Citations

SummaryThe oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double‐blind, placebo‐controlled Phase III TOURMALINE‐MM1 study of ixazomib‐Rd (IRd) versus placebo‐Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression‐free survival versus placebo‐Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo‐Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long‐term IRd treatment. Safety data from TOURMALINE‐MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.

AbstractBackgroundUnilateral radiotherapy (RT) of oropharyngeal carcinomas is accepted for patients with lateralized primary and low‐volume nodal disease. Utilizing prospectively defined criteria of laterality and staging positron emission tomography (PET)/CT, we studied outcomes in patients with advanced‐stage oropharyngeal cancer undergoing unilateral RT.MethodsThirty‐seven patients with oropharyngeal tumors >1 cm from midline regardless of node status underwent unilateral RT and were followed prospectively. Patient characteristics: T1 = 11; T2 = 22; T3 = 4; N0 = 3; N1 = 9; N2a = 3; N2b = 21; and Nx = 1. Dosimetry were determined and weekly National Comprehensive Cancer Network (NCCN) distress thermometer data were collected.ResultsAt median follow‐up of 32 months, 3‐year locoregional control, contralateral regional failure, distant metastasis‐free survival, and disease‐free survival were 96%, 0%, 7%, and 93%, respectively.ConclusionLow rates of contralateral neck failure are demonstrated utilizing prospectively defined criteria for unilateral RT. The tolerances of contralateral organs are respected and patients report low to moderate levels of distress throughout treatment.

ObjectiveDegeneration of oligodendroglial distal processes has been identified as an early event in multiple sclerosis (MS) lesion development. Our objective was to further define the development of the “dying‐back” oligodendrocyte lesion in situ and to model the development and potential reversibility of such responses using dissociated cultures of adult human brain‐derived oligodendrocytes.MethodsIn situ analyses were performed on glutaraldehyde‐fixed thin sections of clinically acute and pathologically active cases of MS. In vitro studies were conducted using adult human brain‐derived oligodendrocytes challenged by metabolic stress conditions (low nutrient/glucose).ResultsIn situ analyses indicated a spectrum of myelin changes in the presence of morphologically intact oligodendrocytes; these included degeneration of the inner cytoplasmic tongue with increasing sizes of intramyelinic bleb formation that could result in radial fractures of the myelin sheath. Macrophages with ingested myelin fragments were identified only once the fragmentation was established. In vitro studies indicated that oligodendrocyte process retraction, which was linked to reduced glycolytic respiratory activity, is reversible until a critical time point. Subsequent cell death was not linked to caspase‐3–dependent programs. Gene expression studies conducted at the latest reversible time point revealed reduced expression of pathways associated with cell process outgrowth and myelination, as well as with metabolic activity.InterpretationOur findings reveal the potential to protect and possibly restore myelin elaborated by existent oligodendrocytes in early and evolving MS lesions, and suggest the necessity of ongoing studies of the mechanisms underlying subsequent adult human oligodendrocyte cell death. Ann Neurol 2017;81:811–824

Objectives To define the prognostic contribution of global and regional left ventricular (LV) function measurements in patients with ischaemic cardiomyopathy randomised to coronary artery bypass graft surgery (CABG) with (n=501) or without (n=499) surgical ventricular reconstruction (SVR). Methods Novel multivariable methods to analyse global and regional LV systolic function were used to better formulate prediction models for long-term mortality following CABG with or without SVR in the entire cohort of 1000 randomised SVR hypothesis patients. Key clinical variables were included in the analysis. Regional function was classified according to the discreteness of anteroapical hypokinesia and akinesia into those most likely to benefit from SVR, those least likely and those felt to have intermediate likelihood of benefit from SVR. Results The most prognostic clinical variables identified in multivariable models include creatinine, LV end-systolic volume index (ESVI), age and NYHA (New York Heart Association) class. Addition of LV ejection fraction, LV end-diastolic volume index and regional function assessment did not contribute additional power to the model. Subgroup analysis based on regional function did not identify a cohort in which SVR improved mortality. Conclusions ESVI is the single parameter of LV function most predictive of mortality in patients with LV systolic dysfunction following CABG with or without SVR in multivariable models that include all key clinical and LV systolic function parameters. Assessment of regional cardiac function does not enhance prediction of mortality nor identify a subgroup for which SVR improves mortality. These results do not support elective addition of LV reconstruction surgery in patients undergoing CABG. Trial registration number NCT00023595.

AbstractBackgroundData on the effect of systemic immunoglobulin light chain amyloidosis (AL amyloidosis) on thyroid function are limited.ObjectiveTo assess the prevalence of hypothyroidism in AL amyloidosis patients and determine its predictors.Methods1142 newly diagnosed AL amyloidosis patients were grouped based on the thyroid‐stimulating hormone (TSH) measurement at diagnosis: hypothyroid group (TSH above upper normal reference; >5 mIU L−1; n = 217, 19% of study participants) and euthyroid group (n = 925, 81%). Predictors for hypothyroidism were assessed in a binary multivariate model. Survival between groups was compared using the log‐rank test and a multivariate analysis.ResultsPatients with hypothyroidism were older, more likely to present with renal and hepatic involvement and had a higher light chain burden compared to patients in the euthyroid group. Higher proteinuria in patients with renal involvement and lower albumin in patients with hepatic involvement were associated with hypothyroidism. In a binary logistic regression model, age ≥65 years, female sex, renal involvement, hepatic involvement, kappa light chain restriction and amiodarone use were independently associated with hypothyroidism. Ninety‐three per cent of patients in the hypothyroid group with free thyroxine measurement had normal values, consistent with subclinical hypothyroidism. Patients in the hypothyroid group had a shorter survival compared to patients in the euthyroid group (4‐year survival 36% vs 43%; P = 0.008), a difference that was maintained in a multivariate analysis.ConclusionA significant proportion of patients with AL amyloidosis present with hypothyroidism, predominantly subclinical, which carries a survival disadvantage. Routine assessment of TSH in these patients is warranted.

Key Points Pembrolizumab was first shown to be clinically active in CLL patients with RT. PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select RT patients for PD-1 blockade.