Citations

Abstract Background Anal squamous cell carcinoma is a rare cancer with increased occurrence of multiple cancers before and after the anal squamous cell carcinoma diagnosis. However, there are limited data on this aspect. This multi-institutional analysis aimed to define the occurrence of malignancies before and after anal squamous cell carcinoma, time trends, and impact on survival and to identify prognostic factors. Methods Initial primary malignancy was defined as a malignancy occurring before the anal squamous cell carcinoma. Second primary malignancy was defined as a distinct primary cancer that developed after anal squamous cell carcinoma diagnosis. Retrospective multi-institutional chart review was done. Progression-free survival (PFS), overall survival, and prognostic factors were evaluated. Results A total of 647 patients with anal squamous cell carcinoma treated with curative intent were analyzed. Median age was 61.2 years with 72% as females. Of these, 150 (23.3%) patients had multiple malignancies with initial primary malignancy in 16% and second primary malignancy in 8%. Patients without prior cancer had better 5-year PFS (81.2% vs 67.2%, P = .011) and overall survival (81% vs 69%, P = .008) compared with those with prior cancer. Second primary malignancies had a statistically significant adverse impact on PFS (hazard ratio [HR] = 4.22) and overall survival (HR = 3.56). Females had better 5-year PFS (82% vs 70%, P = .016) as compared with males. The median time interval for developing anal squamous cell carcinoma (as second primary malignancy) after initial primary malignancy was 9.32 years. Conclusions Anal squamous cell carcinoma patients have an increased risk of multiple malignancies. These patients who have prior cancers have inferior outcomes. Second primary malignancy is a poor prognostic factor in patients with anal cancer. Second primary malignancy can develop years after treatment of primary anal squamous cell carcinoma.

INTRODUCTION: We aimed to compare pregnancy outcomes of women with inflammatory bowel disease using biosimilar vs originator infliximab (IFX). METHODS: In a prospective cohort of pregnant women with inflammatory bowel disease, we collected characteristics, medications, pregnancy outcomes, and developmental milestones. We compared outcomes by IFX biosimilar or originator use via bivariate statistics. RESULTS: A total of 100 pregnant women on originator IFX and 20 on biosimilar IFX were included. There were no differences in pregnancy complications between groups (48% vs 35%, P = 0.29). Infant developmental milestones were comparable at 12 months. DISCUSSION: Biosimilar IFX is not associated with adverse pregnancy or infant outcomes.

Background: Mavacamten was approved by the US Food and Drug Administration (FDA) in April 2022 for the treatment of adults with New York Heart Association (NYHA) class II-III symptomatic obstructive hypertrophic cardiomyopathy (HCM). Few studies have reported on the long-term real-world effectiveness and safety of mavacamten. We evaluated clinical outcomes in patients on mavacamten in multiple health centers across the United States. Research Questions: This study assessed the real-world effectiveness and safety of mavacamten in patients with symptomatic obstructive HCM. Methods: In this multi-center observational study, we evaluated patient characteristics at baseline, NYHA class, left ventricular outflow tract gradients (LVOTg) at rest and Valsalva, and left ventricular ejection fraction (LVEF) in patients with symptomatic obstructive HCM treated with mavacamten for up to 72 weeks. Results: Mavacamten was initiated in 172 patients across 4 US centers (UCSF, Mayo Arizona, Stanford, and Atlantic Health System/Morristown Medical Center). Baseline characteristics included: 56% female, mean age 64 (standard deviation ±13) years, 47% NYHA class III, mean resting LVOTg of 47 mmHg and mean Valsalva LVOTg of 89 mmHg, and 23% non-White. Comorbidities included hypertension (56%) and atrial fibrillation (25%) at baseline (Table). Patients experienced a notable early response to mavacamten in resting and Valsalva gradients by week 4, which was sustained through week 72 (Figure A). No patients were NYHA class III at week 72, compared to 47% at baseline (Figure B). Mean LVEF did not change substantially between baseline and week 72. No patients experienced an LVEF of <40% and 2% experienced an LVEF of <50%. Conclusions: This is the largest observational study to date demonstrating the effectiveness and safety of mavacamten with substantial sustained reductions in resting and Valsalva LVOTg, and progressive improvements in NYHA class without considerable changes in mean LVEF up to 72 weeks.

Abstract The field of infectious diseases (ID) offers a rewarding career path and is widely viewed as an essential subspecialty in medicine. However, in recent years, these positive aspects have been overshadowed by concerns surrounding low fellowship match rates, undercompensation, and burnout. The Infectious Diseases Society of America Fellowship Training Program Directors Committee met in 2023, discussed the future of ID as a specialty, and sought to develop strategies to highlight the value and opportunities of ID for future generations, as well as underscore the importance of and provide tools for positive messaging to trainees about the subspecialty. This paper presents ideas generated at this meeting and is meant to serve as a reference for ID training program directors, as well as the wider ID community, in uplifting and shaping the future of the field.

Abstract BACKGROUND Despite changes in national policy, women and minority patients remain under-accrued in glioma clinical trials. Supervised machine learning may serve as a novel approach to understanding which variables and their complex interplay most influence enrollment for underrepresented patients. We aimed to design and externally validate machine learning models to predict therapeutic clinical trial enrollment for a) all patients, b) women, and c) NIH-designated minority patients with low- and high-grade glioma. METHODS In a 20-year retrospective cohort of 1042 adult patients with low- and high-grade glioma, boosted neural network (BNN) models for the whole, women, and minority cohorts were used to analyze the combined effects of demographic, socioeconomic, and oncologic variables on clinical trial enrollment. These models were validated using an external cohort (n=103). RESULTS In the development cohort (445 [42.7%] women; 151 [14.5%] minorities; median age, 51.5 [interquartile range: 39.4-62.5] years), 350 patients (33.6%) enrolled in a therapeutic clinical trial. The whole cohort BNN (AUC: 0.827, misclassification rate (MR): 0.175), the women cohort BNN (AUC: 0.895, MR: 0.125), and the minority cohort BNN (AUC: 0.983, MR: 0.053) models accurately predicted trial enrollment on external validation. For the whole cohort and women models, several demographic (race, ethnicity, minority status, sex), socioeconomic (insurance, employment status), and oncologic variables (seizure, chemotherapy, KPS, WHO grade, tumor lobe) were equally influential (Main effect (ME): 1.000, Total effect (TE): 1.000) on enrollment. For the minority model, socioeconomic variables including insurance status (ME: 0.089, TE: 0.417) and occupation classification (ME: 0.087, TE: 0.381) drove enrollment. CONCLUSION We designed and externally validated the first machine learning model for predicting therapeutic clinical trial enrollment for patients with diffuse glioma. Model features driving trial enrollment varied for underrepresented patients. These results may help prioritize personalized patient-specific initiatives to address barriers to equitable patient accrual.

Abstract INTRODUCTION Immunotherapy has not improved survival in recurrent GBM (rGBM). Indoleamine 2,3 dioxygenase 1 (IDO1), highly expressed in ~90% of patients with malignant glioma, is a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn) and enables immune escape. METHODS We hypothesized combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies would overcome tumor-related immunosuppression. This was an open-label Phase II study of two regimens: Arm A consisted of retifanlimab (anti-PD1, 500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B added the IDO inhibitor, epacadostat (400mg po BID), initiated prior to HFRT. Key inclusion criteria included dexamethasone ≤ 4 mg/day. The primary endpoint was overall survival (OS) at 9 months (OS-9). 24 evaluable patients were required to detect an OS-9 of 60% with 80% power, compared to 38% in historical controls (bevacizumab alone) by 1-sided 1-sample log rank test at alpha=0.1. RESULTS We previously reported Arm A. Here, we present results from Arm B. 25 of the 27 patients enrolled to regimen B were evaluable: median age 58years (23-71); 28% female; 23% MGMT promotor methylated; median KPS 90 (70 - 100); a median of 6 cycles of epacadostat as of May 2024 (1 - 13). 18 of 25 died with a median follow up 9.23 months. Median PFS was 7.52 months (95%CI: 5.52-9.43). Median OS was 9.5 months (95%CI 8.08-11.96). Regimen B met its primary endpoint with OS-9 of 61.07% (95%CI: 38.23-77.65%). There were 5 possible immune-related grade 3+ toxicities to date (2 ALT/AST increase; 3 rash). CONCLUSIONS Retifanlimab, epacadostat, HFRT, and bevacizumab in rGBM is well-tolerated, with encouraging OS and PFS at the time of submission. Arm B met its primary endpoint. Further studies are warranted to identify biomarkers to predict long-term responders.

Abstract Patients with NF1-PN experience pain and other symptoms that negatively impact functioning and quality-of-life. We present patient- and parent proxy-reported HRQoL outcomes from ReNeu (NCT03962543), a pivotal, phase 2b trial of mirdametinib, an investigational MEK1/2 inhibitor, in adults and children (≥2 y) with NF1-PN causing morbidities. Fifty-eight adults and 56 children received mirdametinib (2 mg/m2 BID; 3-weeks-on/1-week-off, 28-d cycles). Change in HRQoL was assessed by Pediatric QoL Inventory (PedsQL) 4.0 Generic Core Scales from baseline across the 24-cycle treatment phase; change from baseline at Cycle 13 (C13) was a prespecified secondary endpoint. PedsQL is a HRQoL measure for adults and children with a Total Score (TS) and 4 subscales: physical, emotional, social, and school/work. Items are reported on a 0-100 scale (higher scores=better HRQoL). Clinically meaningful improvement was defined as change from baseline &gt;9.7 points for adults, &gt;8.5 points for child self-report, and &gt;9.0 points for parent proxy-report. PedsQL-TS improvement (least-squares mean, LSM [SE] change) from baseline at C13 was 3.9 (1.6; P=.018; n=34) for adults, 4.0 (2.4; P=.096; n=38) for children by self-report, and 5.6 (1.9; P=.005; n=43) by parent proxy-report. PedsQL-TS improvements for adults and children by parent proxy-report (not by children self-report) were observed early (at C5 and C3, respectively) and sustained through C24. Clinically meaningful improvement in PedsQL-TS from baseline at C13 was achieved by 37% (10/27) adults, 45% (13/29) children by self-report, and 47% (15/32) children by parent proxy-report (among patients who could have achieved a clinically meaningful change from baseline). Significant (P&lt;.05) improvement from baseline to C13 was reported for physical (adults, children, and parent proxy-report), school/work (adults), and emotional and social (parent proxy-report) subscales. Adults and children (by parent proxy-report) with NF1-PN had clinically meaningful, early, and sustained improvement in HRQoL over the course of mirdametinib treatment.

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.