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ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.

Importance People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS). Design, Setting, and Participants SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021. Exposures Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV 1 ] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls. Main Outcomes and Measures The primary outcome was assessment for accelerated decline in lung function (FEV 1 ) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic–defined airway wall thickening or emphysema. Results Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV 1 was −31.3 mL/y for participants with symptomatic TEPS vs −38.8 mL/y for those with asymptomatic TEPS (between-group difference, −7.5 mL/y [95% CI, −16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001). Conclusions and Relevance Participants with symptomatic TEPS did not have accelerated rates of decline in FEV 1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

ABSTRACT Aims Takotsubo syndrome (TTS) is associated with a substantial rate of adverse events. We sought to design a machine learning (ML)-based model to predict the risk of in-hospital death and to perform a clustering of TTS patients to identify different risk profiles. Methods and results A ridge logistic regression-based ML model for predicting in-hospital death was developed on 3482 TTS patients from the International Takotsubo (InterTAK) Registry, randomly split in a train and an internal validation cohort (75% and 25% of the sample size, respectively) and evaluated in an external validation cohort (1037 patients). Thirty-one clinically relevant variables were included in the prediction model. Model performance represented the primary endpoint and was assessed according to area under the curve (AUC), sensitivity and specificity. As secondary endpoint, a K-medoids clustering algorithm was designed to stratify patients into phenotypic groups based on the 10 most relevant features emerging from the main model. The overall incidence of in-hospital death was 5.2%. The InterTAK-ML model showed an AUC of 0.89 (0.85–0.92), a sensitivity of 0.85 (0.78–0.95) and a specificity of 0.76 (0.74–0.79) in the internal validation cohort and an AUC of 0.82 (0.73–0.91), a sensitivity of 0.74 (0.61–0.87) and a specificity of 0.79 (0.77–0.81) in the external cohort for in-hospital death prediction. By exploiting the 10 variables showing the highest feature importance, TTS patients were clustered into six groups associated with different risks of in-hospital death (28.8% vs. 15.5% vs. 5.4% vs. 1.0.8% vs. 0.5%) which were consistent also in the external cohort. Conclusion A ML-based approach for the identification of TTS patients at risk of adverse short-term prognosis is feasible and effective. The InterTAK-ML model showed unprecedented discriminative capability for the prediction of in-hospital death.

Abstract The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus <CR. Persistent MRD in the 10−6 logarithmic range and reappearance of normal plasma cells in MRD-negative patients were associated with inferior PFS. This study unveils different prognostic implications of serological and MRD response dynamics after ide-cel and suggests the potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T-cell functionality. Significance: This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337

Objectives: To report the results of a rigorous quality control (QC) process in the grading of total mesorectal excision (TME) specimens during a multicenter prospective phase 2 trial of transanal TME. Background: Grading of TME specimens is based on the macroscopic assessment of the mesorectum and standardized through synoptic pathology reporting. TME grade is a strong predictor of outcomes with incomplete (IC) TME associated with increased rates of local recurrence relative to complete or near complete (NC) TME. Although TME grade serves as an endpoint in most rectal cancer trials, in protocols incorporating centralized review of TME specimens for quality assurance, discordance in grading and the management thereof has not been previously described. Methods: A phase 2 prospective transanal TME trial was conducted from 2017 to 2022 across 11 North American centers with TME quality as the primary study endpoint. QC measures included (1) training of site pathologists in TME protocols, (2) blinded grading of de-identified TME specimen photographs by central pathologists, and (3) reconciliation of major discordance before trial reporting. Cohen Kappa statistic was used to assess agreement in grading. Results: Overall agreement in grading of 100 TME specimens between site and central reviewer was rated as fair, (κ = 0.35; 95% CI: 0.10–0.61; P < 0.0001). Concordance was noted in 54%, with minor and major discordance in 32% and 14% of cases, respectively. Upon reconciliation, 13/14 (93%) major discordances were resolved. Pre versus postreconciliation rates of complete or NC and IC TME are 77%/16% and 7% versus 69%/21% and 10%. Reconciliation resulted in a major upgrade (IC–NC; N = 1) or major downgrade (NC/C–IC, N = 4) in 5 cases overall (5%). Conclusions: A 14% rate of major discordance was observed in TME grading between the site and central reviewers. The resolution resulted in a major change in final TME grade in 5% of cases, which suggests that reported rates or TME completeness are likely overestimated in trials. QC through a central review of TME photographs and reconciliation of major discordances is strongly recommended.

Background: Nasal septal perforation repair is commonly attempted utilizing bilateral nasal mucosal flaps supported with an interposition graft. Objectives: To compare the failure rates for bilateral flap repairs utilizing four different autologous interposition grafts. Methods: This is a retrospective review of a single surgeon's bilateral flap perforation repairs supported with an autologous interposition graft. Study inclusion over the 18-year review period required at least one examination 1 month after surgery. Repair failure rates were calculated and compared for each graft type, and logistic regression was performed for multivariate analysis. Results: For the 356 study patients, median (range) age was 51 years (14–81) and 63.0% were women. Mean (range) perforation length was 13.9 mm (1–45). Median (range) at last follow-up was 11.2 months (1–192). Graft types used (percentage of patients and failure rate) were temporalis fascia (58.7/4.4), septal cartilage (23.3/7.3), auricular perichondrium (13.8/4.1), and septal bone (4.2/6.7) ( p > 0.05). Conclusion: There was no significant difference in bilateral mucosal flap perforation repair failure rate when either a temporalis fascia, septal cartilage, auricular perichondrium, or septal bone interposition graft was used.

Abstract Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. Methods: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. Results: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88–1.22; MR-Egger OR, 0.89; 95% CI, 0.65–1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90–1.27; MR-Egger OR, 0.93; 95% CI, 0.67–1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. Conclusions: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. Impact: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Abstract Aims It is widely held that heart failure (HF) does not cause exertional hypoxaemia, based upon studies in HF with reduced ejection fraction, but this may not apply to patients with HF and preserved ejection fraction (HFpEF). Here, we characterize the prevalence, pathophysiology, and clinical implications of exertional arterial hypoxaemia in HFpEF. Methods and results Patients with HFpEF (n = 539) and no coexisting lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxaemia (oxyhaemoglobin saturation &lt;94%) was observed in 136 patients (25%). As compared to those without hypoxaemia (n = 403), patients with hypoxaemia were older and more obese. Patients with HFpEF and hypoxaemia had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar–arterial oxygen difference, increased dead space fraction, and greater physiologic shunt compared to those without hypoxaemia. These differences were replicated in a sensitivity analysis where patients with spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and pulmonary capillary pressures were related to lower arterial oxygen tension (PaO2), especially during exercise. Body mass index (BMI) was not correlated with the arterial PaO2, and hypoxaemia was associated with increased risk for death over 2.8 (interquartile range 0.7–5.5) years of follow-up, even after adjusting for age, sex, and BMI (hazard ratio 2.00, 95% confidence interval 1.01–3.96; p = 0.046). Conclusion Between 10% and 25% of patients with HFpEF display arterial desaturation during exercise that is not ascribable to lung disease. Exertional hypoxaemia is associated with more severe haemodynamic abnormalities and increased mortality. Further study is required to better understand the mechanisms and treatment of gas exchange abnormalities in HFpEF.

Abstract Embedded pragmatic clinical trials (ePCTs) play a vital role in addressing current population health problems, and their use of electronic health record (EHR) systems promises efficiencies that will increase the speed and volume of relevant and generalizable research. However, as the number of ePCTs using EHR-derived data grows, so does the risk that research will become more vulnerable to biases due to differences in data capture and access to care for different subsets of the population, thereby propagating inequities in health and the healthcare system. We identify 3 challenges—incomplete and variable capture of data on social determinants of health, lack of representation of vulnerable populations that do not access or receive treatment, and data loss due to variable use of technology—that exacerbate bias when working with EHR data and offer recommendations and examples of ways to actively mitigate bias.