Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS

Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study

IMPORTANCE The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study. OBJECTIVE To determine the efficacy and safety of vemurafenib in adults with ECD or LCH enrolled in the VE-BASKET study. DESIGN, SETTING, AND PARTICIPANTS The VE-BASKET study was an open-label, nonrandomized, multicohort study for patients with nonmelanoma cancers harboring the BRAF V600 mutation. Patients with BRAF V600-mutant ECD or LCH were enrolled in an other solid tumor cohort of the VE-BASKET study, and they were enrolled in the present study. INTERVENTIONS Patients received vemurafenib, 960mg, twice daily continuously until disease progression, study withdrawal, or occurrence of intolerable adverse effects. MAIN OUTCOMES AND MEASURES The primary end point was confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), metabolic response by modified positron-emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) using F-18-fluorodeoxyglucose (FDG)-PET/computed tomography (CT), and safety. RESULTS A total of 26 patients from the VE-BASKET trial (22 with ECD, 4 with LCH) were included in the present study (14 women and 12 men; median age, 61 years; age range, 51-74 years). The confirmed ORR was 61.5%(95% CI, 40.6%-79.8%) in the overall cohort and 54.5%(95% CI, 32.2%-75.6%) in patients with ECD. All evaluable patients achieved stable disease or better. The median PFS and OS had not been reached in the overall cohort at study closure despite a median follow-up of 28.8 months; 2-year PFS was 86%(95% CI, 72%-100%), and 2-year OS was 96%(95% CI, 87%-100%). All 15 patients evaluated by FDG-PET/CT achieved a metabolic response, including 12 patients (80%) with a complete metabolic response. The most common adverse events (AEs) in the overall cohort included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma, and hyperkeratosis. Hypertension and dermatologic AEs occurred at higher rates than those reported in metastatic melanoma. CONCLUSIONS AND RELEVANCE In this study, vemurafenib had prolonged efficacy in patients with BRAF V600-mutant ECD and LCH and warrants consideration as a new standard of care for these patients

Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.

Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors

Citrus juices technology

Citrus fruits are widely grown throughout the world and contain various bioactive compounds with antioxidant activities including vitamin C, carotenoids, and phenolic compounds. These components are very important for human health and provide protection against harmful free radicals. Citrus fruits are mostly consumed as fresh fruits or fruit juices. To obtain high quality and safe citrus juice, certain critical points (oil extraction from peel, juice extraction, pulp removing, pasteurization, evaporation, and aseptic filling) need to be taken into consideration during citrus juice processing. Firstly, oil extraction from the peel is a necessary step to limit the level of peel oil components in the juice. Secondly, selected juice extraction techniques and process conditions are very important for the yield and total quality of the juice. Thirdly, the pulp removal is an important step to remove most of pectinmethylesterase (PME) and its heat resistance isoenzymes. Further inactivation of remaining PME enzymes and pathogenic or spoilage microorganisms is also obtained with the pasteurization step. Finally, equipment used for the juice production and the concentration conditions have various effects on the sensory properties of the citrus juices. As a result, minimal processing would be applied to citrus juices if the processing steps detailed above are optimized. Obtaining clarified citrus juices from the citruses which have lower carotenoid content including lemon and lime juice is a new trend these days. It is needed to be focused on enzymation (depectinization), clarification assistance agents, and filtration conditions during the clarified juices production. Citrus peel (flavedo) and layer of albedo are the main byproducts of the citrus juice industry. Citrus peel oil is obtained from flavedo layer which has a significant commercial value. Recently, promising nonthermal food preservation technologies were developed including pulsed electric fields (PEF), high pressure processing (HPP), and ultrasonication process (US). These technologies are highly appreciated for their ability to extend the shelf life of food products without the application of heat, thus also preserving the quality attributes such as sensory quality and nutritional value, as well as controlling the microbiological safety of food products. © 2014, Springer Science+Business Media New York