Measurable Pharmacodynamic Biomarkers of MET Activation

Purpose: Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect.

Experimental Design: Sandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/1235, pY1235, and pY1356. Using pMET:MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and -compensated (VEGFR blockade) models.

Results: By limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET:MET, pY1235-MET:MET, and pY1356-MET:MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET:MET and pY1356-MET:MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation.

Conclusions: These validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field. Clin Cancer Res; 22(14); 3683–94. ©2016 AACR.

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Micrometastatic Disease in Ewing Sarcoma

Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma.

Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as "positive" for bone marrow micrometastatic disease if their CD99⁺/CD45^– values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples.

Results: The median total bone marrow CD99⁺CD45^– percent was 0.0012% (range 0%–1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as "positive." In the PCR cohort, 19.6% (44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as "positive" versus "negative" by either method. CD99⁺CD45^– cells had significantly higher IGF-1R expression compared with CD45⁺ hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P < 0.001).

Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. Clin Cancer Res; 22(14); 3643–50. ©2016 AACR.

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EMT and Inflammatory Tumor Microenvironment in Lung Cancer

Purpose: Promising results in the treatment of non–small cell lung cancer (NSCLC) have been seen with agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed death ligand-1 (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents.

Methods: We conducted an integrated analysis of three independent large datasets, including The Cancer Genome Atlas of lung adenocarcinoma and two datasets from MD Anderson Cancer Center (Houston, TX), Profiling of Resistance Patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (named PROSPECT) and Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (named BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse-phase protein array, IHC, and correlation with clinical data were performed.

Results: Epithelial–mesenchymal transition (EMT) is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation coexistent with elevation of multiple targetable immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, B7-H3, BTLA, and CTLA-4, along with increases in tumor infiltration by CD4⁺Foxp3⁺ regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Furthermore, we identify B7-H3 as a prognostic marker for NSCLC.

Conclusions: The strong association between EMT status and an inflammatory tumor microenvironment with elevation of multiple targetable immune checkpoint molecules warrants further investigation of using EMT as a predictive biomarker for immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly a broad range of other cancers. Clin Cancer Res; 22(14); 3630–42. ©2016 AACR.

See related commentary by Datar and Schalper, p. 3422

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Patterns of microRNA Expression through the Course of Disease

Purpose: Molecular evolution of tumors during progression, therapy, and metastasis is a major clinical challenge and the main reason for resistance to therapy. We hypothesized that microRNAs (miRNAs) that exhibit similar variation of expression through the course of disease in several patients have a significant function in the tumorigenic process.

Experimental design: Exploration of evolving disease by profiling 800 miRNA expression from serial samples of individual breast cancer patients at several time points: pretreatment, posttreatment, lymph nodes, and recurrence sites when available (58 unique samples from 19 patients). Using a dynamic approach for analysis, we identified expression modulation patterns and classified varying miRNAs into one of the eight possible temporal expression patterns.

Results: The various patterns were found to be associated with different tumorigenic pathways. The dominant pattern identified an miRNA set that significantly differentiated between disease stages, and its pattern in each patient was also associated with response to therapy. These miRNAs were related to tumor proliferation and to the cell-cycle pathway, and their mRNA targets showed anticorrelated expression. Interestingly, the level of these miRNAs was lowest in matched recurrent samples from distant metastasis, indicating a gradual increase in proliferative potential through the course of disease. Finally, the average expression level of these miRNAs in the pretreatment biopsy was significantly different comparing patients experiencing recurrence to recurrence-free patients.

Conclusions: Serial tumor sampling combined with analysis of temporal expression patterns enabled to pinpoint significant signatures characterizing breast cancer progression, associated with response to therapy and with risk of recurrence. Clin Cancer Res; 22(14); 3651–62. ©2016 AACR.

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Immunologic and Metabolic Features can Define PDA Prognosis

Purpose: Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive microenvironment that supports the growth of the malignancy as well as immune system evasion. Here we examine markers of immunosuppression in PDA within the context of the glycolytic tumor microenvironment, their interrelationship with tumor biology and association with overall survival.

Experimental Design: We utilized tissue microarrays consisting of 223 PDA patients annotated for clinical stage, tumor size, lymph node involvement, and survival. Expression of CD163, FoxP3, PD-L1, and MCT4 was assessed by IHC and statistical associations were evaluated by univariate and multivariate analysis. Multimarker subtypes were defined by random forest analysis. Mechanistic interactions were evaluated using PDA cell lines and models for myeloid differentiation.

Results: PDA exhibits discrete expression of CD163, FoxP3, and PD-L1 with modest individual significance. However, combined low expression of these markers was associated with improved prognosis (P = 0.02). PDA tumor cells altered macrophage phenotype and function, which supported enhanced invasiveness in cell-based models. Lactate efflux mediated by MCT4 was associated with, and required for, the selective conversion of myeloid cells. Correspondingly, MCT4 expression correlated with immune markers in PDA cases, and increased the significance of prognostic subtypes (P = 0.002).

Conclusions: There exists a complex interplay between PDA tumor cells and the host immune system wherein immunosuppression is associated with negative outcome. MCT4 expression, representative of the glycolytic state of PDA, contributes to the phenotypic conversion of myeloid cells. Thus, metabolic status of PDA tumors is an important determinant of the immunosuppressive environment. Clin Cancer Res; 22(14); 3606–17. ©2016 AACR.

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MYC Mutations in DLBCL Have Variable Prognostic Impact

Purpose: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.

Experimental Design: We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP–treated patients.

Results: The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3' untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts.

Conclusions: Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593–605. ©2016 AACR.

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Large Cell Neuroendocrine Carcinoma Genomics

Purpose: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types.

Experimental Design: LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242).

Results: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation.

Conclusions: LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618–29. ©2016 AACR.

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Selective PD-L1 Expression on CD44+ SCCHN Cells

Purpose: Human tumors consist of heterogeneous populations of cells with distinct marker expression and functional properties. In squamous cell carcinoma of the head and neck (SCCHN), CD44 is a well-characterized marker of a resilient subpopulation of cells associated with increased tumorigenesis, radioresistance, and chemoresistance. Evidence indicates that these cells have an immunosuppressive phenotype; however, mechanisms have been elusive.

Experimental Design: Using primary human SCCHN tumor samples and patient-derived xenografts, we examined the phenotypes of subsets of tumor cells and investigated mechanisms regulating their immunogenicity.

Results: CD44⁺ cells in primary human SCCHN were found to have an epithelial-to-mesenchymal (EMT) phenotype and were less immunogenic than CD44^– cells when cultured with autologous CD8⁺ tumor-infiltrating T cells. Selective expression of the programmed death-ligand 1 (PD-L1) was observed on CD44⁺ cells compared with CD44^– cells and was associated with constitutive phosphorylation of STAT3 on CD44⁺ cells. Importantly, inhibition of STAT3 decreased expression of PD-L1 on CD44⁺ cells. IFN treatment preferentially induced even further PD-L1 expression on CD44⁺ cells and was associated with enhanced IFN receptor expression and phosphorylation of STAT1. Finally, the decreased immunogenicity of CD44⁺ cells was partially reversed by antibody blockade of the programmed death 1 (PD-1) receptor, indicating that the differences in PD-L1 expression between CD44⁺ and CD44^– cells are biologically and clinically relevant.

Conclusions: Our findings provide a mechanism by which long-lived CD44⁺ tumor-initiating cells can selectively evade host immune responses and provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of SCCHN. Clin Cancer Res; 22(14); 3571–81. ©2016 AACR.

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Inhibition of FOXM1-Mediated DNA Repair by Imipramine Blue

Purpose: The approaches aimed at inhibiting the ability of cancer cells to repair DNA strand breaks have emerged as promising targets for treating cancers. Here, we assessed the potential of imipramine blue (IB), a novel analogue of antidepressant imipramine, to suppress breast cancer growth and metastasis by inhibiting the ability of breast cancer cells to repair DNA strand breaks by homologous recombination (HR).

Experimental Design: The effect of IB on breast cancer growth and metastasis was assessed in vitro as well as in preclinical mouse models. Besides, the therapeutic efficacy and safety of IB was determined in ex vivo explants from breast cancer patients. The mechanism of action of IB was evaluated by performing gene-expression, drug–protein interaction, cell-cycle, and DNA repair studies.

Results: We show that the systemic delivery of IB using nanoparticle-based delivery approach suppressed breast cancer growth and metastasis without inducing toxicity in preclinical mouse models. Using ex vivo explants from breast cancer patients, we demonstrated that IB inhibited breast cancer growth without affecting normal mammary epithelial cells. Furthermore, our mechanistic studies revealed that IB may interact and inhibit the activity of proto-oncogene FoxM1 and associated signaling that play critical roles in HR-mediated DNA repair.

Conclusions: These findings highlight the potential of IB to be applied as a safe regimen for treating breast cancer patients. Given that FoxM1 is an established therapeutic target for several cancers, the identification of a compound that inhibits FoxM1- and FoxM1-mediated DNA repair has immense translational potential for treating many aggressive cancers. Clin Cancer Res; 22(14); 3524–36. ©2016 AACR.

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MiR-182 Targets RAD51 and HR in AML

Purpose: The double-strand breaks elicited by sapacitabine, a clinically active nucleoside analogue prodrug, are repaired by RAD51 and the homologous recombination repair (HR) pathway, which could potentially limit its toxicity. We investigated the mechanism by which histone deacetylase (HDAC) inhibitors targeted RAD51 and HR to sensitize acute myelogenous leukemia (AML) cells to sapacitabine.

Experimental Design: Chromatin immunoprecipitation identified the role of HDACs in silencing miR-182 in AML. Immunoblotting, gene expression, overexpression, or inhibition of miR-182 and luciferase assays established that miR-182 directly targeted RAD51. HR reporter assays, apoptotic assays, and colony-forming assays established that the miR-182, as well as the HDAC inhibition–mediated decreases in RAD51 inhibited HR repair and sensitized cells to sapacitabine.

Results: The gene repressors, HDAC1 and HDAC2, became recruited to the promoter of miR-182 to silence its expression in AML. HDAC inhibition induced miR-182 in AML cell lines and primary AML blasts. miR-182 targeted RAD51 protein both in luciferase assays and in AML cells. Overexpression of miR-182, as well as HDAC inhibition–mediated induction of miR-182 were linked to time- and dose-dependent decreases in the levels of RAD51, an inhibition of HR, increased levels of residual damage, and decreased survival after exposure to double-strand damage-inducing agents.

Conclusions: Our findings define the mechanism by which HDAC inhibition induces miR-182 to target RAD51 and highlights a novel pharmacologic strategy that compromises the ability of AML cells to conduct HR, thereby sensitizing AML cells to DNA-damaging agents that activate HR as a repair and potential resistance mechanism. Clin Cancer Res; 22(14); 3537–49. ©2016 AACR.

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Notch1 Regulates the Aggressiveness of DTC

Purpose: Notch1, a transmembrane receptor, has been recently shown to aid in the determination of thyroid cell fate associated with tumorigenesis. This study aimed to investigate the clinical relevance of Notch1 and its role in the regulation of differentiated thyroid cancer (DTC) behavior.

Experimental Design: We examined Notch1 expression level and its relationship with clinicopathologic features and outcomes of DTC. Notch1 intracellular domain (NICD) was further characterized both in vitro and in vivo by gain-of-function assays using an inducible system.

Results: Notch1 expression levels were downregulated in primary DTC tissue samples compared with contralateral nontumor and benign thyroid tissues. Decreased Notch1 expression in DTC was associated with advanced patient age (P = 0.032) and the presence of extrathyroidal invasion (P = 0.005). Patients with lower Notch1 expression had a significantly higher recurrence rate (P = 0.038). Restoration of NICD in a stably doxycycline-inducible metastatic DTC cell line reduced cell growth and migration profoundly. Using an orthotopic thyroid cancer model, NICD induction significantly reduced the growth of the primary thyroid tumor and inhibited the development of lung metastasis. Serpin peptidase inhibitor, clade E, member 1 (SERPINE1) was discovered by microarray as the most significant gene downregulated by NICD. Further validation showed that the induction of NICD reduced SERPINE1 expression in a dose-dependent manner, whereas restoration of a relative higher level of SERPINE1 was observed with NICD back to minimal level. In addition, SERPINE1 knock-down inhibited DTC cell migration.

Conclusions: Notch1 regulates the aggressive phenotypes of DTC, which could be mediated by SERPINE1 inhibition. Notch1/SERPINE1 axis warrants further investigation as a novel therapeutic target for advanced DTC. Clin Cancer Res; 22(14); 3582–92. ©2016 AACR.

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Circulating microRNA-196a/b are novel biomarkers associated with metastatic gastric cancer

Publication date: September 2016
Source:European Journal of Cancer, Volume 64
Author(s): Ming-Ming Tsai, Chia-Siu Wang, Chung-Ying Tsai, Chung-Guei Huang, Kam-Fai Lee, Hsiang-Wei Huang, Yang-Hsiang Lin, Hsiang-Cheng Chi, Liang-Mou Kuo, Pei-Hsuan Lu, Kwang-Huei Lin
miR-196a and/or miR-196b, involved in cancer initiation and progression, are frequently upregulated in tumour tissues. However, the clinical significance of these microRNAs in gastric cancer (GC) remains to be clarified. In the current study, we investigated the potential utility of circulating miR-196a/b as novel biomarkers for early detection and/or metastatic prognosis of GC. The quantitative real time-polymerase chain reaction data revealed markedly higher pre-operative circulating miR-196a and miR-196b levels in GC patients than healthy controls. Receiver-operating characteristics curve analysis showed that circulating miR-196a, miR-196b and combined miR-196a and miR-196b (miR-196a/b) are more effective than carcinoembryonic antigen or carbohydrate antigen 19-9 alone in distinguishing GC patients from healthy controls, with higher sensitivity and specificity. Circulating miR-196a exhibited higher diagnostic capacity than combined miR-196a/b or miR-196b alone, highlighting its potential as an effective plasma biomarker for GC. In clinicopathological analysis, elevated circulating miR-196a/b levels were highly correlated with metastatic potential or more advanced stages of disease and poorer survival. In addition, the expression levels of circulating miR-196a/b were reduced after surgical resection in GC patients. Taken together, we propose that circulating miR-196a/b serve as a more sensitive and specific novel biomarker than carbohydrate antigen 19-9 for GC monitor, diagnosis and prognosis.



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Response to ‘Letter to the Editor’ by Wendy Hernandez-Fernandez et al.

Publication date: Available online 13 July 2016
Source:European Journal of Cancer
Author(s): Sang-Hee Yoon, Soo-Nyung Kim, Seung-Hyuk Shim, Soon-Beum Kang, Sun-Joo Lee




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RNASeq analysis reveals biological processes governing the clinical behaviour of endometrioid and serous endometrial cancers

Publication date: September 2016
Source:European Journal of Cancer, Volume 64
Author(s): Christophe Lemetre, Begoña Vieites, Charlotte K.Y. Ng, Salvatore Piscuoglio, Anne M. Schultheis, Caterina Marchiò, Rajmohan Murali, Maria A. Lopez-García, Jose C. Palacios, Achim A. Jungbluth, Luigi M. Terracciano, Jorge S. Reis-Filho, Britta Weigelt
BackgroundEndometrial carcinoma comprises a group of tumours with distinct histologic and molecular features and clinical behaviour. Here, we sought to define the biological processes that govern the clinical behaviour of endometrial cancers.MethodsSixteen prototype genes representative of different biological processes that would likely play a role in endometrial and other hormone-driven cancers were defined. RNA-sequencing gene expression data from 323 endometrial cancers from The Cancer Genome Atlas (TCGA) were used to determine the transcription module of each prototype gene. The expression of prototype genes and modules and their association with outcome was assessed in univariate and multivariate survival analyses. The association of MSH6 expression with outcome was validated in an independent cohort of 243 primary endometrial cancers using immunohistochemistry.ResultsWe observed that the clinical behaviour of endometrial cancers as a group was associated with hormone receptor signalling, PI3K pathway signalling and DNA mismatch repair processes. When analysed separately, in endometrioid carcinomas, hormone receptor, PI3K and DNA mismatch repair modules were significantly associated with outcome in univariate analysis, whereas the clinical behaviour of serous cancers was likely governed by apoptosis and Wnt signalling. Multivariate survival analysis revealed that MSH6 gene expression was associated with outcome of endometrial cancer patients independently from traditional prognostic clinicopathologic parameters, which was confirmed in an independent cohort at the protein level.ConclusionEndometrioid and serous endometrial cancers are underpinned by distinct molecular pathways. MSH6 expression levels may be associated with outcome in endometrial cancers as a group.



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Application of glyco-science to the early detection of pancreatic cancer

Summary

The prognosis of pancreatic cancer is extremely poor compared to that of other cancers. One of the reasons for this is the difficulty of early diagnosis. Surveillance using cancer biomarkers and image diagnosis can enable early detection and has improved the prognosis of hepatocellular carcinoma in Japan. However, it is very difficult to detect pancreatic cancer at an early stage using cancer biomarkers and image diagnosis alone. Fucosylation is one of the most important types of glycosylation involved in cancer and inflammation. We have developed a novel glyco-cancer biomarker, fucosylated haptoglobin (Fuc-Hpt), and have investigated its usefulness for the diagnosis of pancreatic cancer over approximately 10 years. Recently, we also found that most pancreatic tissues surrounding pancreatic cancer exhibit chronic pancreatitis with fibrosis and/or fatty degeneration. Certain forms of chronic pancreatitis might indicate high risk for the development of pancreatic cancer. In this review, we provide a historical summary of our research on Fuc-Hpt as a cancer biomarker, and discuss a potential early detection system for pancreatic cancer.

This article is protected by copyright. All rights reserved.

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3-D View of Mutations May Identify Potential Targets for Cancer Drugs

A new computational tool may help expand the known number of mutations in cancer cells that could be targeted with new or existing drugs.

Researchers recently reported that the tool, called HotSpot3D, allowed them to model how genetic mutations change the ways proteins function and interact with each other to potentially drive cancer. It also helped them identify more than 800 novel mutations that potentially could be targeted with existing drugs. 

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Early onset pancreatic malignancies: Clinical characteristics and survival associations

Abstract

Diagnosed before age 50, early onset pancreatic malignancy (EOPM), is hypothesized to be a distinct subset of disease, although research is limited. To better characterize EOPM, and the effect of age at diagnosis on pancreatic cancer survival, we examined clinical characteristics and survival in EOPM and typical age-at-onset pancreatic malignancy (TOPM) cases. Vanderbilt University Medical Center (VUMC) Cancer Registry confirmed pancreatic ductal adenocarcinomas (PDACs) and malignant pancreatic neuroendocrine tumors (PNETs) were evaluated. Clinical characteristics were compared using χ² tests. Overall survival was visualized with Kaplan-Meier functions; Cox proportional hazards regression was used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 1,697 pancreatic malignancies were diagnosed at the VUMC between 1988 and 2013. Of 1,407 PDACs, 118 (8.4%) were EOPM, which was associated with significantly better survival (adjusted HR: 0.82, 95% CI: 0.67-1.00). EOPM and TOPM PDACs significantly differed with regard to having multiple malignancies; survival associations significantly differed by race, stage of disease, treatment, and multiple malignancies. Of 190 PNETs, 63 (33.1%) were EOPM, which was not significantly associated with survival (adjusted HR: 0.80, 95% CI: 0.46-1.40). Malignant neuroendocrine EOPM and TOPM cases significantly differed by stage of disease and tumor location; survival associations significantly differed by family history of pancreatic cancer, stage of disease, and multiple malignancies. Differences in clinical characteristics and associations with survival were identified, indicating that EOPM is distinct from TOPM, and exists among both pancreatic adenocarcinomas and malignant pancreatic neuroendocrine tumors. This article is protected by copyright. All rights reserved.

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Night shift work and chronic lymphocytic leukemia in the MCC-spain case-control study

Abstract

Chronic lymphocytic leukaemia (CLL) has few known modifiable risk factors. Recently, circadian disruption has been proposed as a potential contributor to lymphoid neoplasms' etiology. Serum melatonin levels have been found to be significantly lower in CLL subjects compared with healthy controls, and also, CLL prognosis has been related to alterations in the circadian molecular signaling. We performed the first investigation of an association between night shift work and CLL in 321 incident CLL cases and 1728 population-based controls in five areas of Spain. Participants were interviewed face-to-face by trained interviewers to collect information on socio-demographic factors, familial, medical and occupational history, including work shifts, and other lifestyle factors. We used logistic regression models adjusted for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). Seventy-nine cases (25%) and 339 controls (20%) had performed night work. Overall, working in night shifts was not associated with CLL (OR=1.06; 95%CI=0.78-1.45, compared with day work). However, long-term night shift (>20 years) was positively associated with CLL (OR_{(tertile 3 vs. day-work)} = 1.77; 95%=1.14-2.74), although no linear trend was observed (P-trend =0.18). This association was observed among those with rotating (OR_{(tertile 3 vs. day-work)}= 2.29; 95%CI=1.33-3.92; P-trend = 0.07), but not permanent night shifts (OR_{(tertile 3 vs. day-work)}= 1.16; 95%CI=0.60-2.25; P-trend = 0.86). The association between CLL and long-term rotating night shift warrants further investigation. This article is protected by copyright. All rights reserved.

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Caution: work in progress

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Quantifying the mediating effects of smoking and occupational exposures in the relation between education and lung cancer: the ICARE study

Abstract

Smoking only partly explains the higher lung cancer incidence observed among socially deprived people. Occupational exposures may account for part of these inequalities, but this issue has been little investigated. We investigated the extent to which smoking and occupational exposures to asbestos, silica and diesel motor exhaust mediated the association between education and lung cancer incidence in men. We analyzed data from a large French population-based case–control study (1976 lung cancers, 2648 controls). Detailed information on lifelong tobacco consumption and occupational exposures to various carcinogens was collected. We conducted inverse probability-weighted marginal structural models. A strong association was observed between education and lung cancer. The indirect effect through smoking varied by educational level, with the strongest indirect effect observed for those with the lowest education (OR = 1.34 (1.14–1.57)). The indirect effect through occupational exposures was substantial among men with primary (OR = 1.22 (1.15–1.30) for asbestos and silica) or vocational secondary education (OR = 1.18 (1.12–1.25)). The contribution of smoking to educational differences in lung cancer incidence ranged from 22 % (10–34) for men with primary education to 31 % (−3 to 84) for men with a high school degree. The contribution of occupational exposures to asbestos and silica ranged from 15 % (10–20) for men with a high school degree to 20 % (13–28) for men with vocational secondary education. Our results highlight the urgent need for public health policies that aim at decreasing exposure to carcinogens at work, in addition to tobacco control policies, if we want to reduce socioeconomic inequalities in the cancer field.

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Images from 18 F-DOPA Scan in Congenital Hyperinsulinism: Not Always a Clue for Diagnosis

Abstract

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in childhood (Horm Res 70:65-72, 2008; J Clin Endocr Metab 93:869-875, 2008). ¹⁸⁻Fluoro-L-dihydroxy-phenylalanine (¹⁸F-DOPA) positron emission tomography (PET) can detect areas of increased activity in the pancreas and may differentiate focal from diffuse CHI (J Clin Endocr Metab 93:869-875, 2008; Radiology 253:216-222, 2009). We here report the case of a girl who complained of recurrent episodes of severe hypoglycaemia despite previous partial pancreatectomy. To evaluate the need for additional surgical intervention, we performed ¹⁸F-DOPA PET/computed tomography (CT), which showed a focal lesion corresponding to the anatomical region of the pancreatic tail. On the other hand, abdominal magnetic resonance imaging (MRI) clearly demonstrated that the ¹⁸F-DOPA uptake was in a loop of bowel occupying the previous surgical bed. Our case highlights that bowel uptake can be a possible pitfall in the interpretation of ¹⁸F-DOPA PET/CT in children affected by CHI, suggesting that when ¹⁸F-DOPA PET/CT results do not fit the clinical picture, magnetic resonance imaging (MRI) may allow a more accurate correlation of the radiotracer activity with the underlying anatomical or pathological structure.

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Effects of a bolus injection of 5-fluorouracil on dihydropyrimidine dehydrogenase activity in rats receiving continuous infusion of 5-fluorouracil

Abstract

Purpose

The options for improving the chemotherapeutic regimen consisting of bolus plus infusion of 5-fluorouracil (5-FU) include omitting the 5-FU bolus injection. We examined the effects of a 5-FU bolus injection on the activity of dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of 5-FU catabolism, in rats.

Methods

The rats were divided into three groups, and then continuous infusion (50 mg/m²/h) for 4 h was started with a bolus injection of saline, 20 mg/kg 5-FU, or 60 mg/kg 5-FU. Plasma 5-FU, uracil (Ura), dihydrouracil (UH₂) levels, and hepatic DPD activity were determined after administration of 5-FU.

Results

The half-life after the end of the infusion (t _{1/2, 4–8 h}) of 5-FU in the rats given the bolus injection was significantly longer than in those that had been given saline, and it increased with increasing 5-FU bolus injection dosage (r = 0.801, p < 0.01). The plasma UH₂/Ura ratio, an indirect biomarker of hepatic DPD activity, tended to be lower in the rats that had received a 5-FU bolus injection than in those that had not, and it remained low after infusion ended. The hepatic DPD activity in rats that had received a 5-FU bolus injection was significantly lower than in those that had not. Negative correlation was observed between DPD activity and bolus injection dosage (r = −0.691, p < 0.05).

Conclusions

A bolus injection suppresses hepatic DPD activity and its effects are dependent on dosage, resulting in slower elimination of 5-FU from the blood and contributing to long-term systemic exposure to 5-FU.

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Phase II study of a novel taxane (Cabazitaxel-XRP 6258) in previously treated advanced non-small cell lung cancer (NSCLC) patients

Abstract

Purpose

Given the success of cabazitaxel in patients with prostate cancer who progressed after receiving prior chemotherapy, its preclinical efficacy in various cell lines and possible ability to cross blood-brain barrier, cabazitaxel was hypothesized to increase objective response rate (ORR) in second-line setting in non-small cell lung cancer (NSCLC).

Methods

This was a phase II 2-stage trial in 28 patients using two different treatment schedules (A: 20 mg/m² every 3 weeks intravenously and B: 8.4 mg/m² intravenously weekly) to determine the ORR of cabazitaxel with secondary end points including progression-free survival (PFS), safety, and overall survival (OS).

Results

There was one objective response in schedule B. PFS and OS of schedule A was 3 and 6 months, respectively. PFS and OS of schedule B was 3 and 13 months, respectively. The stable disease rate was higher in schedule A (SD = 69.23 %; 95 % CL 38.57, 90.90) as compared to schedule B (SD = 38.46 %; 95 % CL 13.86, 68.42), but this difference was not statistically significant (P value = 0.1156). There were two grade 5 toxicities from sepsis. Hematuria of any grade developed in greater percentage of patients (35%) as compared to previous cabazitaxel phase 3 trial and led to change in our protocol.

Conclusions

Response to cabazitaxel in NSCLC was not as robust as seen in prostate cancer and not superior to currently used agents such as docetaxel, pemetrexed, and erlotinib. In absence of significant objective responses, the second stage of the study was not undertaken.

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Second- and third-line systemic therapy in patients with advanced esophagogastric cancer: a systematic review of the literature

Abstract

The optimal second- and third-line chemotherapy and targeted therapy for patients with advanced esophagogastric cancer is still a matter of debate. Therefore, a literature search was carried out in Medline, EMBASE, CENTRAL, and oncology conferences until January 2016 for randomized controlled trials that compared second- or third-line therapy. We included 28 studies with 4810 patients. Second-line, single-agent taxane/irinotecan showed increased survival compared to best supportive care (BSC) (hazard ratio 0.65, 95 % confidence interval 0.53–0.79). Median survival gain ranged from 1.4 to 2.7 months among individual studies. Taxane- and irinotecan-based regimens showed equal survival benefit. Doublet chemotherapy taxane/irinotecan plus platinum and fluoropyrimidine was not different in survival, but showed increased toxicity vs. taxane/irinotecan monotherapy. Compared to BSC, second-line ramucirumab and second- or third-line everolimus and regorafenib showed limited median survival gain ranging from 1.1 to 1.4 months, and progression-free survival gain, ranging from 0.3 to 1.6 months. Third- or later-line apatinib showed increased survival benefit over BSC (HR 0.50, 0.32–0.79). Median survival gain ranged from 1.8 to 2.3 months. Compared to taxane-alone, survival was superior for second-line ramucirumab plus taxane (HR 0.81, 0.68–0.96), and olaparib plus taxane (HR 0.56, 0.35–0.87), with median survival gains of 2.2 and 4.8 months respectively. Targeted agents, either in monotherapy or combined with chemotherapy showed increased toxicity compared to BSC and chemotherapy-alone. This review indicates that, given the survival benefit in a phase III study setting, ramucirumab plus taxane is the preferred second-line treatment. Taxane or irinotecan monotherapy are alternatives, although the absolute survival benefit was limited. In third-line setting, apatinib monotherapy is preferred.

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Method for semi-automated microscopy of filtration-enriched circulating tumor cells

Abstract

Background

Circulating tumor cell (CTC)-filtration methods capture high numbers of CTCs in non-small-cell lung cancer (NSCLC) and metastatic prostate cancer (mPCa) patients, and hold promise as a non-invasive technique for treatment selection and disease monitoring. However filters have drawbacks that make the automation of microscopy challenging. We report the semi-automated microscopy method we developed to analyze filtration-enriched CTCs from NSCLC and mPCa patients.

Methods

Spiked cell lines in normal blood and CTCs were enriched by ISET (isolation by size of epithelial tumor cells). Fluorescent staining was carried out using epithelial (pan-cytokeratins, EpCAM), mesenchymal (vimentin, N-cadherin), leukocyte (CD45) markers and DAPI. Cytomorphological staining was carried out with Mayer-Hemalun or Diff-Quik. ALK-, ROS1-, ERG-rearrangement were detected by filter-adapted-FISH (FA-FISH). Microscopy was carried out using an Ariol scanner.

Results

Two combined assays were developed. The first assay sequentially combined four-color fluorescent staining, scanning, automated selection of CD45⁻ cells, cytomorphological staining, then scanning and analysis of CD45⁻ cell phenotypical and cytomorphological characteristics. CD45⁻ cell selection was based on DAPI and CD45 intensity, and a nuclear area >55 μm². The second assay sequentially combined fluorescent staining, automated selection of CD45⁻ cells, FISH scanning on CD45⁻ cells, then analysis of CD45⁻ cell FISH signals. Specific scanning parameters were developed to deal with the uneven surface of filters and CTC characteristics. Thirty z-stacks spaced 0.6 μm apart were defined as the optimal setting, scanning 82 %, 91 %, and 95 % of CTCs in ALK-, ROS1-, and ERG-rearranged patients respectively. A multi-exposure protocol consisting of three separate exposure times for green and red fluorochromes was optimized to analyze the intensity, size and thickness of FISH signals.

Conclusions

The semi-automated microscopy method reported here increases the feasibility and reliability of filtration-enriched CTC assays and can help progress towards their validation and translation to the clinic.

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The Alberta Moving Beyond Breast Cancer (AMBER) Cohort Study: Recruitment, Baseline Assessment, and Description of the First 500 Participants

Abstract

Background

To our knowledge, the Alberta Moving Beyond Breast Cancer (AMBER) Study is the first and only prospective cohort study of breast cancer survivors that includes objectively-measured physical activity (PA), sedentary behavior, health-related fitness (HRF), and biologic mechanisms focused on understanding breast cancer outcomes. The purpose of the present study was to report on the feasibility of recruitment, baseline measurement completion, and the representativeness of the first 500 participants.

Methods

AMBER is enrolling newly diagnosed stage I (≥T1c) to IIIc breast cancer survivors in Alberta, Canada. Baseline assessments are completed soon after diagnosis and include cardiorespiratory fitness, musculoskeletal fitness, body composition, objective and self-reported PA and sedentary behavior, lymphedema, and blood collection.

Results

Between July 2012 and November 2014, AMBER recruited its first 500 participants from a pool of 1,447 (35 %) eligible breast cancer survivors. Baseline HRF assessments were completed on ≥85 % of participants with the exception of upper body strength. Collection of ≥4 days/week of monitoring for the Actigraph GT3X® and ActivPAL® were obtained from 90 % of participants. Completion rates were also high for blood (99 %), lymphedema (98 %), and questionnaires (95 %) including patient-reported outcomes and correlates of exercise. The first 500 participants in AMBER are an average age of 56 years, 60 % are overweight or obese, and 58 % have disease stage II or III.

Conclusion

Despite the modest recruitment rate and younger age, AMBER has demonstrated that many newly diagnosed breast cancer survivors are willing and able to complete a wide array of sophisticated and physically demanding HRF and PA assessments soon after diagnosis. AMBER is a unique breast cancer survivor cohort that may inform future randomized controlled trials on lifestyle and breast cancer outcomes as well as PA behavior change in breast cancer survivors. Moreover, AMBER may also inform guidelines on PA, sedentary behavior, and HRF for improving breast cancer outcomes and survivorship.

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Results of sub-analysis of a phase 2 study on trabectedin treatment for extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma

Abstract

Background

Trabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase 2 study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted, which showed clinical benefit of trabectedin compared with best supportive care (BSC). Extraskeletal myxoid chondrosarcoma (EMCS) and Mesenchymal chondrosarcoma (MCS) are very rare malignant soft tissue sarcomas, and are associated with translocations resulting in fusion genes. In addition, the previous in vivo data showed that trabectedin affect tumor necrosis and reduction in vascularization in a xenograft model of a human high-grade chondrosarcoma. The aim of the present analysis was to clarify the efficacy of trabectedin for EMCS and MCS subjects in the randomized phase 2 study.

Methods

Five subjects with EMCS and MCS received trabectedin treatment in the randomized phase 2 study. Three MCS subjects were allocated to the BSC group. Objective response and progression-free survival (PFS) were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by central radiology imaging review.

Results

The median follow-up time of the randomized phase 2 study was 22.7 months, and one subject with MCS was still receiving trabectedin treatment at the final data cutoff. The median PFS was 12.5 months (95 % CI: 7.4–not reached) in the trabectedin group, while 1.0 months (95 % CI: 0.3–1.0 months) in MCS subjects of the BSC group. The six-month progression-free rate was 100 % in the trabectedin group. One subject with MCS showed partial response, and the others in the trabectedin group showed stable disease. Overall survival of EMCS and MCS subjects was 26.4 months (range, 10.4–26.4 months) in the trabectedin group. At the final data cutoff, two of five subjects were still alive.

Conclusions

This sub-analysis shows that trabectedin is effective for patients with EMCS and MCS compared with BSC. The efficacy results were better than previously reported data of TRS. These facts suggest that trabectedin become an important choice of treatment for patients with advanced EMCS or MCS who failed or were intolerable to standard chemotherapy.

Trial registration

The randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).

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Serum fibrinogen levels are positively correlated with advanced tumor stage and poor survival in patients with gastric cancer undergoing gastrectomy: a large cohort retrospective study

Abstract

Background

Platelet and blood coagulation abnormalities frequently occur in cancer patients. Fibrinogen is an important hemostatic factor that regulates the hemostatic pathway. Hyperfibrinogenemia is increasing recognized as an important risk factor influencing cancer development and outcome. However, few reports have investigated the prognostic potential of fibrinogen for predicting the survival of gastric cancer (GC) patients. The primary aim of this study was to evaluate the usefulness of preoperative serum fibrinogen as a biomarker for predicating tumor progression and survival of patients with GC.

Patients and methods

This retrospective study was conducted in GC patients who underwent gastrectomy from 2005 to 2007. Patient demographics, clinicopathological characteristics, preoperative plasma fibrinogen levels and median survival time (MST) were analyzed. Univariate and multivariate proportional hazard analysis of risk factors were used.

Results

This study included 1196 patients (885 males and 311 females) with GC, more than half of whom had advanced GCs. Radical lymph node dissection was performed in 71.6 % of these patients. MST was 41.9 ± 32.4 months. Patient survival was significantly affected by family GC history (p <0.05), lymph node dissection mode (p <0.001), tumor size (≥5 cm; p <0.001), tumor location (p < 0.001), poor tumor differentiation (p <0.001), tumor histologic classification (p <0.001), extent of tumor invasion (p <0.001), number of metastatic lymph nodes (p <0.001), advanced stage of disease (p <0.001), extended operation duration (>150 min; p <0.001), higher operative bleeding volume (>200 ml; p <0.001), postoperative transfusion, preoperative serum fibrinogen levels, CEA levels and CA 19-9 levels (p <0.001). Multivariate analysis indicated that the independent prognostic factors significantly associated with poor survival included non-radical lymph node dissection, palliative lymph node dissection, multi-organ involvement, advanced TNM stages, poor tumor differentiation, higher preoperative serum fibrinogen levelsand higher CA19-9 levels.

Conclusions

Serum fibrinogen levels are positively correlated with advanced tumor stages and poor survival in GC patients undergoing gastrectomy. Preoperative plasma fibrinogen levels are an independent risk factor for survival in these patients. Serum fibrinogen is a useful biomarker for patients with clinically advanced GC.

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Clinicopathological features and prognosis of gastric cancer in young patients

Abstract

Background

The clinicopathological features and prognosis of gastric cancer in young patients are both limited and controversial. Therefore, the aim of this study was to define the clinicopathological features and prognosis of gastric cancer in young patients after curative resection.

Methods

From May 2008 to December 2014, 198 young patients (age ≤ 40 years) and 1096 middle-aged patients (55 ≤ age ≤ 64 years) were enrolled in this study. The clinicopathological features and prognosis of gastric cancer in these patients were analyzed.

Results

Compared with middle-aged patients, the proportion of females, lower third tumors, tumor size less than 5 cm, poorly differentiated tumors and T1 tumors were significantly higher in young patients (all P < 0.05). The proportions of comorbidity, upper third tumors, well and moderately differentiated tumors, T4 tumors, and positive carcinoembryonic antigen (CEA), alpha fetoprotein (AFP) and carbohydrate antigen (CA) 19–9 were significantly lower in young patients (all P < 0.05). The distributions of N status and CA125 were comparable between young and middle-aged patients (all P > 0.05). The five-year overall survival rates were comparable between young patients and middle-aged patients (62.8 vs 54.7 %, P = 0.307). The tumor location, T status, N status and CA125 were independent predictors of prognosis in young patients. The overall survival of patients with tumors located in the upper or middle third was significantly lower than for those located in the lower third (60.8 vs 50.6 % vs 68.4 %, P = 0.016). The overall survival of CA125-positive patients was significantly lower than CA125-negative patients (49.0 vs 64.4 %, P = 0.001).

Conclusion

The clinicopathological features were significantly different between young and middle-aged patients. The prognosis of gastric cancer in young patients was equivalent to that of middle-aged patients. Tumor location, T status, N status and CA125 were independent risk factors for prognosis in young patients.

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No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone

Abstract

Background

Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study.

Methods

Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines.

Results

Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the same tumour, suggesting that in vitro culturing upregulates IGF1R expression.

Conclusions

The results from this study indicate that the IGF pathway is not essential for chondrosarcoma growth, migration or chemoresistance. Furthermore, IGF1R is only minimally expressed in chondrosarcoma primary tumours. Therefore, the IGF pathway is not expected to be an effective therapeutic target for chondrosarcoma of bone.

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Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models

Abstract

Background

The role of the microbiome has become synonymous with human health and disease. Bile acids, as essential components of the microbiome, have gained sustained credibility as potential modulators of cancer progression in several disease models. At physiological concentrations, bile acids appear to influence cancer phenotypes, although conflicting data surrounds their precise physiological mechanism of action. Previously, we demonstrated bile acids destabilised the HIF-1α subunit of the Hypoxic-Inducible Factor-1 (HIF-1) transcription factor. HIF-1 overexpression is an early biomarker of tumour metastasis and is associated with tumour resistance to conventional therapies, and poor prognosis in a range of different cancers.

Methods

Here we investigated the effects of bile acids on the cancer growth and migratory potential of cell lines where HIF-1α is known to be active under hypoxic conditions. HIF-1α status was investigated in A-549 lung, DU-145 prostate and MCF-7 breast cancer cell lines exposed to bile acids (CDCA and DCA). Cell adhesion, invasion, migration was assessed in DU-145 cells while clonogenic growth was assessed in all cell lines.

Results

Intracellular HIF-1α was destabilised in the presence of bile acids in all cell lines tested. Bile acids were not cytotoxic but exhibited greatly reduced clonogenic potential in two out of three cell lines. In the migratory prostate cancer cell line DU-145, bile acids impaired cell adhesion, migration and invasion. CDCA and DCA destabilised HIF-1α in all cells and significantly suppressed key cancer progression associated phenotypes; clonogenic growth, invasion and migration in DU-145 cells.

Conclusions

These findings suggest previously unobserved roles for bile acids as physiologically relevant molecules targeting hypoxic tumour progression.

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Lack of TMEM27 expression is associated with postoperative progression of clinically localized conventional renal cell carcinoma

Abstract

Purpose

In spite of early detection of conventional renal cell carcinoma (RCC) by widespread use of abdominal imaging, approximately 10–15 % of patients will die due to disease. The aim of this study was to identify new biomarkers predicting the postoperative progression of conventional RCC.

Methods

Tissue multiarrays (TMA) of conventional RCC from a cohort of 486 patients were analysed by immunohistochemistry for expression of the transmembrane protein TMEM27, which was identified as a candidate biomarker by Affymetrix U133 Plus 2.0 array. Univariate and multivariate Cox regression models were addressed to assess cancer-specific survival in association with clinicopathological variables and TMEM27 expression. Cancer-specific survival time was estimated with Kaplan–Meier analysis, and the comparison of survival curves was made with the log-rank test.

Results

The Kaplan–Meier survival analysis indicated a poor disease-specific survival rates for tumours without TMEM27 staining. Univariate analysis revealed an association of patient survival with T stadium, grade, stage and size of tumour and TMEM27 expression in all cases as well as in the cohort of patients with postoperative tumour progression. In multivariate analysis, only T stadium and TMEM27 staining showed a significant association with postoperative cancer-specific death (p < 0.001).

Conclusions

Lack of expression of the TMEM27 in conventional RCC defines a group of patients at high risk for cancer-related death.

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Use of post-mastectomy radiotherapy in patients receiving completion axillary lymph node dissection after a positive sentinel lymph node biopsy

Publication date: Available online 13 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Michael C. Stauder, Abigail S. Caudle, Pamela K. Allen, Simona F. Shaitelman, Benjamin D. Smith, Karen E. Hoffman, Thomas A. Buchholz, Mariana Chavez-Macgregor, Kelly K. Hunt, Funda Meric-Bernstam, Wendy A. Woodward
PurposeWe sought to determine the rate of PMRT among women treated with ALND after a positive SLN biopsy and to establish the effect of a negative ALND and PMRT on local-regional recurrence (LRR) and overall survival (OS).MethodsAll patients were treated with mastectomy and ALND after a positive SLN biopsy. All patients were clinical N0 or Nx at the time of mastectomy and received no neoadjuvant therapy. The presence of LVSI, multifocality, number of positive SLN and non-sentinel lymph nodes, clinical/pathologic stage, extranodal extension, age, and use of PMRT were evaluated for significance on the rates of OS and LRR.ResultsA total of 345 patients were analyzed. ALND after positive SLN biopsy was negative in 235 patients (68.1%), and a total of 112 patients (32.5%) received XRT. On multivariate analysis, only pathologic stage III predicted for lower OS (HR 3.32, p<0.001). The rate of 10-year freedom from LRR was 87.9% and 95.3% in patients with positive and negative ALND, respectively. In negative ALND patients with >3 positive SLN, freedom from LRR was 74.7% compared to 96.7% in those with < 3 positive SLN (p=0.009). In patients with negative ALND, >3 positive SLN predicted for an increase in LRR on MVA (HR 10.10, p=0.034).ConclusionsA low proportion of cT1-2, N0 patients with positive SLNs who undergo mastectomy receive PMRT after ALND. Even in this low risk cohort, patients with >3 positive SLN and a negative ALND are at increased risk for LRR and may benefit from PMRT.

Teaser

In a cohort of clinically node negative patients who are found to have a positive SLN, PMRT after completion ALND is often not indicated. In a group of patients with clinical N0, Stage 1-2A disease with >3 positive SLN and a negative completion ALND, PMRT may provide a benefit by reducing the rate LRR.


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Towards the ultimate radiotherapy goal- “freezing” the tumour in a known position during radiotherapy

Publication date: Available online 13 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Michael John Parkes, Stuart Green, Jason Cashmore, Andrea Mary Stevens, Thomas Henry Clutton-Brock, Arjan Bel, Eelco Lens, Frank Lohr, Judit Boda-Heggemann




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The involvement of mitochondrial membrane potential in cross-resistance between radiation and docetaxel

Publication date: Available online 13 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yoshikazu Kuwahara, Mehryar Habibi Roudkenar, Masatoshi Suzuki, Yusuke Urushihara, Motoi Fukumoto, Yohei Saito, Manabu Fukumoto
PurposeTo understand the molecular mechanisms underlying cancer cell radioresistance, clinically relevant radioresistant (CRR) cells that continue to proliferate during exposure to 2 Gy/day X-rays for more than 30 days were established. A modified high-density survival assay for anticancer-drug screening revealed that CRR cells were resistant to an anti-microtubule agent, docetaxel (DTX). The involvement of reactive oxygen species (ROS) from mitochondria (mtROS) in the cross-resistance to X-rays and DTX was studied.Methods and MaterialsSensitivity to anti-cancer agents was determined by a modified high-density cell survival or water-soluble tetrazolium salt assay. DTX induced mtROS generation was determined by MitoSOX red staining. JC-1 staining was used to visualize mitochondrial membrane potential. DTX induced DNA double-strand breaks were determined by γ-H2AX staining. To obtain mitochondrial DNA-lacking (ρ0) cells, the cells were cultured for 3 to 4 weeks in medium containing ethidium bromide.ResultsTreatment with DTX increased mtROS in parental but not in CRR cells. DTX induced DNA double-strand breaks in parental cells. Mitochondrial membrane potential of CRR cells was lower in CRR cells than that in parental cells. Depletion of mtDNA induced DTX resistance in parental cells. Treatment with dimethyl sulfoxide also induced DTX resistance in parental cells.ConclusionsThe mitochondrial dysfunction observed in CRR cells contributes to X-ray and DTX cross-resistance. The activation of oxidative phosphorylation in CRR cells may represent an effective approach to overcome radioresistant cancers. In general, the overexpression of beta-tubulin or multidrug efflux pumps is thought to be involved in DTX resistance. In the present study, we discovered another DTX resistant mechanism by investigating CRR cells. (260/300 words)

Teaser

Clinically relevant radioresistant (CRR) cells were resistant to an anti-microtubule agent, docetaxel (DTX). After treatment with DTX or exposure to X-rays reactive oxygen species from mitochondria (mtROS) were generated in parental cells but not in CRR cells, suggesting an involvement of mtROS in the cross-resistance to DTX and X-rays. In the present study, novel DTX resistant mechanism was found by investigating CRR cells and ρ0 cells which lack mitochondrial DNA.


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Ethnicity and the prostate cancer experience: a qualitative metasynthesis

Abstract

Objectives

To summarise black and minority ethnic (BME) patients' and partners experiences of prostate cancer (PCa) by examining the findings of existing qualitative studies

Methods

We undertook a systematic metasynthesis of qualitative studies using a modified version of Noblit and Hare's 'meta-ethnography' approach, with a 2000-2015 search of seven databases.

Results

Thirteen studies of men from US and UK BME groups were included. We explored constructs with BME-specific features. Healthcare provider relationships, formation of a spiritual alliance with God (which enhanced the participants' feeling of empowerment and ability to cope with the cancer) and living on for others (generally to increase cancer awareness), often connected to spiritual regrowth, were the three constructs most commonly reported. A magnified effect from erectile dysfunction was also common. Initially this affected men's disclosure to others about their cancer and their sexual problems, but eventually men responded by shifting their conceptualisations of masculinity to sustain self and social identities. There was also evidence of inequality resulting from financial constraints and adversity that necessitated resilience in coping.

Conclusions

The prostate cancer experience of BME men and their partners is affected by a complex intersection of ethnicity with other factors. Healthcare services should acknowledge this. If providers recognise the men's felt masculinities, social identities and spiritual beliefs and their shifting nature, services could be improved, with community as well as individual benefits. More studies are needed in diverse ethnic groups.

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Visual Pattern and Serial Quantitation of 18 F-Sodium Fluoride PET/CT in Asymptomatic Patients After Hip and Knee Arthroplasty

Abstract

Purpose

We investigated the visual tracer distribution pattern and serial changes in uptake ratio in different anatomical zones during the natural postoperative course in order to establish a reference for evaluation of patients with complications.

Methods

A total of 36 patients without symptoms after hip or knee arthroplasty were grouped according to the interval between surgery and the scan. The serial changes in SUVmean in each periprosthetic zone were quantified using the volume of interest isocontour method. Images were classified according to the uptake distribution pattern. The uptake ratios in the postoperative period groups were then compared using the Kruskal-Wallis test. The correlation between uptake ratio and postoperative period was then determined.

Results

Tracer distribution patterns in hip prostheses were classified into three types and the patterns in knee prostheses into five types. In hip prostheses, intense osteoblastic activity was observed during 3–6 months and then declined in most patients, but showed a slight increase over 15–25 months in 5–10 % of patients. The correlation coefficients varied among the zones. Significant differences in uptake ratios among the period groups was found for all zones, except zone 8. Porous coated areas showed higher uptake than uncoated areas only for the period the 3–6 months. In knee prostheses, uptake ratios showed a curvilinear pattern, increasing from 3–6 to 8–15 months and declining later. The uptake ratios were different among the period groups. Every zone showed a positive correlation from 3–6 to 8–15 months, and negative correlations from 8–15 to 22–25 months.

Conclusions

This is the first ¹⁸F-sodium fluoride PET/CT study investigating the stability of implants and sets a reference for evaluation of patients with complications.

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Zoledronate as effective treatment for minimal trauma fractures in a child with STAT3 deficiency and osteonecrosis of the hip

Abstract

Signal transducer and activator of transcription 3 (STAT3) deficiency is a primary immunodeficiency characterized by eczema, complicated recurrent infections, elevated serum immunoglobulin E (IgE), osteopenia, and minimal trauma fractures. Zoledronic acid (ZA) is a long-acting bisphosphonate that has been successfully used in children with secondary osteoporosis and osteogenesis imperfecta. We describe the case of a 7-year-old male with STAT3 deficiency and minimal trauma fractures, who also developed osteonecrosis of the hip. He responded well to intravenous ZA every 6 months for 18 months. Three years later, he walks independently and unaided, and has not suffered any other fractures. Although more studies are needed, ZA might help reduce minimal trauma fractures in patients with STAT3 deficiency.

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The intentional oblique transection double stapling technique in anterior resection for rectal cancer

Abstract

The double stapling technique (DST) is an intestinal reconstruction technique that has been widely adopted in anterior resection (AR) for rectal cancer. However, anastomotic leakage (AL) after the operation remains a major concern for colorectal surgeons. The sharp-angled corner of the remnant rectum that is often created by the ordinary DST can be a risk factor for AL. We have developed a new method of performing intentional oblique transection DST (IOT-DST). Using this technique, the anal side of the rectum is intentionally obliquely transected with linear staplers, and the area of the sharp-angled edge is totally punched out with a circular stapler. Between September 2015 and March 2016, we used the IOT-DST technique in the treatment of 15 consecutive rectal cancer patients and experienced no anastomosis-related complications, including leakage and stenosis. IOT-DST is easy to use and less stressful to perform than other techniques. IOT-DST has the potential to become the standard technique for AR in rectal cancer surgery.

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Issue Information — UICC

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Issue Information — Table of Contents

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Issue Information — Information for Authors

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Tiny channels, giant dreams

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2016 publication schedule

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Issue Information

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Reverse transcription–polymerase chain reaction molecular testing of cytology specimens: Pre-analytic and analytic factors

The introduction of molecular testing into cytopathology laboratory practice has expanded the types of samples considered feasible for identifying genetic alterations that play an essential role in cancer diagnosis and treatment. Reverse transcription–polymerase chain reaction (RT-PCR), a sensitive and specific technical approach for amplifying a defined segment of RNA after it has been reverse-transcribed into its DNA complement, is commonly used in clinical practice for the identification of recurrent or tumor-specific fusion gene events. Real-time RT-PCR (quantitative RT-PCR), a technical variation, also permits the quantitation of products generated during each cycle of the polymerase chain reaction process. This review addresses qualitative and quantitative pre-analytic and analytic considerations of RT-PCR as they relate to various cytologic specimens. An understanding of these aspects of genetic testing is central to attaining optimal results in the face of the challenges that cytology specimens may present. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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Pediatric thyroid FNA biopsy: Outcomes and impact on management over 24 years at a tertiary care center

BACKGROUND

Thyroid malignancy is rare in young children, although the incidence increases sharply during adolescence. Nodular thyroid disease and thyroid cancer in children differ substantially from those in adults, because the rates of malignancy among children are roughly 5-fold higher, and local and distant metastases as well as recurrences are more common. Even with the recent introduction of pediatric guidelines, there remains a paucity of pediatric data on which to base clinical decision making. The objectives of this study were to characterize the outcomes of fine-needle aspiration biopsy (FNAB) of nodular thyroid disease at a pediatric tertiary-care institution over a 24-year period and to relate cytopathology to histopathology and management decisions in this population.

METHODS

A retrospective review of patients who underwent preoperative FNAB and thyroid surgery between 1992 and 2015 was conducted. In total, 207 nodules were biopsied among 178 patients.

RESULTS

Adequate FNAB samples were obtained in 74% of biopsies. Sixty-five patients underwent thyroidectomy after FNAB. In this group, the malignancy rates for lesions deemed benign, atypical, suspicious, and malignant on FNAB cytology were 16%, 67%, 71%, and 100%, respectively. Twenty-seven individuals underwent >1 biopsy; however, no malignancies were identified in these patients. Surprisingly, the rate of malignancy in patients who underwent preoperative FNAB was not significantly different from the rate in those who proceeded directly to surgery (n = 146).

CONCLUSIONS

FNAB remains a valuable tool for preoperative assessment of pediatric thyroid nodules. When samples are adequate for assessment, cytology other than clearly "benign" merits referral for diagnostic or therapeutic thyroidectomy. In this series, FNAB did not reduce rates of surgery for benign disease. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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Lung Cancer Screening

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Deciphering the real incidence of medulloblastoma with extensive nodularity in adult patients

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Weekly paclitaxel, capecitabine, and bevacizumab with maintenance capecitabine and bevacizumab as first-line therapy for triple-negative, metastatic, or locally advanced breast cancer: Results from the GINECO A-TaXel phase 2 study

BACKGROUND

The current study was performed to determine the efficacy and safety of first-line combination therapy with bevacizumab, paclitaxel, and capecitabine for triple-negative, locally advanced/metastatic breast cancer (LA/MBC).

METHODS

Patients with measurable triple-negative LA/MBC who had received no prior chemotherapy for their disease received 4-weekly cycles of paclitaxel (80 mg/m² on days 1, 8, and 15 for up to 6 cycles) combined with capecitabine (800 mg/m² twice daily on days 1-5, 8-12, and 15-19) and bevacizumab (10 mg/kg on days 1 and 14) repeated every 4 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was the objective response rate; secondary endpoints were progression-free survival, duration of response, overall survival, and safety.

RESULTS

Between April 2010 and March 2012, 62 eligible patients were enrolled. The median age of the patients was 57 years, 74% had received adjuvant chemotherapy, and 65% had visceral metastases. Patients received a median of 6 cycles (range, 1-45 cycles). The objective response rate was 77% (95% confidence interval [95% CI] 66%-88%), including complete response in 19% of patients. The median duration of response was 5.6 months (range, 1.3-27.6 months). The median progression-free survival was 7.6 months (95% CI, 6.3-9.0 months) and the median overall survival was 19.2 months (95% CI, 17.4-20.9 months). The most common grade ≥3 adverse events were hypertension (35% of patients) and neutropenia (23% of patients); 5% of patients experienced febrile neutropenia. Grade ≥2 hand-foot syndrome, alopecia, and nail toxicity each occurred in 40% of patients (adverse events were recorded before every cycle and graded according to Common Terminology Criteria for Adverse Events [version 4.0]). Treatment was interrupted because of toxicity in 22% of patients.

CONCLUSIONS

A triplet regimen of paclitaxel, capecitabine, and bevacizumab followed by maintenance therapy with capecitabine and bevacizumab demonstrated high activity and manageable safety in this difficult-to-treat population. Cancer 2016. © 2016 American Cancer Society.

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Nestin overexpression in hepatocellular carcinoma associates with epithelial-mesenchymal transition and chemoresistance

Nestin expression has been reported to be associated with the prognosis of many solid tumors including human hepatocellular carcinoma (HCC). The present study aimed to identify the role, if any, of Nestin in t...

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1-methylnicotinamide and its structural analog 1,4-dimethylpyridine for the prevention of cancer metastasis

1-methylnicotinamide (1-MNA), an endogenous metabolite of nicotinamide, has recently gained interest due to its anti-inflammatory and anti-thrombotic activities linked to the COX-2/PGI2 pathway. Given the previou...

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Communicating Uncertain News in Cancer Consultations

Abstract

In cancer communication, most of the literature is in the realm of delivering bad news while much less attention has been given to the communication of uncertain news around the diagnosis and the possible outcomes of the illness. Drawing on video-recorded cancer consultations collected in two Italian hospitals, this article analyzes three communication practices used by oncologists to interactionally manage the uncertainty during the visit: alternating between uncertain bad news and certain good news, anticipating scenarios, and guessing test results. Both diagnostic and personal uncertainties are not hidden to the patient, yet they are reduced through these practices. Such communication practices are present in 32 % of the visits in the data set, indicating that the interactional management of uncertainty is a relevant phenomenon in oncological encounters. Further studies are needed to improve both its understanding and its teaching.

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