The association of diabetes and obesity with prostate cancer aggressiveness among Black Americans and White Americans in a population-based study

Abstract

Purpose

Few studies have investigated the role of race in the association of diabetes and obesity with prostate cancer aggressiveness. Here we evaluate the independent association between diabetes and obesity with prostate cancer aggressiveness in White Americans and Black Americans.

Methods

Our cross-sectional, case-only study consisted of 1,058 White Americans and 991 Black Americans from the North Carolina-Louisiana Prostate Cancer (PCaP) project. Diabetes status was determined by self-report. Obesity was determined using body mass index and calculated based on anthropometric measurements. High aggressive prostate cancer was defined as Gleason sum ≥8, or prostate-specific antigen >20 ng/ml, or Gleason sum = 7 and clinical stage cT3–cT4. The association between diabetes and obesity with high aggressive prostate cancer at diagnosis was evaluated using multivariable logistic regression and adjusted for potential confounders.

Results

Diabetes was not associated with high aggressive prostate cancer in the overall sample (OR 1.04; 95% CI 0.79, 1.37), White Americans (OR 1.00; 95% CI 0.65, 1.57) or Black Americans (OR 1.07; 95% CI 0.75, 1.53). Obesity, independent of diabetes, was positively associated with high aggressive prostate cancer in White Americans (OR 1.98; 95% CI 1.14, 3.43), but not in the overall sample (OR 1.37; 95% CI 0.99, 1.92) or Black Americans (OR 1.09; 95% CI 0.71, 1.67).

Conclusions

Diabetes was not associated with prostate cancer aggressiveness, overall, or in either race group. Obesity, independent of diabetes, was associated with high aggressive prostate cancer only in White Americans.

http://link.springer.com/10.1007/s10552-016-0828-0

Characteristics associated with nonadherence to medications for hypertension, diabetes, and dyslipidemia among breast cancer survivors

Abstract

Objective

Comorbidity among breast cancer survivors is prevalent, and adherence to medication management of comorbidities may be important for both chronic disease and cancer-related outcomes. Our objective was to determine characteristics associated with nonadherence to common chronic medications among breast cancer survivors.

Methods

We conducted a retrospective cohort study of 4216 women in an integrated care system diagnosed with early-stage breast cancer between 1990 and 2008 and alive without recurrence or second primary breast cancer in the second-year following diagnosis. Adherence to antihypertensives, oral diabetes medications, and statins was measured during the second-year post-breast cancer diagnosis using medication possession ratios (MPR). Nonadherence was defined as MPR <0.80. We estimated odds ratios (OR) and 95% confidence intervals (CI) for nonadherence to antihypertensives, oral diabetes medications, and statins by various characteristics using multivariable logistic regression.

Results

Among 2308 users of antihypertensives (n = 1779), diabetes medications (n = 499) and/or statins (n = 1072), 37% were nonadherent to antihypertensives; 75% were nonadherent to diabetes medications; 39% were nonadherent to statins. In adjusted models, younger age was associated with nonadherence to all three therapeutic classes. Certain cancer treatments were associated with nonadherence to antihypertensives (radiation: OR 1.21, 95% CI 1.01–1.47; endocrine therapy: OR 1.27, 95% CI 1.03–1.52) and diabetes medications (chemotherapy: OR 1.69, 95% CI 1.17–2.21). Less frequent primary care provider visits were associated with higher odds of nonadherence to antihypertensives (OR 1.70, 95% CI 1.19–2.22); and trends showed higher Charlson comorbidity scores associated with greater adherence to diabetes medications (P < 0.001) and statins (P = 0.032).

Conclusions

Nonadherence to medications is high among breast cancer survivors, particularly diabetes medications, and is associated with cancer treatments and other patient characteristics. Additional research is warranted to understand the needs of cancer patients taking chronic medications and explore patient and provider factors influencing adherence.

http://link.springer.com/10.1007/s10549-016-4043-1

Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is a global public health issue, as it is the eighth most common cancer worldwide. The mechanisms behind ESCC invasion and progression are still poorly understood, and warrant further investigation into these processes and their drivers. In recent years, the ligand Activin A has been implicated as a player in the progression of a number of cancers. The objective of this study was to investigate the role of Activin A signaling in ESCC.

Methods

To investigate the role Activin A plays in ESCC biology, tissue microarrays containing 200 cores from 120 ESCC patients were analyzed upon immunofluorescence staining. We utilized three-dimensional organotypic reconstruct cultures of dysplastic and esophageal squamous tumor cells lines, in the context of fibroblast-secreted Activin A, to identify the effects of Activin A on cell invasion and determine protein expression and localization in epithelial and stromal compartments by immunofluorescence. To identify the functional consequences of stromal-derived Activin A on angiogenesis, we performed endothelial tube formation assays.

Results

Analysis of ESCC patient samples indicated that patients with high stromal Activin A expression had low epithelial ACVRIB, the Activin type I receptor. We found that overexpression of stromal-derived Activin A inhibited invasion of esophageal dysplastic squamous cells, ECdnT, and TE-2 ESCC cells, both positive for ACVRIB. This inhibition was accompanied by a decrease in expression of the extracellular matrix (ECM) protein fibronectin and podoplanin, which is often expressed at the leading edge during invasion. Endothelial tube formation was disrupted in the presence of conditioned media from fibroblasts overexpressing Activin A. Interestingly, ACVRIB-negative TE-11 cells did not show the prior observed effects in the context of Activin A overexpression, indicating a dependence on the presence of ACVRIB.

Conclusions

We describe the first observation of an inhibitory role for Activin A in ESCC progression that is dependent on the expression of ACVRIB.

http://link.springer.com/10.1186/s12885-016-2920-y

Investigation of optical coherence micro-elastography as a method to visualize micro-architecture in human axillary lymph nodes

Abstract

Background

Evaluation of lymph node involvement is an important factor in detecting metastasis and deciding whether to perform axillary lymph node dissection (ALND) in breast cancer surgery. As ALND is associated with potentially severe long term morbidity, the accuracy of lymph node assessment is imperative in avoiding unnecessary ALND. The mechanical properties of malignant lymph nodes are often distinct from those of normal nodes. A method to image the micro-scale mechanical properties of lymph nodes could, thus, provide diagnostic information to aid in the assessment of lymph node involvement in metastatic cancer. In this study, we scan axillary lymph nodes, freshly excised from breast cancer patients, with optical coherence micro-elastography (OCME), a method of imaging micro-scale mechanical strain, to assess its potential for the intraoperative assessment of lymph node involvement.

Methods

Twenty-six fresh, unstained lymph nodes were imaged from 15 patients undergoing mastectomy or breast-conserving surgery with axillary clearance. Lymph node specimens were bisected to allow imaging of the internal face of each node. Co-located OCME and optical coherence tomography (OCT) scans were taken of each sample, and the results compared to standard post-operative hematoxylin-and-eosin-stained histology.

Results

The optical backscattering signal provided by OCT alone may not provide reliable differentiation by inspection between benign and malignant lymphoid tissue. Alternatively, OCME highlights local changes in tissue strain that correspond to malignancy and are distinct from strain patterns in benign lymphoid tissue. The mechanical contrast provided by OCME complements the optical contrast provided by OCT and aids in the differentiation of malignant tumor from uninvolved lymphoid tissue.

Conclusion

The combination of OCME and OCT images represents a promising method for the identification of malignant lymphoid tissue. This method shows potential to provide intraoperative assessment of lymph node involvement, thus, preventing unnecessary removal of uninvolved tissues and improving patient outcomes.

http://link.springer.com/10.1186/s12885-016-2911-z

Complete response of extramedullary relapse in breast of acute T lymphoblastic leukemia after bone marrow transplantation to chemoradiotherapy: a case report and literature review

Abstract

Background

Relapse of acute lymphoblastic leukemia (ALL) occurring in the breast after allografting is extremely rare, with only 22 reported cases in the literature thus far. Further, the lack of a systemic analysis provides little information about this entity. We present a case of isolated extramedullary relapse from acute T lymphoblastic leukemia (ATLL) after allogeneic hematopoietic stem cell transplantation (HSCT).

Case presentation

A 32-year-old Chinese woman diagnosed with ATLL with myeloid antigen expression received HSCT from her human leukocyte antigen (HLA)-matched sister and presented with two lesions in her right breast 6 months later. Pathology investigation revealed breast relapse, with complete remission on the basis of bone marrow findings. Combined modality treatment including chemotherapy and local radiotherapy helped achieve complete remission with mild side effects.

Conclusion

The findings from this case indicate that the breast is a potentially involved extramedullary site of relapse for ALL patients after HSCT. In the case of a newly developed breast lump in such patients, clinicians consider local relapse even if the bone marrow findings indicate remission. Combined modality treatment will contribute to better local control and improve prognosis.

http://link.springer.com/10.1186/s12885-016-2910-0

Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is a global public health issue, as it is the eighth most common cancer worldwide. The mechanisms behind ESCC invasion and progression are still poorly understood, and warrant further investigation into these processes and their drivers. In recent years, the ligand Activin A has been implicated as a player in the progression of a number of cancers. The objective of this study was to investigate the role of Activin A signaling in ESCC.

Methods

To investigate the role Activin A plays in ESCC biology, tissue microarrays containing 200 cores from 120 ESCC patients were analyzed upon immunofluorescence staining. We utilized three-dimensional organotypic reconstruct cultures of dysplastic and esophageal squamous tumor cells lines, in the context of fibroblast-secreted Activin A, to identify the effects of Activin A on cell invasion and determine protein expression and localization in epithelial and stromal compartments by immunofluorescence. To identify the functional consequences of stromal-derived Activin A on angiogenesis, we performed endothelial tube formation assays.

Results

Analysis of ESCC patient samples indicated that patients with high stromal Activin A expression had low epithelial ACVRIB, the Activin type I receptor. We found that overexpression of stromal-derived Activin A inhibited invasion of esophageal dysplastic squamous cells, ECdnT, and TE-2 ESCC cells, both positive for ACVRIB. This inhibition was accompanied by a decrease in expression of the extracellular matrix (ECM) protein fibronectin and podoplanin, which is often expressed at the leading edge during invasion. Endothelial tube formation was disrupted in the presence of conditioned media from fibroblasts overexpressing Activin A. Interestingly, ACVRIB-negative TE-11 cells did not show the prior observed effects in the context of Activin A overexpression, indicating a dependence on the presence of ACVRIB.

Conclusions

We describe the first observation of an inhibitory role for Activin A in ESCC progression that is dependent on the expression of ACVRIB.

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Investigation of optical coherence micro-elastography as a method to visualize micro-architecture in human axillary lymph nodes

Abstract

Background

Evaluation of lymph node involvement is an important factor in detecting metastasis and deciding whether to perform axillary lymph node dissection (ALND) in breast cancer surgery. As ALND is associated with potentially severe long term morbidity, the accuracy of lymph node assessment is imperative in avoiding unnecessary ALND. The mechanical properties of malignant lymph nodes are often distinct from those of normal nodes. A method to image the micro-scale mechanical properties of lymph nodes could, thus, provide diagnostic information to aid in the assessment of lymph node involvement in metastatic cancer. In this study, we scan axillary lymph nodes, freshly excised from breast cancer patients, with optical coherence micro-elastography (OCME), a method of imaging micro-scale mechanical strain, to assess its potential for the intraoperative assessment of lymph node involvement.

Methods

Twenty-six fresh, unstained lymph nodes were imaged from 15 patients undergoing mastectomy or breast-conserving surgery with axillary clearance. Lymph node specimens were bisected to allow imaging of the internal face of each node. Co-located OCME and optical coherence tomography (OCT) scans were taken of each sample, and the results compared to standard post-operative hematoxylin-and-eosin-stained histology.

Results

The optical backscattering signal provided by OCT alone may not provide reliable differentiation by inspection between benign and malignant lymphoid tissue. Alternatively, OCME highlights local changes in tissue strain that correspond to malignancy and are distinct from strain patterns in benign lymphoid tissue. The mechanical contrast provided by OCME complements the optical contrast provided by OCT and aids in the differentiation of malignant tumor from uninvolved lymphoid tissue.

Conclusion

The combination of OCME and OCT images represents a promising method for the identification of malignant lymphoid tissue. This method shows potential to provide intraoperative assessment of lymph node involvement, thus, preventing unnecessary removal of uninvolved tissues and improving patient outcomes.

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Complete response of extramedullary relapse in breast of acute T lymphoblastic leukemia after bone marrow transplantation to chemoradiotherapy: a case report and literature review

Abstract

Background

Relapse of acute lymphoblastic leukemia (ALL) occurring in the breast after allografting is extremely rare, with only 22 reported cases in the literature thus far. Further, the lack of a systemic analysis provides little information about this entity. We present a case of isolated extramedullary relapse from acute T lymphoblastic leukemia (ATLL) after allogeneic hematopoietic stem cell transplantation (HSCT).

Case presentation

A 32-year-old Chinese woman diagnosed with ATLL with myeloid antigen expression received HSCT from her human leukocyte antigen (HLA)-matched sister and presented with two lesions in her right breast 6 months later. Pathology investigation revealed breast relapse, with complete remission on the basis of bone marrow findings. Combined modality treatment including chemotherapy and local radiotherapy helped achieve complete remission with mild side effects.

Conclusion

The findings from this case indicate that the breast is a potentially involved extramedullary site of relapse for ALL patients after HSCT. In the case of a newly developed breast lump in such patients, clinicians consider local relapse even if the bone marrow findings indicate remission. Combined modality treatment will contribute to better local control and improve prognosis.

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Brain cancer risk: the weight of obesity

http://link.springer.com/10.1007/s11060-016-2315-6

Association of thyroid hormone concentrations with quality of life of primary brain tumor patients: a pilot study

Abstract

Reduced triiodothyronine (T3) concentrations were implicated in worse prognosis of brain tumor patients. In this study we investigated the association of normal and abnormal thyroid hormone concentrations with health-related quality of life (HRQoL) of patients with primary brain tumors. Sixty-three patients (67% women and a mean age of 55.5 ± 13.8 years) before brain tumor surgery were evaluated for: (1) HRQoL using the EORTC questionnaire for cancer patients (QLQ-C30) and the Brain Cancer-Specific Quality of Life Questionnaire (QLQ-BN20); (2) functional status (Barthel Index); and (3) clinical disease severity. Blood samples were obtained for assessment of thyroid hormone concentrations before surgery. After adjusting for the brain tumor histological diagnosis, patients' age, gender and functional status, lower thyroid stimulating hormone (TSH) concentrations were associated with poor levels of functioning on the QLQ-C30 scales: physical functioning (β = 0.395, p < 0.001), role functioning (β = 0.334, p = 0.003) and cognitive functioning (β = 0.327, p = 0.009), and with greater QLQ-BN20 fatigue symptom severity (β = −0.406, p < 0.001). Lower free T3 concentrations were associated with worse HRQOL on the QLQ-C30 global health status (β = 0.302, p = 0.017), emotional functioning (β= 0.422, p < 0.001) and cognitive functioning (β= 0.259, p = 0.042) domains, and with greater symptom severity on the QLQ-BN20 fatigue (β = −0.238, p = 0.041), motor dysfunction (β = −0.283, p = 0.013) and weakness of legs (β = −0.269. p = 0.027) domains. In conclusion, reduced T3 and TSH hormone concentrations are associated with impaired emotional and physical aspects of HRQoL of primary brain tumor patients independent of brain tumor histological diagnosis, patients' age, gender and functional status. Assessment for thyroid axis dysfunction should be addressed and appropriately managed in neuro-oncology patient care.

http://link.springer.com/10.1007/s11060-016-2311-x

Brain cancer risk: the weight of obesity

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Association of thyroid hormone concentrations with quality of life of primary brain tumor patients: a pilot study

Abstract

Reduced triiodothyronine (T3) concentrations were implicated in worse prognosis of brain tumor patients. In this study we investigated the association of normal and abnormal thyroid hormone concentrations with health-related quality of life (HRQoL) of patients with primary brain tumors. Sixty-three patients (67% women and a mean age of 55.5 ± 13.8 years) before brain tumor surgery were evaluated for: (1) HRQoL using the EORTC questionnaire for cancer patients (QLQ-C30) and the Brain Cancer-Specific Quality of Life Questionnaire (QLQ-BN20); (2) functional status (Barthel Index); and (3) clinical disease severity. Blood samples were obtained for assessment of thyroid hormone concentrations before surgery. After adjusting for the brain tumor histological diagnosis, patients' age, gender and functional status, lower thyroid stimulating hormone (TSH) concentrations were associated with poor levels of functioning on the QLQ-C30 scales: physical functioning (β = 0.395, p < 0.001), role functioning (β = 0.334, p = 0.003) and cognitive functioning (β = 0.327, p = 0.009), and with greater QLQ-BN20 fatigue symptom severity (β = −0.406, p < 0.001). Lower free T3 concentrations were associated with worse HRQOL on the QLQ-C30 global health status (β = 0.302, p = 0.017), emotional functioning (β= 0.422, p < 0.001) and cognitive functioning (β= 0.259, p = 0.042) domains, and with greater symptom severity on the QLQ-BN20 fatigue (β = −0.238, p = 0.041), motor dysfunction (β = −0.283, p = 0.013) and weakness of legs (β = −0.269. p = 0.027) domains. In conclusion, reduced T3 and TSH hormone concentrations are associated with impaired emotional and physical aspects of HRQoL of primary brain tumor patients independent of brain tumor histological diagnosis, patients' age, gender and functional status. Assessment for thyroid axis dysfunction should be addressed and appropriately managed in neuro-oncology patient care.

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Retraction Note to: Prognostic investigations of B7-H1 and B7-H4 expression levels as independent predictor markers of renal cell carcinoma

http://link.springer.com/10.1007/s13277-016-5484-1

Retraction Note to: Evaluation of gene expression level of CDC5L and MACC1 in poor prognosis and progression of osteosarcoma

http://link.springer.com/10.1007/s13277-016-5485-0

Retraction Note to: Overexpression of interleukins IL-17 and IL-8 with poor prognosis in colorectal cancer induces metastasis

http://link.springer.com/10.1007/s13277-016-5483-2

Retraction Note to: Prognostic investigations of B7-H1 and B7-H4 expression levels as independent predictor markers of renal cell carcinoma

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Retraction Note to: Evaluation of gene expression level of CDC5L and MACC1 in poor prognosis and progression of osteosarcoma

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Retraction Note to: Overexpression of interleukins IL-17 and IL-8 with poor prognosis in colorectal cancer induces metastasis

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Effects of preservative and temperature on ctDNA analysis

Purpose:Analysis of genomic alterations in cell-free DNA (cfDNA) is evolving as an approach to detect, monitor and genotype malignancies. Methods to separate the liquid from the cellular fraction of whole blood for circulating tumor DNA (ctDNA) analyses have been largely unstudied although these may be a critical consideration for assay performance. Experimental Design:To evaluate the influence of blood processing on cfDNA and ctDNA quality and yield, we compared the cfDNA levels in serum to those in plasma. Given the limitations of serum for ctDNA analyses, we evaluated the effects of two plasma processing approaches, K2EDTA and Cell-Free DNA™ BCT (BCT) tubes, on cfDNA and ctDNA recovery. A total of 45 samples from 9 cancer patients were collected in both tube types. Once collected, blood was processed into plasma immediately or kept at room temperature and processed into plasma at 1, 3, 5, or 7 days. Results:As early as 24 hours after collection, plasma isolated from blood collected in K2EDTA tubes contained an elevated level of cfDNA that increased over time compared with BCT tubes where no significant increase in cfDNA levels was observed. When samples from an additional six cancer patients, collected in the same manner, were stored at 4°C in K2EDTA tubes over the course of 3 days, total cfDNA and ctDNA levels were comparable between samples collected in BCT tubes.

http://clincancerres.aacrjournals.org/cgi/content/short/1078-0432.CCR-16-1691v1?rss=1

lncRNA signature with prognostic relevance in stage I EOC

Purpose: Stage I epithelial ovarian cancer (EOC) represents about 10% of all EOCs and is characterized by good prognosis with fewer than 20% of patients relapsing. As it occurs less frequently than advanced stage EOC, its molecular features have not been thoroughly investigated. We have demonstrated that in stage I EOC hsa-miR-200c-3p can predict patients' outcome. In the present study, we analyzed the expression of long non-coding RNAs (lncRNAs) to enable potential definition of a non coding transcriptional signature with prognostic relevance for stage I EOC. Experimental Design: 202 snap-frozen stage I EOC tumor biopsies, 47 of which relapsed, were gathered together from three independent tumor tissue collections and subdivided into a training set (n=73) and a validation set (n=129). Median follow up was 9 years. LncRNAs' expression profiles were correlated in univariate and multivariate analysis with overall survival (OS) and progression free survival (PFS). Results: The expression of lnc-SERTAD2-3, lnc-SOX4-1, lnc-HRCT1-1 and PVT1 are associated in univariate and multivariate analyses with relapse and poor outcome in both training and validation sets (p<0.001). Using the expression profiles of PVT1, lnc-SERTAD2-3 and hsa-miR-200c-3p simultaneously, it was possible to stratify patients into high and low risk. The OS for high and low risk individuals are 36 and 123 months respectively (OR=15.55 3.81-63.36 CI 95%). Conclusions: We have identified a non-coding transcriptional signature predictor of survival and biomarker of relapse for stage I EOC.

http://clincancerres.aacrjournals.org/cgi/content/short/1078-0432.CCR-16-1402v1?rss=1

Hyperprogressive disease with anti PD-1/PD-L1 therapy

Purpose While Immune checkpoint inhibitors are disrupting the management of cancer patients, anecdotal occurrences of rapid progression (i.e. hyperprogressive disease or HPD) under these agents have been described, suggesting potentially deleterious effects of these drugs. The prevalence, the natural history and the predictive factors of HPD in cancer patients treated by anti PD-1/PD-L1 remain unknown. Experimental design Medical records from all patients (N =218) prospectively treated in Gustave Roussy by anti PD-1/PD-L1 within phase I clinical trials were analyzed. The tumor growth rate (TGR) prior ("REFERENCE") and upon ("EXPERIMENTAL") anti-PD-1/PD-L1 therapy was compared to identify patients with accelerated tumor growth. Associations between TGR, clinico-pathological characteristics and overall survival (OS) were computed. Results HPD was defined as a RECIST progression at the first evaluation and as a ≥ two-fold increase of the TGR between the REF and the EXP periods. Out of 131 evaluable patients, 12 patients (9%) were considered as HPD. HPD was not associated with higher tumor burden at baseline, nor with any specific tumor type. At progression, HPD patients had a lower rate of new lesions than progressive non-HPD patients (p<0.05). HPD is associated with a higher age (p<0.05) and a worse outcome (Overall Survival). Interestingly, REFERENCE TGR (before treatment) was inversely correlated with response to anti-PD-1/PD-L1 (P<0.05). Conclusion A novel aggressive pattern of hyper-progression exists in a fraction of patients treated with anti-PD-1/PD-L1. This observation raises potentially some concerns about treating elderly patients (>65 y.o) with anti-PD-1/PD-L1 monotherapy.

http://clincancerres.aacrjournals.org/cgi/content/short/1078-0432.CCR-16-1741v1?rss=1

BRM Polymorphisms and Lung Cancer Prognosis

Purpose: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741, BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression. Experimental Design: Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models. Promoter swap, luciferase assays, and chromatin immunoprecipitation (ChIP) experiments evaluated polymorphism function. In silico analysis of publicly available gene expression datasets with outcome were performed. Results: Carrying the homozygous variants of both polymorphisms ("double homozygotes", DH) when compared with those carrying the double wild-type, was associated with worse overall survival, with an adjusted hazard ratios (aHR) of 2.74 (95%CI: 1.9-4.0). This was confirmed in the BR.24 trial (aHR 8.97, 95%CI: 3.3-18.5). Lower BRM gene expression (by RNA-Seq or microarray) was associated with worse outcome (p<0.04). ChIP and promoter swap experiments confirmed binding of MEF2D and HDAC9 only to homozygotes of each polymorphism, associated with reduced promoter activity in the DH. Conclusions: Epigenetic regulatory molecules bind to two BRM promoter sequence variants but not to their wild-type sequences. These variants are associated with adverse overall and progression free survival. Decreased BRM gene expression, seen with these variants, is also associated with worse overall survival.

http://clincancerres.aacrjournals.org/cgi/content/short/1078-0432.CCR-16-1640v1?rss=1

miRNA-487a promotes proliferation and metastasis in HCC

Purpose: Hepatocellular carcinoma (HCC) harbors highly metastatic properties, accounting for postoperative recurrence and metastasis. However, the mechanisms for metastasis and recurrence remain incompletely clear. This study aimed to investigate the role of hsa-miR-487a (miR-487a) in promoting the proliferation and metastasis of HCC and to elucidate the underlying molecular mechanisms. Experimental Design: 198 HCC samples were analyzed for association between miR-487a expression and patient clinicopathological features and prognosis. The roles of miR-487a in proliferation and metastasis were validated both in vivo and in vitro. The upstream regulator and downstream targets of miR-487a were determined using a dual luciferase reporter assay, chromatin immunoprecipitation and immunohistochemistry. Result: Our results demonstrate that up-regulated miR-487a correlates with a poor prognosis for HCC patients. miR-487a enhances proliferation and metastasis of HCC cells by directly binding to sprouty-related EVH1 domain containing 2 (SPRED2) or phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1). Interestingly, miR-487a mainly promotes metastasis via SPRED2 induced mitogen activated protein kinase signaling and promotes proliferation via PIK3R1 mediated AKT signaling. Transcription of miR-487a was found to be activated by up-regulated heat shock factor 1, which we previously demonstrated to be an important metastasis-associated transcription factor in a previous study. Phosphorodiamidate morpholino oligomers effectively silenced miR-487a and inhibited HCC tumor progression in mouse models. Conclusions: Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of HCC by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC.

http://clincancerres.aacrjournals.org/cgi/content/short/1078-0432.CCR-16-0851v1?rss=1

Isolation of tumor associated mutation reactive TCRs

Purpose: The adoptive transfer of lymphocytes genetically modified to express tumor reactive T cell receptors (TCRs) can mediate tumor regression. Some tumor infiltrating lymphocytes (TIL) recognize somatic mutations expressed only in the patient's tumors, and evidence suggests that clinically effective TIL target tumor specific neoantigens. Here we attempted to isolate neoantigen reactive TCRs as a prelude to the treatment of patients with autologous T cells genetically modified to express such TCRs. Experimental Design: Mutations expressed by tumors were identified using whole exome and RNA sequencing. Tandem minigene (TMG) constructs encoding 12-24 mutated gene products were synthesized, each encoding the mutated amino acid flanked by 12 amino acids of the normal protein sequence. TIL were cultured with autologous dendritic cells (DCs) transfected with in vitro transcribed (IVT) mRNAs encoding TMGs and were evaluated for IFN secretion and CD137 expression. Neoantigen-reactive T cells were enriched from TIL by sorting for CD137+ CD8+ T cells and expanded in vitro. Dominant TCR α and β chains were identified in the enriched populations using a combination of 5' rapid amplification of cDNA ends, deep sequencing of genomic DNA, PairSeq™ analysis, and single cell RT-PCR analysis. Human PBL retrovirally transduced to express the TCRs were evaluated for recognition of relevant neoantigens. Results: We identified 27 TCRs from 6 patients that recognized 14 neoantigens expressed by autologous tumor cells. Conclusions: This strategy provides the means to generate T cells expressing neoantigen reactive TCRs for use in future adoptive cell transfer immunotherapy trials for patients with cancer.

http://clincancerres.aacrjournals.org/cgi/content/short/1078-0432.CCR-16-2680v1?rss=1

Effects of preservative and temperature on ctDNA analysis

Purpose:Analysis of genomic alterations in cell-free DNA (cfDNA) is evolving as an approach to detect, monitor and genotype malignancies. Methods to separate the liquid from the cellular fraction of whole blood for circulating tumor DNA (ctDNA) analyses have been largely unstudied although these may be a critical consideration for assay performance. Experimental Design:To evaluate the influence of blood processing on cfDNA and ctDNA quality and yield, we compared the cfDNA levels in serum to those in plasma. Given the limitations of serum for ctDNA analyses, we evaluated the effects of two plasma processing approaches, K2EDTA and Cell-Free DNA™ BCT (BCT) tubes, on cfDNA and ctDNA recovery. A total of 45 samples from 9 cancer patients were collected in both tube types. Once collected, blood was processed into plasma immediately or kept at room temperature and processed into plasma at 1, 3, 5, or 7 days. Results:As early as 24 hours after collection, plasma isolated from blood collected in K2EDTA tubes contained an elevated level of cfDNA that increased over time compared with BCT tubes where no significant increase in cfDNA levels was observed. When samples from an additional six cancer patients, collected in the same manner, were stored at 4°C in K2EDTA tubes over the course of 3 days, total cfDNA and ctDNA levels were comparable between samples collected in BCT tubes.

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lncRNA signature with prognostic relevance in stage I EOC

Purpose: Stage I epithelial ovarian cancer (EOC) represents about 10% of all EOCs and is characterized by good prognosis with fewer than 20% of patients relapsing. As it occurs less frequently than advanced stage EOC, its molecular features have not been thoroughly investigated. We have demonstrated that in stage I EOC hsa-miR-200c-3p can predict patients' outcome. In the present study, we analyzed the expression of long non-coding RNAs (lncRNAs) to enable potential definition of a non coding transcriptional signature with prognostic relevance for stage I EOC. Experimental Design: 202 snap-frozen stage I EOC tumor biopsies, 47 of which relapsed, were gathered together from three independent tumor tissue collections and subdivided into a training set (n=73) and a validation set (n=129). Median follow up was 9 years. LncRNAs' expression profiles were correlated in univariate and multivariate analysis with overall survival (OS) and progression free survival (PFS). Results: The expression of lnc-SERTAD2-3, lnc-SOX4-1, lnc-HRCT1-1 and PVT1 are associated in univariate and multivariate analyses with relapse and poor outcome in both training and validation sets (p<0.001). Using the expression profiles of PVT1, lnc-SERTAD2-3 and hsa-miR-200c-3p simultaneously, it was possible to stratify patients into high and low risk. The OS for high and low risk individuals are 36 and 123 months respectively (OR=15.55 3.81-63.36 CI 95%). Conclusions: We have identified a non-coding transcriptional signature predictor of survival and biomarker of relapse for stage I EOC.

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Hyperprogressive disease with anti PD-1/PD-L1 therapy

Purpose While Immune checkpoint inhibitors are disrupting the management of cancer patients, anecdotal occurrences of rapid progression (i.e. hyperprogressive disease or HPD) under these agents have been described, suggesting potentially deleterious effects of these drugs. The prevalence, the natural history and the predictive factors of HPD in cancer patients treated by anti PD-1/PD-L1 remain unknown. Experimental design Medical records from all patients (N =218) prospectively treated in Gustave Roussy by anti PD-1/PD-L1 within phase I clinical trials were analyzed. The tumor growth rate (TGR) prior ("REFERENCE") and upon ("EXPERIMENTAL") anti-PD-1/PD-L1 therapy was compared to identify patients with accelerated tumor growth. Associations between TGR, clinico-pathological characteristics and overall survival (OS) were computed. Results HPD was defined as a RECIST progression at the first evaluation and as a ≥ two-fold increase of the TGR between the REF and the EXP periods. Out of 131 evaluable patients, 12 patients (9%) were considered as HPD. HPD was not associated with higher tumor burden at baseline, nor with any specific tumor type. At progression, HPD patients had a lower rate of new lesions than progressive non-HPD patients (p<0.05). HPD is associated with a higher age (p<0.05) and a worse outcome (Overall Survival). Interestingly, REFERENCE TGR (before treatment) was inversely correlated with response to anti-PD-1/PD-L1 (P<0.05). Conclusion A novel aggressive pattern of hyper-progression exists in a fraction of patients treated with anti-PD-1/PD-L1. This observation raises potentially some concerns about treating elderly patients (>65 y.o) with anti-PD-1/PD-L1 monotherapy.

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BRM Polymorphisms and Lung Cancer Prognosis

Purpose: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741, BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression. Experimental Design: Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models. Promoter swap, luciferase assays, and chromatin immunoprecipitation (ChIP) experiments evaluated polymorphism function. In silico analysis of publicly available gene expression datasets with outcome were performed. Results: Carrying the homozygous variants of both polymorphisms ("double homozygotes", DH) when compared with those carrying the double wild-type, was associated with worse overall survival, with an adjusted hazard ratios (aHR) of 2.74 (95%CI: 1.9-4.0). This was confirmed in the BR.24 trial (aHR 8.97, 95%CI: 3.3-18.5). Lower BRM gene expression (by RNA-Seq or microarray) was associated with worse outcome (p<0.04). ChIP and promoter swap experiments confirmed binding of MEF2D and HDAC9 only to homozygotes of each polymorphism, associated with reduced promoter activity in the DH. Conclusions: Epigenetic regulatory molecules bind to two BRM promoter sequence variants but not to their wild-type sequences. These variants are associated with adverse overall and progression free survival. Decreased BRM gene expression, seen with these variants, is also associated with worse overall survival.

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miRNA-487a promotes proliferation and metastasis in HCC

Purpose: Hepatocellular carcinoma (HCC) harbors highly metastatic properties, accounting for postoperative recurrence and metastasis. However, the mechanisms for metastasis and recurrence remain incompletely clear. This study aimed to investigate the role of hsa-miR-487a (miR-487a) in promoting the proliferation and metastasis of HCC and to elucidate the underlying molecular mechanisms. Experimental Design: 198 HCC samples were analyzed for association between miR-487a expression and patient clinicopathological features and prognosis. The roles of miR-487a in proliferation and metastasis were validated both in vivo and in vitro. The upstream regulator and downstream targets of miR-487a were determined using a dual luciferase reporter assay, chromatin immunoprecipitation and immunohistochemistry. Result: Our results demonstrate that up-regulated miR-487a correlates with a poor prognosis for HCC patients. miR-487a enhances proliferation and metastasis of HCC cells by directly binding to sprouty-related EVH1 domain containing 2 (SPRED2) or phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1). Interestingly, miR-487a mainly promotes metastasis via SPRED2 induced mitogen activated protein kinase signaling and promotes proliferation via PIK3R1 mediated AKT signaling. Transcription of miR-487a was found to be activated by up-regulated heat shock factor 1, which we previously demonstrated to be an important metastasis-associated transcription factor in a previous study. Phosphorodiamidate morpholino oligomers effectively silenced miR-487a and inhibited HCC tumor progression in mouse models. Conclusions: Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of HCC by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC.

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Isolation of tumor associated mutation reactive TCRs

Purpose: The adoptive transfer of lymphocytes genetically modified to express tumor reactive T cell receptors (TCRs) can mediate tumor regression. Some tumor infiltrating lymphocytes (TIL) recognize somatic mutations expressed only in the patient's tumors, and evidence suggests that clinically effective TIL target tumor specific neoantigens. Here we attempted to isolate neoantigen reactive TCRs as a prelude to the treatment of patients with autologous T cells genetically modified to express such TCRs. Experimental Design: Mutations expressed by tumors were identified using whole exome and RNA sequencing. Tandem minigene (TMG) constructs encoding 12-24 mutated gene products were synthesized, each encoding the mutated amino acid flanked by 12 amino acids of the normal protein sequence. TIL were cultured with autologous dendritic cells (DCs) transfected with in vitro transcribed (IVT) mRNAs encoding TMGs and were evaluated for IFN secretion and CD137 expression. Neoantigen-reactive T cells were enriched from TIL by sorting for CD137+ CD8+ T cells and expanded in vitro. Dominant TCR α and β chains were identified in the enriched populations using a combination of 5' rapid amplification of cDNA ends, deep sequencing of genomic DNA, PairSeq™ analysis, and single cell RT-PCR analysis. Human PBL retrovirally transduced to express the TCRs were evaluated for recognition of relevant neoantigens. Results: We identified 27 TCRs from 6 patients that recognized 14 neoantigens expressed by autologous tumor cells. Conclusions: This strategy provides the means to generate T cells expressing neoantigen reactive TCRs for use in future adoptive cell transfer immunotherapy trials for patients with cancer.

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Case Report of a Child after Hematopoietic Cell Transplantation with Acute Aspergillus Tracheobronchitis as a Cause for Respiratory Failure

Rapid respiratory failure due to invasive mycosis of the airways is an uncommon presentation of Aspergillus infection, even in immunocompromised patients, and very few pediatric cases have been reported. Patients with Aspergillus tracheobronchitis present with nonspecific symptoms, and radiologic studies are often noninformative, leading to a delay in diagnosis. Prompt initiation of adequate antifungal therapies is of utmost importance to improve outcome. We report the case of a 9-year-old girl with chronic myelogenous leukemia who developed respiratory distress 41 days after hematopoietic cell transplantation and rapidly deteriorated despite multiple interventions and treatment modalities.

http://www.hindawi.com/journals/cripe/2016/9676234/

Life-threatening Wunderlich's syndrome with concurrent clopidogrel use

Spontaneous non-traumatic renal haemorrhage, or Wunderlich's syndrome, is a rare but potentially life-threatening event. We present the case of a 63-year-old man on clopidogrel who became haemodynamically unstable as a result of this condition. Angioembolisation revealed the unusual finding of active bleeding from multiple distinct subsegmental renal vessels, for which haemostasis was successfully achieved by coil placement. The patient remains well and with near-normal renal function on follow-up.

http://casereports.bmj.com/cgi/content/short/2016/nov08_2/bcr2016216171?rss=1

Q fever hepatitis and endocarditis in the context of haemochromatosis

Hereditary haemochromatosis is associated with increased susceptibility to some infections. We report here a case of Q fever in a patient with coexistent haemochromatosis. The literature is reviewed in regard to the effect of haemochromatosis on susceptibility to infectious disease in general and Q fever in particular. Although there is documented increased risk in these patients for some infectious conditions, a specific association with Q fever has not been previously reported. The present report raises the possibility of such a clinically relevant connection.

http://casereports.bmj.com/cgi/content/short/2016/nov08_2/bcr2016215214?rss=1

Acute aortic dissection in postpartum

Description

A Caucasian woman aged 35 years, with no relevant personal history or history of drug abuse and an uneventful pregnancy, presented in the emergency room (ER) at 34 weeks of gestation, with preterm premature rupture of membranes. On physical examination, she had elevated blood pressure and bilateral peripheral oedema. An extensive blood panel was performed, providing the diagnosis of pre-eclampsia. Four hours after admission, she had a vaginal delivery and, 36 hours later, discharged herself against medical advice. A few hours later, she returned to the ER, reporting of severe thoracic pain of sudden onset, sweating and nausea. Her vitals were within normal range, and peripheral pulses were present and symmetrical.

Suspecting a pulmonary embolism, a thoracic CT was performed (figures 1–3), showing 'extensive dissection of the ascending aorta, extending from the aortic root to the origin of the celiac artery. No aneurism is...

http://casereports.bmj.com/cgi/content/short/2016/nov08_2/bcr2016218236?rss=1

Aneurysmal wall imaging in a case of cortical superficial siderosis and multiple unruptured aneurysms

We report a case of interhemispheric and bifrontal cortical superficial siderosis in association with two intracranial aneurysms. The patient had no clinical history suggestive of aneurysm rupture, no feature of amyloid angiopathy or other apparent etiology for cortical siderosis. We performed high resolution brain MRI with dark blood T1 sequences before and after IV contrast injection. An anterior communicating aneurysm showed partial wall enhancement on the posterior wall whereas a left posterior communicating aneurysm did not. In the light of recent reports of the association of wall enhancement with unstable aneurysms, we considered wall enhancement to be a marker of inflammation and remodeling of the aneurysm wall, resulting in chronic hemorrhagic suffusion in the subarachnoid spaces. To our knowledge, this is the first report offering proof for a possible link between apparently unruptured aneurysms and cortical siderosis.

http://casereports.bmj.com/cgi/content/short/2016/nov08_2/bcr2016012680?rss=1

Pilot study of FMC (5-fluorouracil, mitomycin C, and cisplatin) with radiotherapy for patients with anal cancer

Abstract

Objectives

Concurrent chemoradiotherapy (CRT) is the current standard of treatment for anal squamous carcinoma. However, local or metastatic recurrences remain significant after CRT with 5-fluorouracil (5-FU) and mitomycin C (MMC). Therefore, the present study evaluated the feasibility and efficacy of adding cisplatin to the classic CRT (5-FU, MMC, and radiotherapy).

Methods

Twenty patients with histologically confirmed squamous cell carcinoma of the anus without metastatic disease were enrolled at Kyungpook National University Medical Center (Daegu, Korea) between January 2005 and December 2014. The CRT comprised of two cycles of 5-FU 750 mg/m² days 1–4, MMC 10 mg/m² day 1, and cisplatin 60 mg/m² day 1 every 4 weeks and radiotherapy (59.6 Gy in 33 daily fractions). The primary endpoint was to determine the feasibility of FMC, while the secondary endpoints were the pathologic complete response (pCR) rate at 8 weeks following the completion of CRT, progression-free survival (PFS), and overall survival (OS).

Results

The treatment was generally well tolerated, and all patients received two cycles of FMC chemotherapy. Among the 20 patients, 17 were assessed for their pathologic response and 12 patients (70.6%) achieved pCR. The most common grade 3 or 4 hematologic toxicity was neutropenia (n = 3), while the most frequent severe non-hematologic toxicity was radiation dermatitis (n = 6, 30%). After a median follow-up duration of 45.5 months, the estimated 5-year PFS and overall survival rates were 88.9 and 88.1%, respectively.

Conclusion

CRT with two cycles of a FMC regimen was found to be feasible for patients with anal squamous carcinoma. Further study is warranted to evaluate the efficacy of CRT with a FMC regimen.

http://link.springer.com/10.1007/s00280-016-3185-5

Pilot study of FMC (5-fluorouracil, mitomycin C, and cisplatin) with radiotherapy for patients with anal cancer

Abstract

Objectives

Concurrent chemoradiotherapy (CRT) is the current standard of treatment for anal squamous carcinoma. However, local or metastatic recurrences remain significant after CRT with 5-fluorouracil (5-FU) and mitomycin C (MMC). Therefore, the present study evaluated the feasibility and efficacy of adding cisplatin to the classic CRT (5-FU, MMC, and radiotherapy).

Methods

Twenty patients with histologically confirmed squamous cell carcinoma of the anus without metastatic disease were enrolled at Kyungpook National University Medical Center (Daegu, Korea) between January 2005 and December 2014. The CRT comprised of two cycles of 5-FU 750 mg/m² days 1–4, MMC 10 mg/m² day 1, and cisplatin 60 mg/m² day 1 every 4 weeks and radiotherapy (59.6 Gy in 33 daily fractions). The primary endpoint was to determine the feasibility of FMC, while the secondary endpoints were the pathologic complete response (pCR) rate at 8 weeks following the completion of CRT, progression-free survival (PFS), and overall survival (OS).

Results

The treatment was generally well tolerated, and all patients received two cycles of FMC chemotherapy. Among the 20 patients, 17 were assessed for their pathologic response and 12 patients (70.6%) achieved pCR. The most common grade 3 or 4 hematologic toxicity was neutropenia (n = 3), while the most frequent severe non-hematologic toxicity was radiation dermatitis (n = 6, 30%). After a median follow-up duration of 45.5 months, the estimated 5-year PFS and overall survival rates were 88.9 and 88.1%, respectively.

Conclusion

CRT with two cycles of a FMC regimen was found to be feasible for patients with anal squamous carcinoma. Further study is warranted to evaluate the efficacy of CRT with a FMC regimen.

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A Rare Case Report of Thoracic Ectopia Cordis: An Obstetrician’s Point of View in Multidisciplinary Approach

Ectopia cordis is a rare congenital anomaly associated with the heart positioned outside of the thoracic cavity either partially or completely. It can be associated with other congenital abnormalities. Overall, the prognosis for infants with ectopia cordis is very poor but depends greatly on the type and severity of ectopia cordis and intracardiac and associated malformations. We present one case of a fetus with prenatally diagnosed thoracic ectopia cordis with intracardiac defects and omphalocele, all the abnormalities seen in pentalogy of Cantrell except a diaphragmatic defect. Considering poor prognosis for fetus, conservative management of prenatal care has been chosen. At the 42nd gestational week, during the active stage of labor, due to fetal distress, cesarean section was performed at a tertiary level hospital. The condition of the infant was impairing rapidly and the newborn succumbed within 24 hours. We discuss the perinatal care concerning this rare anomaly.

http://www.hindawi.com/journals/cripe/2016/5097059/

Validation and development of MTH1 inhibitors for treatment of cancer

Different MTH1 inhibitors have different ability to kill cancer cells. Here we demonstrate that the lack of efficiency of some MTH1 inhibitors is explained by their inability introduce the toxic oxidized nucleotides into DNA. Furthermore, we describe TH1579, Karonudib, which is a potent, selective MTH1 inhibitor with good oral availability and with excellent anti-cancer properties in vivo.

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Validation and development of MTH1 inhibitors for treatment of cancer

Different MTH1 inhibitors have different ability to kill cancer cells. Here we demonstrate that the lack of efficiency of some MTH1 inhibitors is explained by their inability introduce the toxic oxidized nucleotides into DNA. Furthermore, we describe TH1579, Karonudib, which is a potent, selective MTH1 inhibitor with good oral availability and with excellent anti-cancer properties in vivo.

http://annonc.oxfordjournals.org/cgi/content/short/mdw429v1?rss=1

Collective cell migration of thyroid carcinoma cells: a beneficial ability to override unfavourable substrates

Abstract

Purpose

Tumor cell invasion and metastasis are life threatening events. Invasive tumor cells tend to migrate as collective sheets. In the present in vitro study we aimed to (i) assess whether collective tumor cells gain benefits in their migratory potential compared to single cells and (ii) to identify its putative underlying molecular mechanisms.

Methods

The migratory potential of single and collective carcinoma cells was assessed using video time lapse microscopy and cell migration assays in the absence and presence of seven potential gap junction inhibitors or the Rac1 inhibitor Z62954982. The perturbation of gap junctions was assessed using a dye diffusion assay. In addition, LDH-based cytotoxicity and RT-PCR-based expression analyses were performed.

Results

Whereas single breast, cervix and thyroid carcinoma cells were virtually immobile on unfavourable plastic surfaces, we found that they gained pronounced migratory capacities as collectives under comparable conditions. Thyroid carcinoma cells, that were studied in more detail, were found to express specific subsets of connexins and to form active gap junctions as revealed by dye diffusion analysis. Although all potential gap junction blockers suppressed intercellular dye diffusion in at least one of the cell lines tested, only two of them were found to inhibit collective cell migration and none of them to inhibit single cell migration. In the presence of the Rac1 inhibitor Z62954982 collective migration, but not single cell migration, was found to be reduced up to 20 %.

Conclusions

Our data indicate that collective migration enables tumor cells to cross otherwise unfavourable substrate areas. This capacity seems to be independent of intercellular communication via gap junctions, whereas Rac1-dependent intracellular signalling seems to be essential.

http://ift.tt/2ei6UAA

Collective cell migration of thyroid carcinoma cells: a beneficial ability to override unfavourable substrates

Abstract

Purpose

Tumor cell invasion and metastasis are life threatening events. Invasive tumor cells tend to migrate as collective sheets. In the present in vitro study we aimed to (i) assess whether collective tumor cells gain benefits in their migratory potential compared to single cells and (ii) to identify its putative underlying molecular mechanisms.

Methods

The migratory potential of single and collective carcinoma cells was assessed using video time lapse microscopy and cell migration assays in the absence and presence of seven potential gap junction inhibitors or the Rac1 inhibitor Z62954982. The perturbation of gap junctions was assessed using a dye diffusion assay. In addition, LDH-based cytotoxicity and RT-PCR-based expression analyses were performed.

Results

Whereas single breast, cervix and thyroid carcinoma cells were virtually immobile on unfavourable plastic surfaces, we found that they gained pronounced migratory capacities as collectives under comparable conditions. Thyroid carcinoma cells, that were studied in more detail, were found to express specific subsets of connexins and to form active gap junctions as revealed by dye diffusion analysis. Although all potential gap junction blockers suppressed intercellular dye diffusion in at least one of the cell lines tested, only two of them were found to inhibit collective cell migration and none of them to inhibit single cell migration. In the presence of the Rac1 inhibitor Z62954982 collective migration, but not single cell migration, was found to be reduced up to 20 %.

Conclusions

Our data indicate that collective migration enables tumor cells to cross otherwise unfavourable substrate areas. This capacity seems to be independent of intercellular communication via gap junctions, whereas Rac1-dependent intracellular signalling seems to be essential.

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Pilot study of FMC (5-fluorouracil, mitomycin C, and cisplatin) with radiotherapy for patients with anal cancer

Abstract

Objectives

Concurrent chemoradiotherapy (CRT) is the current standard of treatment for anal squamous carcinoma. However, local or metastatic recurrences remain significant after CRT with 5-fluorouracil (5-FU) and mitomycin C (MMC). Therefore, the present study evaluated the feasibility and efficacy of adding cisplatin to the classic CRT (5-FU, MMC, and radiotherapy).

Methods

Twenty patients with histologically confirmed squamous cell carcinoma of the anus without metastatic disease were enrolled at Kyungpook National University Medical Center (Daegu, Korea) between January 2005 and December 2014. The CRT comprised of two cycles of 5-FU 750 mg/m² days 1–4, MMC 10 mg/m² day 1, and cisplatin 60 mg/m² day 1 every 4 weeks and radiotherapy (59.6 Gy in 33 daily fractions). The primary endpoint was to determine the feasibility of FMC, while the secondary endpoints were the pathologic complete response (pCR) rate at 8 weeks following the completion of CRT, progression-free survival (PFS), and overall survival (OS).

Results

The treatment was generally well tolerated, and all patients received two cycles of FMC chemotherapy. Among the 20 patients, 17 were assessed for their pathologic response and 12 patients (70.6%) achieved pCR. The most common grade 3 or 4 hematologic toxicity was neutropenia (n = 3), while the most frequent severe non-hematologic toxicity was radiation dermatitis (n = 6, 30%). After a median follow-up duration of 45.5 months, the estimated 5-year PFS and overall survival rates were 88.9 and 88.1%, respectively.

Conclusion

CRT with two cycles of a FMC regimen was found to be feasible for patients with anal squamous carcinoma. Further study is warranted to evaluate the efficacy of CRT with a FMC regimen.

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Retraction Note to: Prognostic investigations of B7-H1 and B7-H4 expression levels as independent predictor markers of renal cell carcinoma

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Retraction Note to: Evaluation of gene expression level of CDC5L and MACC1 in poor prognosis and progression of osteosarcoma

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Retraction Note to: Overexpression of interleukins IL-17 and IL-8 with poor prognosis in colorectal cancer induces metastasis

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Effect of the lymphocyte-to-monocyte ratio on the clinical outcome of chemotherapy administration in advanced melanoma patients.

Skin cancer affects more individuals in the USA than any other malignancy and malignant melanoma is particularly deadly because of its metastatic potential. Melanoma has been recognized as one of the most immunogenic malignancies; therefore, understanding the mechanisms of tumor-immune interaction is key for developing more efficient treatments. As the tumor microenvironment shows an immunosuppressive action, immunotherapeutic agents promoting endogenous immune response to cancer have been tested (interleukin-2, anticytotoxic-T-lymphocyte-associated antigen 4, and antiprogrammed cell death protein 1 monoclonal antibodies) as well as combinations of cytotoxic chemotherapy agents and inhibitors of angiogenesis (taxol/carboplatin/avastin). However, clinical outcomes are variable, with only a minority of patients achieving durable complete responses. The variability of immune homeostasis, which may be more active or more tolerant at any given time, in cancer patients and the interaction of the immune system with the tumor could explain the inconsistency in clinical outcomes among these patients. Recently, the role of the lymphocyte-to-monocyte-ratio (LMR) in the peripheral blood has been investigated and has been proven to be an independent predictor of survival in different hematological malignancies and in solid tumors. In melanoma, our group has validated the significance of LMR as a predictor of relapse after resection of advanced melanoma. In this study, we examined the dynamics in the immune system of patients with advanced melanoma by performing serial multiday concentration measurements of cytokines and immune cell subsets in the peripheral blood. The analysis of outcomes of chemotherapy administration as related to LMR on the day of treatment initiation showed that progression-free survival was improved in the patients who received chemotherapy on the day when LMR was elevated. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

http://pdfs.journals.lww.com/melanomaresearch/9000/00000/Effect_of_the_lymphocyte_to_monocyte_ratio_on_the.99431.pdf

Diagnosis reliability of combined flexible sigmoidoscopy and fecal-immunochemical test in colorectal neoplasia screening

https://www.dovepress.com/diagnosis-reliability-of-combined-flexible-sigmoidoscopy-and-fecal-imm-peer-reviewed-article-OTT

Benefit of percutaneous endoscopic gastrostomy in patients undergoing definitive chemoradiotherapy for locally advanced nasopharyngeal carcinoma

https://www.dovepress.com/benefit-of-percutaneous-endoscopic-gastrostomy-in-patients-undergoing--peer-reviewed-article-OTT

Local recurrence following mastectomy and autologous breast reconstruction: incidence, risk factors, and management

https://www.dovepress.com/local-recurrence-following-mastectomy-and-autologous-breast-reconstruc-peer-reviewed-article-OTT