)—Health Professional Version

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Metastatic squamous neck cancer with occult primary treatment options include surgery, radiation therapy or a combination of both. Get detailed information about newly diagnosed or recurrent metastatic squamous neck cancer in this summary for clinicians.

MRI of metastatic adenocarcinomas to the brain. Differential diagnosis of colorectal and pulmonary cancer

International Nuclear Information System (INIS)

Fukusumi, Akio; Nakagawa, Hiroyuki; Takayama, Katsutoshi

1998-01-01

To clarify the characteristic features of MR imagings of metastatic adenocarcinomas to the brain and search for differential points between the lesions from colorectal cancer and those of lung cancer, we evaluated retrospectively intraparenchymal metastatic lesions of 13 colorectal origins and 13 pulmonary origins on MR imagings, compared with resected specimens. Metastatic lesions from colorectal cancer showed marked hypointense solid components on T2WI, which correspond to the dense tumor cells and coagulated necrosis pathologically. Metastatic lesions from lung cancers showed mixed intensity and various components on T2WI, which correspond to various histological components, such as solid tumor cell's nests, hemorrhage, necrosis and cystic fluid collection. Pathological specimens suggested that the low signal intensity on T2WI of MRI derived from concentration of tumor cells and coagulated necrosis including macrophages and lymphocytes. This study may contribute to make the differential diagnosis of metastatic adenocarcinomas to the brain from colorectal and pulmonary cancers. (author)

Metastatic spinal tumor. Assessment with fat-saturation T1-weighted MR imaging

International Nuclear Information System (INIS)

Kasai, Toshifumi; Sugimura, Kazuro; Uchida, Nobue; Kawamitsu, Hideaki; Komatsu, Akio; Okui, Shouji; Kimino, Katsuji.

1994-01-01

The purpose of this study was to compare conventional T1-weighted imaging (T1-WI) and chemical shift fat-saturation T1-weighted imaging (fat-sat T1-WI) by a diagnosis of the bone metastases. Thirty-two patients (143 vertebrae) with non-neoplastic lesions (normal group) and 32 patients (82 vertebrae) with spinal metastases (metastatic group) were evaluated using both images. The signal intensity (SI) distribution of both groups regarding T1-WI provided various patterns, and the SI measurements were not significantly different between the two groups ; however, the metastases which were mixed, showed a low SI. Regarding fat-sat T1-WI, all non-neoplastic lesions had a low-intensity homogeneous appearance ; however, the metastases were mixed to a high SI. The SI measurement data of the metastatic group was significantly higher than that of the normal group. In conclusion, fat-sat T1-WI was useful for evaluating the vertebral metastases. When fat-sat T1-WI demonstrated a mixed to high SI in patients suspected of having vertebral metastasis, Gd-DTPA enhancement was thought to be the problem. (author)

Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

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2017-12-01

deprivation therapy (ADT) or androgen receptor (AR) pathway inhibition (ARPI) but eventually develops into lethal castration resistance prostate cancer ...AWARD NUMBER: W81XWH-14-1-0553 TITLE: Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer PRINCIPAL INVESTIGATOR: Martin Gleave...Siah2 as Novel Therapy for Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0553 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Martin Gleave 5d

Diffuse metastatic infiltration of a carcinoma into skeletal muscle

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Hundt, W.; Braunschweig, R.; Reiser, M. [Dept. of Diagnostic Radiology, Ludwig-Maximilians-Univ., Muenchen (Germany)

1999-03-01

Skeletal muscle is one of the most unusual sites of metastasis from any malignancy. We report a patient with rapidly progressive contractures due to metastatic infiltration of a carcinoma of unknown origin into the skeletal muscle. This 61-year-old man presented with a 1-month history of rapidly evolving, painful restriction of mobility of his right arm and his legs. Computed tomography showed diffuse metastatic nodules in all muscles, particularly in the hip abductors. Muscle biopsy revealed extensive infiltration of the muscle with carcinoma cells. (orig.) With 4 figs., 21 refs.

Characterizing the outcomes of metastatic papillary renal cell carcinoma

DEFF Research Database (Denmark)

Connor Wells, John; Donskov, Frede; Fraccon, Anna P

2017-01-01

Outcomes of metastatic papillary renal cell carcinoma (pRCC) patients are poorly characterized in the era of targeted therapy. A total of 5474 patients with metastatic renal cell carcinoma (mRCC) in the International mRCC Database Consortium (IMDC) were retrospectively analyzed. Outcomes were...... compared between clear cell (ccRCC; n = 5008) and papillary patients (n = 466), and recorded type I and type II papillary patients (n = 30 and n = 165, respectively). Overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) favored ccRCC over pRCC. OS was 8 months longer...

Limited role of murine ATM in oncogene-induced senescence and p53-dependent tumor suppression.

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Alejo Efeyan

Full Text Available Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability.

Dual Inhibition of EGFR and VEGF in Heavily Pretreated Patients with Metastatic Colorectal Cancer

DEFF Research Database (Denmark)

Larsen, Finn Ole; Markussen, Alice; Nielsen, Dorte

2017-01-01

: The combination of irinotecan, bevacizumab, and cetuximab/panitumumab is safe and shows a toxicity profile corresponding to what is expected from the agents alone. The results indicate that the combination in the 4th line may result in a high rate of disease control in heavily pretreated patients with metastatic...

Exploring the role of CHI3L1 in pre-metastatic lungs of mammary tumor-bearing mice

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Stephania eLibreros

2013-12-01

Full Text Available Elevated levels of chitinase-3-like-1 (CHI3L1 are associated with poor prognosis, shorter recurrence-free intervals and low survival in breast cancer patients. Breast cancer often metastasizes to the lung. We hypothesized that molecules expressed in the pre-metastatic lung microenvironment could support the newly immigrant tumor cells by providing growth and angiogenic factors. Macrophages are known to play an important role in tumor growth by releasing pro-angiogenic molecules. Using mouse mammary tumor models, we have previously shown that during neoplastic progression both the mammary tumor cells and splenic macrophages from tumor-bearing mice express higher levels of CHI3L1 compared to normal control mice. However, the role of CHI3L1 in inducing angiogenesis by macrophages at the pulmonary microenvironment to support newly arriving breast cancer cells is not yet known. In this study, we determined the expression of CHI3L1 in bronchoalveolar lavage macrophages and interstitial macrophages in regulating angiogenesis that could support the growth of newly immigrant mammary tumor cells into the lung. Here we show that in vitro treatment of pulmonary macrophages with recombinant murine CHI3L1 resulted in enhanced expression of pro-angiogenic molecules including CCL2, CXCL2 and MMP-9. We and others have previously shown that inhibition of CHI3L1 decreases the production of angiogenic molecules. In this study, we explored if in vivo administration of chitin microparticles has an effect on the expression of CHI3L1 and pro-angiogenic molecules in the lungs of mammary tumor-bearing mice. We show that treatment with chitin microparticles decreases the expression of CHI3L1 and pro-angiogenic molecules in the metastatic lung. These studies suggest that targeting CHI3L1 may serve as a potential therapeutic agent to inhibit angiogenesis and thus possibly tumor growth and metastasis.

Murine CMV Expressing the High Affinity NKG2D Ligand MULT-1: A Model for the Development of Cytomegalovirus-Based Vaccines

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Lea Hiršl

2018-05-01

Full Text Available The development of a vaccine against human cytomegalovirus (CMV has been a subject of long-term medical interest. The research during recent years identified CMV as an attractive vaccine vector against infectious diseases and tumors. The immune response to CMV persists over a lifetime and its unique feature is the inflationary T cell response to certain viral epitopes. CMV encodes numerous genes involved in immunoevasion, which are non-essential for virus growth in vitro. The deletion of those genes results in virus attenuation in vivo, which enables us to dramatically manipulate its virulence and the immune response. We have previously shown that the murine CMV (MCMV expressing RAE-1γ, one of the cellular ligands for the NKG2D receptor, is highly attenuated in vivo but retains the ability to induce a strong CD8+ T cell response. Here, we demonstrate that recombinant MCMV expressing high affinity NKG2D ligand murine UL16 binding protein-like transcript (MULT-1 (MULT-1MCMV inserted in the place of its viral inhibitor is dramatically attenuated in vivo in a NK cell-dependent manner, both in immunocompetent adult mice and in immunologically immature newborns. MULT-1MCMV was more attenuated than the recombinant virus expressing RAE-1γ. Despite the drastic sensitivity to innate immune control, MULT-1MCMV induced an efficient CD8+ T cell response to viral and vectored antigens. By using in vitro assay, we showed that similar to RAE-1γMCMV, MULT-1 expressing virus provided strong priming of CD8+ T cells. Moreover, MULT-1MCMV was able to induce anti-viral antibodies, which after passing the transplacental barrier protect offspring of immunized mothers from challenge infection. Altogether, this study further supports the concept that CMV expressing NKG2D ligand possesses excellent characteristics to serve as a vaccine or vaccine vector.

Approaches to radiotherapy in metastatic spinal cord compression.

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Suppl, Morten Hiul

2018-04-01

Metastatic spinal cord compression is caused by the progression of metastatic lesions within the vicinity of the spinal cord. The consequences are very severe with loss of neurological function and severe pain. The standard treatment is surgical intervention followed by radiotherapy or radiotherapy alone. However, the majority of patients are treated with radiotherapy only due to contraindications to surgery and technical inoperability. Stereotactic body radiotherapy is a technology to deliver higher radiation dose to the radiotherapy target with the use of spatial coordinates. This modality has shown positive results in treating lesions in brain and lungs. Hence, it could prove beneficial in metastatic spinal cord compression. We designed and planned a trial to investigate this method in patients with metastatic spinal cord compression. The method was usable but the trial was stopped prematurely due to low accrual that made comparison with surgery impossible. Low accrual is a known problem for trials evaluating new approaches in radiotherapy. Target definition in radiotherapy of metastatic spinal cord compression is defined by patient history, examination and imaging. Functional imaging could provide information to guide target definition with the sparring of normal tissue e.g. spinal cord and hematopoietic tissue of the bone marrow. In future trials this may be used for dose escalation of spinal metastases. The trial showed that PET/MRI was feasible in this group of patients but did not change the radiotherapy target in the included patients. Neurological outcome is similar irrespective of course length and therefore single fraction radiotherapy is recommended for the majority of patients. In-field recurrence is a risk factor of both short and long fractionation schemes and re-irradiation have the potential risk of radiation-induced myelopathy. In a retrospective study of re-irradiation, we investigated the incidence of radiation-induced myelopathy. In our study

The prognostic values of CYP2B6 genetic polymorphisms and metastatic sites for advanced breast cancer patients treated with docetaxel and thiotepa.

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Song, Qingkun; Zhou, Xinna; Yu, Jing; Dong, Ningning; Wang, Xiaoli; Yang, Huabing; Ren, Jun; Lyerly, H Kim

2015-11-25

This study investigated interactive effects of CYP2B6 genotypes and liver metastasis on the prognosis of metastatic breast cancer patients who received combined chemotherapy of docetaxel and thiotepa. Totally 153 patients were retrospectively genotyped rs8192719 (c.1294 + 53C > T) and rs2279343 (c.785A > G). Kaplan-Meier method and Cox Proportional Hazard Regression model were used to estimate the survival. Patients with liver metastasis had worsen prognosis, conferring a 2.26-fold high risk of progression and 1.93-fold high risk of death (p T) and AG genotype of rs2279343 (c.785A > G) prolonged survival (p G) was associated with a 47% reduced risk of death and a 6-month-longer overall survival (p T) were 0.45 for progression and 0.40 for death; and the corresponding survival was improved by 6 months and 16 months, respectively (p < 0.05). Genotypes of CYP2B6 had an interaction with clinical efficacy of docetaxel and thiotepa on metastatic breast cancer patients; and metastatic sites also affected clinical responses. Further therapies should take into account of chemotherapy regimen, genotypes of metabolizing enzymes and metastatic sites for the particular subpopulation.

Behavior of a cloned murine interferon alpha/beta receptor expressed in homospecific or heterospecific background.

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Uzé, G; Lutfalla, G; Bandu, M T; Proudhon, D; Mogensen, K E

1992-05-15

A murine interferon (IFN) alpha/beta receptor was cloned from the IFN-sensitive L1210 cell line on the basis of its homology with the human receptor. A combination of methods that includes the screening of random-primed and oligo(dT)-primed cDNA libraries and polymerase chain reactions with a single-side specificity was used. At the amino acid level, the murine IFN-alpha/beta shows 46% identity with its human counterpart. Both human WISH cells presenting a low sensitivity to mouse IFN and a murine L1210 mutant subline that does not express the receptor have been stably transfected with the murine IFN-alpha/beta receptor. Whereas transfected human cells became sensitive to a limited number of mouse IFN-alpha/beta subtypes, the transfected murine L1210 mutant was found to be fully complemented and became sensitive to all mouse IFN-alpha/beta subtypes tested, including those that were not active on transfected human cells. These results strongly suggest that the receptor described here is implicated in the mediation of the activities of all murine IFN-alpha/beta subtypes.

Morphogenetic events in the perinodal connective tissue in a metastatic cancer model.

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Conti, G; Minicozzi, A; Merigo, F; Marzola, P; Osculati, F; Cordiano, C; Sbarbati, A

2013-02-01

The modifications of connective tissue surrounding metastatic lymph nodes in a murine model of rectal cancer are described. Athymic nude mice (n=36) were inoculated with 10×10(5) ht-29 cancer cells into the submucosal layer of the rectum. Control mice (n=5) were treated with a sterile buffer. Tumor and the involved lymph nodes were visualized in vivo by magnetic resonance imaging at 1 to 4 weeks after cell injection. After the sacrifice, the excised samples were processed for histology. After one week from cell injection all treated animals developed rectal cancer. Since the first week, neoplastic cells were visible in the nodes. In the surrounding connective tissue, the diameter of the adipocytes was reduced and a mesenchymal-like pattern with stellate cells embedded in an oedematous environment was visible. Since the second week, in the perinodal connective an enlargement of the stroma was present. The tissue was organized in cords and areas with extracellular accumulation of lipids were found. At the fourth week, we observed an enlargement of multilocular areas and lobules of elongated elements almost devoid of lipid droplets. In control animals, in absence of neoplastic masses, pelvic nodes were surrounded by a typical connective tissue characterized by unilocular adipocytes with groups of multilocular adipocytes. We have developed a model of rectal cancer with nodal metastases. Using this model, the work demonstrates that around secondary lesions, the morphogenetic events follow a standard evolution characterized by an early phase with lipolysis and mesenchymalization and later phases with a brown-like phenotype acquisition. Copyright © 2012. Published by Elsevier SAS.

Prediction of treatment response and metastatic disease in soft tissue sarcoma

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Farhidzadeh, Hamidreza; Zhou, Mu; Goldgof, Dmitry B.; Hall, Lawrence O.; Raghavan, Meera.; Gatenby, Robert A.

2014-03-01

Soft tissue sarcomas (STS) are a heterogenous group of malignant tumors comprised of more than 50 histologic subtypes. Based on spatial variations of the tumor, predictions of the development of necrosis in response to therapy as well as eventual progression to metastatic disease are made. Optimization of treatment, as well as management of therapy-related side effects, may be improved using progression information earlier in the course of therapy. Multimodality pre- and post-gadolinium enhanced magnetic resonance images (MRI) were taken before and after treatment for 30 patients. Regional variations in the tumor bed were measured quantitatively. The voxel values from the tumor region were used as features and a fuzzy clustering algorithm was used to segment the tumor into three spatial regions. The regions were given labels of high, intermediate and low based on the average signal intensity of pixels from the post-contrast T1 modality. These spatially distinct regions were viewed as essential meta-features to predict the response of the tumor to therapy based on necrosis (dead tissue in tumor bed) and metastatic disease (spread of tumor to sites other than primary). The best feature was the difference in the number of pixels in the highest intensity regions of tumors before and after treatment. This enabled prediction of patients with metastatic disease and lack of positive treatment response (i.e. less necrosis). The best accuracy, 73.33%, was achieved by a Support Vector Machine in a leave-one-out cross validation on 30 cases predicting necrosis treatment and metastasis.

Ziv-aflibercept in metastatic colorectal cancer

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Patel A

2013-12-01

Full Text Available Anuj Patel, Weijing Sun Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Abstract: The combination of cytotoxic chemotherapy and antiangiogenic agents has become a conventional treatment option for patients with metastatic colorectal cancer. Ziv-aflibercept is a fusion protein which acts as a decoy receptor for vascular endothelial growth factor (VEGF-A, VEGF-B, and placental growth factor (PlGF; it was approved in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing fluoropyrimidine-based regimen. Herein we review the role of tumor angiogenesis as the rationale for antiangiogenic therapy, the clinical data associated with ziv-aflibercept, and its current role as a treatment option compared to other antiangiogenic agents, such as bevacizumab and regorafenib. Keywords: aflibercept, angiogenesis, colorectal cancer

Living with Metastatic Breast Cancer: A Qualitative Analysis of Physical, Psychological, and Social Sequelae

OpenAIRE

Mosher, Catherine E.; Johnson, Courtney; Dickler, Maura; Norton, Larry; Massie, Mary Jane; DuHamel, Katherine

2013-01-01

Women with metastatic breast cancer face a wide range of medical, practical, and emotional challenges that impact their quality of life. Research to date, however, has not focused on the quality-of-life concerns of metastatic breast cancer patients with significant distress. The present study examined a range of concerns among distressed metastatic breast cancer patients, including physical and emotional distress, social functioning, and existential issues. Forty-four distressed women with me...

Histological heterogeneity in primary and metastatic classic combined hepatocellular-cholangiocarcinoma: a case series.

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De Vito, Claudio; Sarker, Debashis; Ross, Paul; Heaton, Nigel; Quaglia, Alberto

2017-11-01

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare and aggressive primary liver cancer with both hepatocellular and cholangiocellular differentiation. Due to its bi-phenotypic component, cHCC-CC is a heterogeneous tumour and histopathological analysis of metastatic deposits is poorly characterized. In this retrospective study, we describe four patients in whom the histology from resected specimens of both primary and recurrent and/or metastatic tumour was available for comparison and immunohistochemical characterization. Our study shows that recurrent or metastatic deposits replicate the heterogeneity of the primary cHCC-CC, that even originally small foci of divergent differentiation can become predominant later on and that hepatocellular and cholangiocellular components can show different tropism in distant organs. In our experience, the behaviour of recurrent/metastatic cHCC-CC is unpredictable and histological examination is necessary to guide treatment options at present.

The murine Cd48 gene: allelic polymorphism in the IgV-like region.

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Cabrero, J G; Freeman, G J; Reiser, H

1998-12-01

The murine CD48 molecule is a member of the immunoglobulin superfamily which regulates the activation of T lymphocytes. prior cloning experiments using mRNA from two different mouse strains had yielded discrepant sequences within the IgV-like domain of murine CD48. To resolve this issue, we have directly sequenced genomic DNA of 10 laboratory strains and two inbred strains of wild origin. The results of our analysis reveal an allelic polymorphism within the IgV-like domain of murine CD48.

Higher cell stiffness indicating lower metastatic potential in B16 melanoma cell variants and in (-)-epigallocatechin gallate-treated cells.

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Watanabe, Tatsuro; Kuramochi, Hiromi; Takahashi, Atsushi; Imai, Kazue; Katsuta, Naoko; Nakayama, Tomonobu; Fujiki, Hirota; Suganuma, Masami

2012-05-01

To understand how nanomechanical stiffness affects metastatic potential, we studied the relationship between cell migration, a characteristic of metastasis, and cell stiffness using atomic force microscopy (AFM), which can measure stiffness (elasticity) of individual living cells. Migration and cell stiffness of three metastatic B16 melanoma variants (B16-F10, B16-BL6, and B16-F1 cells), and also effects of (-)-epigallocatechin gallate (EGCG), were studied using Transwell assay and AFM. Migration of B16-F10 and B16-BL6 cells was 3 and 2 times higher than that of B16-F1 cells in Transwell assay, and cell stiffness determined by AFM was also different among the three variants, although they have similar morphologies and the same growth rates: Means of Young's modulus were 350.8 ± 4.8 Pa for B16-F10 cells, 661.9 ± 16.5 Pa for B16-BL6 cells, and 727.2 ± 13.0 Pa for B16-F1 cells. AFM measurements revealed that highly motile B16-F10 cells have low cell stiffness, and low motile and metastatic B16-F1 cells have high cell stiffness: Nanomechanical stiffness is inversely correlated with migration potential. Treatment of highly motile B16-F10 cells with EGCG increased cell stiffness 2-fold and inhibited migration of the cells. Our study with AFM clearly demonstrates that cell stiffness is a reliable quantitative indicator of migration potential, and very likely metastatic potential, even in morphologically similar cells. And increased cell stiffness may be a key nanomechanical feature in inhibition of metastasis.

Characterization of a Novel Murine Model to Study Zika Virus.

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Rossi, Shannan L; Tesh, Robert B; Azar, Sasha R; Muruato, Antonio E; Hanley, Kathryn A; Auguste, Albert J; Langsjoen, Rose M; Paessler, Slobodan; Vasilakis, Nikos; Weaver, Scott C

2016-06-01

The mosquito-borne Zika virus (ZIKV) is responsible for an explosive ongoing outbreak of febrile illness across the Americas. ZIKV was previously thought to cause only a mild, flu-like illness, but during the current outbreak, an association with Guillain-Barré syndrome and microcephaly in neonates has been detected. A previous study showed that ZIKV requires murine adaptation to generate reproducible murine disease. In our study, a low-passage Cambodian isolate caused disease and mortality in mice lacking the interferon (IFN) alpha receptor (A129 mice) in an age-dependent manner, but not in similarly aged immunocompetent mice. In A129 mice, viremia peaked at ∼10(7) plaque-forming units/mL by day 2 postinfection (PI) and reached high titers in the spleen by day 1. ZIKV was detected in the brain on day 3 PI and caused signs of neurologic disease, including tremors, by day 6. Robust replication was also noted in the testis. In this model, all mice infected at the youngest age (3 weeks) succumbed to illness by day 7 PI. Older mice (11 weeks) showed signs of illness, viremia, and weight loss but recovered starting on day 8. In addition, AG129 mice, which lack both type I and II IFN responses, supported similar infection kinetics to A129 mice, but with exaggerated disease signs. This characterization of an Asian lineage ZIKV strain in a murine model, and one of the few studies reporting a model of Zika disease and demonstrating age-dependent morbidity and mortality, could provide a platform for testing the efficacy of antivirals and vaccines. © The American Society of Tropical Medicine and Hygiene.

Analysis of T cell receptor alpha beta variability in lymphocytes infiltrating melanoma primary tumours and metastatic lesions

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Schøller, J; thor Straten, P; Jakobsen, Annette Birck

1994-01-01

The T cell receptor (TCR) alpha beta variable (V) gene family usage of tumour-infiltrating lymphocytes (TIL) in four different primary human malignant melanomas and their corresponding metastatic lesions was characterized using a recently developed method based on the reverse-transcription-couple......The T cell receptor (TCR) alpha beta variable (V) gene family usage of tumour-infiltrating lymphocytes (TIL) in four different primary human malignant melanomas and their corresponding metastatic lesions was characterized using a recently developed method based on the reverse...... usage of the TCR V gene families V alpha 4, V alpha 5, V alpha 22 and V beta 8, whereas the V beta 3 gene family appeared to be expressed together with HLA-A1. Other highly expressed V gene families, apparently not restricted to either HLA-A1 or -A2, were V alpha 1 (expressed in three of four primary...... tumours) and V alpha 21 (expressed in two of four tumours). We found no evidence suggesting any correlations between the haplotypes HLA-A1 and -A2 and preferential V gene family expression in the metastatic lesions, and the only common feature was V alpha 8, which was found to be highly expressed in two...

Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis.

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Cai, Jun; Ma, Hong; Huang, Fang; Zhu, Dichao; Bi, Jianping; Ke, Yang; Zhang, Tao

2013-11-28

With the wide application of targeted drug therapies, the relevance of prognostic and predictive markers in patient selection has become increasingly important. Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer. However, there are currently no predictive or prognostic biomarkers for bevacizumab. Several clinical studies have evaluated bevacizumab-induced hypertension in patients with metastatic colorectal cancer. This meta-analysis was performed to better determine the association of bevacizumab-induced hypertension with outcome in patients with metastatic colorectal cancer, and to assess whether bevacizumab-induced hypertension can be used as a prognostic factor in these patients. We performed a systematic review and meta-analysis on seven published studies to investigate the relationship between hypertension and outcome of patients with metastatic colorectal cancer treated with bevacizumab. Our primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and overall response rate (ORR). Hazard ratios (HRs) for PFS and OS were extracted from each trial, and the log of the relative risk ratio (RR) was estimated for ORR. The occurrence of bevacizumab-induced hypertension in patients was highly associated with improvements in PFS (HR = 0.57, 95% CI: 0.46-0.72; P hypertension. Bevacizumab-induced hypertension may represent a prognostic factor in patients with metastatic colorectal cancer.

Avelumab: a new standard for treating metastatic Merkel cell carcinoma.

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Baker, Mairead; Cordes, Lisa; Brownell, Isaac

2018-04-01

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Although MCC is chemosensitive, responses to traditional chemotherapeutic agents are not durable. Avelumab, a novel anti-PD-L1 immune checkpoint inhibitor, recently became the first FDA-approved agent for the treatment of metastatic MCC and represents a new option to improve patient survival. Areas covered: This article presents an overview of MCC and summarizes the development of avelumab in the treatment of metastatic MCC. Preclinical studies, phase 1 and phase 2 clinical trials, and the safety profile of avelumab are reviewed. Future perspectives and ongoing studies are also discussed. Expert commentary: Avelumab demonstrated rapid and durable responses and a manageable safety profile in the treatment of metastatic MCC. Patient outcomes are favorable when compared to historical responses to standard chemotherapy. Ongoing clinical trials will continue to characterize avelumab and its optimal use in MCC therapy.

Characterization of TEM1/endosialin in human and murine brain tumors

International Nuclear Information System (INIS)

Carson-Walter, Eleanor B; Walter, Kevin A; Winans, Bethany N; Whiteman, Melissa C; Liu, Yang; Jarvela, Sally; Haapasalo, Hannu; Tyler, Betty M; Huso, David L; Johnson, Mahlon D

2009-01-01

TEM1/endosialin is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of TEM1/endosialin in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models. In situ hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize TEM1/endosialin expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in TEM1/endosialin expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown in vitro. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude TEM1/endosialin knockout (KO) and wildtype (WT) mice. TEM1/endosialin was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated TEM1/endosialin expression in 79% of tumors. Robust TEM1/endosialin expression occurred in 31% of glioblastomas (grade IV astroctyomas). TEM1/endosialin expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, αSMA and fibronectin in clinical specimens. In vitro, TEM1/endosialin was upregulated in human endothelial cells cultured in matrigel. Vascular Tem1/endosialin was induced in intracranial U87MG GBM xenografts grown in mice. Tem1/endosialin KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although Tem1/endosialin KO tumors were significantly more vascular than the WT counterparts. TEM1/endosialin was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of TEM1/endosialin did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of TEM1

Protective, elective lung irradiation in non-metastatic Ewing's sarcoma.

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Marinova, L; Hristozova, I; Mihaylova, I; Perenovska, P

2015-07-01

Ewing's sarcoma in childhood is a disease from family of the peripheral primitive neuroectodermal tumours. For a period of 16 y (1984-2000), 34 children with Ewing's sarcoma were treated and followed in our department. Twenty-seven of these patients were without distant metastases. Complex treatment was applied to all these patients-chemotherapy VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin), local radiotherapy to a total dose of 50-56 Gy +/- surgery. After, a local tumour control was achieved in 11 children with non-metastatic Ewing's sarcoma, elective whole lung irradiation to a total dose of 12-15 Gy was applied. Our experience in these 11 patients with non-metastatic Ewing's sarcoma, in whom elective lung irradiation was applied, showed significant reduction in the lung metastases, improved free of disease survival and overall survival. The achieved good treatment results necessitate extending this treatment approach through defining the risk groups of patients, suitable for elective lung radiotherapy combined with chemotherapy in non-metastatic Ewing's sarcoma. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Consistent expression of guanylyl cyclase-C in primary and metastatic gastrointestinal cancers.

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Hadi Danaee

Full Text Available The transmembrane receptor guanylate cyclase-C (GCC has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues.GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627 with gastrointestinal tumors, including esophageal (n = 130, gastric (n = 276, pancreatic (n = 136, and colorectal (n = 85 primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors.Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients.This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease.

Analysis of the capacity to produce IL-3 in murine AIDS

DEFF Research Database (Denmark)

Neuenschwander, A U; Marker, O; Thomsen, Allan Randrup

1994-01-01

Adult C57BL/6 mice infected with LP-BM5 murine leukaemia virus represent a model of murine AIDS (MAIDS). In this study we have analysed the capacity of CD4+ T cells from infected mice to produce IL-3 following stimulation with ConA for 24-72 h. In contrast to the position with IL-2, the production...

Knee pain and swelling: An atypical presentation of metastatic colon cancer to the patella

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Bethany Gasagranda, DO

2014-01-01

Full Text Available Knee pain is a common reason for a patient to seek medical evaluation. Of the many causes of knee pain, malignancy is one of the least common. When malignancy is the etiology of the pain, it is usually due to a primary tumor of the osseous structures or soft tissues of the knee joint. Metastatic disease involving the knee joint is uncommon, with few cases reported in the literature. Of these reported cases, metastatic colon cancer is exceedingly rare. However, in a patient with new onset knee pain and the proper clinical history, metastatic disease should be considered as a potential explanation of symptoms. We report a case of knee pain and swelling due to metastatic colon cancer to the patella.

Prognostic significance of the lymphocyte-to-monocyte ratio in patients with metastatic colorectal cancer.

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Shibutani, Masatsune; Maeda, Kiyoshi; Nagahara, Hisashi; Ohtani, Hiroshi; Sakurai, Katsunobu; Yamazoe, Sadaaki; Kimura, Kenjiro; Toyokawa, Takahiro; Amano, Ryosuke; Tanaka, Hiroaki; Muguruma, Kazuya; Hirakawa, Kosei

2015-09-14

To evaluate the prognostic significance of the lymphocyte to monocyte ratio (LMR) in patients with unresectable metastatic colorectal cancer who received palliative chemotherapy. A total of 104 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy were enrolled. The LMR was calculated from blood samples by dividing the absolute lymphocyte count by the absolute monocyte count. Pre-treatment LMR values were measured within one week before the initiation of chemotherapy, while post-treatment LMR values were measured eight weeks after the initiation of chemotherapy. The median pre-treatment LMR was 4.16 (range: 0.58-14.06). We set 3.38 as the cut-off level based on the receiver operating characteristic curve. Based on the cut-off level of 3.38, 66 patients were classified into the high pre-treatment LMR group and 38 patients were classified into the low pre-treatment LMR group. The low pre-treatment LMR group had a significantly worse overall survival rate (P = 0.0011). Moreover, patients who demonstrated low pre-treatment LMR and normalization after treatment exhibited a better overall survival rate than the patients with low pre-treatment and post-treatment LMR values. The lymphocyte to monocyte ratio is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy.

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer.

Science.gov (United States)

Michael, M; Chander, S; McKendrick, J; MacKay, J R; Steel, M; Hicks, R; Heriot, A; Leong, T; Cooray, P; Jefford, M; Zalcberg, J; Bressel, M; McClure, B; Ngan, S Y

2014-11-11

Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

Prostate Specific Membrane Antigen (PSMA) Targeted Bio-orthogonal Therapy for Metastatic Prostate Cancer

Science.gov (United States)

2017-10-01

AWARD NUMBER: W81XWH-16-1-0595 TITLE: Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate Cancer...Sep 2016 - 14 Sep 2017 4. TITLE AND SUBTITLE Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate

Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

Directory of Open Access Journals (Sweden)

Yi-Chieh Li

Full Text Available Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

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Li, Yi-Chieh; Hsieh, Chang-Chi

2014-01-01

Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

High molecular weight hyaluronic acid increases the differentiation potential of the murine chondrocytic ATDC5 cell line.

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Sato, Eiichi; Ando, Takashi; Ichikawa, Jiro; Okita, Genki; Sato, Nobutaka; Wako, Masanori; Ohba, Tetsuro; Ochiai, Satoshi; Hagino, Tetsuo; Jacobson, Richard; Haro, Hirotaka

2014-12-01

Osteoarthritis (OA) is a group of common, chronic, and painful inflammatory joint diseases. One important finding in OA patients is a remarkable decrease in the molecular weight of hyaluronic acid (HA) in the synovial fluid of affected joints. Therapeutic HA is available to patients in most parts of the world as a viscosupplementation product for the treatment of OA. Previous clinical reports show that high molecular weight HA (HMWHA) more effectively relieves pain than low molecular weight HA (LMWHA). However, the mechanism behind this finding remains unclear. In this study, we investigated whether a LMWHA (Low-0.9 MDa) and two types of HMWHA (High-1.9 MDa and 6 MDa) differentially affected chondroregulatory action. We tested this using ATDC5 cell, a murine chondrocytic cell line widely used in culture systems to study chondrogenic differentiation. We found that HMWHA, especially hylan G-F 20 (High-6 MDa), significantly induced aggrecan and proteoglycan accumulation, nodule formation, and mRNA expression of chondrogenic differentiation markers in a time- and dose-dependent manner. In addition, we showed that HMWHA prevented TNF-α induced inhibition of chondrogenic differentiation, with no effect on cell proliferation or viability. These results reveal that HMWHA significantly promotes chondrogenic differentiation of ATDC5 cells in vitro, and suggest that HMWHA plays a significant chondroregulatory role in vivo. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Differential diagnosis between metastatic tumors and nonsolid benign lesions of the liver using ferucarbotran-enhanced MR imaging

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Higashihara, Hiroki [Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 5650871 (Japan)], E-mail: h-higashihara@radiol.med.osaka-u.ac.jp; Murakami, Takamichi [Department of Radiology, Kinki University School of Medicine 377-2 Oonohigashi, Osakasayama, Osaka 5898511 (Japan); Kim, Tonsok; Hori, Masatoshi; Onishi, Hiromitsu [Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 5650871 (Japan); Nakata, Saki [Department of Radiology, Toyonaka Municipal Hospital, 4-14-1 Shibahara Chou, Toyonaka, Osaka 5608565 (Japan); Osuga, Keigo; Tomoda, Kaname; Nakamura, Hironobu [Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 5650871 (Japan)

2010-01-15

Purpose: To evaluate ability of ferucarbotran-enhanced MR imaging (MRI) in differentiating metastases from nonsolid benign lesions of the liver according to signal-intensity characteristics. Materials and methods: Sixty-six consecutive patients, who had 138 focal hepatic lesions (26 cysts, 11 hemangiomas, and 101 metastases), underwent ferucarbotran-enhanced MRI. The signal-intensity pattern of each kind of lesion relative to the liver parenchyma on ferucarbotran-enhanced T2* and heavily T1-weighted gradient-echo images were assessed and categorized into the following three categories: high-intensity and iso-intensity, respectively (category A), high and low (category B), and iso- and low-intensity (category C). For category B, lesions were subdivided into two groups based on single-shot half-Fourier RARE images: category B1 (not significantly high-intensity) and category B2 (significantly high-intensity). Results: Category A had 11 hemangiomas and 2 metastatic tumors, category B1 had 97 metastatic tumors, category B2 had 2 metastatic tumors and 9 cysts, and category C had 17 cysts. When a tumor with a signal intensity of category A was considered to be hemangioma, category B1 metastasis, and category B2 and C cyst, the diagnostic accuracy for differentiating these lesions was 97% (134/138). Conclusion: The combination of signal-intensity pattern on ferucarbotran-enhanced T2*- and heavily T1-weighted gradient-echo MRI has ability to differentiate liver metastases from nonsolid benign lesions. However, T2-weighted single-shot half-Fourier RARE imaging should also be employed to achieve better performance.

Promising oncolytic agents for metastatic breast cancer treatment

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Cody JJ

2015-06-01

Full Text Available James J Cody,1 Douglas R Hurst2 1ImQuest BioSciences, Frederick, MD, 2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA Abstract: New therapies for metastatic breast cancer patients are urgently needed. The long-term survival rates remain unacceptably low for patients with recurrent disease or disseminated metastases. In addition, existing therapies often cause a variety of debilitating side effects that severely impact quality of life. Oncolytic viruses constitute a developing therapeutic modality in which interest continues to build due to their ability to spare normal tissue while selectively destroying tumor cells. A number of different viruses have been used to develop oncolytic agents for breast cancer, including herpes simplex virus, adenovirus, vaccinia virus, measles virus, reovirus, and others. In general, clinical trials for several cancers have demonstrated excellent safety records and evidence of efficacy. However, the impressive tumor responses often observed in preclinical studies have yet to be realized in the clinic. In order for the promise of oncolytic virotherapy to be fully realized for breast cancer patients, effectiveness must be demonstrated in metastatic disease. This review provides a summary of oncolytic virotherapy strategies being developed to target metastatic breast cancer. Keywords: oncolytic virus, virotherapy, breast cancer, metastasis 

CD44 antibodies and immune thrombocytopenia in the amelioration of murine inflammatory arthritis.

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Patrick J Mott

Full Text Available Antibodies to CD44 have been used to successfully ameliorate murine models of autoimmune disease. The most often studied disease model has been murine inflammatory arthritis, where a clear mechanism for the efficacy of CD44 antibodies has not been established. We have recently shown in a murine passive-model of the autoimmune disease immune thrombocytopenia (ITP that some CD44 antibodies themselves can induce thrombocytopenia in mice, and the CD44 antibody causing the most severe thrombocytopenia (IM7, also is known to be highly effective in ameliorating murine models of arthritis. Recent work in the K/BxN serum-induced model of arthritis demonstrated that antibody-induced thrombocytopenia reduced arthritis, causing us to question whether CD44 antibodies might primarily ameliorate arthritis through their thrombocytopenic effect. We evaluated IM7, IRAWB14.4, 5035-41.1D, KM201, KM114, and KM81, and found that while all could induce thrombocytopenia, the degree of protection against serum-induced arthritis was not closely related to the length or severity of the thrombocytopenia. CD44 antibody treatment was also able to reverse established inflammation, while thrombocytopenia induced by an anti-platelet antibody targeting the GPIIbIIIa platelet antigen, could not mediate this effect. While CD44 antibody-induced thrombocytopenia may contribute to some of its therapeutic effect against the initiation of arthritis, for established disease there are likely other mechanisms contributing to its efficacy. Humans are not known to express CD44 on platelets, and are therefore unlikely to develop thrombocytopenia after CD44 antibody treatment. An understanding of the relationship between arthritis, thrombocytopenia, and CD44 antibody treatment remains critical for continued development of CD44 antibody therapeutics.

Murine models of H. pylori-induced gastritis and gastric adenocarcinoma.

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Krueger, Sabine; Roessner, Albert; Kuester, Doerthe

2011-10-15

Laboratory mice have become one of the best animal species for mechanistic studies in gastrointestinal research. Their abundant genetic information, the way of causing carcinogenesis easily by transgenic and gene knockout techniques, limited effort in time and costs, and their practicability provide advantages over other animal models. Meanwhile, several murine practical models have been established for the investigation of the initiation, expansion, and progression of gastritis and gastric carcinoma, for assessing the effects of bacterial, genetic and environmental factors, and for evaluating therapeutic and preventive strategies in gastric diseases. This article gives a review of murine models of gastritis and gastric cancer, placing emphasis on the models associated with Helicobacter pylori infection and techniques used in our laboratory. We discuss matters of murine gastric anatomy, as well as techniques of infection, tissue preparation, and histology. Copyright © 2011 Elsevier GmbH. All rights reserved.

Can urologists introduce the concept of "oligometastasis" for metastatic bladder cancer after total cystectomy?

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Ogihara, Koichiro; Kikuchi, Eiji; Watanabe, Keitaro; Kufukihara, Ryohei; Yanai, Yoshinori; Takamatsu, Kimiharu; Matsumoto, Kazuhiro; Hara, Satoshi; Oyama, Masafumi; Monma, Tetsuo; Masuda, Takeshi; Hasegawa, Shintaro; Oya, Mototsugu

2017-12-19

We investigated whether the concept of oligometastasis may be introduced to the clinical management of metastatic bladder cancer patients. Our study population comprised 128 patients diagnosed with metastatic bladder cancer after total cystectomy at our 6 institutions between 2004 and 2014. We extracted independent predictors for identifying a favorable. Occurrence that fulfilled all 4 criteria which were independently associated with cancer-specific death was defined as oligometastasis: a solitary metastatic organ; number of metastatic lesions of 3 or less; the largest diameter of metastatic foci of 5cm or less; and no liver metastasis. We evaluated differences in clinical outcomes between patients with oligometastasis (oligometastasis group) and those without oligometastasis (non-oligometastasis group). Overall, there were 43 patients in the oligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 53.3%, which was significantly higher than that in the non-oligometastasis group (16.1%, poligometastasis (poligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 55.0%, which was significantly higher than that in the non-oligometastasis group (22.0%, p=0.005). Non-oligometastasis (p=0.009) was the only independent risk factor for cancer-specific death. We presented that urothelial carcinoma with oligometastasis had a favorable prognosis and responded to systemic chemotherapy. Oligometastasis may be treated as a separate entity in the field of metastatic urothelial carcinoma.

Stochastic and Deterministic Models for the Metastatic Emission Process: Formalisms and Crosslinks.

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Gomez, Christophe; Hartung, Niklas

2018-01-01

Although the detection of metastases radically changes prognosis of and treatment decisions for a cancer patient, clinically undetectable micrometastases hamper a consistent classification into localized or metastatic disease. This chapter discusses mathematical modeling efforts that could help to estimate the metastatic risk in such a situation. We focus on two approaches: (1) a stochastic framework describing metastatic emission events at random times, formalized via Poisson processes, and (2) a deterministic framework describing the micrometastatic state through a size-structured density function in a partial differential equation model. Three aspects are addressed in this chapter. First, a motivation for the Poisson process framework is presented and modeling hypotheses and mechanisms are introduced. Second, we extend the Poisson model to account for secondary metastatic emission. Third, we highlight an inherent crosslink between the stochastic and deterministic frameworks and discuss its implications. For increased accessibility the chapter is split into an informal presentation of the results using a minimum of mathematical formalism and a rigorous mathematical treatment for more theoretically interested readers.

Gene expression profiles help identify the Tissue of Origin for metastatic brain cancers

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VandenBerg Scott R

2010-04-01

Full Text Available Abstract Background Metastatic brain cancers are the most common intracranial tumor and occur in about 15% of all cancer patients. In up to 10% of these patients, the primary tumor tissue remains unknown, even after a time consuming and costly workup. The Pathwork® Tissue of Origin Test (Pathwork Diagnostics, Redwood City, CA, USA is a gene expression test to aid in the diagnosis of metastatic, poorly differentiated and undifferentiated tumors. It measures the expression pattern of 1,550 genes in these tumors and compares it to the expression pattern of a panel of 15 known tumor types. The purpose of this study was to evaluate the performance of the Tissue of Origin Test in the diagnosis of primary sites for metastatic brain cancer patients. Methods Fifteen fresh-frozen metastatic brain tumor specimens of known origins met specimen requirements. These specimens were entered into the study and processed using the Tissue of Origin Test. Results were compared to the known primary site and the agreement between the two results was assessed. Results Fourteen of the fifteen specimens produced microarray data files that passed all quality metrics. One originated from a tissue type that was off-panel. Among the remaining 13 cases, the Tissue of Origin Test accurately predicted the available diagnosis in 12/13 (92.3% cases. Discussion This study demonstrates the accuracy of the Tissue of Origin Test when applied to predict the tissue of origin of metastatic brain tumors. This test could be a very useful tool for pathologists as they classify metastatic brain cancers.

Aggressive palliative surgery in metastatic phyllodes tumor: Impact on quality of life

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A S Kapali

2010-01-01

Full Text Available Metastatic phyllodes tumor has very few treatment options. Phyllodes tumor in metastatic setting has limited role of surgery, radiotherapy and chemotherapy or combined treatment. Most of the patients receive symptomatic management only. We present a case of metastatic phyllodes tumor managed with aggressive margin negative resection of primary tumor leading to palliation of almost all the symptoms, which eventually led to improved quality of life and probably to improved survival. The improved quality of life was objectively assessed with Hamilton depression rating scale. Surgery may be the only mode of palliation in selected patients that provides a better quality of life and directly or indirectly may lead to improved survival.

Immunizing Patients With Metastatic Melanoma Using Recombinant Adenoviruses Encoding MART-1 or gp100 Melanoma Antigens

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Rosenberg, Steven A.; Zhai, Yifan; Yang, James C.; Schwartzentruber, Douglas J.; Hwu, Patrick; Marincola, Francesco M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Seipp, Claudia A.; Einhorn, Jan H.; Roberts, Bruce; White, Donald E.

2008-01-01

Background: The characterization of the genes encoding melanoma-associated antigens MART-1 or gp100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma. With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations. Methods: In phase I studies, 54 patients received escalating doses (between 107 and 1011 plaque-forming units) of recombinant adenovirus encoding either MART-1 or gp100 melanoma antigen administered either alone or followed by the administration of interleukin 2 (IL-2). The immunologic impact of these immunizations on the development of cellular and antibody reactivity was assayed. Results: Recombinant adenoviruses expressing MART-1 or gp100 were safely administered. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine. Immunologic assays showed no consistent immunization to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neutralizing antibody were found in the pretreatment sera of the patients. Conclusions: High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients' sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens. PMID:9862627

A novel method for murine intrahepatic islet transplantation via cecal vein.

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Byun, Nari; Kim, Hyun-Je; Min, Byoung-Hoon; Shin, Jun-Seop; Yoon, Il-Hee; Kim, Jong-Min; Kim, Yong-Hee; Park, Chung-Gyu

2015-12-01

Islet transplantation is one of the most beneficial treatment modality to treat type 1 diabetic patients with frequent hypoglycemic unawareness. In clinical setting, human islets are infused via portal vein and are settled in the end-portal venules in the liver. However, mouse islets are transplanted into kidney subcapsule or liver through direct portal vein. These conventional transplantation methods have several drawbacks such as different physiological environments around the transplanted islets in kidney subcapsule from the liver and high mortality rate in direct portal vein approach. In this study, we introduced murine intrahepatic islet transplantation method via cecal vein to have the same surgical operation route in humans as well as guaranteeing low mortality rate after islet transplantation. With this protocol, consistent normoglycemia can be obtained in diabetic mice, while keeping operation-related mortality extremely low. This approach with easier accessibility and low mortality will make murine intrahepatic islet transplantation a useful model for studying immunological mechanisms such as strong innate and adaptive immune responses that occur in human islet transplantation. Copyright © 2015 Elsevier B.V. All rights reserved.

Highly sensitive detection of ESR1 mutations in cell-free DNA from patients with metastatic breast cancer using molecular barcode sequencing.

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Masunaga, Nanae; Kagara, Naofumi; Motooka, Daisuke; Nakamura, Shota; Miyake, Tomohiro; Tanei, Tomonori; Naoi, Yasuto; Shimoda, Masafumi; Shimazu, Kenzo; Kim, Seung Jin; Noguchi, Shinzaburo

2018-01-01

We aimed to develop a highly sensitive method to detect ESR1 mutations in cell-free DNA (cfDNA) using next-generation sequencing with molecular barcode (MB-NGS) targeting the hotspot segment (c.1600-1713). The sensitivity of MB-NGS was tested using serially diluted ESR1 mutant DNA and then cfDNA samples from 34 patients with metastatic breast cancer were analyzed with MB-NGS. The results of MB-NGS were validated in comparison with conventional NGS and droplet digital PCR (ddPCR). MB-NGS showed a higher sensitivity (0.1%) than NGS without barcode (1%) by reducing background errors. Of the cfDNA samples from 34 patients with metastatic breast cancer, NGS without barcode revealed seven mutations in six patients (17.6%) and MB-NGS revealed six additional mutations including three mutations not reported in the COSMIC database of breast cancer, resulting in total 13 ESR1 mutations in ten patients (29.4%). Regarding the three hotspot mutations, all the patients with mutations detected by MB-NGS had identical mutations detected by droplet digital PCR (ddPCR), and mutant allele frequency correlated very well between both (r = 0.850, p < 0.01). Moreover, all the patients without these mutations by MB-NGS were found to have no mutations by ddPCR. In conclusion, MB-NGS could successfully detect ESR1 mutations in cfDNA with a higher sensitivity of 0.1% than conventional NGS and was considered as clinically useful as ddPCR.

Whole exome sequencing of a patient with metastatic hidradenocarcinoma and review of the literature

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Eva Gupta

2015-02-01

Full Text Available Hidradenocarcinoma is a rare malignancy of the sweat glands with only a few cases reported in literature. The management of these tumors is based on the extent of disease with local disease managed with surgical resection. These can tumors carry a high potential of lymphatic and vascular spread and local and distant metastases are not uncommon. Given the rarity of the tumor and lack of genetic and clinical data about these tumors, there is no consensus on the proper management of metastatic disease. Here in we report the first case of metastatic hidradenocarcinoma with detailed molecular profiling including whole exome sequencing. We identified mutations in multiple genes including two that are potentially targetable: PTCH1 and TCF7L1. Further work is necessary to not only confirm the presence of these mutations but also to confirm the clinical significance.

Whole exome sequencing of a patient with metastatic hidradenocarcinoma and review of the literature.

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Gupta, Eva; Guthrie, Kimberly J; Krishna, Murli; Asmann, Yan; Parker, Alexander S; Joseph, Richard W

2015-02-11

Hidradenocarcinoma is a rare malignancy of the sweat glands with only a few cases reported in literature. The management of these tumors is based on the extent of disease with local disease managed with surgical resection. These can tumors carry a high potential of lymphatic and vascular spread and local and distant metastases are not uncommon. Given the rarity of the tumor and lack of genetic and clinical data about these tumors, there is no consensus on the proper management of metastatic disease. Here in we report the first case of metastatic hidradenocarcinoma with detailed molecular profiling including whole exome sequencing. We identified mutations in multiple genes including two that are potentially targetable: PTCH1 and TCF7L1. Further work is necessary to not only confirm the presence of these mutations but also to confirm the clinical significance.

Acute Febrile Illness and Complications Due to Murine Typhus, Texas, USA1,2.

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Afzal, Zeeshan; Kallumadanda, Sunand; Wang, Feng; Hemmige, Vagish; Musher, Daniel

2017-08-01

Murine typhus occurs relatively commonly in southern Texas, as well as in California. We reviewed records of 90 adults and children in whom murine typhus was diagnosed during a 3-year period in 2 hospitals in southern Texas, USA. Most patients lacked notable comorbidities; all were immunocompetent. Initial signs and symptoms included fever (99%), malaise (82%), headache (77%), fatigue (70%), myalgias (68%), and rash (39%). Complications, often severe, in 28% of patients included bronchiolitis, pneumonia, meningitis, septic shock, cholecystitis, pancreatitis, myositis, and rhabdomyolysis; the last 3 are previously unreported in murine typhus. Low serum albumin and elevated procalcitonin, consistent with bacterial sepsis, were observed in >70% of cases. Rash was more common in children; thrombocytopenia, hyponatremia, elevated hepatic transaminases, and complications were more frequent in adults. Murine typhus should be considered as a diagnostic possibility in cases of acute febrile illness in southern and even in more northern US states.

A gene signature to determine metastatic behavior in thymomas.

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Yesim Gökmen-Polar

Full Text Available PURPOSE: Thymoma represents one of the rarest of all malignancies. Stage and completeness of resection have been used to ascertain postoperative therapeutic strategies albeit with limited prognostic accuracy. A molecular classifier would be useful to improve the assessment of metastatic behaviour and optimize patient management. METHODS: qRT-PCR assay for 23 genes (19 test and four reference genes was performed on multi-institutional archival primary thymomas (n = 36. Gene expression levels were used to compute a signature, classifying tumors into classes 1 and 2, corresponding to low or high likelihood for metastases. The signature was validated in an independent multi-institutional cohort of patients (n = 75. RESULTS: A nine-gene signature that can predict metastatic behavior of thymomas was developed and validated. Using radial basis machine modeling in the training set, 5-year and 10-year metastasis-free survival rates were 77% and 26% for predicted low (class 1 and high (class 2 risk of metastasis (P = 0.0047, log-rank, respectively. For the validation set, 5-year metastasis-free survival rates were 97% and 30% for predicted low- and high-risk patients (P = 0.0004, log-rank, respectively. The 5-year metastasis-free survival rates for the validation set were 49% and 41% for Masaoka stages I/II and III/IV (P = 0.0537, log-rank, respectively. In univariate and multivariate Cox models evaluating common prognostic factors for thymoma metastasis, the nine-gene signature was the only independent indicator of metastases (P = 0.036. CONCLUSION: A nine-gene signature was established and validated which predicts the likelihood of metastasis more accurately than traditional staging. This further underscores the biologic determinants of the clinical course of thymoma and may improve patient management.

Role of P2X7 on steroid synthesis in murine luteal cells

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Chunping Zhang

2016-03-01

Full Text Available The extracellular adenosine triphosphate (ATP regulates different cellular functions through activating purinergic receptors as a signalling molecule or neurotransmitter. P2X7 is highly expressed in murine small luteal cells. In this study, murine luteal cells were cultured in vitro and treated with P2X7 agonists – ATP and 2′(3′-O-(4-benzoyl-benzoyl-adenosine 50-triphosphate (BzATP and with P2X7 antagonist – brilliant blue G (BBG. We found that ATP and BzATP increased the production of progesterone and had no influence on the production of estradiol. BBG reversed the effect of BzATP and ATP. Further studies demonstrated that ATP and BzATP promoted the expression of CYP11A. These results revealed that P2X7 receptor activation is involved in the steroid synthesis in corpus luteum.

Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma

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Wersaell, Peter J.; Blomgren, Henric; Lax, Ingmar; Kaelkner, Karl-Mikael; Linder, Christina; Lundell, Goeran; Nilsson, Bo; Nilsson, Sten; Naeslund, Ingemar; Pisa, Pavel; Svedman, Christer

2005-01-01

Background and purpose: We investigated the results of using stereotactic radiotherapy (SRT) for 58 patients with renal cell carcinomas (RCC) who were evaluated restrospectively for response rates, local control rates and side effects. Patients and methods: From October 1997 to January 2003, 50 patients suffering from metastatic RCC and eight patients with inoperable primary RCC received high-dose fraction SRT while placed in a stereotactic body-frame. The most common dose/fractionation schedules used were 8 Gyx4, 10 Gyx4 and 15 Gyx3 during approximately 1 week. Results: SRT-treated tumor lesions regressed totally in 30% of the patients at 3-36 months, whereas 60% of the patients had a partial volume reduction or no change after a median follow-up of 37 months (SD 17.4) for censored and 13 months (SD 12.9) for uncensored patients. Side effects were generally mild. Of 162 treated tumors, only three recurred, yielding a local control rate of 90-98%, considering the 8% non-evaluable sites as defined here. For patients with one to three metastases, the time to new spread was 9 months. Conclusions: Our use of SRT for patients with primary and metastatic RCC yielded a high local control rate with low toxicity. Patients with one to three metastases, local recurrences after nephrectomy or inoperable primary tumors benefited the most, i.e. had fewer distant recurrences (13/23) and longer survival times compared to patients with >3 metastases (24/27 recurrences)

Carotid body paraganglioma metastatic to bone: report of two cases

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Kawai, A.; Healey, J.H.; Wilson, S.C.; Huvos, A.G.; Yeh, S.D.J.

1998-01-01

Two patients with carotid body paraganglioma developed bone metastases 3 and 6 years respectively after surgical excision of the primary tumors. Plain radiographs showed ill-defined metastatic lesions. Scintigram using radiolabeled metaiodobenzylguanidine, an analogue of noradrenaline that is taken up by neurosecretary granules, showed an abnormal accumulation in the corresponding metastatic lesion. Histologically, nests of epithelioid cells with clear cytoplasm and pyknotic nuclei and abundant collagen fibers were observed within destroyed trabeculae. Treatment including external radiation and surgery provided pain relief and early local disease control. (orig.)

EphA2 Is a Potential Player of Malignant Cellular Behavior in Non-Metastatic Renal Cell Carcinoma Cells but Not in Metastatic Renal Cell Carcinoma Cells.

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Cho, Min Chul; Cho, Sung Yong; Yoon, Cheol Yong; Lee, Seung Bae; Kwak, Cheol; Kim, Hyeon Hoe; Jeong, Hyeon

2015-01-01

To investigate the role of EphA2 in malignant cellular behavior in renal cell carcinoma (RCC) cells and whether FAK/RhoA signaling can act as downstream effectors of EphA2 on RCC cells. Expression of EphA2 protein in non-metastatic RCC (Caki-2 and A498), metastatic RCC cells (Caki-1 and ACHN), HEK-293 cells and prostate cancer cells (PC-3 and DU-145; positive controls of EphA2 expression) was evaluated by Western blot. Changes in mRNA or protein expression of EphA2, FAK or membrane-bound RhoA following EphA2, FAK or RhoA small interfering RNA (siRNA) transfection were determined by reverse transcription polymerase chain reaction or Western blot. The effect of siRNA treatment on cellular viability, apoptosis and invasion was analyzed by cell counting kit-8, Annexin-V and modified Matrigel-Boyden assays, respectively. In all RCC cell lines, the expression of EphA2 protein was detectable at variable levels; however, in HEK-293 cells, EphA2 expression was very low. Treatment with EphA2 siRNA significantly reduced the expression of EphA2 mRNA and protein in all RCC cell lines. For non-metastatic RCC cells (Caki-2 and A498) but not metastatic RCC cells (Caki-1 and ACHN), cellular viability, invasiveness, resistance to apoptosis, expression of membrane-bound RhoA protein and FAK phosphorylation were significantly decreased in EphA2 siRNA-treated cells compared to the control. In non-metastatic RCC cells, FAK siRNA significantly attenuated the invasiveness, resistance to apoptosis, as well as expression of membrane-bound RhoA protein without changing protein expression of EphA2. RhoA siRNA significantly decreased the malignant cellular behavior and expression of membrane-bound RhoA protein without changing EphA2 protein expression or FAK phosphorylation. Our data provide the first functional evidence that the EphA2/FAK/RhoA signaling pathway plays a critical role in the malignant cellular behavior of RCC and appears to be functional particularly in the early stage of

Reemergence of Murine Typhus in the US

Centers for Disease Control (CDC) Podcasts

2015-04-21

Dr. Lucas Blanton discusses the Reemergence of Murine Typhus in Galveston Texas in 2013.  Created: 4/21/2015 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 4/27/2015.

Biological Therapy in Treating Patients With Metastatic Cancer

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2013-02-21

Breast Cancer; Colorectal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastric Cancer; Head and Neck Cancer; Liver Cancer; Lung Cancer; Metastatic Cancer; Ovarian Cancer; Pancreatic Cancer; Testicular Germ Cell Tumor

Advancements in the Treatment of Metastatic Breast Cancer (MBC: The Role of Ixabepilone

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Massimo Cristofanilli

2012-01-01

Full Text Available Successful management of breast cancer in the metastatic setting is often confounded by resistance to chemotherapeutics, in particular anthracyclines and taxanes. The limited number of effective treatment options for patients with more aggressive biological subtypes, such as triple-negative metastatic breast cancer, is especially concerning. As such, a therapy clinically proven to be effective in this subtype would be of great value. Ixabepilone, a novel synthetic lactam analog of epothilone B, demonstrated better clinical outcomes in metastatic disease, particularly in triple-negative breast cancer. Most recently, studies have shown the activity of ixabepilone in the neoadjuvant setting, suggesting a role for this drug in primary disease. Notably, treating in the neoadjuvant setting might allow clinicians to explore the predictive value of biomarkers and response to treatment, as pharmacogenomic approaches to therapy continue to evolve. In this article, we review the efficacy and safety data of ixabepilone as a monotherapy and as a component of combination therapy for metastatic and primary breast cancer.

Whole body MRI (WB-MRI) assessment of metastatic spread in prostate cancer: Therapeutic perspectives on targeted management of oligometastatic disease.

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Larbi, Ahmed; Dallaudière, Benjamin; Pasoglou, Vasiliki; Padhani, Anwar; Michoux, Nicolas; Vande Berg, Bruno C; Tombal, Bertrand; Lecouvet, Frédéric E

2016-08-01

To determine the proportion of prostate cancer (PCa) patients with oligometastatic disease (≤3 synchronous lesions) using whole body magnetic resonance imaging with diffusion-weighted imaging (WB-MRI/DWI). To determine the proportion of patients with nodal disease confined within currently accepted target areas for extended lymph node dissection (eLND) and pelvic external beam radiation therapy (EBRT). Two radiologists reviewed WB-MRI/DWI studies in 96 consecutive newly diagnosed metastatic PCa patients; 46 patients with newly diagnosed castration naive PCa (mHNPC) and 50 patients with first appearance of metastasis during monitoring for non-metastatic castration resistant PCa (M0 to mCRPC). The distribution of metastatic deposits was assessed and the proportions of patients with oligometastatic disease and with LN metastases located within eLND and EBRT targets were determined. Twenty-eight percent of mHNPC and 50% of mCPRC entered the metastatic disease with ≤3 sites. Bone metastases (BM) were identified in 68.8% patients; 71.7% of mHNPC and 66% mCRPC patients. Most commonly involved areas were iliac bones and lumbar spine. Enlarged lymph nodes (LN) were detected in 68.7% of patients; 69.6% of mHNPC and 68.0% of mCRPC. Most commonly involved areas were para-aortic, inter-aortico-cava, and external iliac areas. BM and LN were detected concomitantly in 41% of mHNPC and 34% of mCRPC. Visceral metastases were detected in 6.7%. Metastatic disease was confined to LN located within the accepted boundaries of eLND or pelvic EBRT target areas in only ≤25% and ≤30% of patients, respectively. Non-invasive mapping of metastatic landing sites in PCa using WB-MRI/DWI shows that 28% of the mHNPC patients, and 52% of the mCRPC can be classified as oligometastatic, thus challenging the concept of metastatic targeted therapy. More than two thirds of metastatic patients have LN located outside the usually recommended targets of eLND and pelvic EBRT. Prophylactic or salvage

Efficacy of chemotherapy after hormone therapy for hormone receptor-positive metastatic breast cancer.

Science.gov (United States)

Mori, Ryutaro; Nagao, Yasuko

2014-01-01

According to the guidelines for metastatic breast cancer, hormone therapy for hormone receptor-positive metastatic breast cancer without life-threatening metastasis should be received prior to chemotherapy. Previous trials have investigated the sensitivity of chemotherapy for preoperative breast cancer based on the efficacy of neoadjuvant hormone therapy. In this retrospective study, we investigated the efficacy of chemotherapy for metastatic breast cancer in hormone therapy-effective and hormone therapy-ineffective cases. Patients who received chemotherapy after hormone therapy for metastatic breast cancer between 2006 and 2013 at our institution were investigated. A total of 32 patients received chemotherapy after hormone therapy for metastatic breast cancer. The median patient age was 59 years, and most of the primary tumors exhibited a T2 status. A total of 26 patients had an N(+) status, while 7 patients had human epidermal growth factor receptor 2-positive tumors. A total of 13 patients received clinical benefits from hormone therapy, with a rate of clinical benefit of subsequent chemotherapy of 30.8%, which was not significantly different from that observed in the hormone therapy-ineffective patients (52.6%). A total of 13 patients were able to continue the hormone therapy for more than 1 year, with a rate of clinical benefit of chemotherapy of 38.5%, which was not significantly different from that observed in the short-term hormone therapy patients (47.4%). The luminal A patients were able to continue hormone therapy for a significantly longer period than the non-luminal A patients (median survival time: 17.8 months vs 6.35 months, p = 0.0085). However, there were no significant differences in the response to or duration of chemotherapy. The efficacy of chemotherapy for metastatic breast cancer cannot be predicted based on the efficacy of prior hormone therapy or tumor subtype, and clinicians should administer chemotherapy in all cases of

Photo-nano immunotherapy for metastatic cancers (Conference Presentation)

Science.gov (United States)

Zhou, Feifan

2016-03-01

We constructed a multifunction nano system SWNT-GC and investigated the synergize photothermal and immunological effects. Here, we improve the SWNT-GC nano system and design a new synergistic nano-particle, both have the photothermal effects and immunological effects. We investigate the therapeutic effects and detect the immune response with metastatic mouse tumor models. We also study the therapeutic mechanism after treatment in vitro and in vivo. With the enhancement of nano-materials on photothermal effects, laser treatment could destroy primary tumor and protect normal tissue with low dose laser irradiation. With the immunological effects of nano-materials, the treatment could trigger specific antitumor immune response, to eliminate the metastasis tumor. It is providing a promising treatment modality for the metastatic cancers.

Acute lethal toxicity following passive immunization for treatment of murine cryptococcosis.

OpenAIRE

Savoy, A C; Lupan, D M; Manalo, P B; Roberts, J S; Schlageter, A M; Weinhold, L C; Kozel, T R

1997-01-01

Passive immunization with monoclonal antibodies (MAbs) specific for the major capsular polysaccharide of Cryptococcus neoformans alters the course of murine cryptococcosis. During studies of passive immunization for treatment of murine cryptococcosis, we noted the occurrence of an acute, lethal toxicity. Toxicity was characterized by scratching, lethargy, respiratory distress, collapse, and death within 20 to 60 min after injection of antibody. The toxic effect was observed only in mice with ...

Intraarterial infusion chemotherapy for the treatment of metastatic liver cancer

International Nuclear Information System (INIS)

Arai, Yasuaki; Kido, Choichiro

1987-01-01

Some techniques of the most recent interventional radiology are very useful for the treatment of metastatic liver cancer and changing the style of hepatic infusion chemotherapy. This report shows our latest results and methods of hepatic infusion chemotherapy for metastatic liver cancer. 1. For the catheter placement, a new catheterization route via the left subclavian artery into the hepatic artery was developed and performed in 132 cases. Superselective catheterization succeeded in 123 cases (93.2 %). This procedure is less invasive than laparotomy and less troublesome than other percutaneous routes. 2. For useful infusion system, an implantable injection port ''Reservoir'' was developed and it was used in 87 cases. This method makes arterial infusion chemotherapy easy, and imploves their quality of life. 3. To acquire adequate drug delivery, arterial redistribution by steel coils was done, and 109 arteries in 80 cases were occluded. This method is very useful to make multiple hepatic artery single and it is important to avoid gasroduodenal complications. 4. Now, using these techniques, the phase II study of 5FU, ADM, MMC combined hepatic infusion in patients with non-resectable metastatic liver cancer is done. Up to this time, such a phase study on arterial infusion chemotherapy was difficult because of technical problems, but these new techniques make it possible. In conclusion, these new methods change the style and conception of hepatic infusion, and these make much progress on the treatment of patients with metastatic liver cancer. (author)

Metastatic Gastric Linitis Plastica from Bladder Cancer Mimicking a Primary Gastric Carcinoma: a Case Report

International Nuclear Information System (INIS)

Hong, Won Sun; Chung, Dong Jin; Lee, Jae Mun; Byun, Jae Ho; Hahn, Seong Tae

2009-01-01

Primary gastric carcinoma is the most common cause of linitis plastica. Less frequently, metastatic gastric cancer from the breast, omental metastases and non-Hodgkin lymphoma involving the stomach have been reported to show similar radiographic findings as for linitis plastica. A metastatic gastric cancer from bladder cancer is extremely rare. We present an unusual case, the first to our knowledge, of gastric linitis plastica that resulted from a metastatic urothelial carcinoma of the bladder

Murine model of long term obstructive jaundice

Science.gov (United States)

Aoki, Hiroaki; Aoki, Masayo; Yang, Jing; Katsuta, Eriko; Mukhopadhyay, Partha; Ramanathan, Rajesh; Woelfel, Ingrid A.; Wang, Xuan; Spiegel, Sarah; Zhou, Huiping; Takabe, Kazuaki

2016-01-01

Background With the recent emergence of conjugated bile acids as signaling molecules in cancer, a murine model of obstructive jaundice by cholestasis with long-term survival is in need. Here, we investigated the characteristics of 3 murine models of obstructive jaundice. Methods C57BL/6J mice were used for total ligation of the common bile duct (tCL), partial common bile duct ligation (pCL), and ligation of left and median hepatic bile duct with gallbladder removal (LMHL) models. Survival was assessed by Kaplan-Meier method. Fibrotic change was determined by Masson-Trichrome staining and Collagen expression. Results 70% (7/10) of tCL mice died by Day 7, whereas majority 67% (10/15) of pCL mice survived with loss of jaundice. 19% (3/16) of LMHL mice died; however, jaundice continued beyond Day 14, with survival of more than a month. Compensatory enlargement of the right lobe was observed in both pCL and LMHL models. The pCL model demonstrated acute inflammation due to obstructive jaundice 3 days after ligation but jaundice rapidly decreased by Day 7. The LHML group developed portal hypertension as well as severe fibrosis by Day 14 in addition to prolonged jaundice. Conclusion The standard tCL model is too unstable with high mortality for long-term studies. pCL may be an appropriate model for acute inflammation with obstructive jaundice but long term survivors are no longer jaundiced. The LHML model was identified to be the most feasible model to study the effect of long-term obstructive jaundice. PMID:27916350

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

International Nuclear Information System (INIS)

Hanif, R.

2014-01-01

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

Clinical Relevance of Gene Copy Number Variation in Metastatic Clear Cell Renal Cell Carcinoma.

Science.gov (United States)

Nouhaud, François-Xavier; Blanchard, France; Sesboue, Richard; Flaman, Jean-Michel; Sabourin, Jean-Christophe; Pfister, Christian; Di Fiore, Frédéric

2018-02-23

Gene copy number variations (CNVs) have been reported to be frequent in renal cell carcinoma (RCC), with potential prognostic value for some. However, their clinical utility, especially to guide treatment of metastatic disease remains to be established. Our objectives were to assess CNVs on a panel of selected genes and determine their clinical relevance in patients who underwent treatment of metastatic RCC. The genetic assessment was performed on frozen tissue samples of clear cell metastatic RCC using quantitative multiplex polymerase chain reaction of short fluorescent fragment method to detect CNVs on a panel of 14 genes of interest. The comparison of the electropherogram obtained from both tumor and normal renal adjacent tissue allowed for CNV identification. The clinical, biologic, and survival characteristics were assessed for their associations with the most frequent CNVs. Fifty patients with clear cell metastatic RCC were included. The CNV rate was 21.4%. The loss of CDKN2A and PLG was associated with a higher tumor stage (P relevance, especially those located on CDKN2A, PLG, and ALDOB, in a homogeneous cohort of patients with clear cell metastatic RCC. Copyright © 2018 Elsevier Inc. All rights reserved.

The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts.

Science.gov (United States)

Peinado, Héctor; Lavotshkin, Simon; Lyden, David

2011-04-01

Metastasis is a multistep process that requires acquisition of malignant cell phenotypes which allow tumor cells to escape from the primary tumor site. Each of the steps during metastatic progression involves co-evolution of the tumor and its microenvironment. Although tumor cells are the driving force of metastasis, new findings suggest that the host cells within the tumor microenvironment play a key role in influencing metastatic behavior. Many of these contributing cells are derived from the bone marrow; in particular, recruited bone marrow progenitor cells generate the "pre-metastatic niche" to which the tumor cells metastasize. Analysis of the molecular mechanisms involved in pre-metastatic niche formation has revealed that secreted soluble factors are key players in bone marrow cell mobilization during metastasis. In addition, membrane vesicles derived from both tumor and host cells have recently been recognized as new candidates with important roles in the promotion of tumor growth and metastasis. This review describes old ideas and presents new insights into the role of tumor and bone marrow-derived microvesicles and exosomes in pre-metastatic niche formation and metastasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Metastatic renal cell carcinoma in the nasopharynx.

Science.gov (United States)

Atar, Yavuz; Topaloglu, Ilhan; Ozcan, Deniz

2013-01-01

Metastatic renal cell carcinoma of the nasopharynx, nasal cavity, and paranasal sinuses can be misdiagnosed as primary malignant or benign diseases. A 33-year-old male attended our outpatient clinic complaining of difficulty breathing through the nose, bloody nasal discharge, postnasal drop, snoring, and discharge of phlegm. Endoscopic nasopharyngeal examination showed a vascularized nasopharyngeal mass. Under general anesthesia, multiple punch biopsies were taken from the nasopharynx. Pathologically, the tumor cells had clear cytoplasm and were arranged in a trabecular pattern lined by a layer of endothelial cells. After the initial pathological examination, the pathologist requested more information about the patient's clinical status. A careful history revealed that the patient had undergone left a nephrectomy for a kidney mass diagnosed as renal cell carcinoma 3 years earlier. Subsequently, nasopharyngeal metastatic renal cell carcinoma was diagnosed by immunohistochemical staining with CD10 and vimentin. Radiotherapy was recommended for treatment.

Metastatic renal cell carcinoma in the nasopharynx

Directory of Open Access Journals (Sweden)

Yavuz Atar

2013-01-01

Full Text Available Metastatic renal cell carcinoma of the nasopharynx, nasal cavity, and paranasal sinuses can be misdiagnosed as primary malignant or benign diseases. A 33-year-old male attended our outpatient clinic complaining of difficulty breathing through the nose, bloody nasal discharge, postnasal drop, snoring, and discharge of phlegm. Endoscopic nasopharyngeal examination showed a vascularized nasopharyngeal mass. Under general anesthesia, multiple punch biopsies were taken from the nasopharynx. Pathologically, the tumor cells had clear cytoplasm and were arranged in a trabecular pattern lined by a layer of endothelial cells. After the initial pathological examination, the pathologist requested more information about the patient′s clinical status. A careful history revealed that the patient had undergone left a nephrectomy for a kidney mass diagnosed as renal cell carcinoma 3 years earlier. Subsequently, nasopharyngeal metastatic renal cell carcinoma was diagnosed by immunohistochemical staining with CD10 and vimentin. Radiotherapy was recommended for treatment.

Metastatic transitional cell carcinoma of the tibia radiologically mimicking osteosarcoma.

LENUS (Irish Health Repository)

Cunningham, Laurence Patrick

2013-01-01

We report a case of a 73-year-old lady with transitional cell carcinoma and no evidence of metastatic disease presenting with gradual weight loss, pretibial swelling and painful weightbearing. Investigations revealed a lesion of the right tibial diaphysis. The radiological and clinical appearance was that of primary osteosarcoma. Biopsy results revealed metastatic transitional cell carcinoma of the tibia. Intramedullary nailing was performed which relieved pain on weightbearing. The patient declined radiotherapy and was started on a palliative care regimen. This case illustrates the importance of histological diagnosis in the treatment of diaphyseal lesions.

Metastatic Ewing's Sarcoma: Revisiting the “Evidence on the Fence”

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Khanna, Nehal; Pandey, Avinash; Bajpai, Jyoti

2017-01-01

Metastatic Ewing's sarcoma is a challenging disease for oncology care providers with wide spectrum of disease at presentation, widely varying approach to the treatment and varied outcomes. The paucity of randomized evidence is a barrier in developing a consensus. This perspective provides the evidence ”for and against” the benefit of aggressive approach including local and systemic therapy in patients presenting with metastatic Ewing's sarcoma and provide general recommendations so as to help select patients who will benefit with definitive intent treatment and also, avoid aggressive approach in patients with dismal outcome. PMID:28900327

Studies on murine plasmocytoma treatment with mistletoe lectin I

International Nuclear Information System (INIS)

Raabe, F.; Storch, H.

1987-01-01

Mistletoe lectin I was tested in vivo and in vitro for its cytotoxic activity against murine plasmacytoma cells P3/X63-Ag8. As a result of this treatment, 30 to 60% of the BALB/c mice developed complete tumor regressions. 83% of the mice treated with mistletoe lectin I were resistant to viable tumor cell challenge after 100 days. The cytotoxic activity in vitro tested by 3 H-thymidine incorporation into P3/X63-Ag8 cells was very high. The rate was markedly reduced at concentrations up to 0.07 ng/ml. (author)

Combined therapy of radiation and hyperthermia on a metastatic tumor of angiosarcoma

International Nuclear Information System (INIS)

Yasuda, Hiroshi; Kitayama, Yoshiaki

1987-01-01

A combined therapy of radiation and hyperthermia is said to be fairly effective when applied to certain malignant tumors. However, the utility of this therapy for the treatment of angiosarcoma has not been well discussed. Recently, we have had a chance to treat a patient with metastatic angiosarcoma of the neck by using this combined therapy. In this paper, the clinical course of this patient and the availability of this combined therapy for angiosarcoma is reported. The patient was a 77-year-old man, having a primary lesion on the head and a metastatic tumor over the left cheek and neck. This combined therapy was used for the treatment of the metastatic tumor which caused severe pain and uncontrollable bleeding. The results were considered good ; the tumor decreased in size, pain disappeared and no further bleeding or severe side effects were observed. Though the patient died of another metastatic lesion which could not be treated with this combined therapy because the area of its localization could not allow placement in our hyperthermal apparatus, it is concluded that the combined therapy of radiation and hyperthermia is useful selectively for the treatment for angiosarcoma. (author)

Toxicity and profile and objective response of Paclitaxel in metastatic breast cancer

International Nuclear Information System (INIS)

Ansari, T.N.; Mahmood, A; Rasul, S.; Syed, A.S.

2005-01-01

Objective: To evaluate the efficacy and toxicity of 1-hour weekly Paclitaxel in metastatic breast cancer along with evaluation of overall survival. Patients and Methods: Thirty six patients were enrolled in the study. All patients with histologically confirmed and bi- dimensionally measurable metastatic breast cancer who had received previously either chemotherapy or hormone therapy were included in the study. Paclitaxel was administered in 1-hour weekly infusion in a dose of 100 mg/m/sup 2/ for 12 doses. Results: All patients had received previous chemotherapy with either CAF or CMF. Twenty five patients had also received hormone therapy, 61% had two or more metastatic sites involved, and lung was the common site of involvement. Complete response was observed in 4 (11.1 %) patients, partial response in 14 (38.8%) patients, with an overall response rate of 50.0%. Clinical benefit was 94.4% and median overall survival was 11 months. Treatment was well-tolerated with no grade 3 or 4 toxicity. Common side effects were arthralgias, myalgias and neutropenia. Conclusion: Treatment with 1-hour weekly infusion of Paclitaxel is a well-tolerated chemotherapy with a substantial degree of efficacy in patients with metastatic breast cancer. (author)

Cetuximab in treatment of metastatic colorectal cancer

DEFF Research Database (Denmark)

Guren, Tormod Kyrre; Thomsen, Maria Morandi; Kure, Elin H

2017-01-01

BACKGROUND: The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival...

Optimising diffusion weighted MRI for imaging metastatic and myeloma bone disease and assessing reproducibility

International Nuclear Information System (INIS)

Messiou, C.; Collins, D.J.; Morgan, V.A.; DeSouza, N.M.

2011-01-01

To establish normal bone marrow values of apparent diffusion coefficient (ADC) over an age range, compare them with metastatic and myelomatous involvement, to establish reproducibility and to optimise b values. The ADCs of bone marrow in 7 volunteers (mean age 29.7 years), 34 volunteers (mean age 63.3 years) and 43 patients with metastatic and myelomatous involvement (mean age 65.5 years) were measured. In 9 volunteers diffusion weighted MRI was repeated within 7 days. b values were derived to optimise contrast between normal and pathological marrow. The mean ADC of bone marrow in younger volunteers was significantly higher than that of older volunteers. The coefficient of reproducibility was 14.8%. The ADC mean of metastatic and myeloma bone disease was 1054+/-456 x 10 -6 mm 2 s -1 . An ADC threshold of 655 x 10 -6 mm 2 s -1 separated normal and abnormal marrow with a sensitivity and specificity of 90% and 93% respectively. Contrast between normal and abnormal marrow was optimal at b = 1389 smm -2 . The reproducibility of ADC measurements in bone is equivalent to published data for soft tissue with a high sensitivity and specificity for separating abnormal from age matched normal bone marrow. A b value of around 1,400 smm -2 is optimal for imaging bone marrow. (orig.)

Optimising diffusion weighted MRI for imaging metastatic and myeloma bone disease and assessing reproducibility

Energy Technology Data Exchange (ETDEWEB)

Messiou, C. [Institute of Cancer Research and Royal Marsden, NHS Foundation Trust, Cancer Research UK Clinical Magnetic Resonance Research Group, Surrey (United Kingdom); Institute of Cancer Research and Royal Marsden, NHS Foundation Trust, MRI Department, Surrey (United Kingdom); Collins, D.J.; Morgan, V.A.; DeSouza, N.M. [Institute of Cancer Research and Royal Marsden, NHS Foundation Trust, Cancer Research UK Clinical Magnetic Resonance Research Group, Surrey (United Kingdom)

2011-08-15

To establish normal bone marrow values of apparent diffusion coefficient (ADC) over an age range, compare them with metastatic and myelomatous involvement, to establish reproducibility and to optimise b values. The ADCs of bone marrow in 7 volunteers (mean age 29.7 years), 34 volunteers (mean age 63.3 years) and 43 patients with metastatic and myelomatous involvement (mean age 65.5 years) were measured. In 9 volunteers diffusion weighted MRI was repeated within 7 days. b values were derived to optimise contrast between normal and pathological marrow. The mean ADC of bone marrow in younger volunteers was significantly higher than that of older volunteers. The coefficient of reproducibility was 14.8%. The ADC mean of metastatic and myeloma bone disease was 1054+/-456 x 10{sup -6} mm{sup 2}s{sup -1}. An ADC threshold of 655 x 10{sup -6} mm{sup 2}s{sup -1} separated normal and abnormal marrow with a sensitivity and specificity of 90% and 93% respectively. Contrast between normal and abnormal marrow was optimal at b = 1389 smm{sup -2}. The reproducibility of ADC measurements in bone is equivalent to published data for soft tissue with a high sensitivity and specificity for separating abnormal from age matched normal bone marrow. A b value of around 1,400 smm{sup -2} is optimal for imaging bone marrow. (orig.)

Expression of biologically active murine interleukin-18 in Lactococcus lactis.

Science.gov (United States)

Feizollahzadeh, Sadegh; Khanahmad, Hossein; Rahimmanesh, Ilnaz; Ganjalikhani-Hakemi, Mazdak; Andalib, Alireza; Sanei, Mohammad Hossein; Rezaei, Abbas

2016-11-01

The food-grade bacterium Lactococcus lactis is increasingly used for heterologous protein expression in therapeutic and industrial applications. The ability of L. lactis to secrete biologically active cytokines may be used for the generation of therapeutic cytokines. Interleukin (IL)-18 enhances the immune response, especially on mucosal surfaces, emphasizing its therapeutic potential. However, it is produced as an inactive precursor and has to be enzymatically cleaved for maturation. We genetically manipulated L. lactis to secrete murine IL-18. The mature murine IL-18 gene was inserted downstream of a nisin promoter in pNZ8149 plasmid and the construct was used to transform L. lactis NZ3900. The transformants were selected on Elliker agar and confirmed by restriction enzyme digestion and sequencing. The expression and secretion of IL-18 protein was verified by SDS-PAGE, western blotting and ELISA. The biological activity of recombinant IL-18 was determined by its ability to induce interferon (IFN)-γ production in L. lactis co-cultured with murine splenic T cells. The amounts of IL-18 in bacterial lysates and supernatants were 3-4 μg mL -1 and 0.6-0.7 ng mL -1 , respectively. The successfully generated L. lactis strain that expressed biologically active murine IL-18 can be used to evaluate the possible therapeutic effects of IL-18 on mucosal surfaces. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effectiveness of radiation therapy for metastatic spinal tumors producing neurologic impairment

International Nuclear Information System (INIS)

Yamamoto, Shuichiro; Nomoto, Satoshi; Imada, Hajime; Nakata, Hajime

2002-01-01

The purpose of this study was to evaluate the efficacy of radiation therapy (RT) for treating neurological impairment and improving quality of life (QOL) in patients with metastatic spinal tumors. From 1985 through 2001, 75 patients with metastatic spinal tumors were treated with RT. Neurologic status and Karnofsky performance status were assessed before and after RT. The rate of neurologic improvement was significantly higher in patients with radio-sensitive tumors (75%) than in patients with radio-resistant tumors (37%). Few patients with Karnofsky performance status less than 40% before RT had good QOL after RT. The response to RT did not differ significantly on the basis of duration of paralysis before RT. RT is useful for treating neurologic impairment caused by metastatic spinal tumors, particularly those that are radiosensitive. To have good QOL after RT, treatment should be started in the early stage of neurological impairment. (author)

Murine typhus in two travelers returning from Bali, Indonesia: an underdiagnosed disease.

Science.gov (United States)

Takeshita, Nozomi; Imoto, Kazuya; Ando, Shuji; Yanagisawa, Kunio; Ohji, Goh; Kato, Yasuyuki; Sakata, Akiko; Hosokawa, Naoto; Kishimoto, Toshio

2010-01-01

Two Japanese travelers from Bali were diagnosed with murine typhus in Japan during the same period. Although one had only mild illness, the other experienced liver and kidney dysfunction. Murine typhus may be missed not only in endemic areas around the world, but also in travelers, especially those returning from marine resorts in these areas. © 2010 International Society of Travel Medicine.

Extratumoral Heme Oxygenase-1 (HO-1 Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth.

Directory of Open Access Journals (Sweden)

Sofia Halin Bergström

Full Text Available Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1. To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.

A microculture system for the measurement of antigen-induced murine lymphocyte proliferation: advantages of 5% horse serum and 5 X 10(-5) M mercaptoethanol.

Science.gov (United States)

Brummer, E; Vris, T W; Lawrence, H S

1977-01-01

Short term microculture systems which measure murine lymphocyte proliferative responses to mitogens are well established. We demonstrate here that these microculture methods are not suitable for antigen-induced responses because of the high levels of murine lymphocyte proliferation in control cultures associated with the use of fetal calf serum or human serum. We also show that this problem can be eliminated with the use of a combination of 5% horse serum and 5 X 10(-5) M mercaptoethanol. We describe an antigen-induced murine lymphocyte proliferation microculture system in which good stimulation indices are achieved and the lymphocyte proliferation in control cultures remain at a low level throughout the 7 day culture period.

Targeting Neutrophil Protease-Mediated Degradation of Tsp-1 to Induce Metastatic Dormancy

Science.gov (United States)

2017-10-01

AWARD NUMBER: W81XWH-16-1-0615 TITLE: Targeting Neutrophil Protease-Mediated Degradation of Tsp-1 to Induce Metastatic Dormancy PRINCIPAL...29 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Neutrophil Protease-Mediated Degradation of Tsp-1 to Induce Metastatic Dormancy...infection or cigarette smoke enhanced pulmonary metastasis from breast cancer in humans and mice. Similarly, autoimmune arthritis, characterized by

High RBM3 expression is associated with an improved survival and oxaliplatin response in patients with metastatic colorectal cancer.

Directory of Open Access Journals (Sweden)

Christina Siesing

Full Text Available High expression of the RNA-binding motif protein 3 (RBM3 has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinum-based chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy.Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan-Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS and progression-free survival (PFS.High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively. PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively.High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

Cytoreductive surgery for men with metastatic prostate cancer

Directory of Open Access Journals (Sweden)

Nikolas Katelaris

2016-09-01

Conclusions: This data supports recent findings demonstrating that radical prostatectomy for metastatic prostate cancer is feasible. Further studies are needed to explore the role of cytoreductive surgery with regards to the potential oncological benefit.

Can urologists introduce the concept of “oligometastasis” for metastatic bladder cancer after total cystectomy?

Science.gov (United States)

Ogihara, Koichiro; Kikuchi, Eiji; Watanabe, Keitaro; Kufukihara, Ryohei; Yanai, Yoshinori; Takamatsu, Kimiharu; Matsumoto, Kazuhiro; Hara, Satoshi; Oyama, Masafumi; Monma, Tetsuo; Masuda, Takeshi; Hasegawa, Shintaro; Oya, Mototsugu

2017-01-01

We investigated whether the concept of oligometastasis may be introduced to the clinical management of metastatic bladder cancer patients. Our study population comprised 128 patients diagnosed with metastatic bladder cancer after total cystectomy at our 6 institutions between 2004 and 2014. We extracted independent predictors for identifying a favorable. Occurrence that fulfilled all 4 criteria which were independently associated with cancer-specific death was defined as oligometastasis: a solitary metastatic organ; number of metastatic lesions of 3 or less; the largest diameter of metastatic foci of 5cm or less; and no liver metastasis. We evaluated differences in clinical outcomes between patients with oligometastasis (oligometastasis group) and those without oligometastasis (non-oligometastasis group). Overall, there were 43 patients in the oligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 53.3%, which was significantly higher than that in the non-oligometastasis group (16.1%, poligometastasis (poligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 55.0%, which was significantly higher than that in the non-oligometastasis group (22.0%, p=0.005). Non-oligometastasis (p=0.009) was the only independent risk factor for cancer-specific death. We presented that urothelial carcinoma with oligometastasis had a favorable prognosis and responded to systemic chemotherapy. Oligometastasis may be treated as a separate entity in the field of metastatic urothelial carcinoma. PMID:29340094

WITHDRAWN: Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma.

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Sasse, Andre D; Sasse, Emma C; Clark, Luciana Go; Clark, Otavio Augusto Camara

2018-02-06

Malignant melanoma, one of the most aggressive of all skin cancers, is increasing in incidence throughout the world. Surgery remains the cornerstone of curative treatment in earlier stages. Metastatic disease is incurable in most affected people, because melanoma does not respond to most systemic treatments. A number of novel approaches are under evaluation and have shown promising results, but they are usually associated with increased toxicity and cost. The combination of chemotherapy and immunotherapy has been reported to improve treatment results, but it is still unclear whether evidence exists to support this choice, compared with chemotherapy alone. No language restrictions were imposed. To compare the effects of therapy with chemotherapy and immunotherapy (chemoimmunotherapy) versus chemotherapy alone in people with metastatic malignant melanoma. We searched the Cochrane Skin Group Specialised Register (14 February 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (2003 to 30 January 2006 ), EMBASE (2003 to 20 July 2005) and LILACS (1982 to 20 February 2006). References, conference proceedings, and databases of ongoing trials were also used to locate trials. All randomised controlled trials that compared the use of chemotherapy versus chemoimmunotherapy on people of any age, diagnosed with metastatic melanoma. Two authors independently assessed each study to determine whether it met the pre-defined selection criteria, with differences being resolved through discussion with the review team. Two authors independently extracted the data from the articles using data extraction forms. Quality assessment included an evaluation of various components associated with biased estimates of treatment effect. Whenever possible, a meta-analysis was performed on the extracted data, in order to calculate a weighed treatment effect across trials. Eighteen studies met our criteria and were included in the meta

Changing costs of metastatic non small cell lung cancer in the Netherlands.

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Keusters, W R; de Weger, V A; Hövels, A; Schellens, J H M; Frederix, G W J

2017-12-01

The primary objective of this study was to identify the total intramural cost of illness of metastatic non-small cell lung cancer (NSCLC) in the Netherlands between 2006-2012. Secondary objective was to identify whether changes in cost patterns of metastatic NSCLC have occurred over the last years. Patients diagnosed with metastatic NSCLC between 1-1-2006 and 31-12-2012, who had follow-up to death or the date of data cut-off and no trial participation were included. A structured chart review was performed using a case report form. Data collection started after diagnosis of metastatic NSCLC and ended at death or April first, 2015. Data regarding outpatient visits, clinical attendance, oncolytic drug use, imaging, lab tests, radiotherapy and surgery were collected. Sixty-seven patients were included with a median age of 67 years. The median follow-up was 234days. On average patients had 28 outpatient visits and 11 inpatient days. Oncolytic drugs were administered to 76% of the patients. Mean per patient expenditures amounted up to €17,463, with oncolytic drugs (€6,390) as the main cost driver. In comparison with the time-period of 2003-2005 total per patient per year expenses decreased by 44%. The contribution to total yearly costs of oncolytic drugs increased from 18% to 35%, while costs for inpatient stay decreased from 52% to 28% of total expenditures. Outcomes in this study demonstrate that average treatment costs for metastatic NSCLC in the Netherlands Cancer Institute amount to €17,463. Compared to a prior study the average cost for metastatic NSCLC over time in the Netherlands has decreased. A shift of main cost drivers seems to have occurred from inpatient stay, to oncolytic drugs as main contributor. The shift towards treatment cost might become more visible with the introduction of immunotherapy. These results mark the importance of up-to-date cost of illness studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Management of metastatic apocrine hidradenocarcinoma with chemotherapy and radiation

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Daniel H. Miller

2015-10-01

Full Text Available Hidradenocarcinoma is a rare aggressive form of cutaneous adnexal skin carcinoma originating from the sweat gland. Due to its low incidence, prognostic and treatment strategies are still being explored both for primary and advanced disease. This tumor most often presents as either solid or cystic appearing subcutaneous nodules, which may be associated with pruritus or ulceration. To date the mainstay of treatment for local disease has been surgical excision; however, the paucity of historical data available has shown that these tumors often behave aggressively with high rates of local recurrence, metastasis, and poor overall outcomes. There are few case reports describing the utility of radiation therapy in the treatment of hidradenocarcinoma. Herein, we present a case of metastatic apocrine hidradenocarcinoma in a 32-year-old Caucasian male. The patient initially underwent excisional biopsy which confirmed the diagnosis of poorly differentiated, highly infiltrative, apocrine hidradenocarcinoma. He received systemic chemotherapy for metastatic disease, followed by radiation therapy to areas of grossly palpable adenopathy. Prior to radiation therapy the patient had an enlarged hypermetabolic conglomerate of lymph nodes in the right axilla, and borderline enlarged low activity nodes within the left axilla. He received 3 cycles of chemotherapy followed by tamoxifen and radiation therapy (50.4 Gy in 28 fractions to areas of progressive disease in the bilateral axilla, lower neck, and axillary skin. Following treatment, the patient had complete resolution of skin nodules and improvement of his pruritus. While the role of radiation therapy in the treatment of hidradenocarcinoma has not been well established, this case report demonstrated the potential benefit of external beam radiotherapy in the management of this rare disease

Management of Metastatic Apocrine Hidradenocarcinoma with Chemotherapy and Radiation.

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Miller, Daniel H; Peterson, Jennifer L; Buskirk, Steven J; Vallow, Laura A; Ta, Randy; Joseph, Richard; Krishna, Murli; Ko, Stephen J; Tzou, Katherine S

2015-09-07

Hidradenocarcinoma is a rare aggressive form of cutaneous adnexal skin carcinoma originating from the sweat gland. Due to its low incidence, prognostic and treatment strategies are still being explored both for primary and advanced disease. This tumor most often presents as either solid or cystic appearing subcutaneous nodules, which may be associated with pruritus or ulceration. To date the mainstay of treatment for local disease has been surgical excision; however, the paucity of historical data available has shown that these tumors often behave aggressively with high rates of local recurrence, metastasis, and poor overall outcomes. There are few case reports describing the utility of radiation therapy in the treatment of hidradenocarcinoma. Herein, we present a case of metastatic apocrine hidradenocarcinoma in a 32-year-old Caucasian male. The patient initially underwent excisional biopsy which confirmed the diagnosis of poorly differentiated, highly infiltrative, apocrine hidradenocarcinoma. He received systemic chemotherapy for metastatic disease, followed by radiation therapy to areas of grossly palpable adenopathy. Prior to radiation therapy the patient had an enlarged hypermetabolic conglomerate of lymph nodes in the right axilla, and borderline enlarged low activity nodes within the left axilla. He received 3 cycles of chemotherapy followed by tamoxifen and radiation therapy (50.4 Gy in 28 fractions) to areas of progressive disease in the bilateral axilla, lower neck, and axillary skin. Following treatment, the patient had complete resolution of skin nodules and improvement of his pruritus. While the role of radiation therapy in the treatment of hidradenocarcinoma has not been well established, this case report demonstrated the potential benefit of external beam radiotherapy in the management of this rare disease.

Combination Drug Delivery Approaches in Metastatic Breast Cancer

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Jun H. Lee

2012-01-01

Full Text Available Disseminated metastatic breast cancer needs aggressive treatment due to its reduced response to anticancer treatment and hence low survival and quality of life. Although in theory a combination drug therapy has advantages over single-agent therapy, no appreciable survival enhancement is generally reported whereas increased toxicity is frequently seen in combination treatment especially in chemotherapy. Currently used combination treatments in metastatic breast cancer will be discussed with their challenges leading to the introduction of novel combination anticancer drug delivery systems that aim to overcome these challenges. Widely studied drug delivery systems such as liposomes, dendrimers, polymeric nanoparticles, and water-soluble polymers can concurrently carry multiple anticancer drugs in one platform. These carriers can provide improved target specificity achieved by passive and/or active targeting mechanisms.

Metastatic melanoma cells escape from immunosurveillance through the novel mechanism of releasing nitric oxide to induce dysfunction of immunocytes.

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Zhang, X M; Xu, Q

2001-12-01

Nitric oxide (NO) is known to facilitate tumour metastasis through the promotion of angiogenesis, vascular dilation, platelet aggregation, etc. In the present study we explored its novel role in producing dysfunction of the host immune system in the metastasis of murine metastatic melanoma B16-BL6 cells. A significant reduction in the mixed lymphocyte reaction (MLR) was observed in the spleen cells from B16-BL6-bearing mice, but not in those from mice bearing the parent cell B16. When B16-BL6 cells were added in vitro to the MLR, a significant decrease was also found, even when they were co-cultured with the lymphocytes in two compartments of a Transwell chamber separated by an 8.0 microm filter. The supernatant from cultured B16-BL6 but not B16 cells, which had a greatly increased NO activity, significantly inhibited concanavalin A- and lipopolysaccharide-induced lymphocyte proliferation. A remarkably higher expression of inducible NO synthase (iNOS) was detected in B16-BL6 cells than in B16 cells. Nomega-Nitro-l-arginine (l-NNA), a NO synthase inhibitor and superoxide dismutase, significantly antagonized the above inhibition by B16-BL6 cells, while l-arginine, a NO precursor, and S-nitroso-N-acetyl-d,l-penicillamine, a NO donor, strengthened the inhibition. Furthermore, l-NNA significantly inhibited lung metastasis of B16-BL6 cells, while l-arginine tended to enhance the metastasis. The cytotoxicity of B16-BL6-specific T-cells was significantly decreased by pre-culture with B16-BL6 cells in a Transwell chamber or the culture supernatants of B16-BL6 cells, whereas l-iminoethyl-lysine, a selective inhibitor of iNOS, showed a significant recovery from the disease. These results suggest that NO released by metastatic tumour cells may impair the immune system, which facilitates the escape from immunosurveillance and metastasis of tumour cells.

Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients

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Ekaterina A. Semenova

2016-07-01

Full Text Available Small cell lung cancer (SCLC is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.

Intrapulmonary Versus Nasal Transduction of Murine Airways With GP64-pseudotyped Viral Vectors

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Mayumi Oakland

2013-01-01

Full Text Available Persistent viral vector-mediated transgene expression in the airways requires delivery to cells with progenitor capacity and avoidance of immune responses. Previously, we observed that GP64-pseudotyped feline immunodeficiency virus (FIV-mediated gene transfer was more efficient in the nasal airways than the large airways of the murine lung. We hypothesized that in vivo gene transfer was limited by immunological and physiological barriers in the murine intrapulmonary airways. Here, we systematically investigate multiple potential barriers to lentiviral gene transfer in the airways of mice. We show that GP64-FIV vector transduced primary cultures of well-differentiated murine nasal epithelia with greater efficiency than primary cultures of murine tracheal epithelia. We further demonstrate that neutrophils, type I interferon (IFN responses, as well as T and B lymphocytes are not the major factors limiting the transduction of murine conducting airways. In addition, we observed better transduction of GP64-pseudotyped vesicular stomatitis virus (VSV in the nasal epithelia compared with the intrapulmonary airways in mice. VSVG glycoprotein pseudotyped VSV transduced intrapulmonary epithelia with similar efficiency as nasal epithelia. Our results suggest that the differential transduction efficiency of nasal versus intrapulmonary airways by FIV vector is not a result of immunological barriers or surface area, but rather differential expression of cellular factors specific for FIV vector transduction.

Isolation and characterisation of Ebolavirus-specific recombinant antibody fragments from murine and shark immune libraries.

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Goodchild, Sarah A; Dooley, Helen; Schoepp, Randal J; Flajnik, Martin; Lonsdale, Stephen G

2011-09-01

Members of the genus Ebolavirus cause fulminating outbreaks of disease in human and non-human primate populations with a mortality rate up to 90%. To facilitate rapid detection of these pathogens in clinical and environmental samples, robust reagents capable of providing sensitive and specific detection are required. In this work recombinant antibody libraries were generated from murine (single chain variable domain fragment; scFv) and nurse shark, Ginglymostoma cirratum (IgNAR V) hosts immunised with Zaire ebolavirus. This provides the first recorded IgNAR V response against a particulate antigen in the nurse shark. Both murine scFv and shark IgNAR V libraries were panned by phage display technology to identify useful antibodies for the generation of immunological detection reagents. Two murine scFv were shown to have specificity to the Zaire ebolavirus viral matrix protein VP40. Two isolated IgNAR V were shown to bind to the viral nucleoprotein (NP) and to capture viable Zaire ebolavirus with a high degree of sensitivity. Assays developed with IgNAR V cross-reacted to Reston ebolavirus, Sudan ebolavirus and Bundibugyo ebolavirus. Despite this broad reactivity, neither of IgNAR V showed reactivity to Côte d'Ivoire ebolavirus. IgNAR V was substantially more resistant to irreversible thermal denaturation than murine scFv and monoclonal IgG in a comparative test. The demonstrable robustness of the IgNAR V domains may offer enhanced utility as immunological detection reagents in fieldable biosensor applications for use in tropical or subtropical countries where outbreaks of Ebolavirus haemorrhagic fever occur. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Tumor attributes predicting cutaneous metastatic destiny: a report of two interesting cases.

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Gurumurthi, Ravichandran; Thirumalai, Raja; Easow, Jose M; Mohan, Subhashini

2014-07-01

Cutaneous metastases are the result of complex interaction between the tumor cells ("seed") and the host environment ("soil"). Metastases to the skin can be an early sign of internal malignancy or represent recurrence of the primary tumor and portends a poorer prognosis. Invasion and metastasis are the hallmarks of on cogenesis. Skin is the largest organ in the body, but the incidence of metastases is low. With advances in molecular biology, factors responsible for the initiation and perpetuation of metastatic tumor cells at distant sites are being elucidated. The concept of "pre-metastatic niche" and interaction between various chemokines has given a new outlook in understanding the organ specificity of metastatic tumor cells. We present two cases of cutaneous metastases with interesting clinical findings correlating with its biologic subtypes.

Metastatic craniopharyngioma: case report and literature review.

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Frangou, Evan Mark; Tynan, Jennifer Ruth; Robinson, Christopher Adam; Ogieglo, Lissa Marie; Vitali, Aleksander Michal

2009-09-01

Distant spread of craniopharyngioma is a rare but important complication. Most cases are a result of spread along the surgical path. We describe a rare case of metastatic leptomeningeal craniopharyngioma as a result of dissemination along CSF pathways in a child. A review of previously described cases is provided. A 14-year-old male was diagnosed with metastatic craniopharyngioma on routine follow-up imaging after multiple surgeries and radiation for locally recurrent craniopharyngioma. The lesion was erosive through the right parietal bone, but had remained clinically silent. The lesion was distant from previous surgical paths. The patient underwent right parietal craniotomy and resection of the lesion. Duraplasty and cranioplasty were necessary for closure. Histopathology confirmed adamantinomatous craniopharyngioma. One-year follow-up demonstrated no recurrence. A review of reported cases suggests that leptomeningeal implantation may be an important step in metastases of craniopharyngioma, although the mechanism is poorly understood. Attention to tumor spillage at the time of surgery may be important in preventing distant recurrences.

Collision tumours, squamous cell carcinoma of larynx, papillary thyroid carcinoma, metastatic lymphatic node. Clinical Presentation

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Villalba, V; Gomez, R; Yoffe, I.; Liu, T.; Arias, J.; Quiroz, J.; Gonzalez, M; Ayala, E.

2010-01-01

Male patient with 35 years old, merchant from Capiata, no history of smoking or alcoholism, with 2 months history of bilateral neck nodes, sore throat, weight loss of 8 kg., dysphonia, progressive dyspne a on medium efforts dyspne a at rest so you see the urgency of the Hospital de Clinicas. On examination: lucid, collaborator, normosomico, with dysphonia, stri dor and dyspne a. P S: 2. No hemodynamic or fever. Neck: tumor mass of 6 cm in diameter, infrahiodea right, accompanying the movement of swallowing, bilateral jugular carotid lymphadenopathy high of 2 cm in diameter, solid-elastic smooth, mobile; lymphadenopathy average lower right carotid and jugular similar characteristics. Laryngoscopy smooth, submucosal, nodular lesion on right vocal cord, paralytic in middle position; aritenoides edematous law, glottal gap of 10%. Mobile left vocal cord. Remainder of the examination: Normal. Emergency tracheotomy performed. Biopsy of the lesion: invasive carcinoma, without other specifications. Laboratory tests: Hb: 11gr% eosinophilia. ECG, Rx. Chest and abdominal ultrasound: within normal limits. CT: tumor mass of 4.5 cm in diameter in right vocal cord, which is in middle position, and infiltrates the thyroid cartilage soft tissue. In thyroid lobe right: node 5 cm diameter. Cervical lymphadenopathy 2 cm in diameter in bilateral high carotid jugular region, medium and low carotid jugular right. 2/9/09 Surgery: Tumor infiltrating infrahiodea right muscles, jugular Total laryngectomy with bilateral carotid dissection, level 2,3 and 4. Right Thyroid lobectomy. Infrahiodea muscle resection. Pathology: 1-larynx neoplasms consist collision, poorly differentiated right infraglotis (3.2 cm.) Keratinizing squamous carcinoma infiltrating focally in depth the laryngeal cartilage through it, and a papillary carcinoma right thyroid lobe (3.4 cm.) massively infiltrating peritiroideo fibroadipose and skeletal muscle tissue infiltrating through the laryngeal cartilage and extending to

Retrospective Analysis of Outcome of Patients with Metastatic Leiomyosarcoma in a Tertiary Referral Center.

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van Cann, Tom; Cornillie, Jasmien; Wozniak, Agnieszka; Debiec-Rychter, Maria; Sciot, Raf; Hompes, Daphne; Vergote, Ignace; Schöffski, Patrick

2018-01-01

Leiomyosarcoma is a common subtype of soft tissue sarcoma originating from smooth muscle. We evaluated the clinical course and treatment outcome of patients with metastatic leiomyosarcoma. We retrospectively reviewed the records of patients at the University Hospitals Leuven. We identified 122 patients with metastatic leiomyosarcoma, 77 female, median age 59.5 years. Most patients developed leiomyosarcoma in the extremities (35%), the uterus (20%) or the abdomen (19%); 69% developed metachronous metastasis, 31% had synchronous metastatic disease. Most patients (74%) received palliative systemic therapy. The most common first-line treatments were doxorubicin (n = 47) and an anthracycline combined with an alkylator (n = 28). The objective response rate to first-line palliative systemic therapy was 20% and the median progression-free survival was 4.9 months (range 0.1-17.1). The median survival from diagnosis of metastasis was 20.5 months (range 0.4-126.9). On multivariate analysis, metachronous disease, no progressive disease as best response to first-line treatment, the possibility of metastasectomy with curative intent and use of palliative radiotherapy were indicators for better survival. The prognosis of patients with metastatic leiomyosarcoma is limited and objective responses to first-line systemic therapy are rare. The treatment of metastatic leiomyosarcoma remains an unmet medical need. © 2018 S. Karger GmbH, Freiburg.

Outcomes in Patients with Obstructive Jaundice from Metastatic Colorectal Cancer and Implications for Management

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Nichols, Shawnn D.; Albert, Scott; Shirley, Lawrence; Schmidt, Carl; Abdel-Misih, Sherif; El-Dika, Samer; Groce, J. Royce; Wu, Christina; Goldberg, Richard M.; Bekaii-Saab, Tanios; Bloomston, Mark

2016-01-01

Introduction Patients with metastatic colorectal cancer can develop jaundice from intrahepatic or extrahepatic causes. Currently, there is little data on the underlying causes and overall survival after onset of jaundice. The purpose of this study was to characterize the causes of jaundice and determine outcomes. Methods Six hundred twenty-nine patients treated for metastatic colorectal cancer between 2004 and 2010 were retrospectively reviewed. Those developing jaundice were grouped as having intrahepatic or extrahepatic obstruction. Demographics, clinicopathologic, and outcome data were analyzed. Results Sixty-two patients with metastatic colorectal cancer developed jaundice. Intrahepatic biliary obstruction was most common, occurring in younger patients. Time from metastatic diagnosis to presentation of jaundice was similar between groups, as was the mean number of prior lines of chemotherapy. Biliary decompression was successful 41.7 % of the time and was attempted more commonly for extrahepatic causes. Median overall survival after onset of jaundice was 1.5 months and it was similar between groups, but improved to 9.6 months in patients who were able to receive further chemotherapy. Conclusions Jaundice due to metastatic colorectal cancer is an ominous finding, representing aggressive tumor biology or exhaustion of therapies. Biliary decompression is often difficult and should only be pursued when additional treatment options are available. PMID:25300799

The Murine Factor H-Related Protein FHR-B Promotes Complement Activation

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Marcell Cserhalmi

2017-09-01

Full Text Available Factor H-related (FHR proteins consist of varying number of complement control protein domains that display various degrees of sequence identity to respective domains of the alternative pathway complement inhibitor factor H (FH. While such FHR proteins are described in several species, only human FHRs were functionally investigated. Their biological role is still poorly understood and in part controversial. Recent studies on some of the human FHRs strongly suggest a role for FHRs in enhancing complement activation via competing with FH for binding to certain ligands and surfaces. The aim of the current study was the functional characterization of a murine FHR, FHR-B. To this end, FHR-B was expressed in recombinant form. Recombinant FHR-B bound to human C3b and was able to compete with human FH for C3b binding. FHR-B supported the assembly of functionally active C3bBb alternative pathway C3 convertase via its interaction with C3b. This activity was confirmed by demonstrating C3 activation in murine serum. In addition, FHR-B bound to murine pentraxin 3 (PTX3, and this interaction resulted in murine C3 fragment deposition due to enhanced complement activation in mouse serum. FHR-B also induced C3 deposition on C-reactive protein, the extracellular matrix (ECM extract Matrigel, and endothelial cell-derived ECM when exposed to mouse serum. Moreover, mouse C3 deposition was strongly enhanced on necrotic Jurkat T cells and the mouse B cell line A20 by FHR-B. FHR-B also induced lysis of sheep erythrocytes when incubated in mouse serum with FHR-B added in excess. Altogether, these data demonstrate that, similar to human FHR-1 and FHR-5, mouse FHR-B modulates complement activity by promoting complement activation via interaction with C3b and via competition with murine FH.

Retrospective assessment of thoracic radiographic findings in metastatic canine hemangiosarcoma

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Hammer, A.S.; Bailey, M.Q.; Sagartz, J.E.

1994-01-01

Twenty-one dogs with histopathologically confirmed hemangiosarcoma were evaluated by thoracic radiography for metastatic disease. All dogs had histopathologic examinations of the lungs within two weeks of thoracic radiography. Fourteen dogs had histopathologic evidence of pulmonary hemangiosarcoma; metastatic disease was detected radiographically in eleven of these dogs. The most common radiographic pattern was that of poorly defined small coalescing nodules (8 dogs); other radiographic patterns included well-circumscribed nodules (3 dogs) and alveolar infiltrates secondary to hemorrhage (2 dogs). Differential diagnoses for diffuse, poorly defined, coalescing pulmonary opacities should include hemangiosarcoma in addition to edema, lymphoma, systemic mycoses, fibrosis, allergy, toxicosis, and carcinomas

Isolation of Blastomyces dermatitidis yeast from lung tissue during murine infection for in vivo transcriptional profiling.

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Marty, Amber J; Wüthrich, Marcel; Carmen, John C; Sullivan, Thomas D; Klein, Bruce S; Cuomo, Christina A; Gauthier, Gregory M

2013-07-01

Blastomyces dermatitidis belongs to a group of thermally dimorphic fungi that grow as sporulating mold in the soil and convert to pathogenic yeast in the lung following inhalation of spores. Knowledge about the molecular events important for fungal adaptation and survival in the host remains limited. The development of high-throughput analytic tools such as RNA sequencing (RNA-Seq) has potential to provide novel insight on fungal pathogenesis especially if applied in vivo during infection. However, in vivo transcriptional profiling is hindered by the low abundance of fungal cells relative to mammalian tissue and difficulty in isolating fungal cells from the tissues they infect. For the purpose of obtaining B. dermatitidis RNA for in vivo transcriptional analysis by RNA-Seq, we developed a simple technique for isolating yeast from murine lung tissue. Using a two-step approach of filtration and centrifugation following lysis of murine lung cells, 91% of yeast cells causing infection were isolated from lung tissue. B. dermatitidis recovered from the lung yielded high-quality RNA with minimal murine contamination and was suitable for RNA-Seq. Approximately 87% of the sequencing reads obtained from the recovered yeast aligned with the B. dermatitidis genome. This was similar to 93% alignment for yeast grown in vitro. The use of near-freezing temperature along with short ex vivo time minimized transcriptional changes that would have otherwise occurred with higher temperature or longer processing time. In conclusion, we have developed a technique that recovers the majority of yeast causing pulmonary infection and yields high-quality fungal RNA with minimal contamination by mammalian RNA. Copyright © 2013 Elsevier Inc. All rights reserved.