Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.     

Osteoporosis knowledge,self-efficacy,and health beliefs among Chinese individuals with HIV

Summary

The worldwide uptake of FRAX is described.

Introduction

The aim of this report was to determine the usage of FRAX worldwide over a 1-year period from 1 May 2012.

Methods

The number of FRAX calculations from each country was assessed over a 1-year period and expressed as calculations per million of the population aged 50 years or more. Countries were colour coded according to usage to populate a world map.

Results

Over the index year, there were estimated to be 2,391,639 calculations sourced from 173 counties. Uptake was high in North America, the Antipodes and most countries of Europe; intermediate in Latin America and the Middle East; and very low in Africa and much of South East Asia.

Conclusions

It is expected that the comparative data will encourage the development of new FRAX models and the uptake of FRAX into assessment guidelines.     

High Frequency of Serum Chromium Deficiency and Association of Chromium with Triglyceride and Cholesterol Concentrations in Patients Awaiting Bariatric Surgery

Background

To our knowledge, the frequency of serum chromium deficiency in patients awaiting bariatric surgery has not been determined. This study was designed to assess chromium concentration and its association with glycemic levels and lipid profile in patients prior to bariatric surgery.

Methods

This study recruited 73 candidates for bariatric surgery between March and September 2012. Their sociodemographic, anthropometric, and biochemical data were collected.

Results

Of the 73 patients, 55 (75.3 %) were women (75.34 %). Mean patient age was 37.20?±?9.92 years, and mean body mass index was 47.48 kg/m² (range, 43.59 to 52.50 kg/m²). Chromium deficiency was observed in 64 patients (87.7 %). Correlation analysis showed significant negative relationships between chromium concentration and BMI and zinc concentration and a significant positive relationship between chromium and glycated hemoglobin. Multiple linear regression analysis showed that serum chromium concentration was significantly associated with total cholesterol (β?=?0.171, p?=?0.048) and triglyceride (β?=??0.181, p?=?0.039) concentrations.

Conclusions

Serum chromium deficiency is frequent in candidates for bariatric surgery and is associated with total cholesterol and triglyceride concentrations. Early nutritional interventions are needed to reduce nutritional deficiencies and improve the lipid profile of these patients.     

Effects of host-directed therapies on the pathology of tuberculosis

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has co-evolved with the human immune system and utilizes multiple strategies to persist within infected cells, to hijack several immune mechanisms, and to cause severe pathology and tissue damage in the host. This delays the efficacy of current antibiotic therapy and contributes to the evolution of multi-drug-resistant strains. These challenges led to the development of the novel approach in TB treatment that involves therapeutic targeting of host immune response to control disease pathogenesis and pathogen growth, namely, host-directed therapies (HDTs). Such HDT approaches can (1) enhance the effect of antibiotics, (2) shorten treatment duration for any clinical form of TB, (3) promote development of immunological memory that could protect against relapse, and (4) ameliorate the immunopathology including matrix destruction and fibrosis associated with TB. In this review we discuss TB-HDT candidates shown to be of clinical relevance that thus could be developed to reduce pathology, tissue damage, and subsequent impairment of pulmonary function. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Relationship between saliva and plasma rufinamide concentrations in patients with epilepsy

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r² = .78, P < .0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose-normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme-inducing or enzyme-inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.