Citations

BACKGROUND Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double‐blind, placebo‐controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second‐line treatment for metastatic colorectal cancer. METHODS Patients with metastatic colorectal cancer who progressed on first‐line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28‐day cycle. Crossover was not allowed. The primary endpoint was progression‐free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1‐sided α value of .1. RESULTS One hundred eighty‐one patients were randomized (120 to regorafenib‐FOLFIRI and 61 to placebo‐FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib‐FOLFIRI than placebo‐FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53‐1.01; log‐rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71‐1.44). The response rate was higher with regorafenib‐FOLFIRI (34%; 95% CI, 25%‐44%) than placebo‐FOLFIRI (21%; 95% CI, 11%‐33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. CONCLUSIONS The addition of regorafenib to FOLFIRI as second‐line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society .

Objective A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures. Design Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed. Results We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease. Conclusion Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.

Background Genetic causes of dilated cardiomyopathy (DCM) are incompletely understood. LRRC10 (leucine‐rich repeat–containing 10) is a cardiac‐specific protein of unknown function. Heterozygous mutations in LRRC10 have been suggested to cause DCM, and deletion of Lrrc10 in mice results in DCM. Methods and Results Whole‐exome sequencing was carried out on a patient who presented at 6 weeks of age with DCM and her unaffected parents, filtering for rare, deleterious, recessive, and de novo variants. Whole‐exome sequencing followed by trio‐based filtering identified a homozygous recessive variant in LRRC10 , I195T. Coexpression of I195T LRRC10 with the L‐type Ca 2+ channel (Ca v 1.2, β 2CN2 , and α 2 δ subunits) in HEK293 cells resulted in a significant ≈0.5‐fold decrease in I Ca,L at 0 mV, in contrast to the ≈1.4‐fold increase in I Ca,L by coexpression of LRRC10 (n=9–12, P <0.05). Coexpression of LRRC10 or I195T LRRC10 did not alter the surface membrane expression of Ca v 1.2. LRRC10 coexpression with Ca v 1.2 in the absence of auxiliary β 2CN2 and α 2 δ subunits revealed coassociation of Ca v 1.2 and LRRC10 and a hyperpolarizing shift in the voltage dependence of activation (n=6–9, P <0.05). Ventricular myocytes from Lrrc10 −/− mice had significantly smaller I Ca,L , and coimmunoprecipitation experiments confirmed association between LRRC10 and the Ca v 1.2 subunit in mouse hearts. Conclusions Examination of a patient with DCM revealed homozygosity for a previously unreported LRRC10 variant: I195T. Wild‐type and I195T LRRC10 function as cardiac‐specific subunits of L‐type Ca 2+ channels and exert dramatically different effects on channel gating, providing a potential link to DCM.