Public Reporting of Hospital-Level Cancer Surgical Volumes in California: An Opportunity to Inform Decision Making and Improve Quality [Original Contribution]

Purpose:

Most patients, providers, and payers make decisions about cancer hospitals without any objective data regarding quality or outcomes. We developed two online resources allowing users to search and compare timely data regarding hospital cancer surgery volumes.

Methods:

Hospital cancer surgery volumes for all California hospitals were calculated using ICD-9 coded hospital discharge summary data. Cancer surgeries included (bladder, brain, breast, colon, esophagus, liver, lung, pancreas, prostate, rectum, and stomach) were selected on the basis of a rigorous literature review to confirm sufficient evidence of a positive association between volume and mortality. The literature could not identify threshold numbers of surgeries associated with better or worse outcomes. A multidisciplinary working group oversaw the project and ensured sound methodology.

Results:

In California in 2014, about 60% of surgeries were performed at top-quintile–volume hospitals, but the per-hospital median numbers of surgeries for esophageal, pancreatic, stomach, liver, or bladder cancer surgeries were four or fewer. At least 670 patients received cancer surgery at hospitals that performed only one or two surgeries for a particular cancer type; 72% of those patients lived within 50 miles of a top-quintile–volume hospital.

Conclusion:

There is clear potential for more readily available information about hospital volumes to help patient, providers, and payers choose cancer surgery hospitals. Our successful public reporting of hospital volumes in California represents an important first step toward making publicly available even more provider-specific data regarding cancer care quality, costs, and outcomes, so those data can inform decision-making and encourage quality improvement.

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"Little Big Things": A Qualitative Study of Ovarian Cancer Survivors and Their Experiences With the Health Care System [Care Delivery]

Purpose:

Navigation of a complex and ever-changing health care system can be stressful and detrimental to psychosocial well-being for patients with serious illness. This study explored women's experiences with navigating the health care system during treatment for ovarian cancer.

Methods:

Focus groups moderated by trained investigators were conducted with ovarian cancer survivors at an academic cancer center. Personal experiences with cancer treatment, provider relationships, barriers to care, and the health care system were explored. Sessions were audiotaped, transcribed, and coded by using grounded theory. Subsequently, one-on-one interviews were conducted to further evaluate common themes.

Results:

Sixteen ovarian cancer survivors with a median age of 59 years participated in the focus group study. Provider consistency, personal touch, and patient advocacy positively affected the care experience. Treatment with a known provider who was well acquainted with the individual's medical history was deemed an invaluable aspect of care. Negative experiences that burdened patients, referred to as the "little big things," included systems-based challenges, which were scheduling, wait times, pharmacy, transportation, parking, financial, insurance, and discharge. Consistency, a care team approach, effective communication, and efficient connection to resources were suggested as ways to improve patients' experiences.

Conclusion:

Systems-based challenges were perceived as burdens to ovarian cancer survivors at our institution. The role of a consistent, accessible care team and efficient delivery of resources in the care of women with ovarian cancer should be explored further.

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A Retrospective Analysis of Precision Medicine Outcomes in Patients With Advanced Cancer Reveals Improved Progression-Free Survival Without Increased Health Care Costs [Care Delivery]

Purpose:

The advent of genomic diagnostic technologies such as next-generation sequencing has recently enabled the use of genomic information to guide targeted treatment in patients with cancer, an approach known as precision medicine. However, clinical outcomes, including survival and the cost of health care associated with precision cancer medicine, have been challenging to measure and remain largely unreported.

Patients and Methods:

We conducted a matched cohort study of 72 patients with metastatic cancer of diverse subtypes in the setting of a large, integrated health care delivery system. We analyzed the outcomes of 36 patients who received genomic testing and targeted therapy (precision cancer medicine) between July 1, 2013, and January 31, 2015, compared with 36 historical control patients who received standard chemotherapy (n = 29) or best supportive care (n = 7).

Results:

The average progression-free survival was 22.9 weeks for the precision medicine group and 12.0 weeks for the control group (P = .002) with a hazard ratio of 0.47 (95% CI, 0.29 to 0.75) when matching on age, sex, histologic diagnosis, and previous lines of treatment. In a subset analysis of patients who received all care within the Intermountain Healthcare system (n = 44), per patient charges per week were $4,665 in the precision treatment group and $5,000 in the control group (P = .126).

Conclusion:

These findings suggest that precision cancer medicine may improve survival for patients with refractory cancer without increasing health care costs. Although the results of this study warrant further validation, this precision medicine approach may be a viable option for patients with advanced cancer.

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Implementation of Symptom Questionnaires Into Oncology Workflow [Presentation Summary]

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Understanding Teamwork in the Provision of Cancer Care: Highlighting the Role of Trust [Original Contribution]

Team science research has indicated that trust is a critical variable of teamwork, contributing greatly to a team's performance. Trust has long been examined in health care with research focusing on the development of trust by patients with their health care practitioners. Studies have indicated that trust is linked to patient satisfaction, adherence to treatment, continuity of care, and improved outcomes. We explore the construct of trust using a case example of a patient who received a surgical procedure for a precancerous polyp. We apply the principle of trust to the case as well as present the literature on trust and key definitions for understanding trust. Additionally, we apply the definitions presented to the specific case example by highlighting moments where trust is developed or violated. Lastly, we offer insights to health care practitioners on the development of trust in their own patient interactions to improve care.

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Immune patterns after chemotherapy of ovarian cancer

Purpose: Some forms of chemotherapy can enhance anti-tumor immunity through immunogenic cell death, resulting in increased T cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunological changes consistent with this possibility. Methods: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n=90). Results: Neoadjuvant chemotherapy was associated with increased densities of CD3+, CD8+, CD8+ TIA-1+, PD-1+ and CD20+ TIL. Other immune subsets and factors were unchanged, including CD79a+ CD138+ plasma cells, CD68+ macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3+ PD-1+ cells (putative regulatory T cells), IDO-1+ cells, and PD-L1+ cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (1) TILhigh tumors showed increases in multiple immune markers after chemotherapy; (2) TILlow tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (3) TILnegative cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance. Conclusion: Chemotherapy augments pre-existing TIL responses but fails to relieve major immune suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multi-pronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment.

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Genomic study of CTCs in mCRPC.

Purpose: Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach. Experimental design: CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential CTCs aCGH analyses in the context of enzalutamide therapy. Results: All patients had mCRPC and primary or acquired resistance to abiraterone acetate or enzalutamide. We compiled copy gains and losses, with a particular focus on those genes highly implicated in mCRPC progression and previously validated as being aberrant in metastatic tissue samples and genomic studies of reference mCRPC datasets. Genomic gains in >25% of CTCs were observed in AR, FOXA1, ABL1, MET, ERG, CDK12, BRD4, and ZFHX3, while common genomic losses involved PTEN, ZFHX3, PDE4DIP, RAF1, and GATA2. Analysis of aCGH in a sample with sequential enzalutamide resistant visceral progression showed acquired loss of AR amplification concurrent with gain of MYCN, consistent with evolution toward a neuroendocrine-like, AR-independent clone. Conclusions: Genomic analysis of pooled CTCs in men with mCRPC suggests a reproducible, but highly complex molecular profile that includes common aberrations in AR, ERG, c-MET, and PI3K signaling during mCRPC progression, which may be useful for predictive biomarker development.

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Liquid biopsy to detect targetable lung cancer mutations

Purpose: The expanding number of targeted therapeutics for non-small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS. Experimental Design: 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible. Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. While ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (p=0.038). ctDNA sequencing identified 8 patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing wasn't possible. Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution.

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Homologous recombination deficiency in breast cancer

Background: The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity and large-scale state transitions in tumor DNA and combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer. Methods: HRD scores, BRCA mutation status and BRCA1 promoter methylation were assessed in 99 samples from 33 surgically resected, stage I-III breast cancers; each cancer was biopsied in three distinct areas. Homologous recombination repair (HR) deficiency was defined as either high HRD score ({greater than or equal to}42) or tumor BRCA mutation. Results: Eighty-one biopsies from 32 cancers were analyzed. Tumor BRCA status was available for all samples, HRD scores for 70 and BRCA1 methylation values for 76 samples. The BRCA1/2 mutation and promoter methylation status and HR category showed perfect concordance across all biopsies from the same cancer. All tumors with BRCA1/2 mutations or promoter methylation had high HRD scores, as did 17% (4/24) of the BRCA1/2 wild type and non-methylated tumors. The HRD scores were also highly consistent between different biopsies from the same tumor with an intraclass correlation coefficient of 0.977 indicating that only 2.3% of the variance is attributed to within-tumor biopsy-to-biopsy variation. Conclusion: These results indicate that within-tumor spatial heterogeneity for homologous recombination deficiency metrics and the technical noise in the assay are small and do not influence HRD scores and HR status.

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Response to adjuvant chemotherapy in Luminal A patients

Purpose: Luminal A breast cancers have better prognosis than other molecular subtypes. Luminal A cancers may also be insensitive to adjuvant chemotherapy, although there is little high level evidence to confirm this concept. The primary hypothesis in this formal prospective-retrospective analysis was to assess interaction between subtype (Luminal A vs. other) and treatment (chemotherapy vs. not) for the primary endpoint (10-year invasive disease free survival) of a breast cancer trial randomizing women to adjuvant chemotherapy, analyzed in multivariate Cox proportional hazards models using the Wald interaction test. Experimental Design:The Danish Breast Cancer Cooperative Group 77B clinical trial randomized 1072 premenopausal women to no systematic treatment (control), levamisole, cyclophosphamide or cyclophosphamide-methotrexate-fluorouracil arms. All arms included radiotherapy but no endocrine therapy. Researchers with no access to clinical data performed intrinsic subtype analysis on tissue microarrays using published immunohistochemical methods based on estrogen receptor, progesterone receptor, HER2, Ki67 and basal markers. Results:709 patients had tissue available; chemotherapy benefit in these patients was similar to the original trial (hazard ratio (HR) 0.56). Immunohistochemistry classified 165 as Luminal A, 319 Luminal B, 58 HER2-enriched and 82 core basal (among 91 triple negative). Patients with Luminal A breast tumors did not benefit from chemotherapy (HR 1.06, 95% confidence interval 0.53-2.14, p = 0.86), whereas patients with non-luminal A subtypes did (HR 0.50, 95% confidence interval 0.38-0.66, p < 0.001); p (interaction) = 0.048. Conclusions: In a prospective-retrospective analysis of a randomized trial, patients with Luminal A breast cancers did not benefit from adjuvant cyclophosphamide-based chemotherapy.

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Pinatuzumab vedotin for the treatment of B-cell lymphoma

Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This Phase I study determined its recommended Phase II dose (RP2D) and evaluated its safety, tolerability, and anti-tumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of Grade 4 neutropenia >7 days in 1/3 patients and Grade 4 neutropenia <7 days in 2/3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common Grade {greater than or equal to}3 adverse event. Peripheral neuropathy-related Grade {greater than or equal to}2 adverse events most frequently resulted in treatment discontinuation. Rituximab co-treatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2/8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses. Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL.

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CDA deficiency in cancer

Purpose:One of the main challenges in cancer therapy is the identification of molecular mechanisms mediating resistance or sensitivity to treatment. Cytidine deaminase (CDA) was reported to be downregulated in cells derived from patients with Bloom syndrome, a genetic disease associated with a strong predisposition to a wide range of cancers. The purpose of this study was to determine whether CDA deficiency could be associated with tumors from the general population and could constitute a predictive marker of susceptibility to anti-tumor drugs. Experimental Design:We analyzed CDA expression in silico, in large datasets for cancer cell lines and tumors, and in various cancer cell lines and primary tumor tissues using immunohistochemistry, PDXs, RT-qPCR, and western blotting. We also studied the mechanism underlying CDA silencing and searched for molecules that might target specifically CDA deficient tumor cells using in silico analysis coupled to classical cellular experimental approaches. Results:We found that CDA expression is downregulated in about 60% of cancer cells and tissues. We demonstrate that DNA methylation is a prevalent mechanism of CDA silencing in tumors. Finally, we show that CDA-deficient tumor cells can be specifically targeted with epigenetic treatments and with the anticancer drug aminoflavone. Conclusions:CDA expression status identifies new subgroups of cancers, and CDA deficiency appears to be a novel and relevant predictive marker of susceptibility to antitumor drugs, opening up new possibilities for treating cancer.

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miR-188-3p in colorectal cancer

Purpose: Characterization of colorectal cancer (CRC) transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed involving previously unreported microRNAs abnormalities. Here, we followed a systematic approach on a global scale to identify microRNAs as clinical outcome predictors, and further validated them in the clinical and experimental setting. Experimental Design: Genome-wide microRNA sequencing data of 228 CRC patients from the cancer genome atlas (TCGA) dataset were analyzed as a screening cohort to identify microRNAs significantly associated with survival according to stringent pre-specified criteria. A panel of six microRNAs was further validated for their prognostic utility in a large independent validation cohort (n=332). In situ hybridization and functional experiments in a panel of CRC cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results: Six microRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor (screening cohort: hazard ratio = 4.137, 95%CI=1.568-10.917, p=0.004; validation cohort: hazard ratio HR=1.538, 95%CI=1.107-2.137, p=0.010, respectively). Forced miR-188-3p expression increased migratory behavior of CRC cells in vitro and metastases formation in vivo (p<0.05). The pro-migratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in CRC cell migration. Conclusions: MiR-188-3p is a novel independent prognostic factor in CRC patients which can be partly explained by its effect on MLLT4 expression and migration of cancer cells.

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Eligibility and Trial Accrual

Accrual continues to be a challenge for oncology clinical trials. Interventions to enhance accrual after study activation exist, including corrective action plans for National Cancer Institute sponsored trials. Clinical trials would benefit from a proactive rather than a reactive approach. Accrual strategy planning early in trial development is suggested.

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Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials

In a post hoc analysis of the LUX-Lung 3/6 trials, afatinib dose reduction, more likely occurring in patients who had higher afatinib plasma concentrations, led to decreases in incidence and severity of treatment-related adverse events without impacting treatment efficacy. Afatinib should be initiated at the approved dose of 40 mg/day; adjustments can then be used to optimize individual treatment.

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PT2385: A Hypoxia-Inducible Factor-2{alpha} Antagonist

More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 1–10. ©2016 AACR.

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TSLP IN CUTANEOUS T-CELL LYMPHOMA

Thymic stromal lymphopoietin (TSLP) activates dendritic cells to induce Th2-mediated inflammation. Periostin, an extracellular matrix protein produced by fibroblasts, induces chronic inflammation by stimulating TSLP production. Recently, a reinforcing cycle linking Th2-type immune responses with periostin-induced keratinocyte activation has been proposed in atopic dermatitis pathogenesis. In this study, we investigated the role of TSLP and periostin in the development of cutaneous T cell lymphoma (CTCL), where Th2 cytokines and chemokines are also dominant. TSLP and periostin mRNA expression levels were elevated in CTCL lesional skin, both of which correlated with interleukin (IL)-4 expression levels. In vitro and ex vivo, IL-4 or IL-13 stimulated periostin expression by dermal fibroblasts, and fibroblasts from CTCL lesional skin expressed higher levels of periostin than those from control skin. Serum periostin levels of CTCL patients were also significantly higher than those of healthy individuals. Hut78 and MJ, CTCL cell lines, and peripheral blood mononuclear cells from leukemic CTCL patients expressed the TSLP receptor. TSLP induced production of IL-4 and IL-13 by Hut78 and MJ cells through the activation of signal transducer and activator of transcription 5. Moreover, TSLP induced proliferation of CTCL cells both in vitro and in vivo. These data suggest that periostin-mediated TSLP production by keratinocytes directly stimulates CTCL tumor cell growth in addition to inducing a Th2-dominant tumor environment in CTCL.

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Long-term response to sunitinib: everolimus treatment in metastatic clear cell renal cell carcinoma

Future Oncology Ahead of Print.


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Selumetinib attenuate skeletal muscle wasting

Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed MEK inhibitor selumetinib treatment resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway control mass of skeletal muscle. The present study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases and MEK/ERK-related pathways was analyzed. Two independent experiments showed that 30 mg/kg/d selumetinib prevented the loss of body weight in a murine cachexia mice. Muscle wasting was attenuated and the expression of E3 ligases MuRF1 and Fbx32 were inhibited following selumetinib treatment of muscle gastrocnemius. Further, selumetinib efficiently reduced tumor burden without influencing the cancer cell proliferation, cumulative food intake and serum cytokines. These results indicated that the role of selumetinib in attenuating muscle wasting was independent of cancer burden. Detailed mechanism analysis revealed AKT and mTOR were activated, while ERK, FoxO3a and GSK3β were inhibited in selumetinib treated cachexia group. These indicated selumetinib effectively prevented skeletal muscle wasting in cancer cachexia model through ERK inhibition and AKT activation in muscle gastrocnemius via cross-inhibition. The study not only elucidated the mechanism of MEK/ERK inhibition in skeletal muscle anabolism, but also validated selumetinib therapy as an effective intervention against cancer cachexia.

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JNK/MKP-1 interplay determines resistance in breast cancer

Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is overexpressed during malignant transformation of the breast in many patients, and it is usually associated with chemoresistance through interference with JNK-driven apoptotic pathways. Although the molecular settings of the mechanism have been documented, details about the contribution of MKP-1 to the failure of chemotherapeutic interventions are unclear. Transient overexpression of MKP-1 and treatment with JNK-modulating agents in breast carcinoma cells confirmed the mediation of MKP-1 in the resistance to taxanes and anthracyclines in breast cancer, through the inactivation of JNK1/2. We next assessed MKP-1 expression and JNK1/2 phosphorylation status in a large cohort of samples from 350 early breast-cancer patients treated with adjuvant anthracycline-based chemotherapy. We detected that MKP-1 overexpression is a recurrent event predominantly linked to dephosphorylation of JNK1/2 with an adverse impact on relapse of the tumor and overall and disease-free survival. Moreover, MKP-1 and p-JNK1/2 determinations in 64 locally advanced breast-cancer patients treated with neoadjuvant taxane-based chemotherapy showed an inverse correlation between MKP-1 overexpression (together with JNK1/2 inhibition) and the pathological response of the tumors. Our results emphasize the importance of MKP-1 as a potential predictive biomarker for a subset of breast-cancer patients with worse outcome and less susceptibility to treatment.

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A Lesion-Based Response Prediction Model Using Pretherapy PET/CT Image Features for Y90 Radioembolization to Hepatic Malignancies

We present a probabilistic approach to identify patients with primary and secondary hepatic malignancies as responders or nonresponders to yttrium-90 radioembolization therapy. Recent advances in computer-aided detection have decreased false-negative and false-positive rates of perceived abnormalities; however, there is limited research in using similar concepts to predict treatment response. Our approach is driven by the goal of precision medicine to determine pretherapy fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography imaging parameters to facilitate the identification of patients who would benefit most from yttrium-90 radioembolization therapy, while avoiding complex and costly procedures for those who would not. Our algorithm seeks to predict a patient's response by discovering common co-occurring image patterns in the lesions of baseline fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography scans by extracting invariant shape and texture features. The extracted imaging features were represented as a distribution of each subject based on the bag-of-feature paradigm. The distribution was applied in a multinomial naive Bayes classifier to predict whether a patient would be a responder or nonresponder to yttrium-90 radioembolization therapy based on the imaging features of a pretherapy fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography scan. Comprehensive published criteria were used to determine lesion-based clinical treatment response based on fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography imaging findings. Our results show that the model is able to predict a patient with liver cancer as a responder or nonresponder to yttrium-90 radioembolization therapy with a sensitivity of 0.791 using extracted invariant imaging features from the pretherapy fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography test. The sensitivity increased to 0.821 when combining extracted invariant image features with variable features of tumor volume.

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Fiber intake modulates the association of alcohol intake with breast cancer

Abstract

Alcohol intake has been related to an increased risk of breast cancer (BC) while dietary fiber intake has been inversely associated to BC risk. A beneficial effect of fibers on ethanol carcinogenesis through their impact on estrogen levels is still controversial. We investigated the role of dietary fiber as a modifying factor of the association of alcohol and breast cancer using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 334,850 women aged 35-70 years at baseline enrolled in the ten countries of the EPIC study and followed up for 11.0 years on average. Information on fiber and alcohol intake at baseline and average lifetime alcohol intake were calculated from country-specific dietary and lifestyle questionnaires. Hazard ratios (HR) of developing invasive breast cancer according to different levels of alcohol and fiber intake were computed. During 3,670,439 person-years, 11,576 incident breast cancer cases were diagnosed. For subjects with low intake of fiber (<18.5 g/day), the risk of BC per 10g/day of alcohol intake was 1.06 (1.03-1.08) while among subjects with high intake of fiber (>24.2 g/day) the risk of BC was 1.02 (0.99-1.05) (test for interaction p=0.011). This modulating effect was stronger for fiber from vegetables. Our results suggest that fiber intake may modulate the positive association of alcohol intake and BC. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc.

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Bilateral Oophorectomy and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Background: Whether oophorectomy reduces breast cancer risk among BRCA mutation carriers is a matter of debate. We undertook a prospective analysis of bilateral oophorectomy and breast cancer risk in BRCA mutation carriers.

Methods: Subjects had no history of cancer, had both breasts intact, and had information on oophorectomy status (n = 3722). Women were followed until breast cancer diagnosis, prophylactic bilateral mastectomy, or death. A Cox regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with oophorectomy (coded as a time-dependent variable). All statistical tests were two-sided.

Results: Over a mean follow-up of 5.6 years, 350 new breast cancers were diagnosed. Among women with a BRCA1 or BRCA2 mutation, oophorectomy was not associated with breast cancer risk compared with women who did not undergo an oophorectomy. The age-adjusted hazard ratio associated with oophorectomy was 0.96 (95% CI = 0.73 to 1.26, P = .76) for BRCA1 and was 0.65 (95% CI = 0.37 to 1.16, P = .14) for BRCA2 mutation carriers. In stratified analyses, the effect of oophorectomy was statistically significant for breast cancer in BRCA2 mutation carriers diagnosed prior to age 50 years (age-adjusted HR = 0.18, 95% CI = 0.05 to 0.63, P = .007). Oophorectomy was not associated with risk of breast cancer prior to age 50 years among BRCA1 mutation carriers (age-adjusted HR = 0.79, 95% CI = 0.55 to 1.13, P = .51).

Conclusions: Findings from this large prospective study support a role of oophorectomy for the prevention of premenopausal breast cancer in BRCA2, but not BRCA1 mutation carriers. These findings warrant further evaluation.

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The phylogenetic similarity of hydatid cyst isolated from humans and sheep in Ilam Province southwest of Iran

Abstract

Hydatid cyst is a chronic zoonotic disease caused by the larval stage of the dog tapeworm, Echinococcus granulosus. To identify genotype of hydatid cysts of human and sheep jackal in Ilam Province (South West of Iran), the PCR-RFLP and DNA sequencing were used. A total of 10 human and 20 sheep protoscoleces hydatid cyst samples were collected from different hospitals and slaughterhouses. Then, the gene of cox1 of mitDNA of the parasite was amplified and PCR products were cut using AluI and HpaII restriction enzymes. Finally, a number of PCR products were bi-directionally sequenced. Based on the DNA sequencing and PCR-RFLP results, human and sheep samples indicated to pertain the genotypic similarities. Our data indicated that, the genotypes of larval stage of E. granulosus is similar in both intermediate hosts. According to the phylogenetic tree, there is at least one genotype of parasite, which belongs to E. granulosous sensu stricto (G1–G3) complex and overall isolates sequences of mtDNA indicated 100 % homology with references G1, G2, and G3 sequences in the GenBank database. G1 genotype was the dominant genotype of human and livestock.

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Re-irradiation strategies in combination with bevacizumab for recurrent malignant glioma

Abstract

The place of bevacizumab (BEV) in salvage re-irradiation (Re-RT) settings of malignant glioma is poorly defined. In the current study risk/benefit profiles of two BEV-based Re-RT protocols were analyzed and compared with that of salvage BEV plus irinotecan (BEV/IRI). According to interdisciplinary tumor board recommendations, patients were assigned to one of three BEV-based treatment protocols: (1) BEV/IRI, (2) Re-RT (36 Gy/18 fx) with concomitant BEV (Re-RT/BEV), and (3) Re-RT with concomitant/maintenance BEV (Re-RT/BEV→BEV). Prognostic factors were obtained from proportional hazards models. Adverse events were classified according to the NCI CTCAE, v4.0. 105 consecutive patients were enrolled from 08/2008 to 05/2014. Patients undergoing Re-RT experienced longer time intervals from initial diagnosis to BEV treatment (median: 22.0 months vs. 13.7 months, p = 0.001); those assigned to Re-RT/BEV→BEV rated better on the performance scale (median KPS_REC: 90 vs. 70, p = 0.013). Post-recurrence survival after BEV-based treatment (PRS) was longest after Re-RT/BEV→BEV (median: 13.1 months vs. 8 months, p = 0.006). PRS after Re-RT/BEV and BEV/IRI was similar. Multivariately, higher KPS_REC and Re-RT/BEV→BEV were associated with longer PRS. Treatment toxicity did not differ among groups. Re-RT/BEV→BEV is safe, feasible and effective and deserves further prospective evaluation.

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Radiosurgical decompression for benign perioptic tumors causing compressive cranial neuropathies: a feasible alternative to microsurgery?

Abstract

Several studies have reported the efficacy and safety of hypofractionated stereotactic radiosurgery (hSRS) in the treatment of benign perioptic tumors. This study went further and evaluated the feasibility of hSRS in the treatment of those causing compressive cranial neuropathies (CCNs) among perioptic tumors with special consideration of functional improvement. Twenty-six patients with CCNs (CN II = 19; CN III/IV/VI = 9; CN V = 3) caused by perioptic tumors underwent hSRS between 2011 and 2015. hSRS was delivered in five fractions with a median marginal dose of 27.8 Gy (≈14 Gy in a single fraction, assuming an α/β of three) to a tumor volume of 8.2 ± 8.3 cm³. All tumors except one shrank after treatment, with a mean volume decrease of 35 % (range 4−84 %) during the mean follow-up period of 20 months. In 19 patients (38 eyes) with compressive optic neuropathy, vision improved in 55.3 % of eyes (n = 21), was unchanged in 36.8 % (n = 14), and worsened in 7.9 % (n = 3) (2.6 % after excluding two eyes deteriorated due to transient tumor swelling). A higher conformity index (p = 0.034) and volume of the optic apparatus receiving >23.0 Gy (p = 0.019) were associated with greater tumor shrinkage. A greater decrease in tumor volume (p = 0.035) was associated with a better improvement in vision. Ophthalmoplegia and facial hypesthesia improved in six of nine (66.7 %) and three of three (100 %) patients, respectively. There was no newly developed neurological deficit. Decompressive SRS for benign perioptic tumors causing CCN is feasible using hypofractionation, representing a useful alternative to microsurgical resection.

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Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia

Abstract

Purpose

Normal white blood cell counts (WBC) are unknown in children with acute lymphoblastic leukemia (ALL). Accordingly, 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy is adjusted by a common WBC target of 1.5–3.0 × 10⁹/L. Consequently, the absolute degree of myelosuppression is unknown for the individual child and we wanted to evaluate this.

Methods

A median of 22 (range 8–27) 6MP/MTX metabolite samples and 100 (range 25–130) blood counts during therapy and 10 (range 2–15) off therapy were collected in 50 children with ALL. Differences between off-therapy and on-therapy WBCs [including absolute neutrophil (ANC) and lymphocyte counts (ALC)] were used to retrospectively approximate the absolute myelosuppression (="delta-") and association with age, sex and 6MP/MTX doses explored. We applied linear mixed models to estimate on-therapy counts by 6MP/MTX metabolites: DNA-incorporated thioguanine nucleotides (DNA-TGN), erythrocyte thioguanine nucleotides (ery-TGN), erythrocyte-methylated 6MP metabolites (ery-MeMP) and erythrocyte MTX polyglutamates with 2–6 glutamate residues (ery-MTXpg_2–6).

Results

On-therapy WBC was correlated with ANC and ALC (r _s  = 0.84 and r _s  = 0.33, p values <0.001), whereas ANC was weakly correlated with ALC (r _s  = −0.11, p < 0.001), and neither significantly correlated with age. Off-therapy ALC, but not ANC, was strongly correlated with age (r _s  = −0.68 and −0.18, p < 0.001 and p = 0.22). Delta-ALC decreased with increasing age (r _s  = −0.69, p < 0.001). Incorporation of DNA-TGN was positively associated with ery-TGN (p < 0.001), ery-MeMP (p < 0.001) and ery-MTXpg_2–6 (p = 0.047). On-therapy ALC decreased with increasing DNA-TGN level (p < 0.001, model adjusted for off-therapy ALC), whereas on-therapy ANC could not be modeled reliably.

Conclusion

Measurements of 6MP/MTX metabolites could supplement blood counts in assessing therapy intensity, but require prospective validation.

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Selenium Ameliorate Peripheral Nerve Ischemic-Reperfusion Injury via Decreased TNF-α

Abstract

Selenium is considered as a trace element that plays antioxidant role in the body. So, the aim of this study was to evaluate the effect of selenium on ameliorating of sciatic nerve ischemia-reperfusion injury. Eighty (80) adult male Wistar rats weighing 250–300 g were used. They were divided into 10 groups (n = 8). Then, femoral vessels were obstructed by using 4/0 silk and splitknot techniques. After 3-h ischemia for all the groups, reperfusion was applied for different periods: 3, 7, 14, and 28 days. In half of each experimental group, 0.2 mg/kg selenium was injected intraperitoneally, coinciding with ischemia. After reperfusion, according to the grouping, rats were killed by using high dose of anesthetic drug and then sciatic nerve was removed and fixed. Then, tissue samples were processed and subsequently stained with hematoxylin-eosin, apoptosis, and immunohistochemistry stains. On the third day of reperfusion, the amount of TNF-α as an inflammatory marker of ischemia-reperfusion acute phase increased. On the seventh day of reperfusion, the amount of NF-кB as an apoptotic index and infiltration of mast cells increased in the tissue as a result of development of inflammation. But, on the 14th day of reperfusion, the amount of NF-кB as an apoptotic index decreased to the lowest amount. On the 28th day of reperfusion, the amount of TNF-α as an inflammatory marker decreased to its lowest level. Prescription of selenium concurrent with development of ischemia can reduce the damage caused by sciatic nerve ischemia-reperfusion.

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The Role of Blood Lead, Cadmium, Zinc and Copper in Development and Severity of Acne Vulgaris in a Nigerian Population

Abstract

Acne vulgaris is a very common skin disorder affecting human beings. There is a paucity of report on the role of heavy metals—lead (Pb) and cadmium (Cd)—globally, and trace metals—zinc (Zn) and copper (Cd)—particularly in Nigeria in the development/severity of acne vulgaris. This study is aimed to determine the blood levels of some heavy metals—cadmium and lead—and trace metals—zinc and copper—in acne vulgaris sufferers in a Nigerian population. Venous blood samples were collected from a total number of 90 non-obese female subjects consisting of 30 mild, 30 moderate and 30 severe acne vulgaris sufferers for blood Cd, Pb, Cu and Zn determination. They were age-matched with 60 females without acne vulgaris who served as the control subjects. Acne sufferers had significantly higher blood Cd and Pb (P = 0.0143 and P = 0.0001 respectively) and non-significantly different blood levels of Cu and Zn (P = 0.910 and P = 0.2140 respectively) compared to controls. There were significant progressive increases in blood levels of Cd and Pb (P = 0.0330 and P = 0.0001 respectively) and non-significant differences in the mean blood level of Cu and Zn (P = 0.1821 and P = 0.2728 respectively) from mild to moderate and severe acne vulgaris sufferers. Increases in blood Cd and Pb may play critical roles in the pathogenesis/severity of acne vulgaris, while Cu and Zn seem to play less significant roles in the development of this disorder in this environment.

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Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer

Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screening...

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Inhibition of YAP suppresses CML cell proliferation and enhances efficacy of imatinib in vitro and in vivo

Yes-associated protein (YAP), an essential component of Hippo pathway, was identified as an oncoprotein which participated in the progression of various malignancies. However, its role in chronic myeloid leuke...

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Reactivation of mutant p53 by capsaicin, the major constituent of peppers

Mutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes de...

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New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study

The antimalarial drug Pyrimethamine has been suggested to exert an antitumor activity by inducing apoptotic cell death in cancer cells, including metastatic melanoma cells. However, the dose of Pyrimethamine t...

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Prognostic sub-classification of intermediate-stage hepatocellular carcinoma: a multicenter cohort study with propensity score analysis

Abstract

There is significant heterogeneity in the clinicopathological characteristics of intermediate hepatocellular carcinoma (IHCC). This also translates to treatment as transarterial chemoembolization (TACE) is used as first-line therapy for patients with IHCC; however, in Asia liver resection (LR) is preferred. Prognostic tools are required to help guide clinicians in deciding treatment options. This study evaluates the prognostic impact of the Intermediate Stage Score (ISS) on overall survival (OS) in a large, multicenter cohort study of patients with IHCC treated with TACE or surgery LR. Consecutive patients from centers in Japan, Korea, Italy and the United Kingdom who underwent TACE or LR between 2001 and 2015 were enrolled. Propensity score (PS) adjustment was used to remove residual confounding and applied to LR (n = 162) and TACE (n = 449) to determine the prognostic significance of ISS. Among 611 patients, 75 % were men and 25 % women, with a mean age of 70 years. ISS is a valid prognostic tool in the BCLC-B population with a median OS ISS 1–51, 2–38.3, 3–24.3, 4–15.6, 5–16 months (p < 0.0001). ISS was analyzed within each treatment modality, and this was a valid prognostic score among those treated with TACE and LR (p < 0.001 vs. p = 0.008). In the PS-adjusted model, ISS retained its prognostic utility in TACE and LR groups (p < 0.001 vs. p = 0.007). ISS optimizes prognostic prediction in IHCC, reducing clinical heterogeneity, and is a useful tool for patients treated for TACE or LR.

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The combination of serum insulin, osteopontin, and hepatocyte growth factor predicts time to castration-resistant progression in androgen dependent metastatic prostate cancer- an exploratory study

Abstract

Background

We hypothesized that pretreatment serum levels of insulin and other serum markers would predict Progression-free survival (PFS), defined as time to castration-resistant progression or death, in metastatic androgen-dependent prostate cancer (mADPC).

Methods

Serum samples from treatment-naïve men participating in a randomized phase 3 trial of ADT +/- chemotherapy were retrospectively analyzed using multiplex assays for insulin and multiple other soluble factors. Cox proportional hazards regression models were used to identify associations between individual factor levels and PFS.

Results

Sixty six patients were evaluable (median age = 72 years; median prostate surface antigen [PSA] = 31.5 ng/mL; Caucasian = 86 %; Gleason score ≥8 = 77 %). In the univariable analysis, higher insulin (HR = 0.81 [0.67, 0.98] p = 0.03) and C-peptide (HR = 0.62 [0.39, 1.00]; p = 0.05) levels were associated with a longer PFS, while higher Hepatocyte Growth Factor (HGF; HR = 1.63 [1.06, 2.51] p = 0.03) and Osteopontin (OPN; HR = 1.56 [1.13, 2.15]; p = 0.01) levels were associated with a shorter PFS. In multivariable analysis, insulin below 2.1 (ln scale; HR = 2.55 [1.24, 5.23]; p = 0.011) and HGF above 8.9 (ln scale; HR = 2.67 [1.08, 3.70]; p = 0.027) levels were associated with longer PFS, while adjusted by OPN, C-peptide, trial therapy and metastatic volume. Four distinct risk groups were identified by counting the number of risk factors (RF) including low insulin, high HGF, high OPN levels, and low C-peptide levels (0, 1, 2, and 3). Median PFS was 9.8, 2.0, 1.6, and 0.7 years for each, respectively (p < 0.001).

Conclusion

Pretreatment serum insulin, HGF, OPN, and C-peptide levels can predict PFS in men with mADPC treated with ADT. Risk groups based on these factors are superior predictors of PFS than each marker alone.

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Malignant mesothelioma of the pleura with desmoplastic histology: a case series and literature review

Abstract

Background

Desmoplastic malignant pleural mesothelioma (DMM) is rare histological subtype of diffuse malignant pleural mesothelioma (MPM), accounting for 5–10 % of cases. It has a poor prognosis, with direct invasion of the chest wall or lungs and distant metastases. Its pathological characteristics include dense collagen fibers in a storiform pattern. Its pretreatment pathological diagnosis is difficult, with fibrous pleuritis and reactive mesothelial hyperplasia as potential differential diagnoses.

Case presentation

We retrospectively reviewed the medical charts of patients with MPM from 1996 to 2012. Among 60 patients with MPM, four patients with the desmoplastic subtype were identified and their clinical characteristics, including asbestos exposure, treatment, and prognosis, were reviewed. All of the patients with DMM were men, with a median age of 69 years (range: 63–74 years). All four patients had been exposed to asbestos. The definitive diagnosis was made histologically and the International Mesothelioma Interest Group classification was advanced (III/IV: 2/3) in all four patients. Three patients were treated with chemotherapy (two with cisplatin/pemetrexed and one with cisplatin/gemcitabine) and one patient underwent surgery. The median survival time in the patients with DMM was 3.8 months (range: 0.9–11.5 months), compared with 10.5 months in patients with other subtypes of MPM in our institution.

Conclusions

DMM continues to have a poor prognosis. It is important to recognize this variant and distinguish it from pleural plaques, non-specific reactive pleural fibrosis, pleurisy, and other lung diseases.

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The pretreatment Controlling Nutritional Status (CONUT) score is an independent prognostic factor in patients with resectable thoracic esophageal squamous cell carcinoma: results from a retrospective study

Abstract

Background

The purpose of this study was to investigate the impact of the Controlling Nutritional Status (CONUT) score on survival compared with the platelet to lymphocyte ratio (PLR), the neutrophil to lymphocyte ratio (NLR), and the Glasgow Prognostic Score (GPS) in patients with resectable thoracic esophageal squamous cell carcinoma (ESCC).

Methods

One hundred eighty-five consecutive patients who underwent subtotal esophagectomy with curative intent for resectable thoracic ESCC were retrospectively reviewed. Time-dependent receiver operating characteristic curve analyses for 3-year overall survival (OS) as the endpoint were performed, and the maximal Youden indices were calculated to assess discrimination ability and to determine the appropriate cut-off values of CONUT, PLR, and NLR. The patients were then classified into high and low groups based on these cut-off values. Correlations between CONUT and other clinicopathological characteristics were analyzed. Prognostic factors predicting overall survival (OS) and relapse-free survival (RFS) were analyzed using Cox proportional hazards models.

Results

The areas under the curve predicting 3-year OS were 0.603 for CONUT, 0.561 for PLR, 0.564 for NLR, and 0.563 for GPS. The optimal cut-off values were two for the CONUT score, 193 for PLR, and 3.612 for NLR. The high-CONUT group was significantly associated with lower BMI, high-PLR, high-NLR, and GPS1/2 groups. On univariate analysis, high-CONUT, high-PLR, high-NLR, and GPS 1/2 groups were significantly associated with poorer OS and RFS. Of these factors, multivariate analysis revealed that only the CONUT score was an independent prognostic factor for OS (HR 2.303, 95 % CI 1.191–4.455; p = 0.013) and RFS (HR 2.163, 95 % CI 1.139–4.109; p = 0.018).

Conclusions

The CONUT score was an independent predictor of OS and RFS before treatment and was superior to PLR, NLR, and GPS in terms of predictive ability for prognosis in patients with resectable thoracic ESCC.

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Genome-wide analyses of long noncoding RNA expression profiles correlated with radioresistance in nasopharyngeal carcinoma via next-generation deep sequencing

Abstract

Background

Radioresistance is one of the major factors limiting the therapeutic efficacy and prognosis of patients with nasopharyngeal carcinoma (NPC). Accumulating evidence has suggested that aberrant expression of long noncoding RNAs (lncRNAs) contributes to cancer progression. Therefore, here we identified lncRNAs associated with radioresistance in NPC.

Methods

The differential expression profiles of lncRNAs associated with NPC radioresistance were constructed by next-generation deep sequencing by comparing radioresistant NPC cells with their parental cells. LncRNA-related mRNAs were predicted and analyzed using bioinformatics algorithms compared with the mRNA profiles related to radioresistance obtained in our previous study. Several lncRNAs and associated mRNAs were validated in established NPC radioresistant cell models and NPC tissues.

Results

By comparison between radioresistant CNE-2-Rs and parental CNE-2 cells by next-generation deep sequencing, a total of 781 known lncRNAs and 2054 novel lncRNAs were annotated. The top five upregulated and downregulated known/novel lncRNAs were detected using quantitative real-time reverse transcription-polymerase chain reaction, and 7/10 known lncRNAs and 3/10 novel lncRNAs were demonstrated to have significant differential expression trends that were the same as those predicted by deep sequencing. From the prediction process, 13 pairs of lncRNAs and their associated genes were acquired, and the prediction trends of three pairs were validated in both radioresistant CNE-2-Rs and 6-10B-Rs cell lines, including lncRNA n373932 and SLITRK5, n409627 and PRSS12, and n386034 and RIMKLB. LncRNA n373932 and its related SLITRK5 showed dramatic expression changes in post-irradiation radioresistant cells and a negative expression correlation in NPC tissues (R = −0.595, p < 0.05).

Conclusions

Our study provides an overview of the expression profiles of radioresistant lncRNAs and potentially related mRNAs, which will facilitate future investigations into the function of lncRNAs in NPC radioresistance.

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Protocol for a mixed methods longitudinal enquiry into the impact of a community based supportive service for people affected by cancer

Abstract

Background

Globally, cancer rates are increasing. In Scotland, it is estimated that 2 in 5 people will develop cancer in their lifetime. Therefore, this is crucial time to provide personalised care and support to individuals affected by cancer. In response to this a community based supportive cancer service was launched in Glasgow, Scotland. The aim of this service is to proactively provide those affected by cancer with an assessment of their needs and personalised support where needed. To our knowledge, there is no other service like this in the United Kingdom.

Methods

The aim of this study is to understand if and how the service impacts upon the experiences and outcomes of people living with and affected by cancer. The study uses a sequential mixed methods design across a 5 year time point. Data gathering includes questionnaires, interviews, observations and reflective diaries. Participants include people affected by cancer who have used the service, a comparative sample who have not used the service, individuals who deliver the service and wider stakeholders. Outcomes include measures of patient activation, quality of life, health status, and social support. Data collection occurs at baseline, 2.5 years and 4 years with data from observations and reflective diaries supplemented throughout.

Discussion

This study evaluates an innovative community based cancer service. It focuses on impact and process issues relevant to a) the individuals in receipt of the service, b) the service providers, and c) the wider culture. As the programme evolves overtime, the research has been designed to draw out learning from the programme in order to support future commissioning both within Scotland and across the UK.

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Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia

Abstract

Purpose

Normal white blood cell counts (WBC) are unknown in children with acute lymphoblastic leukemia (ALL). Accordingly, 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy is adjusted by a common WBC target of 1.5–3.0 × 10⁹/L. Consequently, the absolute degree of myelosuppression is unknown for the individual child and we wanted to evaluate this.

Methods

A median of 22 (range 8–27) 6MP/MTX metabolite samples and 100 (range 25–130) blood counts during therapy and 10 (range 2–15) off therapy were collected in 50 children with ALL. Differences between off-therapy and on-therapy WBCs [including absolute neutrophil (ANC) and lymphocyte counts (ALC)] were used to retrospectively approximate the absolute myelosuppression (="delta-") and association with age, sex and 6MP/MTX doses explored. We applied linear mixed models to estimate on-therapy counts by 6MP/MTX metabolites: DNA-incorporated thioguanine nucleotides (DNA-TGN), erythrocyte thioguanine nucleotides (ery-TGN), erythrocyte-methylated 6MP metabolites (ery-MeMP) and erythrocyte MTX polyglutamates with 2–6 glutamate residues (ery-MTXpg_2–6).

Results

On-therapy WBC was correlated with ANC and ALC (r _s  = 0.84 and r _s  = 0.33, p values <0.001), whereas ANC was weakly correlated with ALC (r _s  = −0.11, p < 0.001), and neither significantly correlated with age. Off-therapy ALC, but not ANC, was strongly correlated with age (r _s  = −0.68 and −0.18, p < 0.001 and p = 0.22). Delta-ALC decreased with increasing age (r _s  = −0.69, p < 0.001). Incorporation of DNA-TGN was positively associated with ery-TGN (p < 0.001), ery-MeMP (p < 0.001) and ery-MTXpg_2–6 (p = 0.047). On-therapy ALC decreased with increasing DNA-TGN level (p < 0.001, model adjusted for off-therapy ALC), whereas on-therapy ANC could not be modeled reliably.

Conclusion

Measurements of 6MP/MTX metabolites could supplement blood counts in assessing therapy intensity, but require prospective validation.

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Associations between BRAF V600E and prognostic factors and poor outcomes in papillary thyroid carcinoma: a meta-analysis

Abstract

Background

The objective of this study is to perform a meta-analysis to evaluate the associations between the BRAF^V600E mutation status and aggressive clinicopathological features and poor prognostic factors in papillary thyroid cancer.

Methods

A literature search was performed within the PubMed, MEDLINE, Web of Science databases, and EMBASE databases using the Medical Subject Headings and keywords from January 2003 to July 2015. Individual study-specific odds ratios and confidence intervals were calculated, as were the Mantel-Haenszel pooled odds ratios for the combined studies.

Results

Sixty-three studies of 20,764 patients were included in the final analysis. Compared with wild-type BRAF, the BRAF^V600E mutation was associated with aggressive clinicopathological factors, including extrathyroidal extension, higher TNM stage, lymph node metastasis, and recurrence, and was associated with reduced overall survival; however, there was no significant association between the presence of BRAF mutation and distant metastasis.

Conclusions

BRAF mutations are closely associated with aggressive clinicopathological characteristics and poorer prognosis in papillary thyroid cancer. Accordingly, aggressive treatment should be considered for papillary thyroid cancer patients with BRAF mutation.

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miR-582-5P induces colorectal cancer cell proliferation by targeting adenomatous polyposis coli

Abstract

Background

microRNA (miRNAs) dysregulation is widely involved in cancer progression and contributed to sustained cell proliferation by directly targeting multiple targets. Therefore, better understand the underlying mechanism of miRNA in carcinogenesis may improve diagnostic and therapeutic strategies for malignancy.

Methods

We assessed microRNA-582 (miR-582-5P) expression in colorectal cancer (CRC) specimens and cell lines by real-time PCR. Luciferase reporter assay was used to confirm the target associations. Colony formation assay and anchorage-independent growth assay were used to analyze the effect of miR-582-5P on cell proliferation. Adenomatous polyposis coli (APC) gene and protein expression were examined using real-time PCR and western blotting, respectively.

Results

miR-582-5P was upregulated in the CRC specimens and cell lines and targeted the 3′ untranslated region of APC directly. miR-582-5P overexpression increased cyclin D1 and c-MYC expression, which subsequently induced CRC cell proliferation in an APC-dependent manner.

Conclusions

Our findings suggest that miR-582-5P plays an important role in the progression of CRC by inducing proliferation and may identify new targets for anti-cancer treatment.

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Decreased expression of CDH1 or CTNNB1 affects poor prognosis of patients with esophageal cancer

Abstract

Background

E-cadherin/CDH1 is one of the proteins involved in cell adhesion, and it is known that decreased expression of E-cadherin induces lymph node metastasis in esophageal cancer. Beta catenin/CTNNB1, which is an important component of the Wnt signaling pathway, binds to E-cadherin at the cell membrane, where the complex of these two proteins functions in the stabilization of cell adhesion. However, its role in the pathogenesis of esophageal cancer is still unknown.

Methods

This study included 86 patients with esophageal cancer who underwent surgery between 1998 and 2007. The expression of the E-cadherin/CDH1 gene product (E-cadherin/CDH1) and that of the beta catenin/CTNNB1 protein in the cell membrane were analyzed by immunohistochemistry. We examined the correlations among CDH1 or CTNNB1 expression, clinicopathological factors, and the prognosis of patients with ESCC.

Results

CDH1 and CTNNB1 were expressed in 52.3 % (45/86) and 36.0 % (31/86) of tumor samples, respectively. Both CDH1 and CTNNB1 were co-expressed in 22.1 % (19/86) of esophageal cancer tissues. CDH1 expression correlated with the p-stage (stages I–II vs stages III–IV, p = 0.032), T factor (T1–2 vs T3–4, p = 0.0088), and lymphatic invasion (p = 0.019). However, CDH1 expression did not correlate with the N factor or the blood vessel invasion. CTNNB1 expression correlated with the T factor (T1–2 vs T3–4, p = 0.0015), p-stage (stages I–II vs stages III–IV, p = 0.030), and lymphatic invasion (p = 0.007). The CDH1(+)/CTNNB1(+) phenotype was inversely correlated with the T factor, N factor, p-stage, lymphatic invasion, and blood vessel invasion. Furthermore, patients whose tumors were double-positive for CDH1 and CTNNB1 had a significantly higher survival rate than those whose tumors were negative for CDH1 or CTNNB1 (log-rank test, p = 0.0192). The T factor and N factor had a strong negative correlation with double-positive tumors. These were both independent prognostic factors, as was the double-positive phenotype. A univariate analysis indicated that the T factor, the N factor, and CDH1 and CTNNB1 co-expression were significant variables that predicted survival (hazard ratio, 2.387; 95 % confidence interval, 1.115–5.102; p = 0.025).

Conclusions

Decreased expression of CDH1 or CTNNB1 in the cell membranes of cancer cells is associated with poor survival of patients with esophageal cancer.

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Mass spectrometric analysis of the HLA class I peptidome of melanoma cell lines as a promising tool for the identification of putative tumor-associated HLA epitopes

Abstract

Melanoma is one of the most immunogenic tumors, and extensive lists of potential tumor rejection antigens have been collected during the last decades. By isolating human leukocyte antigen (HLA) class I complexes from five melanoma cell lines (FM-82, FM-93/2, Mel-624, MeWo and SK-Mel-5) and sequencing HLA-eluted peptides by mass spectrometry, we identified over 10,000 unique peptides with high confidence. The majority of the peptides were 8–11 amino acids in length and were predicted to bind to the respective HLA alleles. Over 250 epitopes, corresponding to previously described tumor-associated antigens, were identified, suggesting that HLA peptidome analysis may facilitate the characterization of putative tumor rejection antigens. MeWo and SK-Mel-5 cell lines were further interrogated for neo-epitopes, revealing one peptide from MeWo cells carrying an amino acid mutation. We also observed a remarkable overlap between A*03:01 peptides eluted from Mel-624 cells and A*03:01 peptides recovered from soluble HLA complexes purified from two melanoma patients, shedding light on the similarity of the HLA peptidome in cell lines and in patient-derived material. The reliable characterization of the HLA class I peptidome in melanoma promises to facilitate the identification of tumor rejection antigens and the development of immunotherapeutic strategies.

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Osimertinib-induced interstitial lung disease after treatment with anti-PD1 antibody

Summary

We report a case of a 38-year-old woman who was diagnosed with stage IV lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790 M mutation on exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1) antibody. After initiating osimertinib treatment, the patient began to complain of low-grade fever and shortness of breath without hypoxemia, and her chest radiograph and a CT scan revealed a remarkable antitumor response, although faint infiltrations were observed in the bilateral lung field. Bronchoalveolar lavage fluid mainly contained lymphocytes (CD4+/CD8+ ratio of 0.3), and a transbronchial lung biopsy specimen showed lymphocytic alveolitis with partial organization in several alveolar spaces. Therefore we diagnosed the patient with osimertinib-induced interstitial lung disease (ILD) after treatment with anti-PD1 antibody. We considered anti-PD1 therapies may be the risk factor of EGFR-TKI-induced ILD.

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A critical review of recent developments in radiotherapy for non-small cell lung cancer

Lung cancer is the leading cause of cancer mortality, and radiotherapy plays a key role in both curative and palliative treatments for this disease. Recent advances include stereotactic ablative radiotherapy (...

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Two novel sequence variants in MSH2 gene in a patient who underwent cancer genetic counseling for a very early-onset epithelial ovarian cancer

Abstract

Background

Early-onset or hereditary ovarian cancer is mostly associated with BRCA1 or BRCA2 mutations. Mismatch repair genes sequence alteration frequently cause colorectal cancer, and, in less extent, other tumors, such as ovarian cancer. Subjects with personal and/or family history suggestive for hereditary cancer should be addressed to cancer genetic counseling, aimed to the identification, definition and management of hereditary cancer syndrome, by a multidisciplinary approach.

Case presentation

A woman with a very early onset epithelial ovarian cancer underwent to cancer genetic counseling and genetic testing. Pedigree analysis suggested a clinical diagnosis of Lynch II syndrome, according to the Amsterdam criteria. The MMRpro model showed a cumulative risk of mutation of 50.3 %, thus, genetic testing was offered to the patient. Two germ-line mutations have been identified in exon 11 of MSH2 gene: c.1706A > T (p.Glu569Val) and c.1711G > T (p.Glu571*). Both DNA alterations were novel mutations not yet described in literature. The first is a missense mutation that is to be considered an unclassified variant; the second is nonsense mutation that created a premature stop codon resulting in a truncated not functioning protein. Both genetic alterations were found in the patients' father DNA.

Conclusions

The present report finds out two unpublished sequence alterations in exon 11 of the MSH2 gene, one on which can be considered causative of Lynch phenotype. Moreover, it stresses the importance of the multidisciplinary onco-genetic counselling in order to correctly frame the hereditary syndrome, suggest the right genetic test, and offer the most appropriate management of the cancer risk for the patients and her family members.

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Molecular testing of gynecologic cytology specimens: Beyond HPV

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Technical and US regulatory issues in triaging material for the molecular laboratory

Cytology samples offer many advantages for molecular testing, but the devil is in the details. In addition, regulatory issues may end up being the most significant challenge for cytology.

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Erratum to: Toxicity and radiation dosimetry studies of the serotonin transporter radioligand [ 18 F]AFM in rats and monkeys

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The activity and tissue distribution of thioredoxin reductase in basal cell carcinoma

Abstract

Purpose

Basal cell carcinoma (BCC) is the most prevalent cancer worldwide. Different mechanisms are proposed to be involved in its pathogenesis such as oxidative stress. Oxidative stress, which is the consequence of the disruption of redox balance in favor of oxidants, is involved in the initiation or progression of many tumors. Thioredoxin reductase (TrxR) is a key enzyme of the thioredoxin (Trx) system, containing Trx and TrxR and NADPH, which is one of the main cellular oxidoreductases with an essential role in cellular health and survival through providing and maintaining redox balance. Therefore, we aimed to study and compare the activity and tissue distribution of TrxR in tumoral tissue and its healthy margin in patients with BCC.

Methods

After biopsy and taking samples from 18 patients, TrxR activity was measured using a commercial kit and its tissue distribution was assessed immunohistochemically.

Results

Both the activity and tissue distribution of TrxR in tumoral tissues were significantly higher compared to their healthy margins. Regarding the tissue distribution, this significant increase in TrxR in tumoral tissues was documented based on both staining intensity and abundance of positive cells in immunohistochemistry.

Conclusions

Based on these results, it is concluded that TrxR is involved in the pathogenesis of BCC; however, more investigations are required to clarify whether this increase is a consequence of BCC or it is an initiating mechanism.

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New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study

Abstract

Background

The antimalarial drug Pyrimethamine has been suggested to exert an antitumor activity by inducing apoptotic cell death in cancer cells, including metastatic melanoma cells. However, the dose of Pyrimethamine to be considered as an anticancer agent appears to be significantly higher than the maximum dose used as an antiprotozoal drug.

Methods

Hence, a series of Pyrimethamine analogs has been synthesized and screened for their apoptosis induction in two cultured metastatic melanoma cell lines. One of these analogs, the Methylbenzoprim, was further analyzed to evaluate cell-cycle and the mechanisms of cell death. The effects of Methylbenzoprim were also analyzed in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model.

Results

Low dose of Methylbenzoprim was capable of inducing cytotoxic activity and a potent growth-inhibitory effect by arresting cell cycle in S-phase in melanoma cells. Methylbenzoprim was also detected as powerful antineoplastic agents in SCID-mouse although used at very low dose and as a single agent.

Conclusions

Our screening approach led to the identification of a "low cost" newly synthesized drug (methylbenzoprim), which is able to act as an antineoplastic agent in vitro and in vivo, inhibiting melanoma tumor growth at very low concentrations.

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Japanese childhood cancer survivors’ readiness for care as adults: a cross-sectional survey using the transition scales

Abstract

Background

Childhood cancer survivors' (CCSs') readiness for adult care has not been evaluated in Japan. We conducted a survey to examine transition barriers and facilitators in CCSs and compared the results to those of CCSs in Canada.

Methods

Participants were selected from the Heart Link mutual-aid health insurance membership directory and the Millefeuille Childhood Cancer Frontiers. We conducted a cross-sectional survey (self-report questionnaire) via mail, using the Transition Scales.

Results

In total, 268 questionnaires were collected by January 2016 (response rate: 42.5%). After confirming the reliability and validity of the Transition Scales, we analyzed 242 questionnaires. After excluding questionnaires for CCSs aged <15 or >26 years, we compared scales scores between Japanese and Canadian CCSs. Relative to that of Japanese CCSs, Canadian CCSs showed greater cancer-related worry for 4 items (p < 0.001) and preference for self-management in 3 items (p < 0.001). Japanese CCSs showed greater preference for self-management, relative to that of Canadian CCSs, in 5 items (p < 0.001). In the expectation scale, Japanese CCSs showed lower levels of expectation concerning adult care in 6 of 12 items (p < 0.001). Relative to that of Canadian CCSs, a significantly higher number of Japanese CCSs preferred to visit the same doctor for long-term care as adults (p < 0.001).

Conclusions

The results confirmed the reliability and validity of the Transition Scales and showed that Japanese CCSs expressed fewer cancer concerns, but a higher number of Japanese CCSs preferred to visit the same doctor for long-term care as adults. This article is protected by copyright. All rights reserved.

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A critical review of recent developments in radiotherapy for non-small cell lung cancer

Abstract

Lung cancer is the leading cause of cancer mortality, and radiotherapy plays a key role in both curative and palliative treatments for this disease. Recent advances include stereotactic ablative radiotherapy (SABR), which is now established as a curative-intent treatment option for patients with peripheral early-stage NSCLC who are medically inoperable, or at high risk for surgical complications. Improved delivery techniques have facilitated studies evaluating the role of SABR in oligometastatic NSCLC, and encouraged the use of high-technology radiotherapy in some palliative settings. Although outcomes in locally advanced NSCLC remain disappointing for many patients, future progress may come about from an improved understanding of disease biology and the development of radiotherapy approaches that further reduce normal tissue irradiation. At the moment, the benefits, if any, of radiotherapy technologies such as proton beam therapy remain unproven. This paper provides a critical review of selected aspects of modern radiotherapy for lung cancer, highlights the current limitations in our understanding and treatment approaches, and discuss future treatment strategies for NSCLC.

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Radiation Oncology Teaching Programmes as Part of the Undergraduate Degree in Medicine in Spanish Universities: the Need for an Update of the Contents and Structure

Abstract

The relevance of radiation oncology (RO) teaching in the Faculty of Medicine Degree Plan is justified by the high number of cancer patients who will require it at some point in their evolution of radiotherapy (RT). About 40 % of the population who will suffer cancer will be cured by RT alone or other related treatment modalities. Therefore, cancer education and RT teaching needs to have an in depth impact in the undergraduate medicine programmes. This education component is highly variable, not only among countries but also within each country, in terms of content (theory and practical training), number of credits and departmental affiliation of the teachers. Our aim is to take a snapshot of the situation of the teaching of RO in undergraduate university education in Spain. We have analysed 40 Spanish universities about specific aspects related to the teaching of RT. Information was obtained by mail or telephone contact throughout 2015. We have analysed the elements involved in teaching performance. In universities with various instructional units, we have taken the average of them. Among the Universities consulted in Spain, during the period of the medical degree, the average time allocated to RT lectures is 12 h (range, 0–36), the mean time allocated to seminars is 4 h (range, 0–22), and the mean time assigned to practices is 11 h (range, 0–38). The subject is mainly taught by a radiation oncologist and 80 % of Spanish universities have at least one radiation oncologist on staff. Undergraduate radiation oncology teaching in Spain shows structural heterogeneity. The Spanish Society of Radiation Oncology (SEOR) University Forum has identified new opportunities and elaborated a proposal to improve undergraduate education in oncology.

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Radiation Oncology Teaching Programmes as Part of the Undergraduate Degree in Medicine in Spanish Universities: the Need for an Update of the Contents and Structure

Abstract

The relevance of radiation oncology (RO) teaching in the Faculty of Medicine Degree Plan is justified by the high number of cancer patients who will require it at some point in their evolution of radiotherapy (RT). About 40 % of the population who will suffer cancer will be cured by RT alone or other related treatment modalities. Therefore, cancer education and RT teaching needs to have an in depth impact in the undergraduate medicine programmes. This education component is highly variable, not only among countries but also within each country, in terms of content (theory and practical training), number of credits and departmental affiliation of the teachers. Our aim is to take a snapshot of the situation of the teaching of RO in undergraduate university education in Spain. We have analysed 40 Spanish universities about specific aspects related to the teaching of RT. Information was obtained by mail or telephone contact throughout 2015. We have analysed the elements involved in teaching performance. In universities with various instructional units, we have taken the average of them. Among the Universities consulted in Spain, during the period of the medical degree, the average time allocated to RT lectures is 12 h (range, 0–36), the mean time allocated to seminars is 4 h (range, 0–22), and the mean time assigned to practices is 11 h (range, 0–38). The subject is mainly taught by a radiation oncologist and 80 % of Spanish universities have at least one radiation oncologist on staff. Undergraduate radiation oncology teaching in Spain shows structural heterogeneity. The Spanish Society of Radiation Oncology (SEOR) University Forum has identified new opportunities and elaborated a proposal to improve undergraduate education in oncology.

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Exploratory analysis of ERCC2 DNA methylation in survival among pediatric medulloblastoma patients

Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Emilyn Banfield, Austin L. Brown, Erin C. Peckham, Surya P. Rednam, Jeffrey Murray, M. Fatih Okcu, Laura E. Mitchell, Murali M. Chintagumpala, Ching C. Lau, Michael E. Scheurer, Philip J. Lupo
AimMedulloblastoma is the most frequent malignant pediatric brain tumor. While survival rates have improved due to multimodal treatment including cisplatin-based chemotherapy, there are few prognostic factors for adverse treatment outcomes. Notably, genes involved in the nucleotide excision repair pathway, including ERCC2, have been implicated in cisplatin sensitivity in other cancers. Therefore, this study evaluated the role of ERCC2 DNA methylation profiles on pediatric medulloblastoma survival.MethodsThe study population included 71 medulloblastoma patients (age <18years at diagnosis) and recruited from Texas Children's Cancer Center between 2004 and 2009. DNA methylation profiles were generated from peripheral blood samples using the Illumina Infinium Human Methylation 450 Beadchip. Sixteen ERCC2-associated CpG sites were evaluated in this analysis. Multivariable regression models were used to determine the adjusted association between DNA methylation and survival. Cox regression and Kaplan-Meier curves were used to compare 5-year overall survival between hyper- and hypo-methylation at each CpG site.ResultsIn total, 12.7% (n=9) of the patient population died within five years of diagnosis. In our population, methylation of the cg02257300 probe (Hazard Ratio=9.33; 95% Confidence Interval: 1.17–74.64) was associated with death (log-rank p=0.01). This association remained suggestive after correcting for multiple comparisons (FDR p<0.2). No other ERCC2-associated CpG site was associated with survival in this population of pediatric medulloblastoma patients.ConclusionThese findings provide the first evidence that DNA methylation within the promoter region of the ERCC2 gene may be associated with survival in pediatric medulloblastoma. If confirmed in future studies, this information may lead to improved risk stratification or promote the development of novel, targeted therapeutics.



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HSP90B1 overexpression predicts poor prognosis in NSCLC patients

Abstract

Non-small cell lung cancer (NSCLC) accounts for 85 % of lung cancer-related mortality worldwide. The heat shock protein 90B1 (HSP90B1) and DNA damage-inducible transcript 3 (DDIT3) are endoplasmic reticulum stress-related proteins that are associated with many malignancies. However, the roles of two proteins on NSCLC remain uncovered. To investigate the correlation between the expressions of HSP90B1 and DDIT3 and clinicopathological parameters of NSCLC as well as the significance of prognosis in NSCLC, a total of 143 NSCLC tissue samples and 45 control tissues samples were assessed. NSCLC patients were followed up from the day of surgery and ended by March 2014. The expressions of HSP90B1 and DDIT3 proteins were detected in all paraffin-embedded biopsy samples by immunochemistry. The HSP90B1 was highly expressed (65.2 %) in the 143 NSCLC patients, and its high expression was correlated with clinical stages (P = 0.001) and lymph node metastasis (P = 0.016). Similarly, DDIT3 was highly expressed in 43 (30.1 %) of 143 NSCLC patients, but only correlated with lymph node metastasis. Furthermore, Log-rank test suggested that high HSP90B1 expression may predict shorter survival (overall survival (OS)) and disease-free survival (DFS) for NSCLC patients. Cox model multivariate analyses indicated that HSP90B1 overexpression was an independent poor prognostic factor for both of OS and DFS. Therefore, HSP90B1 and DDIT3 may the potential biomarker to predict the NSCLC clinicopathological progress. Meanwhile, high HSP90B1 expression means poor prognosis, and HSP90B1 can be a promising prognosis factor for NSCLC.

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HOXA7 plays a critical role in metastasis of liver cancer associated with activation of Snail

Abstract

Background

Liver cancer is one of the main causes of cancer-related death in human. HOXA7 has been proved to be related with several cancers.

Method

The expression levels of HOXA7 were examined by Western blot, qRT-PCR or ICH. MTT was used to detect the proliferative rate of liver cancer cells. The invasive abilities were examined by matrigel and transwell assay. The metastatic abilities of liver cancer cells were revealed in BALB/c nude mice.

Results

In this report, we revealed that HOXA7 promoted metastasis of HCC patients. First, increased levels of HOXA7 were examined in liver cancer especially in metastatic liver cancer. Moreover, higher expression level of HOXA7 was associated with poorer prognosis of liver cancer patients. Overexpression of HOXA7 significantly enhanced proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo meanwhile silencing HOXA7 significantly inhibited the aboves abilities of liver cancer cells. In this research, we identified that HOXA7 performed its oncogenic characteristics through activating Snail.

Conclusion

Collectively, we identify the critical role and possible mechanism of HOXA7 in metastasis of liver cancer which suggest that HOXA7 may be a potential therapeutic target of liver cancer patients.

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Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2 -negative patients with early-onset breast cancer

Abstract

Background

Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screenings not cost-effective yet. Recently, we developed a straightforward, rapid, and inexpensive test based on p53 mitotic centrosomal localization (p53-MCL) in peripheral blood mononuclear cells (PBMCs) that diagnoses mutant ATM zygosity and recognizes tumor-associated ATM polymorphisms.

Methods

Fresh PBMCs from 496 cancer patients were analyzed by p53-MCL: 90 cases with familial BRCA1/2-positive and -negative breast and/or ovarian cancer, 337 with sporadic cancers (ovarian, lung, colon, and post-menopausal breast cancers), and 69 with breast/thyroid cancer. Variants were confirmed by ATM sequencing.

Results

A total of seven individuals with ATM variants were identified, 5/65 (7.7 %) in breast cancer cases of familial breast and/or ovarian cancer and 2/69 (2.9 %) in breast/thyroid cancer. No variant ATM carriers were found among the other cancer cases. Excluding a single case in which both BRCA1 and ATM were mutated, no p53-MCL alterations were observed in BRCA1/2-positive cases.

Conclusions

These data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers.

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Reactivation of mutant p53 by capsaicin, the major constituent of peppers

Abstract

Background

Mutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. Mutant p53 proteins are usually more stable than wild-type p53 and may not only impair wild-type p53 activity but also acquire pro-oncogenic functions. Therefore, targeting mutant p53 to clear the hyperstable proteins or change p53 conformation to reactivate wild-type p53 protein functions is a powerful anticancer strategy. Several small molecules have been tested for p53 reactivation in mutant p53-carrying cells while studies exploiting the effect of natural compounds are limited. Capsaicin (CPS) is the major constituent of peppers and show antitumor activity by targeting several molecular pathway, however, its effect on mutant p53 reactivation has not been assessed yet. In this study we aimed at investigating whether mutant p53 could be a new target of capsaicin-induced cell death and the underlying mechanisms.

Methods

p53 levels were analysed by western blot upon capsaicin treatment in the presence of the autophagy inhibitor chloroquine. The mutant p53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) assay and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The specific wild-type p53 activation was determined by using the inhibitor of p53 transactivation function, pifithrin-α and siRNA for p53.

Results

Here, we show that capsaicin induced autophagy that was, at least in part, responsible of mutant p53 protein degradation. Abrogation of mutant p53 by capsaicin restored wild-type p53 activities over mutant p53 functions, contributing to cancer cell death. Similar effects were confirmed in cancer cells bearing tumor-associated p53 mutations and in H1299 (p53 null) with overexpressed p53R175H and p53R273H mutant proteins.

Conclusion

These findings demonstrate for the first time that capsaicin may reduce mutant p53 levels and reactivate wild-type p53 protein in mutant p53-carrying cells and the p53 reactivation contributes to capsaicin-induced cell death.

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Inhibition of YAP suppresses CML cell proliferation and enhances efficacy of imatinib in vitro and in vivo

Abstract

Background

Yes-associated protein (YAP), an essential component of Hippo pathway, was identified as an oncoprotein which participated in the progression of various malignancies. However, its role in chronic myeloid leukemia (CML) remains to be further clarified.

Methods

The expression of YAP in CML cells was determined by western blotting. Next, the effects of YAP knockdown and YAP inhibitor on CML cells were evaluated by MTT assay, flow cytometry (FCM) and Wright's staining. Moreover, K562 induced mice model was employed to further investigate the role of YAP in vivo.

Results

YAP was overexpressed in CML cells. Knockdown of YAP by si-RNA or inhibition the function of YAP using verteporfin (VP) not only inhibited the proliferation, induced the apoptosis of CML cells but also reduced the expression of YAP target genes c-myc and survivin. Additionally, VP enhanced the efficacy of imatinib (IM) in vitro and suppressed leukemogenesis in vivo.

Conclusion

Our results indicate that YAP may play an important role in the proliferation and leukemogenesis of CML cells. Genetic or pharmacological inhibition of YAP provides a novel treatment strategy for CML.

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Issue Information

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Psycho-oncology, a Quick Reference on the Psychosocial Dimensions of Cancer Symptom Management Jimmie Holland Mitch Golant Donna Greenberg Mary Hughes Jon Levenson Matthew Loscalzo William Pirl (Editors). Oxford University Press, 2015. 248 pages. $49.95. ISBN: 0199988730

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Down-regulation of long non-coding RNA MEG3 in nasopharyngeal carcinoma

ABSTRACT

In our previous whole-transcriptome sequencing analysis, down-regulation of a long non-coding RNA, Maternally Expressed Gene 3 (MEG3), was identified in NPC samples. This finding suggests the possible role of MEG3 as a tumor suppressor in this distinctive disease. In the present study, two MEG3 variants, AF119863 (MEG3-AF) and BX247998 (MEG3-BX), were found abundantly expressed in a normal nasopharyngeal epithelial cell line, NP69. Significant down-regulation of MEG3-AF was further verified in a panel of NPC samples including xenografts and primary biopsies. MEG3 is an imprinted gene located within chromosome 14q32, a common deleted region in NPC. Both DNA copy number loss and aberrant promoter methylation contributed to MEG3 inactivation. Interestingly, MEG3 expression could successfully be rescued by the treatment of a demethylation agent. Besides, ectopic expression of MEG3 in NPC cell lines resulted in considerable repression of in vitro anchorage-independent growth and in vivo tumorigenicity, in addition to significant inhibition in cell proliferation, colony formation and induction of cell cycle arrest. Finally, we revealed the association between MEG3 activity and the p53 signaling cascade. Our findings characterize MEG3 as a tumor suppressive long non-coding RNA in NPC and encourage the development of precise long non-coding RNA-targeted epigenetic therapy against this malignancy. This article is protected by copyright. All rights reserved

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p16INK4A induces senescence and inhibits EMT through microRNA-141/microRNA-146b-5p-dependent repression of AUF1

ABSTRACT

Senescence and epithelial-to-mesenchymal transition (EMT) processes are under the control of common tumor suppressor proteins, EMT transcription factors, and microRNAs. However, the molecular mechanisms that coordinate the functional link between senescence and EMT are still elusive. We have shown here that p16^INK4A-reltaed induction of senescence is mediated through miR-141 and miR-146b-5p. These 2 microRNAs are up-regulated in aging human fibroblast and epithelial cells. Furthermore, miR-141 and miR146b-5p trigger cell cycle arrest at G1 phase and induce senescence in primary human fibroblasts and breast cancer cells in the presence and absence of p16^INK4A. Like p16^INK4A-induced senescence, miR-141/miR146b-5p-related senescence is not associated with secretory phenotype, and is mediated through the RNA binding protein AUF1. We have further demonstrated that p16^INK4A and its downstream miRNA targets inhibit EMT through suppressing the EMT inducer ZEB1 in an AUF1-dependent manner. Indeed, AUF1 binds the mRNA of this gene leading to increase in its level. These results indicate that p16^INK4A controls both senescence and EMT through repressing EMT-related transcription factor via miR-141/miR146b-5p and their target AUF1. This sheds more light on the molecular basis of the tumor suppressive functions of p16^INK4A, which represses both the proliferative and the migratory/invasive capacities of cells. This article is protected by copyright. All rights reserved

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Detection and evaluation of estrogen DNA-adducts and their carcinogenic effects in cultured human cells using biotinylated estradiol

Abstract

The normal female reproductive hormone estrogen has been linked with increased risk of breast and many other forms of cancer. This is largely due to metabolic conversion of estrogens into highly reactive catechol estrogen quinones which can interact with DNA and cause a variety of DNA adducts and lesions. Detection and analysis of these adducts and their associated cellular responses involve complex chemical, enzymatic and LC-MS based methods, which are both laborious and require specialized expertise and instrumentation. Herein, we show that using a biotin-labeled estradiol allows immunodetection of estrogen-induced DNA adducts by slot-blot and single-cell molecular combing and proximity ligation assays. The biotinylated and unlabeled estradiols induced similar levels of DNA single and double strand breaks as measured by comet assays. Using biotinylated estrogen we further show that estrogens are able to activate the Fanconi anemia and BRCA tumor suppressor pathway and cause DNA strand breaks and oxidatively modified DNA bases as well as gross chromosomal aberrations. Utilization of biotin-labeled estrogens could be a powerful tool to detect estrogen adducts and associated DNA damage, and to track estrogen adduct-induced cellular responses and carcinogenic mechanisms in cultured cells. The techniques presented here allow simple and rapid detection and quantitation of estrogen adducts by slot blot as well as direct visualization on the DNA strand and could pave the way for developing new treatments to protect the genome from the effects of reactive estrogen metabolites. This article is protected by copyright. All rights reserved

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