Addressing resistance to PD-1/PD-(L)1 pathway inhibition: considerations for combinatorial clinical trial designs.

With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade.

Pediatric Burn Care in the Developing World: Where Are the Gaps in Research and What Can Be Done?

Burns are the fourth most common cause of injury worldwide. The burden of burn injury is largely carried by low- and middle-income countries (LMICs) with children in these regions being particularly vulnerable to burns. The purpose of this scoping review is to identify knowledge gaps in global pediatric burn care experience in an effort to help prioritize future research. Using the 6-stage Arksey and O'Malley framework for conducting a scoping review, pediatric burn care literature was reviewed over a 10-year period from 2010 to 2020. Studies from low-resource settings were included and categorized by geographic location, study patient population, study type, type of burn, and level of evidence. Of 107 included studies, 34% and 49% originated from LMICs in South Asia and Sub-Saharan Africa, respectively. Qualitative/observational (73%) and epidemiological single-center (20%) publications comprised the majority of included papers. The majority (95%) of all papers regardless of geographical location were lower levels of evidence (Level 3 or below). Our study identified four primary knowledge gaps: 1) a paucity of high-quality studies to guide burn care in LMICs; 2) an under-representation of articles from certain geographical locations; 3) few therapeutic and economic articles to guide resource allocation; and 4) a lack of articles with long-term patient follow-up. Efforts to address these disparities could help reduce the pediatric burn burden of disease in resource-poor settings.

Approaches to Continuing COVID-19-Related Clinical Research Practices After the Pandemic-Must Cinderella Leave the Ball?

This Viewpoint reviews relevant components of federal regulation and guidance followed during the COVID-19 pandemic that may still be feasible and beneficial after the public health emergency ends.

Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons.

Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.