Valsartan in acute myocardial infarction trial (VALIANT): rationale and design

Background Survivors of acute myocardial infarction (MI) complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular events. Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor has consistently been demonstrated to result in reductions in these risks by approximately 20%. The development of angiotensin II receptor blockers offers a new, more specific, and theoretically more complete pharmacologic mode to inhibit the adverse influence of angiotensin II. Methods Valsartan in Acute Myocardial Infarction (VALIANT) is a multicenter, double-blind, randomized, active controlled parallel group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after MI. The trial is designed with 3 arms, giving equal statistical consideration to survival comparisons of captopril versus the angiotensin II receptor blocker valsartan, as well as the combination of captopril plus valsartan, compared with a proven effective dose of captopril. This 14,500-patient trial is designed with an 86% power to detect a 15% reduction in mortality rate with either use of valsartan compared with captopril. The trial encourages optimal individualization of other proven therapies in acute and chronic infarction, and the international patient body ensures good representation of multiple practice patterns. Conclusion VALIANT is a large international investigative effort that will evaluate the role of valsartan in the management of patients with MI associated with heart failure and/or left ventricular dysfunction. The use of a proven dose of captopril and the comparator arms with valsartan alone or in combination with captopril provides a unique test of whether the angiotensin II receptor blocker can make an additional improvement in clinical outcomes beyond angiotensin-converting enzyme inhibitors

Correction of Severe Myelofibrosis, Impaired Platelet Functions and Abnormalities in a Patient with Gray Platelet Syndrome Successfully Treated by Stem Cell Transplantation

Gray platelet syndrome (GPS) is an inherited disorder. Patients harboring GPS have thrombocytopenia with large platelets lacking α-granules. A long-term complication is myelofibrosis with pancytopenia. Hematopoietic stem cell transplant (HSCT) could be a curative treatment. We report a male GPS patient with severe pancytopenia, splenomegaly and a secondary myelofibrosis needing red blood cells transfusion. He received an HSCT from a 10/10 matched HLA-unrelated donor after a myeloablative conditioning regimen. Transfusion independence occurred at day+21, with a documented neutrophil engraftment. At day+ 180, we added ruxolitinib to cyclosporine and steroids for a moderate chronic graft versus host disease (GVHD) and persistent splenomegaly. At day+240 GVHD was controlled and splenomegaly reduced. Complete donor chimesrism was documented in blood and marrow and platelets functions and morphology normalized. At day+ 720, the spleen size normalized and there was no evidence of marrow fibrosis on the biopsy. In GPS, HSCT may be a curative treatment in selected patients with pancytopenia and myelofibrosis

Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy

The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and 135 and 85 an

Distinct regulations driving YAP1 expression loss in poroma, porocarcinoma and RB1 ‐deficient skin carcinoma

International audienceAims: Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, and the diagnostic use of YAP1 immunohistochemistry has been highlighted in this setting. In other organs, loss of YAP1 expression can reflect YAP1 rearrangement or transcriptional repression, notably through RB1 inactivation. In this context, our objective was to re-evaluate the performance of YAP1 immunohistochemistry for the diagnosis of poroma and porocarcinoma.Methods and results: The expression of the C-terminal part of the YAP1 protein was evaluated by immunohistochemistry in 543 cutaneous epithelial tumours, including 27 poromas, 14 porocarcinomas and 502 other cutaneous tumours. Tumours that showed a lack of expression of YAP1 were further investigated for Rb by immunohistochemistry and for fusion transcripts by real-time PCR (YAP1::MAML2 and YAP1::NUTM1). The absence of YAP1 expression was observed in 24 cases of poroma (89%), 10 porocarcinoma (72%), 162 Merkel cell carcinoma (98%), 14 squamous cell carcinoma (SCC) (15%), one trichoblastoma and one sebaceoma. Fusions of YAP1 were detected in only 16 cases of poroma (n = 66%), 10 porocarcinoma (71%) all lacking YAP1 expression, and in one sebaceoma. The loss of Rb expression was detected in all cases except one of YAP1-deficient SCC (n = 14), such tumours showing significant morphological overlap with porocarcinoma. In-vitro experiments in HaCat cells showed that RB1 knockdown resulted in repression of YAP1 protein expression.Conclusion: In addition to gene fusion, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including MCC and a subset of SCC