Local Social Vulnerability as a Predictor for Cancer-Related Mortality Among US Counties.

Substantial gaps in national healthcare spending and disparities in cancer mortality rates are noted across counties in the US. In this cross-sectional analysis, we investigated whether differences in local county-level social vulnerability impacts cancer-related mortality. We linked county-level age-adjusted mortality rates (AAMR) from the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research database, to county-level Social Vulnerability Index (SVI) from the CDC Agency for Toxic Substances and Disease Registry. SVI is a metric comprising 15 social factors including socioeconomic status, household composition and disability, minority status and language, and housing type and transportation. AAMRs were compared between least and most vulnerable counties using robust linear regression models. There were 4 107 273 deaths with an overall AAMR of 173 per 100 000 individuals. Highest AAMRs were noted in older adults, men, non-Hispanic Black individuals, and rural and Southern counties. Highest mortality risk increases between least and most vulnerable counties were noted in Southern and rural counties, individuals aged 45-65, and lung and colorectal cancers, suggesting that these groups may face highest risk for health inequity. These findings inform ongoing deliberations in public health policy at the state and federal level and encourage increased investment into socially disadvantaged counties.

Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. METHODS: We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan-Meier statistics were used for progression-free survival (PFS) and overall survival (OS). RESULTS: FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/- cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3-4 immune related adverse events were observed in 4/19 (21.1%) patients. CONCLUSIONS: ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed.

Trends in Dispensing of Controlled Medications for US Adolescents and Young Adults, 2008 to 2019.

This cohort study examines trends from 2008 to 2019 in dispensations of controlled medications to US adolescents and young adults.

Reporting of clinical trial safety results in ClinicalTrials.gov for FDA-approved drugs: A cross-sectional analysis.

BACKGROUND: Adverse events identified during clinical trials can be important early indicators of drug safety, but complete and timely data on safety results have historically been difficult to access. The aim was to compare the availability, completeness, and concordance of safety results reported in ClinicalTrials.gov and peer-reviewed publications. METHODS: We analyzed clinical trials used in the Food and Drug Administration safety assessment of new drugs approved between 1 July 2018 and 30 June 2019. The key safety outcomes examined were all-cause mortality, serious adverse events, adverse events, and withdrawals due to adverse events. Availability of safety results was measured by the presence and timing of a record of trial-level results in ClinicalTrials.gov and a corresponding peer-reviewed publication. For the subset of trials with available results, completeness was defined as the reporting of safety results for all participants and compared between ClinicalTrials.gov and publications. To assess concordance, we compared the numeric results for safety outcomes reported in ClinicalTrials.gov and publications to results in Food and Drug Administration trial reports. RESULTS: Among 156 trials studying 52 drugs, 91 (58.3%) trials reported safety results in ClinicalTrials.gov and 106 (67.9%) in peer-reviewed publications (risk difference = -9.6%, 95% confidence interval = -20.3 to 1.0). All-cause mortality was reported sooner in published articles compared with ClinicalTrials.gov (log-rank test, p = 0.01). There was no difference in time to reporting for serious adverse events (p = 0.05), adverse events (p = 0.09), or withdrawals due to adverse events (p = 0.20). Complete reporting of all-cause mortality was similar in ClinicalTrials.gov and publications (74.7% vs 78.3%, respectively; risk difference = -3.6%, 95% confidence interval = -15.5 to 8.3) and higher in ClinicalTrials.gov for serious adverse events (100% vs 79.2%; risk difference = 20.8%, 95% confidence interval = 13.0 to 28.5) and adverse events (100% vs 86.8%; risk difference = 13.2%, 95% confidence interval = 6.8 to 19.7). Withdrawals due to adverse events were less often completely reported in ClinicalTrials.gov (62.6% vs 92.5%; risk difference = -29.8%, 95% confidence interval = -40.1 to -18.7). No difference was found in concordance of results between ClinicalTrials.gov and publications for all-cause mortality, serious adverse events, or withdrawals due to adverse events. CONCLUSION: Safety results were available in ClinicalTrials.gov at a similar rate as in peer-reviewed publications, with more complete reporting of certain safety outcomes in ClinicalTrials.gov. Future efforts should consider adverse event reporting in ClinicalTrials.gov as an accessible data source for post-marketing surveillance and other evidence synthesis tasks.

Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells.

CD8 T cells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 T cells directly under cancer immunotherapy settings and identified regulators of tumor infiltration and degranulation. The in vivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterized in T cells. The infiltration and degranulation screens converged on an RNA helicase Dhx37. Dhx37 knockout enhanced the efficacy of antigen-specific CD8 T cells against triple-negative breast cancer in vivo. Immunological characterization in mouse and human CD8 T cells revealed that DHX37 suppresses effector functions, cytokine production, and T cell activation. Transcriptomic profiling and biochemical interrogation revealed a role for DHX37 in modulating NF-κB. These data demonstrate high-throughput in vivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 T cells.