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PURPOSE The recommended duration of adjuvant fluoropyrimidine and oxaliplatin chemotherapy for patients with stage III colon cancer is based on tumor classification into clinically low-risk (T1-3 N1) and high-risk (T4 or N2) groups. We determined whether Immunoscore can enhance prognostication within these risk groups. MATERIALS AND METHODS Patients with stage III colon carcinomas (N = 600) were randomly selected from the infusional fluorouracil, leucovorin, and oxaliplatin arm of adjuvant trial NCCTG N0147 (Alliance for Clinical Trials in Oncology). Tumors were evaluated for Immunoscore that quantifies CD3+ and CD8+ T-cell densities in the tumor center and invasive margin by digital image analysis. Disease-free survival (DFS) by Immunoscore was analyzed using a multivariable Cox regression model in each risk group with adjustment for covariates including KRAS, BRAF V600E, and mismatch repair status. RESULTS Of 559 cancers with Immunoscore data, 299 (53.5%) were classified as clinically low-risk (T1-3 N1) and 260 (46.5%) as clinically high-risk (T4 and/or N2). Among patients with low-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors had significantly worse 5-year DFS rates (77.5% v 91.8%; hazard ratio, 1.70; 95% CI, 1.03 to 2.79; P = .037). Among patients with high-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors also had significantly worse DFS (55.3% v 70.3%; hazard ratio, 1.65; 95% CI, 1.11 to 2.47; P = .013). Tumors that were low-risk/Immunoscore-Low had similar outcomes as did tumors that were high-risk/Immunoscore-High ( P = .174). Prognostication was significantly improved in multivariable models where Immunoscore was added to clinical risk parameters and limited biomarkers (likelihood ratio test P = .0003). CONCLUSION Immunoscore can refine patient prognosis beyond clinical risk group classification, suggesting its potential utility for adjuvant decision making.

PURPOSE To determine the specific types, durations, and intensities of recreational physical activity associated with the greatest improvements in disease-free survival (DFS) of patients with colon cancer. METHODS We conducted a prospective cohort study nested within a randomized multicenter trial of stage III colon cancer that compared 3 versus 6 months of fluorouracil, leucovorin, and oxaliplatin with or without celecoxib. We measured recreational physical activity in the first 3 months of chemotherapy and again 6 months after completion of chemotherapy. The primary end point was DFS. RESULTS During a median follow-up of 5.9 years, 457 of 1,696 patients experienced disease recurrence or death. For total recreational physical activity volume, the 3-year DFS was 76.5% with < 3.0 metabolic equivalent task hours per week (MET-h/wk) and 87.1% with ≥ 18.0 MET-h/wk (risk difference [RD], 10.6%; 95% CI, 4.7 to 19.4; P < .001). For light-intensity to moderate-intensity activities, the 3-year DFS was 65.7% with 0.0 h/wk and 87.1% with ≥ 1.5 h/wk (RD, 21.4%; 95% CI, 9.2 to 37.1; P < .001). For vigorous-intensity activity, the 3-year DFS was 76.0% with 0.0 h/wk and 86.0% with ≥ 1.0 h/wk (RD, 10.0%; 95% CI, 4.5 to 18.9; P < .001). For brisk walking, the 3-year DFS was 81.7% with < 1.0 h/wk and 88.4% with ≥ 3.0 h/wk (RD, 6.7%; 95% CI, 3.0 to 13.8; P < .001). For muscle strengthening activity, the 3-year DFS was 81.8% with 0.0 h/wk and 88.8% for ≥ 0.5 h/wk (RD, 7.0%; 95% CI, 3.1 to 14.2; P = .003). CONCLUSION Among patients with stage III colon cancer enrolled in a trial of postoperative treatment, larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the greatest improvements in DFS.

OBJECTIVE To characterize trends in clinical complexity, treatment burden, health care use, and diabetes-related outcomes among adults with diabetes. RESEARCH DESIGN AND METHODS We used a nationwide claims database to identify enrollees in commercial and Medicare Advantage plans who met claims criteria for diabetes between 1 January 2006 and 31 March 2019 and to quantify annual trends in clinical complexity (e.g., active health conditions), treatment burden (e.g., medications), health care use (e.g., ambulatory, emergency department [ED], and hospital visits), and diabetes-related outcomes (e.g., hemoglobin A1c [HbA1c] levels) between 2006 and 2018. RESULTS Among 1,470,799 commercially insured patients, the proportion with ≥10 active health conditions increased from 33.3% (95% CI 33.1–33.4) in 2006 to 38.9% (38.8–39.1) in 2018 (P = 0.001) and the proportion taking three or more glucose-lowering medications increased from 11.6% (11.5–11.7) to 23.1% (22.9–23.2) (P = 0.007). The proportion with HbA1c ≥8.0% (≥64 mmol/mol) increased from 28.0% (27.7–28.3) in 2006 to 30.5% (30.2–30.7) in 2015, decreasing to 27.8% (27.5–28.0) in 2018 (overall trend P = 0.04). Number of ambulatory visits per patient per year decreased from 6.86 (6.84–6.88) to 6.19 (6.17–6.21), (P = 0.001) while ED visits increased from 0.26 (0.257–0.263) to 0.29 (0.287–0.293) (P = 0.001). Among 1,311,903 Medicare Advantage enrollees, the proportion with ≥10 active conditions increased from 51.6% (51.2–52.0) to 65.1% (65.0–65.2) (P &lt; 0.001); the proportion taking three or more glucose-lowering medications was stable at 16.6% (16.3–16.9) and 18.1% (18.0–18.2) (P = 0.98), and the proportion with HbA1c ≥8.0% increased from 17.4% (16.7–18.1) to 18.6% (18.4–18.7) (P = 0.008). Ambulatory visits per patient per year remained stable at 8.01 (7.96–8.06) and 8.17 (8.16–8.19) (P = 0.23), but ED visits increased from 0.41 (0.40–0.42) to 0.66 (0.66–0.66) (P &lt; 0.001). CONCLUSIONS Among patients with diabetes, clinical complexity and treatment burden have increased over time. ED utilization has also increased, and patients may be using ED services for low-acuity conditions.

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted SARS-CoV-2 strain MA10 produces an acute respiratory distress syndrome in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days after virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of profibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early antifibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

PURPOSE Patients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC. MATERIALS AND METHODS The prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers. RESULTS The institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed. CONCLUSION ICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.

AbstractBackgroundWhole blood (WB) is carried by special operations forces as part of a remote damage control resuscitation strategy. The effects of an underwater mission on the quality and coagulation profile of WB were simulated by exposure to hyperbaric pressures in a chamber.MethodsWB units collected in CPDA‐1 were exposed to three different combinations of hyperbaric pressure and duration of exposure: Group A 153.52 kPa (15.24 msw; 1.52 atm) for 4 h; n = 9, Group B 506.63 kPa (50.29 msw; 5.00 atm) for 1 h; n = 9, Group C 153.52 kPa (15.24 msw; 1.52 atm) for 1 h; n = 7. The following parameters were measured on each unit: prothrombin time/international normalized ratio, activated partial thromboplastin time, thromboelastography and concentration determinations of platelets, lactate, fibrinogen, and lactate dehydrogenase. Each sample underwent baseline, prepressurization, immediate postpressurization, and 6 h postpressurization laboratory testing.ResultsSix hours following hyperbaric exposure, the lactate concentration in group C was higher than prepressurization measurement and the platelet concentration in Group A was lower than prepressurization measurement. There were no changes in any of the other analyzed biochemical, coagulation and thromboelastogram parameters following exposure to hyperbaric stress.DiscussionThese data suggest that pressurization of WB up to 5 atm did not impact parameters tested. Changes observed in lactate and platelet count need further study, as well as complementary testing of red blood cell integrity. Further investigation of the hyperbaric extremes is necessary to determine if there is a damage inducing pressure to which WB should not be exposed.

3553 Background: Higher levels of plasma 25-hydroxyvitamin D [25(OH)D)] are associated with better outcomes in mCRC, but underlying biologic mechanisms are unknown. Key components of the VitD metabolic pathway include CYP27B1 (encodes 1-α-hydroxylase, converts 25(OH)D to active calcitriol), VitD receptor (VDR), and CYP24A1 (encodes 24-hydroxylase, degrades calcitriol and 25(OH)D into excreted metabolites). Since these factors may affect 25(OH)D levels and potentially mediate VitD activity in mCRC, we examined the relationship between tumoral gene expression (GEx) of CYP27B1, VDR, and CYP24A and pt outcome in a study nested in a randomized phase III trial of first-line chemotherapy plus biologics in mCRC pts, CALGB/SWOG 80405. Methods: We determined GEx of CYP27B1, VDR, and CYP24A1 by RNA sequencing (RNA-Seq) of archival tumor samples using the Illumina TruSeq platform. Primary endpoints were overall (OS) and progression-free survival (PFS). Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for prognostic and molecular characteristics. Results: 562 pts with RNA-Seq data were included. Pts with higher CYP27B1 expression (>median) were less likely to have BRAF wild type (WT) (79% vs 90%) compared to pts with lower expression (p=0.0007). Pts with higher VDR expression (>quartile 1 [Q1]) were younger (median age 59 vs 62 years; p=0.03), more likely to have left-sided (63% vs 46%; p=0.0005) and BRAF WT tumors (89% vs 70%; p<0.0001), and less likely to have RAS WT tumors (70% vs 80%; p=0.02) compared to pts with lower VDR. Pts with higher CYP24A1 expression (>median) were more likely to have left-sided tumors compared to pts with lower expression (63% vs 54%; p=0.03). On multivariable analysis, pts with higher CYP27B1 expression had significantly improved OS (HR 0.84; 95% CI, 0.75-0.93; p=0.002) and PFS (HR 0.89; 95% CI, 0.80-0.99; p=0.04). Higher VDR expression (up to Q1) was associated with significantly improved PFS (HR 0.69; 95% CI, 0.53-0.91; p=0.007) but not OS (HR 0.85; 95% CI, 0.66-1.09; p=0.20). Above Q1, this improvement attenuated. Higher CYP24A1 GEx was not associated with improved OS (HR 0.98; 95% CI, 0.88-1.08; p=0.66) or PFS (HR 0.98; 95% CI, 0.89-1.08; p=0.68). We found no significant interactions between GEx of CYP27B1, VDR, or CYP24A with baseline plasma 25(OH)D levels (p for interaction ≥0.10 for all). Conclusions: Our findings suggest an association between GEx of VitD pathway markers, particularly CYP27B1 and VDR, and survival in pts with mCRC, lending biologic plausibility to a role of VitD in CRC pathogenesis. Future studies are needed to confirm these findings and elucidate underlying mechanisms of action. Clinical trial information: NCT00265850 .