Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Pain in patients with pancreatic cancer: prevalence, mechanisms, management and future developments

Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients’ quality of life and survival

Planck intermediate results. XLI. A map of lensing-induced B-modes

The secondary cosmic microwave background (CMB) $B$-modes stem from the post-decoupling distortion of the polarization $E$-modes due to the gravitational lensing effect of large-scale structures. These lensing-induced $B$-modes constitute both a valuable probe of the dark matter distribution and an important contaminant for the extraction of the primary CMB $B$-modes from inflation. Planck provides accurate nearly all-sky measurements of both the polarization $E$-modes and the integrated mass distribution via the reconstruction of the CMB lensing potential. By combining these two data products, we have produced an all-sky template map of the lensing-induced $B$-modes using a real-space algorithm that minimizes the impact of sky masks. The cross-correlation of this template with an observed (primordial and secondary) $B$-mode map can be used to measure the lensing $B$-mode power spectrum at multipoles up to $2000$. In particular, when cross-correlating with the $B$-mode contribution directly derived from the Planck polarization maps, we obtain lensing-induced $B$-mode power spectrum measurement at a significance level of $12\,\sigma$, which agrees with the theoretical expectation derived from the Planck best-fit $\Lambda$CDM model. This unique nearly all-sky secondary $B$-mode template, which includes the lensing-induced information from intermediate to small ($10\lesssim \ell\lesssim 1000$) angular scales, is delivered as part of the Planck 2015 public data release. It will be particularly useful for experiments searching for primordial $B$-modes, such as BICEP2/Keck Array or LiteBIRD, since it will enable an estimate to be made of the lensing-induced contribution to the measured total CMB $B$-modes.Comment: 20 pages, 12 figures; Accepted for publication in A&A; The B-mode map is part of the PR2-2015 Cosmology Products; available as Lensing Products in the Planck Legacy Archive http://pla.esac.esa.int/pla/#cosmology; and described in the 'Explanatory Supplement' https://wiki.cosmos.esa.int/planckpla2015/index.php/Specially_processed_maps#2015_Lensing-induced_B-mode_ma

Intensity modulated radiotherapy (IMRT) in patients with carcinomas of the paranasal sinuses: clinical benefit for complex shaped target volumes

INTRODUCTION: The aim of the study was to evaluate the clinical outcome of intensity modulated radiotherapy (IMRT) in 46 patients with paranasal sinus tumors with special respect to treatment-related toxicity. PATIENTS AND METHODS: We treated 46 patients with histologically proven tumors of the paranasal sinuses with IMRT. Histological classification included squamous cell carcinoma in 6, adenocarcinoma in 8, adenoidcystic carcinoma in 20 and melanoma in 8 patients, respectively. Six patients had been treated with RT during initial therapy after primary diagnosis, and IMRT was performed for the treatment of tumor progression as re-irradiation. RESULTS: Overall survival rates were 96% at 1 year, 90% at 3 years. Calculated from the initiation of IMRT as primary radiotherapy, survival rates at 1 and 3 years were 95% and 80%. In six patients IMRT was performed as re-irradiation, and survival rate calculated from re-irradiation was 63% at 1 year. Local control rates were 85% at 1, 81% at 2 and 49% at 3 years after primary RT and 50% at 1 year after re-irradiation. Distant metastases-free survival in patients treated with IMRT as primary RT was 83% after 1 and 64% after 3 years. For patients treated as primary irradiation with IMRT, the distant control rate was 83% at 1 year and 0% at 2 years. No severe radiation-induced side-effects could be observed. CONCLUSION: IMRT for tumors of the paranasal sinuses is associated with very good tumor control rates. Treatment-related acute and long-term toxicity can be minimized as compared to historical results with conventional RT

Down-Regulation of AP-4 Inhibits Proliferation, Induces Cell Cycle Arrest and Promotes Apoptosis in Human Gastric Cancer Cells

BACKGROUND: AP-4 belongs to the basic helix-loop-helix leucine-zipper subgroup; it controls target gene expression, regulates growth, development and cell apoptosis and has been implicated in tumorigenesis. Our previous studies indicated that AP-4 was frequently overexpressed in gastric cancers and may be associated with the poor prognosis. The purpose of this study is to examine whether silencing of AP-4 can alter biological characteristics of gastric cancer cells. METHODS: Two specific siRNAs targeting AP-4 were designed, synthesized, and transfected into gastric cancer cell lines and human normal mucosa cells. AP-4 expression was measured with real-time quantitative PCR and Western blot. Cell proliferation and chemo-sensitivity were detected by CCK-8 assay. Cell cycle assay and apoptosis assay were performed by flow cytometer, and relative expression of cell cycle regulators were detected by real-time quantitative PCR and Western blot, expression of the factors involved in the apoptosis pathway were examined in mRNA and protein level. RESULTS: The expression of AP-4 was silenced by the siRNAs transfection and the effects of AP-4 knockdown lasted 24 to 96 hrs. The siRNA-mediated silencing of AP-4 suppressed the cellular proliferation, induced apoptosis and sensitized cancer cells to anticancer drugs. In addition, the expression level of p21, p53 and Caspase-9 were increased when AP-4 was knockdown, but the expression of cyclin D1, Bcl-2 and Bcl-x(L) was inhibited. It didn't induce cell cycle arrest when AP-4 was knockdown in p53 defect gastric cancer cell line Kato-III. CONCLUSIONS: These results illustrated that gene silencing of AP-4 can efficiently inhibited cell proliferation, triggered apoptosis and sensitized cancer cells to anticancer drugs in vitro, suggesting that AP-4 siRNAs mediated silencing has a potential value in the treatment of human gastric cancer

Immune Responses Accelerate Ageing: Proof-of-Principle in an Insect Model

The pathology of many of the world's most important infectious diseases is caused by the immune response. Additionally age-related disease is often attributed to inflammatory responses. Consequently a reduction in infections and hence inflammation early in life has been hypothesized to explain the rise in lifespan in industrialized societies. Here we demonstrate experimentally for the first time that eliciting an immune response early in life accelerates ageing. We use the beetle Tenebrio molitor as an inflammation model. We provide a proof of principle for the effects of early infection on morbidity late in life and demonstrate a long-lasting cost of immunopathology. Along with presenting a proof-of-principle study, we discuss a mechanism for the apparently counter-adaptive persistence of immunopathology in natural populations. If immunopathology from early immune response only becomes costly later in life, natural selection on reducing self-harm would be relaxed, which could explain the presence of immune self-harm in nature

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m−2 on day 1, FA 200 mg m−2 as a 2 h infusion followed by bolus 5-FU 400 mg m−2 and a 22 h infusion of 5-FU 600 mg m−2, repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer