Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans, but limited data has made identification of causal proteins in other ancestries challenging. Here we present a multi-ancestry proteome-wide MR analysis pipeline based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the causal effects of 1,545 proteins on eight complex diseases in up to 32,658 individuals of African ancestries and 1.22 million individuals of European ancestries. We identified 45 and seven protein-disease pairs with MR and genetic colocalization evidence in the two ancestries respectively. 15 protein-disease pairs showed evidence of differential effects between males and females. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence of an effect in both ancestries, seven pairs with European-specific effects and seven with African-specific effects. Integrating these MR signals with observational and clinical trial evidence, we were able to evaluate the efficacy of one existing drug, identify seven drug repurposing opportunities and predict seven novel effects of proteins on diseases. Our results highlight the value of proteome-wide MR in informing the generalisability of drug targets across ancestries and illustrate the value of multi-cohort and biobank meta-analysis of genetic data for drug development.

Clinical Trial Eligibility Criteria and Recently Approved Cancer Therapies for Patients With Brain Metastases

Brain metastases cause significant morbidity and mortality in patients with advanced cancer. In the era of precision oncology and immunotherapy, there are rapidly evolving systemic treatment options. These novel therapies may have variable intracranial efficacy, and patients with brain metastases remain a population of special interest. Typically, only patients with stable, asymptomatic and/or treated brain metastases are enrolled in clinical trials, or may be excluded altogether, particularly in the setting of leptomeningeal carcinomatosis. Consequently, this leads to significant concerns on the external validity of clinical trial evidence to real-world clinical practice. Here we describe the current trends in cancer clinical trial eligibility for patients with brain metastases in both early and late phase trials, with a focus on targeted and immunotherapies. We evaluate recent newly FDA approved therapies and the clinical trial evidence base leading to approval. This includes analysis of inclusion and exclusion criteria, requirements for baseline screening for brain metastases, surveillance cerebral imaging and incorporation of trial endpoints for patients with brain metastases. Finally, the use of alternative sources of data such as real-world evidence with registries and collaborative studies will be discussed.

Investigation of Patient Satisfaction with Education in a Biosimilar Multiswitch Scenario - A Comparison Between Rheumatologists and Nurse Specialists

The aim of this project was to understand patients’ knowledge and opinion about biosimilars and to evaluate patient satisfaction with care after education on multiswitching of biosimilars (bsDMARDs) by rheumatologists in comparison to nurse specialists. Adult patients with rheumatoid arthritis, axial spondyloarthritis or psoriatic arthritis who underwent a non-medical switch to the adalimumab biosimilar MSB 11022 were randomized into a group in which information about multiswitching of bsDMARDs was provided by a nurse specialist or a rheumatologist. Validated outcome tools and standardized parameters for assessment of disease activity and function were used at baseline and 12 weeks after switching. Patients’ satisfaction with care was assessed by the Leeds Satisfaction Questionnaire. A structured questionnaire was used to assess patient’s knowledge. A total of 102 patients was randomized, 40 were seen by the rheumatologist (39.2%) and 62 by the nurse (60.8%). Fifty patients (49%) had already undergone one and 52 multiple switches (51%). Less than one third of patients was able to correctly answer questions on manufacturing, effectiveness, clinical trial evidence and cost of bsDMARDs. Patients were generally satisfied with care irrespective of whether the information had been given by the nurse or the rheumatologist. No difference in outcomes was seen.Patient satisfaction and outcomes after education about bsDMARDs and switching by nurses and rheumatologists were similarly good. The number of switches did not have a negative impact on patient satisfaction.

Fluvoxamine for Outpatient COVID-19 to Prevent Hospitalization: A Systematic Review and Meta-Analysis

Importance: Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly therapies that prevent hospitalization. Objective: Perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19. Data Sources: World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Study Selection: Completed outpatient trials with available results which compared fluvoxamine to placebo. Data Extraction and Synthesis: We followed the PRISMA 2020 guidelines. We extracted study details in terms of inclusion criteria, trial demographics and the pre-specified outcome of all-cause hospitalization. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool. We conducted a frequentist random effects meta-analysis, as well as two sensitivity analyses using a Bayesian random effects meta-analysis with different estimates of prior probability: a weakly neutral prior (50% chance of efficacy with 95% confidence interval for Risk Ratio [RR] between 0.5 and 2) and a moderately optimistic prior (85% chance of efficacy). We contextualized the results by estimating the probability of any effect (RR ≤1) and moderate effect (RR ≤0.9) on reducing hospitalization. Main Outcome(s) and Measure(s): All cause hospitalization. Results: 2196 participants were included from 3 identified trials. The risk ratios for hospitalization were 0.75 (95%CI, 0.57-0.97) for the frequentist analysis, 0.78 (95%CI 0.58-1.08) for the Bayesian weakly neutral prior, and 0.73 (95%CI, 0.53-1.01) for the Bayesian moderately optimistic prior. Depending on the scenario, the probability of any effect on hospitalization ranged from 94.1% to 98.3% and a moderate effect from 81.6% to 91.1%. Conclusions and Relevance: Under a variety of assumptions, fluvoxamine shows a high probability of preventing hospitalization in outpatients with COVID-19. While ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates, fluvoxamine could be recommended as a treatment option, particularly in resource-limited settings or persons without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals.

Immunotherapy for Refractory Autoimmune Encephalitis

Autoimmune encephalitis (AE) is an immune-mediated disease involving the central nervous system, usually caused by antigen-antibody reactions. With the advent of autoantibody-associated diseases, AE has become a hot research frontier in neuroimmunology. The first-line conventional treatments of autoimmune encephalitis consist of steroids, intravenous immunoglobulin (IVIG), plasma exchange (PLEX), and second-line therapy includes rituximab. Despite considerable research and expanding clinical experience, current treatments are still ineffective for a significant number of patients. Although there is no clear consensus, clinical trial evidence limited, and the level of evidence for some of the drugs based on single reports, third-line therapy is a viable alternative for refractory encephalitis patients. With the current rapid research progress, a breakthrough in the treatment of AE is critical. This article aims to review the third-line therapy for refractory AE

FDG-PET/CT in Lymphoma: Where Do We Go Now?

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) is an essential part of the management of patients with lymphoma at staging and response evaluation. Efforts to standardize PET acquisition and reporting, including the 5-point Deauville scale, have enabled PET to become a surrogate for treatment success or failure in common lymphoma subtypes. This review summarizes the key clinical-trial evidence that supports PET-directed personalized approaches in lymphoma but also points out the potential place of innovative PET/CT metrics or new radiopharmaceuticals in the future.

Weaning Analgosedation in Patients Requiring Prolonged Mechanical Ventilation

Although research supports the minimization of sedation in mechanically ventilated patients, many patients with severe acute respiratory distress syndrome (ARDS) receive prolonged opioid and sedative infusions. ICU teams face the challenge of weaning these medications, balancing the risks of sedation with the potential to precipitate withdrawal symptoms. In this article, we use a clinical case to discuss our approach to weaning analgosedation in patients recovering from long-term mechanical ventilation. We believe that a protocolized, multimodal weaning strategy implemented by a multidisciplinary care team is required to reduce potential harm from both under- and over-sedation. At present, there is no strong randomized clinical trial evidence to support a particular weaning strategy in adult ICU patients, but appraisal of the existing literature in adults and children can guide decision-making to enhance the recovery of these patients.

Real-World Utilization of Androgen Deprivation Therapy-Intensification Among Older Canadian Men with de Novo Metastatic Prostate Cancer

Background Despite the wealth of evidence demonstrating the efficacy of treatment intensification beyond androgen deprivation therapy (ADT) among patients with de novo metastatic castration-sensitive prostate cancer (mCSPC), little is known of its real-world utilization. This study examined the real-world uptake of ADT treatment intensification among older men in a large Canadian province. Methods We performed a retrospective population-based cohort study using province-wide linked administrative data in Ontario, Canada. Patients 66 years and older with de novo mCSPC were included and their treatment with conventional ADT-based regimens, ADT plus next-generation androgen receptor-axis-targeted therapy (ARAT), and ADT plus docetaxel were identified and stratified by time. Results From 2014 to 2019, 3556 patients were identified with de novo mCSPC. Most patients (n = 2794, 78.6%) were treated with a conventional ADT regimen while 399 (11.2%) patients received ADT intensification with docetaxel and 52 (1.5%) patients received abiraterone acetate plus prednisone (AA+P). In a time-stratified analysis of ADT intensification before and after the pivotal AA+P trial (LATITUDE), AA+P uptake increased from 0.5% to 3.0% while docetaxel use dropped from 12.0% to 10.0%. The median survival of the study population was 18 months (IQR = 10–31). Conclusion The majority of patients with de novo mCSPC are treated with ADT alone in the Canadian real-world setting, despite randomized clinical trial evidence of benefit with the use of ADT-intensified regimens. As ADT treatment intensification is substantially under-used, better understanding the barriers to treatment and targeted education to address these are needed.

The Past, Present, and Future of Economic Evaluations of Precision Medicine at the Committee for Economic Analyses of the Canadian Cancer Trials Group

Precision medicine in oncology poses unique challenges to the generation of clinical and economic evidence used for cost-effectiveness analyses that can inform health technology assessment. The conduct of randomized controlled trials for biomarker-specific therapies targeted towards small populations has limitations in regard to feasibility, timeliness, and cost. These limitations result in associated challenges for groups involved in the generation of economic evidence to inform treatment-related decision making, including the Committee of Economic Analysis (CEA) at the Canadian Cancer Trials Group (CCTG). We provide a high-level description and vision about the new paradigm of clinical trial design, generation of economic evidence, and novel approaches to economic evaluations necessary in the space of precision medicine in oncology in Canada. The CEA’s previous approach to precision medicine, including master protocol designs and single-arm studies, is reviewed. Methods and approaches currently under consideration by the CEA and national collaborators, such as the role of real-world and clinical trial evidence in enabling life-cycle assessment of therapies, are explored. Finally, future initiatives being planned in the space of precision medicine at CCTG, such as the incorporation of correlative studies to identify and test high-performing biomarkers in trials, are discussed.