Clinic, pathogenic mechanisms and drug testing of two inherited thrombocytopenias, ANKRD26- and MYH9-related diseases

Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet count resulting in impaired hemostasis. Patients can have spontaneous hemorrhages and/or excessive bleedings provoked by hemostatic challenges as trauma or surgery. To date, ITs encompass 32 different rare monogenic disorders caused by mutations of 30 genes. This review will focus on the major discoveries that have been made in the last years on the diagnosis, treatment and molecular mechanisms of ANKRD26-Related Thrombocytopenia and MYH9-Related Diseases. Furthermore, we will discuss the use a Thrombopoietin mimetic as a novel approach to treat the thrombocytopenia in these patients. We will propose the use of a new 3D bone marrow model to study the mechanisms of action of these drugs and to test their efficacy and safety in patients. The overall purpose of this review is to point out that important progresses have been made in understanding the pathogenesis of ANKRD26-Related Thrombocytopenia and MYH9-Related Diseases and new therapeutic approaches have been proposed and tested. Future advancement in this research will rely in the development of more physiological models to study the regulation of human platelet biogenesis, disease mechanisms and specific pharmacologic targets

Long-term clinical outcome after beta-interferon therapy in cirrhotic patients with chronic hepatitis C. TVVH Study Group

BACKGROUND/AIMS: Few data are available concerning the short and long-term effects of beta-IFN in patients with chronic hepatitis C. METHODOLOGY: We randomized 61 consecutive patients with HCV-related cirrhosis to receive: a) natural beta-IFN with a 6 MU/tiw for 6 months followed by 3 MU/tiw for 6 months schedule or b) no treatment. Biochemical and virological response was defined by normalization of ALT and negativization of serum HCV-RNA. Patients were followed-up for 5 years. RESULTS: A biochemical end-of-therapy response (ETR) was observed in 5/38 patients (13%) who received beta-IFN compared to 2/23 (9%) of untreated cases, but a virological ETR appeared only in 4/38 (11%) treated cases. At long-term follow-up, 6 cases (16%) who received beta-IFN and 4 untreated (17%) developed a persistent normalization of alanine aminotransferase (ALT) but only 2 (5%) and 1 (4%), respectively, were also HCV-RNA negative. The cumulative probability of liver decompensation (variceal bleeding ascites or hepatic encephalopathy) at 60 months was 24% in treated and 35% in untreated cases. Hepatocellular carcinoma developed in 2 treated and in 1 untreated patients. CONCLUSIONS: beta-IFN therapy was not associated with a significant improvement either in biochemical or virological response in cirrhotic patients with chronic hepatitis C. No significant reduction of cirrhosis related clinical events was linked to treatment

Long-term effect of nadolol or nadolol plus isosorbide-5-mononitrate on renal function and ascites formation in patients with cirrhosis.

IF = 9.82

A synonymous EGFR polymorphism predicting responsiveness to anti-EGFR therapy in metastatic colorectal cancer patients

Genetic factors are known to affect the efficiency of therapy with monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) in patients with metastatic colorectal cancer (mCRC). At present, the only accepted molecular marker predictive of the response to anti-EGFR mAbs, is the somatic mutation of KRAS and NRAS as a marker of resistance to anti-EGFR. However, only a fraction of KRAS wild type patients benefit from that treatment. In this study we show that the EGFR gene polymorphism rs1050171 defines, independently of RAS mutational status, a sub-population of 11% of patients with a better clinical outcome after anti-EGFR treatment. Median PFS for patients with the GG genotype was 10.17 months compared to 5.37 of those with AG+AA genotypes. Taken together our findings could be used to better define CRC populations responding to anti EGFR therapy. Further studies in larger independent cohorts are necessary to validate the present observation that a synonymous polymorphism in EGFR gene impacts on clinical responsiveness

Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis.

It is clearly established that beta-blockers decrease the risk of a first variceal bleeding in cirrhosis. We have recently shown that the addition of isosorbide mononitrate to nadolol decreases the rate of variceal bleeding in patients with cirrhosis and varices, compared with nadolol alone, after a median follow-up of 30 months. It is not established if the long-term treatment with the combination continues to be beneficial. Therefore, we assessed the long-term effect of this combination on first variceal bleeding, complications, and death. One hundred forty-six cirrhotic patients with esophageal varices included in a previously published multicenter, randomized study comparing nadolol (40-160 mg/d) with the combination nadolol plus isosorbide mononitrate (10-20 mg 3 times per day) were followed up for up to 7 years (median follow-up, 55 months). The primary end-point was variceal bleeding of any severity. Twenty-four patients (16 in the nadolol group, and 8 in the combination group) experienced variceal bleeding (log rank test, P =.02). Cumulative risk of bleeding was 29% and 12%, respectively (95% CI for the difference, 1%-23%). Two and 4 patients, respectively, had bleeding from portal hypertensive gastropathy (log rank test, P =.20). Thirty and 25 patients, respectively, died during follow-up (log rank test, P =.13). Twelve and 10 patients, respectively, had de novo occurrence of ascites during follow-up (log rank test, P =.29). In conclusion, nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the long-term use. Side effects are few, and no deleterious effects on ascites occurrence or on survival occur after long-term use of this combination

A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis

Background & Aims: Beta-blockers are extensively used to prevent variceal bleeding in patients with large esophageal varices. It is not established if beta-blockers delay the growth of small varices. Methods: A total of 161 patients with cirrhosis and small esophageal varices (F1 according to the classification of Beppu et al.) without previous bleeding were enrolled. A total of 83 patients were randomized to nadolol (dose adjusted to decrease resting heart rate by 25%; mean dose given, 62 +/- 25 mg/day) and 78 to placebo. The principal end point was occurrence of large esophageal varices (F2 or F3 according to the classification of Beppu et al.). Endoscopic examination was performed after 12, 24, 36, 48, and 60 months of follow-up. Mean follow-up was 36 months. Results: The 2 groups were well matched for demographic and clinical characteristics. During the study period, 9 patients randomized to nadolol and 29 randomized to placebo had growth of esophageal varices. At the end of follow-up, the cumulative riskwas 20% versus 51% (P < 0.001) (absolute risk difference, 31%; 95% confidence interval, 17%\u201345%). When possible confounding factors were taken into account, treatment was a significant factor predicting growth of varices (odds ratio, 4.0; 95% confidence interval, 1.95\u20138.4). The cumulative probability of variceal bleeding was also lower in patients randomized to nadolol (P = 0.02). Survival was not different (P = 0.33). Adverse effects resulting in withdrawal of drug occurred in 9 in the nadolol group and one in the placebo group (P = 0.01). Conclusions: This study suggests that beta-blocker prophylaxis of variceal bleeding in patients with compensated cirrhosis should be started when small esophageal varices are present