Citations

Abstract Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

Abstract Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

Abstract Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

Abstract Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti–PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors. Experimental Design: We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor. Results: PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor. Conclusions: Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti–PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity. See related commentary by Lander and DeNardo, p. 474

BACKGROUND: Arterial hyperoxemia may cause end-organ damage secondary to the increased formation of free oxygen radicals. The clinical evidence on postoperative lung toxicity from arterial hyperoxemia during cardiopulmonary bypass (CPB) is scarce, and the effect of arterial partial pressure of oxygen (Pa o 2 ) during cardiac surgery on lung injury has been underinvestigated. Thus, we aimed to examine the relationship between Pa o 2 during CPB and postoperative lung injury. Secondarily, we examined the relationship between Pa o 2 and global (lactate), and regional tissue malperfusion (acute kidney injury). We further explored the association with regional tissue malperfusion by examining markers of cardiac (troponin) and liver injury (bilirubin). METHODS: This was a retrospective cohort study including patients who underwent elective cardiac surgeries (coronary artery bypass, valve, aortic, or combined) requiring CPB between April 2015 and December 2021 at a large quaternary medical center. The primary outcome was postoperative lung function defined as the ratio of Pa o 2 to fractional inspired oxygen concentration (F io 2 ); P/F ratio 6 hours following surgery or before extubation. The association between CPB in-line sample monitor Pa o 2 and primary, secondary, and exploratory outcomes was evaluated using linear or logistic regression models adjusting for available baseline confounders. RESULTS: A total of 9141 patients met inclusion and exclusion criteria, and 8429 (92.2%) patients had complete baseline variables available and were included in the analysis. The mean age of the sample was 64 (SD = 13), and 68% were men (n = 6208). The time-weighted average (TWA) of in-line sample monitor Pa o 2 during CPB was weakly positively associated with the postoperative P/F ratio. With a 100-unit increase in Pa o 2 , the estimated increase in postoperative P/F ratio was 4.61 (95% CI, 0.71–8.50; P = .02). Our secondary analysis showed no significant association between Pa o 2 with peak lactate 6 hours post CPB (geometric mean ratio [GMR], 1.01; 98.3% CI, 0.98–1.03; P = .55), average lactate 6 hours post CPB (GMR, 1.00; 98.3% CI, 0.97–1.03; P = .93), or acute kidney injury by Kidney Disease Improving Global Outcomes (KDIGO) criteria (odds ratio, 0.91; 98.3% CI, 0.75–1.10; P = .23). CONCLUSIONS: Our investigation found no clinically significant association between Pa o 2 during CPB and postoperative lung function. Similarly, there was no association between Pa o 2 during CPB and lactate levels, postoperative renal function, or other exploratory outcomes.

Importance Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. Objective To identify genes associated with aggressive PCa. Design, Setting, and Participants A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. Exposure Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. Main Outcomes and Measures The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. Results A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM ( P ≤ 1.9 × 10 −6 ), followed by NBN ( P = 1.7 × 10 −4 ). This study found nominal evidence ( P < .05) of association with rare deleterious variants in MSH2 , XRCC2 , and MRE11A . Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53 , RAD51D , BARD1 , GEN1 , and SLX4 . Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. Conclusions and Relevance The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.