Citations

Abstract The lung, one the largest branching organs in our body and vital for survival at first breath, is commonly known as the gas-exchange organ. Recent novel findings on lung sensing cells, molecules, and lung-brain crosstalk in the emerging discipline of interoception have highlighted the consideration of the lung as a sensory organ. Acknowledging the central importance of lung sensing to human health and disease, NHLBI convened a workshop to synthesize the past, current, and future of lung sensing research, with in-person presentations by ∼20 interdisciplinary experts and a large virtual audience. Here, we highlight the key topics discussed and summarize a blueprint for the future in this important field.

ABSTRACT Germline variation shapes cancer risk, yet its influence on the evolutionary dynamics of established tumors remains poorly understood. In multiple myeloma, subclonal diversification drives disease progression and treatment failure, but the heritable factors that modulate this process are unknown. Here, we show that germline variation is associated with tumor evolutionary features, implicating inherited regulation in subclonal expansion. Integrating germline variation with tumor evolutionary parameters identifies variants associated with evolutionary features, with signals enriched in regulatory regions, consistent with a transcriptional basis. We further identify TBKBP1 as a key locus linking germline variation to tumor evolution and clinical outcome. Germline variation at this locus is associated with TBKBP1 expression and subclonal expansion, and TBKBP1 expression correlates with adverse prognosis, consistent across independent cohorts. Functional analyses demonstrate that TBKBP1 promotes proliferation and activates MYC, mTORC1 and non-canonical NF-κB signaling pathway. Together, these findings establish germline regulatory variation as a determinant of tumor evolutionary dynamics and identify TBKBP1 as a mediator linking inherited variation to subclonal expansion and disease progression in multiple myeloma.

Importance Preoperative and perioperative nivolumab improve event-free survival in resectable non–small cell lung cancer. The role of adjuvant nivolumab after upfront surgery is unknown. Objective To determine whether adjuvant nivolumab improves disease-free survival and overall survival in patients with resected non–small cell lung cancer with any tumor programmed death-ligand 1 (PD-L1) expression and in those with at least 50% PD-L1 expression. Design, Setting, and Participants This open-label, randomized phase 3 study enrolled participants from May 2016 through September 2019, with median follow-up of 72.6 months at the data cutoff in December 2025. The study was conducted at 378 centers in the US National Clinical Trials Network. Patients were identified through a screening trial. Those with resected tumors at least 4 cm and/or who were lymph node positive (N1/N2) were eligible for inclusion after completion of planned standard adjuvant therapy if the tumor was adenocarcinoma without sensitizing sequence variants in EGFR and ALK or squamous cell carcinoma. Intervention Patients were randomized in a 1:1 ratio to receive nivolumab 480 mg intravenously every 4 weeks for up to 1 year or standard care observation. Main Outcomes and Measures Co–primary end points were disease-free survival in the intention-to-treat population and in those with tumoral PD-L1 expression at least 50%. Overall survival was examined if the corresponding test of disease-free survival was statistically significant. Results A total of 466 patients (median age, 66 years; 241 [52%] male) were assigned to receive nivolumab and 469 (median age, 67 years; 245 [52%] male) to undergo standard care observation. The median duration of follow-up was 72.6 months. The trial was stopped for futility at 75% information. In the intention-to-treat population, median disease-free survival was 71.3 months with nivolumab and 68.8 months with observation (hazard ratio for progression or death, 0.97 [97% CI, 0.79-1.20]; [95% CI, 0.81-1.17]; 1-sided P = .39). In the subset of participants with PD-L1 of at least 50%, median disease-free survival was 89.8 months with nivolumab and 78.5 months with observation (hazard ratio for progression or death, 0.86 [98% CI, 0.55-1.34]; [95% CI, 0.59-1.25]; 1-sided P = .22). Conclusions and Relevance Adjuvant nivolumab was not associated with improved disease-free survival in patients with resected non–small cell lung cancer without sensitizing EGFR and ALK alterations when given after planned adjuvant chemotherapy and/or radiotherapy. Trial Registration Clinicaltrials.gov Identifier: NCT02595944

Background: Longitudinal assessments are increasingly common as a component of continuing certification programs offered by medical specialty boards. The goal of this study was to understand anesthesiologists’ utilization pattern, performance, and perception of the longitudinal assessment program administered by the American Board of Anesthesiology (Raleigh, North Carolina). Methods: The authors analyzed assessment usage and survey data from all anesthesiologists who participated in the Maintenance of Certification in Anesthesiology (MOCA) Minute from January 2018 to December 2019. Results: During the 24-month study period, 25,404 anesthesiologists completed all 120 questions assigned in at least 1 calendar year, collectively 5,801,160 responses to 1,646 unique questions. Participants were more likely to complete questions at the end of each quarter, with the highest frequency at the end of the year. Seventy-five percent of responses were first-time attempts, and 17% were first repeats. The median interval between original question presentation and first repeat was 314 days. The mean ± SD percent correct score was 68.3 ± 8.0% for first-time questions and 75.5 ± 12.6% for first repeats. The mean ± SD time to answer a first-time question was 26.8 ± 13.1 s, with shorter times for questions with correct than incorrect responses (25.0 ± 12.7 vs . 30.7 ± 13.3 s; time difference, −5.69 s; 95% CI, −5.71 to −5.66; P < 0.001). Of 5.11 million responses with ratings of relevance (88.2% of all responses analyzed), 4.86 million (95.2%) were felt to be somewhat or very relevant to practice. The percent correct scores were higher for responses with higher relevance and confidence ratings. For responses rated “not relevant,” “somewhat relevant,” and “very relevant,” the percent correct was 58.5%, 67.6%, and 77.0%, respectively; for responses rated as “unsure,” “somewhat confident,” and “very confident,” the percent correct was 53.6%, 67.9%, and 84.4%, respectively. Conclusions: MOCA Minute was generally used as designed. Evidence of learning was suggested by improved performance on repeat questions.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

Background: Colorectal cancer (CRC) remains one of the common causes of cancer-related morbidity and mortality in the United States. Emerging increases in early-onset CRC and persistent disparities remain major public health concerns. Objective: To characterize long-term CRC incidence and mortality trends in the United States, with particular emphasis on identifying demographic groups experiencing rising or plateauing disease burden. Methods: We conducted a population-based ecological study using CRC incidence data from the United States Cancer Statistics database (1999–2022) and mortality data from CDC WONDER (1999–2023). Temporal trends were evaluated using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC), stratified by age, sex, race/ethnicity, and urbanization level. Results: Overall CRC incidence and mortality declined during the study period (both AAPC approximately −2.08%). However, incidence increased significantly among adults younger than 55 years, particularly those aged 20–24 years. Mortality also increased among younger adults aged 25–44 years and remained elevated among individuals aged 45–54 years. Non-Hispanic Black individuals consistently experienced the highest incidence and mortality rates. Mortality declines plateaued in several older age groups after 2018–2020. Conclusions: Despite overall improvements in CRC burden, increasing incidence and mortality among younger adults and persistent disparities highlight the need for risk-stratified prevention, earlier detection strategies, and tailored therapeutic approaches.