Citations

Introduction: Cardiotoxicity is a serious side effect of anthracycline treatment, most commonly manifesting as a reduction in left ventricular ejection fraction (LVEF) on cardiac imaging. Cost-effective alternatives to cardiac imaging are currently not available. Artificial intelligence (AI) models have been developed to detect a reduced LVEF from 12-lead electrocardiograms (ECGs) in the general population. Hypothesis: AI-ECG model can detect a reduced LVEF after anthracycline therapy (i.e. cardiotoxicity). Methods: We included an unbiased oncological population of 989 female breast cancer patients receiving (neo)adjuvant anthracycline chemotherapy. Average follow-up time was 9.83±4.2 years. Patients with incomplete transthoracic echocardiography (TTE) data, HER-2-directed therapy, significant comorbidities, upfront metastatic disease, second primary malignancy or pre-existing cardiovascular disease were excluded from the analyses. Patients with LVEF decline for reasons other than anthracycline-induced cardiotoxicity were also excluded. Primary readout was the diagnostic performance of AI-ECG by area under the curve (AUC) for various levels of LVEF <50%. Results: Using 1,877 ECGs from 703 unique patients, the AI-ECG model detected an LVEF <50% and ≤35% after anthracycline therapy with an AUC of 0.93 and 0.94, respectively. Conclusions: These data support the use of AI-ECG for cardiomyopathy (cardiotoxicity) screening after anthracycline-based chemotherapy. This technology could serve as a gatekeeper to more costly testing and could enable patients to monitor themselves over long periods of time.

Background: Robust models exist to predict risk-adjusted mortality following congenital heart surgery. It is known that underlying diagnosis modifies predicted risk of operations, and institution-level outcomes vary based on their unique case mix. We therefore evaluated risk-adjusted outcomes for a subset of diagnosis-procedure (D-P) combinations within the Society of Thoracic Surgeons' (STS) congenital heart surgery database (CHSD). Methods: A clinician panel identified the most frequently encountered D-P combinations in CHSD between 07/2017 and 06/2021. Candidate modeling techniques were compared in a random 80% development cohort. Model performance was assessed using internal and cross-validation calibration, discrimination plots and optimism adjusted C-statistics. The final selected model was evaluated in the 20% validation sample. Results: The chosen subset of D-P combinations represented 45,384 of 87,589 (52%) unique episodes of surgical care in CHSD during this time-period. The development cohort (36,350 episodes) had 1.8% mortality (667 deaths). All candidate models had excellent discrimination with C-statistics ranging from 0.862 to 0.876. The model with the best combination of discrimination, calibration, and clinical face validity was a modified version of the current STS mortality risk model. This version included all current risk model variables with the addition of indicator variables for D-P combinations. In the 20% validation sample (9,034 episodes), this model was well calibrated (Figure) and had excellent discrimination (C = 0.879). Conclusion: We describe a cohort of D-P combinations widely encountered in the STS CHSD. Further, we refined the existing STS CHSD risk model for application to these D-P dyads to derive empirical risk-adjusted benchmark outcomes. This approach will benefit quality improvement efforts at an institutional level and may have implications for publicly reporting congenital heart surgery outcomes.

PURPOSE: This study aimed to analyze organ system-based causes and non-organ system-based mechanisms of death (COD, MOD) in people with myelomeningocele (MMC), comparing urological to other COD. METHODS: A retrospective review was performed of 16 institutions in Canada/United States of non-random convenience sample of people with MMC (born > = 1972) using non-parametric statistics. RESULTS: Of 293 deaths (89% shunted hydrocephalus), 12% occurred in infancy, 35% in childhood, and 53% in adulthood (documented COD: 74%). For 261 shunted individuals, leading COD were neurological (21%) and pulmonary (17%), and leading MOD were infections (34%, including shunt infections: 4%) and non-infectious shunt malfunctions (14%). For 32 unshunted individuals, leading COD were pulmonary (34%) and cardiovascular (13%), and leading MOD were infections (38%) and non-infectious pulmonary (16%). COD and MOD varied by shunt status and age (p < = 0.04), not ambulation or birthyear (p > = 0.16). Urology-related deaths (urosepsis, renal failure, hematuria, bladder perforation/cancer: 10%) were more likely in females (p = 0.01), independent of age, shunt, or ambulatory status (p > = 0.40). COD/MOD were independent of bladder augmentation (p = >0.11). Unexplained deaths while asleep (4%) were independent of age, shunt status, and epilepsy (p >= 0.47). CONCLUSION: COD varied by shunt status. Leading MOD were infectious. Urology-related deaths (10%) were independent of shunt status; 26% of COD were unknown. Life-long multidisciplinary care and accurate mortality documentation are needed.

Abstract During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received BT had a higher baseline risk profile than patients who did not receive BT, and these patients, as a group, had inferior outcomes compared with those who did not receive BT. However, after propensity score matching between the 2 groups, there were no statistically significant differences in overall response rate (77% vs 87%; P = .13), complete response rate (58% vs 70%; P = .1), progression-free survival (hazard ratio [HR], 1.25; P = .23), and overall survival (HR, 1.39; P=.09) between the BT group and the no-BT group, respectively. Analyzing the effects of BT in the whole cohort that underwent leukapheresis regardless of receiving axi-cel (intention-to-treat analysis) showed similar results. Radiation BT resulted in outcomes similar to those observed with nonradiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival for patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage to using radiation-based BT over nonradiation-based BT.

Introduction Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 63.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 5-year OS and PFS (progression-free survival) estimates of 42.6% (95% CI, 32.8-51.9) and 31.8% (95% CI, 22.9-41.1), respectively (Neelapu, Blood 2023). We previously reported outcomes of axi-cel patients treated with standard of care therapy, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 58 months, as well as late outcomes of interest. Results The US Lymphoma CAR-T Consortium is comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel (n=298) as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After a median follow-up of 58 months, median OS was 34.9 months (95% CI 23.4 - 44.8) with the OS at 3, 4, and 5 years of 49.1% (95% CI 42.9 - 54.9%), 43% (95% CI 36.8 - 48.9%), and 40.3% (95% CI 34.2 - 46.4%), respectively. The median PFS was 8.7 months (95% CI 5.87 - 16.6) and the 3-,4-, and 5- year PFS were 36.1% (95% CI 30.4 - 41.8%), 30.7 (95% CI 25.2 - 36.4%), and 28.5% (95% CI 23 - 34.2%), respectively. Results of multi-variable modeling were similar to our prior analysis: male sex (HR 1.56, 95% CI 1.08 - 2.27, p =0.02); LDH above the upper limit of normal (HR 1.6, 95% CI 1.12 - 2.30, p = 0.01); ECOG status of 2-4 (HR 2.02, 95% CI 1.33 - 3.07, p = &lt;0.001); and elevated bilirubin &gt; 1.5 (HR 5.68, 95% CI 2.21 - 14.6, p = &lt;0.001) were associated with decreased OS. Factors associated with decreased PFS included male sex (HR 1.68, 95% CI 1.20 - 2.37, p = 0.003), LDH above the upper limit of normal (HR 1.82, 95% CI 1.31 - 2.53, p = &lt;0.001), ECOG status of 2-4 (HR 1.93, 95% CI 1.30 - 2.86, p = 0.001), elevated bilirubin (HR 3.68, 95% CI 1.45 - 9.37, p = 0.006) and receipt of 3 or more prior lines of therapy (HR 1.49, 95% CI 1.03 - 2.13, p = 0.032). We also assessed events of interest including late PFS events and causes of non-relapse mortality (NRM). One hundred and ninety-one PFS events occurred after axi-cel infusion during the follow-up period, 151 due to lymphoma progression and 40 NRM. In the first 12 months post infusion, 131 progression events occurred,13 between 1 and 2 years post infusion, and 7 relapses after 2 years with the latest occurring 46.4 months after infusion. Thirteen NRM events occurred in the 1st year post infusion, 6 between 1- and 2-years post infusion and 21 occurring later than 2 years after infusion. Of the 40 NRM events, 21 were secondary to infection including fungal infections (n = 3, 2 candidemia, 1 candidemia and pneumocystis jiroveci pneumonia), JC encephalitis (n=1) and COVID-19 (n = 2). Nine deaths were attributed to secondary malignancy. Other causes of NRM included cerebral edema (n=1), HLH (n=1), intracranial hemorrhage (n=1), suicide (n=1), and unknown (n=6). The 5-year cumulative risk of relapse was 55.2% and the 5-year risk of non-relapse mortality was 16.2%. Excluding non-melanoma skin cancers, twenty-three of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=11), AML (n=2), CMML (n=1)); other malignancies included anal squamous cell carcinoma (ca) (n=1); histiocytic sarcoma (n=1); prostate ca (n=1); endometrial ca (n=1); lung ca (n=1); merkel cell ca (n = 1), mesothelioma (n=1), B-ALL (n = 1), and AITL (n=1). Conclusion This multi-center retrospective study showed similar 5-year results to the ZUMA-1 trial with a 5-year PFS and OS of 28.5% and 40.3%, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Non-relapse mortality was primarily due to infection and secondary malignancy. This report supports the curative potential of axi-cel but highlights the competing risk of NRM in this high-risk patient population.

Abstract Objectives To evaluate the gender composition of departmental chairs and program leadership of Accreditation Council for Graduate Medical Education–accredited pathology residencies and American Board of Pathology–certified subspecialty fellowships across the United States. Methods In this cross-sectional analysis, we examined the gender of individuals holding leadership positions in academic pathology in the United States. Using publicly available online data, 2 authors independently coded perceived gender (ie, man/woman/other) with 100% concordance. Results In 144 pathology residency programs, more women hold residency program director positions (52.1% [75/144]). Among 11 pathology subspecialties, women overall hold fewer fellowship program director positions (45.0% [212/471]). Among the residency-associated pathology department chair positions identified, women hold fewer positions (31.8% [42/132]). There is some geographic variation in pathology leadership gender composition when stratified using US Census regions. Conclusions Women in academic pathology departments are well represented in residency and overall fellowship program leadership but are underrepresented in department chair and certain pathology subspecialty leadership positions. The disproportionate number of women in department chair positions is observed across medical specialties, highlighting the need for improved gender equity among high-level academic medicine positions.