Frontline therapy with R-CHOP for diffuse large B-cell lymphoma: Where have we come (or not come)? A Perspective

A major evolution in the treatment of patients with diffuse large B-cell lymphoma (DLBCL) occurred almost two decades ago, with clinical trials demonstrating that the addition of rituximab (R) to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), which had been the “gold standard” of therapy since 1976, significantly improved outcome, including response rate and disease-free survival, of these patients. Since the adoption of R-CHOP, subsequent clinical trials have attempted to improve upon outcomes achieved with R-CHOP, with a variety of approaches examined. These have included dose intensification, which may be applicable in younger patients, but not in the many older or frailer patients with a disease with median age at diagnosis in the 60's. Newer anti-CD20 monoclonal antibodies have been substituted for rituximab in frontline regimens. A series of new agents, with unique mechanisms of action, have been added to the R-CHOP backbone. Rituximab-based, non-anthracycline regimens have been studied for older, more frail patients. The utility of maintenance therapy in responding patients has been re-examined, despite the lack of benefit found in the US Intergroup trial. Advances in molecular and genetic aspects of DLBCL have emerged since the seminal R-CHOP trials, demonstrating the DLBCL is not a single entity, but instead a spectrum of multiple disease subtypes. Attempts have been made to identify those patients at baseline who have poorer outcomes with standard approaches, utilizing laboratory and imaging findings. Moving forward, different risk-adapted treatment approaches will be studied to in an effort to improve overall outcome beyond R-CHOP.     

Valuing height: diagnosis,valuation and the case of idiopathic short stature

This paper proposes a ‘valuographic’ approach to diagnosis, exploring how values and valuation practices are implicated in the contested diagnostic category of idiopathic short stature (ISS). ISS describes children who are ‘abnormally’ short but do not have any other detectable pathology. In the USA growth‐promoting hormone therapy has been approved for ISS children, since 2003. However, no other jurisdiction has approved this treatment and the value of ISS as a diagnostic category remains disputed among healthcare professionals. Drawing on qualitative interviews with paediatric endocrinologists in the UK and the US, this study presents a historical snapshot illustrating how the problematisation of ISS as a diagnosis involved multiple registers of value including epistemic, economic and moral calculations of worth. Contestation of the diagnosis was not just about what counts but about what ought to be counted, as respondents’ accounts of ISS gave differential weight to a range of types of evidence and methods of assessment. Ultimately what was at stake was not just the value of increased height for short patients, but what it meant to properly practice paediatric endocrinology. Consideration is then given to how a valuographic approach can be applied to sociological studies of diagnosis more broadly.     

Exploring healthcare professionals’ perceptions of medication errors in an adult oncology department in Saudi Arabia: A qualitative study

Objective

Adverse events which result from medication errors are considered to be one of the most frequently encountered patient safety issues in clinical settings. We undertook a qualitative investigation to identify and explore factors relating to medication error in an adult oncology department in Saudi Arabia from the perspective of healthcare professionals.

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Short-term administration of glucocorticoids (GCs) impairs muscle insulin sensitivity at least in part via the reduction of undercarboxylated osteocalcin (ucOC). However, whether ucOC treatment reverses the GC-induced muscle insulin resistance remains unclear. To test the hypothesis that ucOC directly ameliorates impaired insulin-stimulated glucose uptake (ISGU) induced by short-term GC administration in mice muscle and to identify the molecular mechanisms, mice were implanted with placebo or corticosterone (CS) slow-release pellets. Two days post-surgery, insulin-tolerance tests (ITTs) were performed. On day 3, serum was collected and extensor digitorum longus (EDL) and soleus muscles were isolated and treated ex vivo with vehicle, ucOC (30 ng/mL), insulin (60 µU/mL), or both. Circulating hormone levels, muscle glucose uptake, and muscle signaling proteins were assessed. CS administration reduced both serum osteocalcin and ucOC levels, whole-body insulin sensitivity, and muscle ISGU in EDL. Ex vivo ucOC treatment restored ISGU in CS-affected muscle, without increasing non-insulin-stimulated glucose uptake. In CS-affected EDL muscle, ucOC enhanced insulin action on phosphorylated (p-)protein kinase B (Akt)^Ser473and the p-extracellular signal-regulated kinase isoform 2 (ERK2)^{Thr202/Tyr204}/total (t)ERK2 ratio, which correlated with ISGU. In CS-affected soleus muscle, ucOC enhanced insulin action on p-mammalian target of rapamycin (mTOR)^Ser2481, the p-mTOR^Ser2481/tmTOR ratio, p-Akt substrate of 160kD (AS160)^Thr642, and p-protein kinase C (PKC) (pan)^Thr410, which correlated with ISGU. Furthermore, p-PKC (pan)^Thr410 correlated with p-Akt^Ser473 and p-AS160^Thr642. ucOC exerts direct insulin-sensitizing effects on CS-affected mouse muscle, likely through an enhancement in activity of key proteins involved in both insulin and ucOC signaling pathways. Furthermore, these effects are muscle type-dependent. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.