Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

An assessment of the correlation between robust CT-derived ventilation and pulmonary function test in a cohort with no respiratory symptoms

Objective:To evaluate CT-ventilation imaging (CTVI) within a well-characterized, healthy cohort with no respiratory symptoms and examine the correlation between CTVI and concurrent pulmonary function test (PFT).Methods:CT scans and PFTs from 77 Caucasian participants in the NORM dataset (clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00848406","term_id":"NCT00848406"}}NCT00848406) were analyzed. CTVI was generated using the robust Integrated Jacobian Formulation (IJF) method. IJF estimated total lung capacity (TLC) was computed from CTVI. Bias-adjusted Pearson’s correlation between PFT and IJF-based TLC was computed.Results:IJF- and PFT-measured TLC showed a good correlation for both males and females [males: 0.657, 95% CI (0.438–0.797); females: 0.667, 95% CI (0.416–0.817)]. When adjusting for age, height, smoking, and abnormal CT scan, correlation moderated [males: 0.432, 95% CI (0.129–0.655); females: 0.540, 95% CI (0.207–0.753)]. Visual inspection of CTVI revealed participants who had functional defects, despite the fact that all participant had normal high-resolution CT scan.Conclusion:In this study, we demonstrate that IJF computed CTVI has good correlation with concurrent PFT in a well-validated patient cohort with no respiratory symptoms.Advances in knowledge:IJF-computed CTVI’s overall numerical robustness and consistency with PFT support its potential as a method for providing spatiotemporal assessment of high and low function areas on volumetric non-contrast CT scan.     

Survival After Stereotactic Body Radiation Therapy for Clinically Diagnosed or Biopsy-Proven Early-Stage NSCLC: A Systematic Review and Meta-Analysis

Introduction

Stereotactic body radiation therapy (SBRT) is a promising curative treatment for early-stage NSCLC. It is unclear if survival outcomes for SBRT are influenced by a lack of pathological confirmation of malignancy and staging of disease in these patients. In this systematic review and meta-analysis, we assess survival outcomes after SBRT in studies with patients with clinically diagnosed versus biopsy-proven early-stage NSCLC.

Entrustment decisions: Implications for curriculum development and assessment

Abstract

With increased interest in the use of entrustable professional activities (EPAs) in undergraduate and postgraduate medical education, comes questions about their implications for curriculum development and assessment. This paper addresses some of those questions, discussed at a symposium of the 2017 conference of AMEE, by presenting the components of an EPA, describing their importance and application, identifying their implications for assessment, and pinpointing some of challenges they pose in undergraduate and postgraduate settings. It defines entrustment, describes the three levels of trust, and presents trainee and supervisor factors that influence it as well as perceived benefits, and risks. Two aspects of EPAs have implications for assessment: units of professional practice and decisions based on entrustment, which impact an assessment’s blueprint, test methods, scores, and standards. In an undergraduate setting EPAs have great appeal, but work is needed to identify and develop a robust assessment system for core EPAs. At the postgraduate level, there is tension between the granularity of the competencies and the integrated nature of the EPAs. Even though work remains, EPAs offer an important step in the evolution of competency-based education.     

Rubella Virus-associated Anterior Uveitis in a Vaccinated Patient: A Case Report

Rubella virus is involved in the pathogenesis of Fuchs heterochromic uveitis and almost all cases in Europe show an active antibody production in the aqueous humor against rubella virus. Herein we report a case of a fully vaccinated patient with common variable immunodeficiency who developed unilateral Fuchs heterochromic uveitis secondary to rubella virus which was proven by intraocular fluid examination. Awareness of rubella associated anterior uveitis should remain also in vaccinated patients, especially those without a fully competent immune system.     

One Week of Hospitalization Following Elective Hip Surgery Induces Substantial Muscle Atrophy in Older Patients

Objectives

Short successive periods of skeletal muscle disuse have been suggested to substantially contribute to the observed loss of skeletal muscle mass over the life span. Hospitalization of older individuals due to acute illness, injury, or major surgery generally results in a mean hospital stay of 5 to 7 days, during which the level of physical activity is strongly reduced. We hypothesized that hospitalization following elective total hip arthroplasty is accompanied by substantial leg muscle atrophy in older men and women.

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

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Successful biventricular cardiac resynchronization therapy in a failing Fontan patient: Implications of ventriculo‐ventricular interdependency in single ventricle physiology

We describe a Fontan patient with severe heart failure who was successfully treated with biventricular cardiac resynchronization therapy (CRT). Our case shows that strain imaging might play a crucial role in guiding placement of pacing leads and in characterizing the electromechanical substrate associated with a favorable CRT response. Furthermore, we demonstrate for the first time that ventriculo‐ventricular interdependency seems an important mechanical concept, which can be utilized to augment cardiac performance in failing Fontan patients with a functional hypoplastic ventricle.     

A review of interprofessional training wards: Enhancing student learning and patient outcomes

Background: In an interprofessional training ward (ITW), students from different health professions collaboratively perform patient care with the goal of improving patient care. In the past two decades, ITWs have been established world-wide and studies have investigated their benefits. We aimed to compare ITWs with respect to their logistics, interprofessional learning outcomes and patient outcomes.

Methods: We explored PubMed, CINAHL, Web of Science and EMBASE (1990–June 2017) and included articles focusing on interprofessional, in-patient training wards with student teams of medical and other health professions students. Two independent reviewers screened studies for eligibility and extracted data.

Results: Thirty-seven articles from twelve different institutions with ITWs were included. ITWs world-wide are organized similarly with groups of 2–12 students (i.e. medical, nursing, physiotherapy, occupational therapy, and pharmacy) being involved in patient care, usually for a period of two weeks. However, the type of clinical ward and the way supervisors are trained differ.

Conclusions: ITWs show promising results in short-term student learning outcomes and patient satisfaction rates. Future ITW studies should measure students’ long-term interprofessional competencies using standardized tools. Furthermore, a research focus on the impact of ITWs on patient satisfaction and relevant patient care outcomes is important.