Viral and metabolic factors influencing alanine aminotransferase activity in patients with chronic hepatitis C

Background/Aims: In chronic hepatitis C, disease progression and clinical manifestations are heterogenous. To clarify the role and interactions of viral and host factors in inducing liver cell injury, we examined the associations of several virological and metabolic variables with serum alanine aminotransferase levels. Methods: Patients with chronic hepatitis C enrolled in three phase III clinical trials of peginterferon alfa-2a (40KD) plus ribavirin (two studies analysing ‘elevated’ and one persistently ‘normal’ alanine aminotransferase) were included. Results: Multivariate analyses of 2881 patients before treatment and of 1403 patients with a sustained virological response indicated that gender, viral factors (genotype, HCV RNA titer) and indicators of metabolic syndrome (body mass index, blood pressure, blood glucose, cholesterol and triglyceride concentration) were associated with alanine aminotransferase levels. In addition, hepatitis C virus infection influenced serum lipids concentration according to a genotype-specific effect. Conclusions: Heterogeneity in alanine aminotransferase levels in patients with chronic hepatitis C partially depends on the degree of derangement of fat and carbohydrate metabolism. As this is the result of an interaction of chronic hepatitis C infection with the patient’s individual characteristics, treatment decisions should not be based on alanine aminotransferase level alone but rather on global evaluation of the patient

Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors.

PURPOSE: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. PATIENTS AND METHODS: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. RESULTS: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC(50)). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15. CONCLUSION: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors

Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study.

BackgroundSystemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics.Patients and methodsMyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR).ResultsAs of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred.ConclusionsOverall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination

Organizing online health content: developing hashtag collections for healthier internet-based people and communities

Twitter use has increased among patients with cancer, advocates, and oncology professionals. Hashtags, a form of metadata, can be used to share content, organize health information, and create virtual communities of interest. Cancer-specific hashtags modeled on a breast cancer community, #bcsm, led to the development of a structured set of hashtags called the cancer tag ontology. In this article, we review how these hashtags have worked with the aim of describing our experience from 2011 to 2017. We discuss useful guidelines for the development and maintenance of health-oriented communities on Twitter, including possible challenges to community sustainability and opportunities for future improvement and research