Citations

Abstract Background Safety is a central consideration when choosing between multiple medications with similar efficacy. We aimed to evaluate whether adverse event (AE) profiles of 3 such drugs in advanced prostate cancer could be distinguished based on published literature. Methods We assessed consistency in AE reporting, AE risk in placebo arms, and methodology used for risk estimates and quantification of statistical uncertainty in randomized placebo-controlled phase III trials of apalutamide, enzalutamide, and darolutamide in advanced prostate cancer. Results Seven included clinical trials enrolled a total of 9215 participants (range = 1051-1715 per trial) across 3 prostate cancer disease states. Within disease states, baseline patient characteristics appeared similar between trials. Of 54 distinct AE types in total, only 3 (fatigue, hypertension, and seizure) were reported by all 7 trials. Absolute risks of AEs in the placebo arms differed systematically and more than twofold between trials, which was associated with visit frequency and resulted in different degrees of uncertainty in AE profiles between trials. No trial used inferential methodology to quantify statistical uncertainty in AE risks, but 6 of 7 trials drew overall conclusions. Two trials concluded that there was no elevated AE risk because of the intervention, including the trial of darolutamide, which had the greatest statistical uncertainty. Conclusions Rigorous comparison of drug safety was precluded by heterogeneity in AE reporting, variation in AE risks in the placebo arms, and lack of inferential statistical methodology, underscoring considerable opportunities to improve how AE data are collected, analyzed, and interpreted in oncology trials.

» Distal radius fractures occur in a bimodal age and sex distribution. Their incidence continues to rise with an increasingly active aging population. » The current American Academy of Orthopaedic Surgeons guidelines for operative intervention are radial shortening of >3 mm, dorsal tilt of >10°, or intra-articular displacement or step-off of >2 mm. » The method of reduction and fixation should be selected on a case-by-case basis with a focus on patient factors, fracture behavior, surgical proficiency, and functional outcomes.

AbstractThe etiology of triple-negative breast cancers (TNBC) is poorly understood. As many TNBCs develop prior to the initiation of breast cancer screening or at younger ages when the sensitivity of mammography is comparatively low, understanding the etiology of TNBCs is critical for discovering novel prevention approaches for these tumors. Furthermore, the higher incidence rate of estrogen receptor–negative breast cancers, and specifically, of TNBCs, among young African American women (AAW) versus white women is a source of racial disparities in breast cancer mortality. Whereas immune responses to TNBCs have received considerable attention in relation to prognosis and treatment, the concept that dysregulated immune responses may predispose to the development of TNBCs has received limited attention. We present evidence that dysregulated immune responses are critical in the pathogenesis of TNBCs, based on the molecular biology of the cancers and the mechanisms proposed to mediate TNBC risk factors. Furthermore, proposed risk factors for TNBC, especially childbearing without breastfeeding, high parity, and obesity, are more prevalent among AAW than white women. Limited data suggest genetic differences in immune responses by race, which favor a stronger Thr type 2 (Th2) immune response among AAW than white women. Th2 responses contribute to wound-healing processes, which are implicated in the pathogenesis of TNBCs. Accordingly, we review data on the link between immune responses and TNBC risk and consider whether the prevalence of risk factors that result in dysregulated immunity is higher among AAW than white women.

Abstract Background and Aims Ileal strictures are the major indication for resective surgery in Crohn’s disease [CD]. We aimed to define ileal gene programmes present at diagnosis and linked with future stricturing behaviour during 5-year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicentre paediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behaviour and for model testing to predict stricturing behaviour. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results A total of 19 of the 249 patients developed isolated B2 stricturing behaviour during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our previous report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix [ECM] gene expression, in those who developed stricturing complications. We further computationally prioritise small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by Year 5 after diagnosis {AUC (area under the curve) (95th CI [confidence interval]) = 0.82 [0.7–0.94)}. Conclusions An ileal gene programme for macrophage and fibroblast activation is linked to stricturing complications in treatment of naïve pediatric CD, and may inform novel small molecule therapeutic approaches.

Abstract PURPOSE We investigated the long term impact of SRS and WBRT in two large prospective phase III trials. METHODS Patients with 1–4 BMs +/- resection were randomized to SRS or WBRT. Cognitive deterioration was a drop of >1 standard deviation from baseline in >2/6 cognitive measures (CM). Quality of life (QOL) scores were scored 0–100 point scale. CM and QOL scores were modeled using baseline adjusted Linear Mixed Models (LMM) with uncorrelated random intercept for subject and random slopes for time. Differences in trend over time between groups and the effect of >2 cognitive scores with >2 SD change from baseline were assessed. RESULTS 88 patients were included with median follow up of 24 months. We observed decreasing CM over time (SRS: 4/6; WBRT: 5/6). Mean CM was significantly higher in SRS for Total recall and Delayed Recall at 3, 6, 9, 12 months. More patients in WBRT arm declined 1 SD in >1 and >2 CM at the 3, 6, 9, and 12 months. A 1 SD decline in >3 CM at 1 year was 21% SRS vs 47% WBRT (p=0.02). SRS had fewer patients with a 2 SD decline in >1 CM at every time point. SRS had fewer patients with a 2 SD decline at >2 and >3 CM. WBRT had lower QOL at 3 months, but switched to SRS having lower QOL at 24 months for PWB, EWB, FWB, FactG, BR, and FactBR (p<0.05). A 2 SD decline in cognition decreased mean FWB by 6.4 units (95% CI: -11, -1.75; p=0.007) and decreased QOL by 5.1 units (95% CI: -7.7, -2.5; p<0.001). CONCLUSIONS We report the first pooled prospective study demonstrating the long term outcomes of patients with BMs after cranial radiation. WBRT was associated with worse cognitive outcomes. Impaired cognition is associated with worse QOL.

PurposeTo develop a novel magnetic resonance elastography (MRE) acquisition using a hybrid radial EPI readout scheme (TURBINE), and to demonstrate its feasibility to obtain wave images and stiffness maps in a phantom and in vivo brain.MethodThe proposed 3D TURBINE‐MRE is based on a spoiled gradient‐echo MRE sequence with the EPI readout radially rotating about the phase‐encoding axis to sample a full 3D k‐space. A polyvinyl chloride phantom and 6 volunteers were scanned on a compact 3T GE scanner with a 32‐channel head coil at 80 Hz and 60 Hz external vibration, respectively. For comparison, a standard 2D, multislice, spin‐echo (SE) EPI‐MRE acquisition was also performed with the same motion encoding and resolution. The TURBINE‐MRE images were off‐line reconstructed with iterative SENSE algorithm. The regional ROI analysis was performed on the 6 volunteers, and the median stiffness values were compared between SE‐EPI‐MRE and TURBINE‐MRE.ResultsThe 3D wave‐field images and the generated stiffness maps were comparable between TURBINE‐MRE and standard SE‐EPI‐MRE for the phantom and the volunteers. The Bland–Altman plot showed no significant difference in the median regional stiffness values between the two methods. The stiffness measured with the 2 methods had a strong linear relationship with a Pearson correlation coefficient of 0.943.ConclusionWe demonstrated the feasibility of the new TURBINE‐MRE sequence for acquiring the desired 3D wave‐field data and stiffness maps in a phantom and in‐vivo brains. This pilot study encourages further exploration of TURBINE‐MRE for functional MRE, free‐breathing abdominal MRE, and cardiac MRE applications.

Objectives: In the field of orthopaedics, it has been evident that Medicare reimbursement rates have been relatively stagnant. Although, objective measures of how these financial trends have changed over the past couple of decades has been limited. If orthopaedic practitioners and hospital administrators wish to make progress and advance the degree of satisfactory reimbursement they can expect, a more thorough understanding of these trends is warranted. In this study, the field of orthopaedic shoulder, elbow, and upper arm surgery is being analyzed specifically. The objective of this analysis was to assess the monetary trends in Medicare reimbursement rates for the 10 most commonly utilized shoulder surgical procedures and the 10 most commonly utilized elbow and upper arm surgical procedures from 2000 to 2019. Methods: For this analysis, the current procedural terminology (CPT) code ranges that corresponded to “Surgical Procedures of the Shoulder” and “Surgical Procedures of the Humerus (Upper Arm) and Elbow” were determined. The Medicare Provider Utilization and Payment Data: Physician and Other Suppliers PUF CY 2017 document was then utilized to objectively determine the 10 most common CPT codes fororthopaedic shoulder surgical procedures and orthopaedic elbow and upper arm surgical procedures. The reimbursement data for each of these procedures was then compiled from The Physician Fee Schedule Look-Up Tool from the Centers for Medicare & Medicaid Services. All monetary data points were adjusted for inflation to 2019 US dollars utilizing changes to the United States consumer price index. The average annual and the total percentage change in reimbursement were based on the adjusted trends for the 10 included shoulder procedures and the 10 included elbow and upper arm procedures. Results: After adjustment for inflation, the average reimbursement for the top 10 orthopaedic shoulder surgery procedures decreased by 25.8% from 2000 to 2019. The greatest mean decrease was observed in the “Repair of ruptured musculotendinous cuff (e.g. rotator cuff) open; chronic (23412)” CPT code (-40.1%). No adjusted reimbursement rates were noted to be positive throughout the study period for surgical shoulder procedures. The procedure with the smallest mean decrease was the “Closed treatment of proximal humeral (surgical or anatomical neck) fracture; without manipulation (23600)” CPT code (-5.4%). From 2000 to 2019, the adjusted reimbursement rate for all included shoulder procedures decreased by an average of 1.6% per year. For the top 10 orthopaedic elbow and upper arm surgical procedures, the average reimbursement decreased by 19.5% from 2000 to 2019. The greatest mean decrease was observed in the “Osteoplasty,humerus (e.g., shortening or lengthening) (24420)” CPT code (-32.1%). The procedure with the only positive mean difference was “Closed treatment of humeral shaft fracture; without manipulation (24500)” CPT code (0.34%). From 2000 to 2019, the adjusted reimbursement rate for all included elbow and upper arm procedures decreased by an average of 1.2% per year. Conclusion: To our knowledge, this is the first study to evaluate the orthopaedic shoulder and elbow subspecialtyand its trends in Medicare reimbursement rates. When monetary data is corrected for inflation, Medicare reimbursement rates have shown a steady decline from 2000 to 2019. The 10 most common procedures of or relating to the shoulder have decreased by an average of 25.8% while the 10 most common procedures of or relating to the elbow or upper arm have decreased by an average of 19.5%. Additionally, only one procedure showed a positive increase in reimbursement rate (Closed treatment of humeral shaft fracture; without manipulation (24500)). If access to high quality and sustainable surgicalorthopaedic care is to persist in the United States, increased awareness of these trends is important for stakeholders to take note of.

Abstract Rationale Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) typically undergo frequent clinical evaluation. The incidence and outcomes of coronavirus disease (COVID-19) and its impact on routine management for patients with pulmonary vascular disease is currently unknown. Objectives To assess the cumulative incidence and outcomes of recognized COVID-19 for patients with PAH/CTEPH followed at accredited pulmonary hypertension centers, and to evaluate the pandemic's impact on clinic operations at these centers. Methods A survey was e-mailed to program directors of centers accredited by the Pulmonary Hypertension Association. Descriptive analyses and linear regression were used to analyze results. Results Seventy-seven center directors were successfully e-mailed a survey, and 58 responded (75%). The cumulative incidence of COVID-19 recognized in individuals with PAH/CTEPH was 2.9 cases per 1,000 patients, similar to the general U.S. population. In patients with PAH/CTEPH for whom COVID-19 was recognized, 30% were hospitalized and 12% died. These outcomes appear worse than the general population. A large impact on clinic operations was observed including fewer clinic visits and substantially increased use of telehealth. A majority of centers curtailed diagnostic testing and a minority limited new starts of medical therapy. Most centers did not use experimental therapies in patients with PAH/CTEPH diagnosed with COVID-19. Conclusions The cumulative incidence of COVID-19 recognized in patients with PAH/CTEPH appears similar to the broader population, although outcomes may be worse. Although the total number of patients with PAH/CTEPH recognized to have COVID-19 was small, the impact of COVID-19 on broader clinic operations, testing, and treatment was substantial.

Background Intracerebral hemorrhage (ICH) risk is higher in elderly patients with atrial fibrillation on antithrombotic therapy as well as those with cerebral amyloid angiopathy (CAA). We investigated if mortality among patients with atrial fibrillation on antithrombotic therapy presenting with non‐traumatic ICH was influenced by underlying CAA. Methods and Results We used the Rochester Epidemiology Project to identify 6045 patients with atrial fibrillation aged >55 years on anticoagulation or antiplatelet therapy from 1995 to 2016. Seventy‐four patients in this cohort presented with non‐traumatic ICH. Medical records including imaging data were reviewed to identify those with CAA and record baseline variables and outcomes of interest; 38 of our 74 patients (51.4%) (mean age 81.5 years) met Modified Boston Criteria for possible or probable CAA. Twenty‐six of 74 patients (35%) died during the first 30 days while 56 of the 74 (76%) patients died by 10 years follow‐up after index ICH. Overall mortality was not significantly different between the CAA and non‐CAA groups at any point of time during follow‐up ( P =0.89) even amongst patients restarted on anticoagulation +/− antiplatelet (n=19) ( P =0.46) or those patients restarted only on antiplatelet therapy (n=22) ( P =0.66). Three of the 41 patients who restarted on antithrombotic therapy had a recurrent ICH; these 3 patients met criteria for possible or probable CAA. Conclusions Although more than half of our patients with atrial fibrillation on antithrombotic therapy and non‐traumatic ICH met Modified Boston Criteria for CAA, CAA did not significantly influence the high mortality seen in this cohort.