Faculty Bibliography

BACKGROUND:Patients with breast cancer and limited English proficiency (LEP) experience barriers to care that may result in greater disease burden. We aim to evaluate breast cancer presentation and pathologic characteristics of patients with LEP compared with patients with English proficiency (EP). PATIENTS AND METHODS/METHODS:We performed an institutional review board (IRB)-approved, retrospective review of prospectively collected patient-reported data among a multilingual population evaluated within a New York City safety-net health system between 2018 and 2025. Comparative analysis and logistic regression were used. RESULTS:) compared with EP (31.2% versus 18.5%; p = 0.012) and was significantly associated with completion axillary lymph node dissection compared with EP (12.8% versus 3.6%; p = 0.0041). Patients with LEP had significantly longer time-to-therapy intervals from biopsy to first therapy compared with EP (52 versus 49 days; p = 0.041). On multivariate analysis, both LEP and delays to first therapy were significantly associated with axillary nodal metastasis. CONCLUSIONS:Patients with breast cancer and LEP were significantly more likely to have axillary nodal metastasis compared with patients with EP. Increased axillary nodal metastasis in this population may, in part, be due to lack of screening and delays to breast cancer treatment.

INTRODUCTION/BACKGROUND:Biological parental donations provide the best option for many pediatric recipients, yielding unique immunological benefits that may enable minimization of immunosuppression in transplanted children. However, living related maternal donation in the postpartum period may introduce an increased risk of donor complications due to the physiological changes of pregnancy and childbirth, and the optimal timing of postpartum living donation is unknown. METHODS:Using US national registry data, we characterized donor and recipient outcomes for pediatric living donor liver transplants performed between 2004 and 2022 where a biological mother donated to a child ≤ 24 months old. RESULTS:Our study population included 256 donor-recipient pairs, with biliary atresia representing the most common indication for transplantation (68.0%). Donors had a median [IQR] age of 30 [25, 34] years, and the median [IQR] time from birth to donation was 9.0 [6.8, 13.0] months. 6.3% of donors experienced a biliary or other complication. When stratifying by donors who donated ≤ 6 vs. > 6 months postpartum, we found no significant differences in donor complications or readmission. Stratified analyses were also comparable for recipient mortality, graft survival, and rejection-free survival. Donors ≤ 6 months postpartum (n = 64) were more likely to experience reoperation than mothers who donated > 6 months postpartum (n = 192) (6.2% vs. 1.0%, p = 0.04). CONCLUSIONS:While maternal living donor liver transplantation is safe for most donors, there is a higher risk of reoperation when donation is performed ≤ 6 months postpartum. Surgeons should be aware that these donors are a higher risk population, requiring discussion upon consent and warranting close post-operative monitoring.

Obesity is a known risk factor for diseases of the pancreas, including diabetes, pancreatic cancer and pancreatitis, but mechanisms remain unclear. Here we show by spatial, transcriptomic and functional profiling of human pancreatic immune cells from obese and non-obese organ donors that obesity profoundly impacts pancreatic immune homeostasis. Obesity is associated with higher density of tissue resident memory T-cells (TRM) in the exocrine pancreas which are characterized by high cytotoxic functions, and aggregate around macrophages. Single cell sequencing of pancreatic macrophages distinguishes two main subsets - FOLR2 + CD11c- foetal-derived macrophages with pro-repair and immunoregulatory function and FOLR2- CD11c+ lipid-associated macrophages with greater T-cell interactions and pro-inflammatory function. In obesity, the pancreatic macrophage landscape shifts to lower predominance of FOLR2 + CD11c- macrophages and expansion of FOLR2- CD11c+ macrophages, which interact selectively with the TRM and inflamed exocrine epithelium. Together, these results identify macrophage-T cell circuits and immune epithelial interactions that might lead to chronic pancreatic inflammation in obesity and might contribute to obesity-related pancreatic diseases.

OBJECTIVE:To evaluate whether there is an association between a maternal classification of Long COVID and adverse pregnancy outcomes. METHODS:RECOVER (Researching COVID to Enhance Recovery)-Adult is a multicenter prospective longitudinal cohort study of adults with and without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection enrolled from October 2021 to January 2024. This analysis included participants with a SARS-CoV-2 infection and at least one symptom survey for classification of Long COVID status recorded before or during pregnancy. Participants were classified as either likely having Long COVID (LCRI [Long COVID Research Index] score of 11 or higher) or as having Long COVID-indeterminate (LCRI score 0-10), with comparisons made between groups. The primary outcome was preterm birth before 37 weeks of gestation. Secondary outcomes included hypertensive disorders of pregnancy, cesarean delivery, neonatal intensive care admission, and small-for-gestational-age birth weight (below the 10th percentile). Propensity score methods with full matching were used to balance differences in baseline characteristics in estimating an average treatment effect, with a sensitivity analysis estimating the average treatment effect among the treated. RESULTS:Among 603 participants, 118 (19.6%) were classified as likely having Long COVID before or during pregnancy. Participants classified as likely having Long COVID were more likely to have specific adverse social determinants of health (difficulty covering expenses and paying bills, food insecurity, missed care because of cost, medical discrimination) and had higher prepregnancy body mass index (BMI) than those who were classified as having Long COVID-indeterminate. In the primary average treatment effect analysis, there was no association between likely Long COVID and preterm delivery (adjusted outcome rate 8.1% exposed vs 9.6% unexposed, absolute risk reduction [ARR] 0.82, 95% CI, 0.36-1.90) or secondary outcomes. In average treatment effect among the treated sensitivity analyses, likely Long COVID was similarly not associated with preterm delivery (ARR 1.11, 95% CI, 0.60-2.06) but was associated with an increased risk of hypertensive disorders of pregnancy (adjusted outcome rate 39.0% exposed vs 25.9% unexposed, ARR 1.51, 95% CI, 1.12-2.03) but not with other secondary outcomes. CONCLUSION/CONCLUSIONS:A classification of likely Long COVID was not significantly associated with preterm birth or several other adverse pregnancy outcomes. However, the association with hypertensive disorders of pregnancy in the average treatment effect among the treated analysis highlights the need for further research.

BACKGROUND/UNASSIGNED:Apixaban is a direct oral anticoagulant (DOAC) that is widely used in the general population; however, its use in solid organ transplant (SOT) recipients has not been extensively studied. Although there is interest in DOACs as the preferred oral anticoagulants in SOT recipients due to their favorable pharmacokinetic properties, there remain concerns for the optimal dose in the setting of organ dysfunction, at the time of engraftment, and for use for off-label indications such as graft thrombosis (GT). OBJECTIVE/UNASSIGNED:To assess "real-world" apixaban utilization in abdominal SOT recipients at a large academic medical center. DESIGN/UNASSIGNED:This was a single-center, observational, retrospective cohort study of 79 adult patients from January 2020 to August 2022 who received apixaban for any indication postabdominal transplant. METHODS/UNASSIGNED:All adult patients, ≥ 18 years of age, who received apixaban for any indication post kidney, liver, simultaneous liver-kidney (SLK), or simultaneous pancreas-kidney (SPK) transplant were included. Electronic health records were retrospectively reviewed for patient demographics, past medical history, and apixaban characteristics, including indication, dose, frequency, and the use of parenteral anticoagulation lead-in for acute thrombosis. The primary outcome was the incidence of thromboembolic events. Secondary outcomes included any bleeding events. In addition, adherence to package label dosing recommendations, based on indication of anticoagulation, was evaluated. RESULTS/UNASSIGNED: = 3), which occurred at a median of 304 (IQR 168-309) days after apixaban initiation. CONCLUSIONS/UNASSIGNED:Apixaban dosing was consistent with labeled dosing for the majority of the cohort for labeled indications, and the observed incidence of thromboembolic events in this cohort was low, with no excess identified relative to published literature. Our data support the use of apixaban for stroke prevention in AF or treatment of VTE or GT in patients who have received an abdominal transplant; however, risk factors for bleeding events, specifically in those with GT, should be further explored.

BACKGROUND:Tumour-infiltrating lymphocytes (TILs) are a robust prognostic marker in patients with triple-negative breast cancer. Artificial intelligence (AI)-derived computational tools assessing TILs could improve efficiency, but require independent validation against clinical outcomes. We aimed to compare the prognostic performance of AI-derived TIL scores with pathologist-scored TILs in a large, prospectively collected dataset pooled from randomised controlled trials. METHODS:CATALINA was an independent, external validation study using prospectively collected long-term clinical outcome data pooled from seven randomised clinical trials conducted at multiple sites. We independently evaluated two previously validated AI pipelines that generate five computationally assessed tumour-infiltrating lymphocyte (cTIL) scores by masked, independent deployment of locked models. cTIL scores were correlated with the mean of the pathologist-scored stromal TILs (sTILs) in 220 digitised haematoxylin and eosin whole slide images in a cohort of patients with early-stage triple-negative or HER-2 positive breast cancer, previously scored by trained pathologists in a TIL-reproducibility study. Prognostic performance was assessed in a separate cohort of patients with early triple-negative breast cancer pooled from seven prospective, randomised adjuvant trials. Multivariable Cox regression models adjusted for clinicopathological factors and study heterogeneity assessed associations of cTIL score and sTIL score with invasive disease-free survival, distant disease-free survival, and overall survival. 5-year discrimination was estimated using time-dependent area under the receiver operating characteristic curve (AUC). FINDINGS/RESULTS:Individual data were collated from 1759 patients, of whom 1356 had complete clinicopathological data, pathologist sTIL scores, and cTIL scores available. Modest correlation (r 0·375-0·473) was observed between cTIL scores and the mean pathologist sTIL score. Both sTIL and cTIL were independently associated with 5-year invasive disease-free survival, distant disease-free survival, and overall survival after adjustment for clinicopathological factors (hazard ratio for invasive disease-free survival was 0·73 [95% CI 0·66-0·82]; q<0·0001, distant disease-free survival was 0·70 [0·61-0·79]; q<0·0001, and overall survival was 0·72 [0·63-0·82]; q<0·0001 for sTIL scores and 0·80 [0·73-0·89]; q<0·0001, 0·77 [0·69-0·86]; q<0·0001, and 0·79 [0·70-0·88]; q=0·0002, respectively, for percentage_lymphocyte scores). In models adjusted for clinicopathological variables and sTIL score, cTIL score did not maintain a statistically significant prognostic association. Both sTIL and cTIL scores improved the 5-year AUC over clinicopathological variables alone, while cTIL score did not significantly further improve AUC when combined with clinicopathological variables and sTIL score. INTERPRETATION/CONCLUSIONS:Two cTIL models deployed entirely without retraining or modification provided statistically significant prognostic information and improved risk discrimination compared with clinicopathological variables alone in this large, platform-based, independent validation study. Although cTIL score did not incrementally improve prognostication compared with models combining clinicopathological variables with sTIL score, these findings support the application of cTILs as a reproducible prognostic biomarker, particularly in settings where routine or widespread pathologist assessment is unavailable. FUNDING/BACKGROUND:Breast Cancer Research Foundation (USA).

PURPOSE/OBJECTIVE:Treatment options for progression on first-line endocrine therapy (ET)+CDK4/6i for ER-positive/HER2-negative (ER+/HER2-) advanced breast cancer (ABC) include ET plus targeted agents (CDK4/6i or PI3K/AKT/mTOR-pathway inhibitors). Elacestrant is the first single-agent oral SERD that significantly improved progression-free survival (PFS) versus standard-of-care ET in ESR1-mutated and overall ER+/HER2- ABC populations. PATIENTS AND METHODS/METHODS:This phase 1b/2, umbrella trial enrolled patients with ER+/HER2- ABC who received 1-2 lines of ET+CDK4/6i (including prior fulvestrant and primary endocrine resistance) and no prior chemotherapy for ABC. Patients received elacestrant with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib, or palbociclib. We evaluated PFS of elacestrant plus everolimus. RESULTS:In phase 1b (n=23), the optimal RP2D was determined as elacestrant 345 mg plus everolimus 7.5 mg. The phase 2 patient population (n=50) included: 100% prior CDK4/6i, 50% prior fulvestrant, 72% visceral metastasis, 20% primary endocrine resistance, 42% ESR1mut, 50% PIK3CAmut. Median PFS was 8.3 months (95% CI:4.0-10.2) in all patients; 8.3 months (95% CI:3.5-12.9) in ESR1mut, 9.0 months (95% CI:4.2-12.7) in ESR1wt, 8.3 months (95% CI:3.6-10.2) in PIK3CAmut, and 9.4 months (95% CI:4.0-NR) in PIK3CAwt. Adverse events (AEs) were consistent with known safety of everolimus plus SOC ET. Most common AEs were grade 1-2. Any AE leading to drug withdrawal or dose reduction was 6% and 2%, respectively. CONCLUSIONS:Elacestrant plus everolimus showed a clinically meaningful PFS benefit across clinical/genomic subgroups, irrespective of ESR1 or PIK3CA-mutation status. Elacestrant has the potential to become an ET backbone for combinations to inhibit the PI3K/AKT/mTOR-pathway with everolimus as a promising all-oral treatment.

Somatic mutations rewire the ubiquitin-proteasome system (UPS) to support tumor growth, but the proteome-wide consequences of cancer-driver alterations on UPS composition remain incompletely understood. Using harmonized proteogenomic data from up to 11 CPTAC cohorts, we performed an integrated pan-cancer analysis of UPS protein dysregulation, prognostic associations, and mutation-driven remodeling. We show that mRNA poorly predicts UPS protein abundance, that a defined set of E3 ligases is recurrently dysregulated across cancers, and that somatic mutations (most strikingly TP53 loss) produce coherent UPS protein-quantitative trait locus (pQTL) signatures. Two case studies (UBR5 and TRIM28) illustrate orthogonal modes of UPS rewiring: a mutation-driven axis in which TP53-mutant tumors elevate UBR5 to support replication stress tolerance, and a lineage-driven axis in which TRIM28 engages tissue-restricted regulatory networks with opposing prognostic effects in glioblastoma versus head and neck cancer. Each axis exposes context-specific therapeutic vulnerabilities, including sensitivity to DNA damage response inhibitors (UBR5-high) and lineage-specific drug responses (TRIM28-high). Together, these analyses define a mechanistic framework for how cancer-driver mutations reshape proteostasis through the UPS and nominate mutation- and lineage-defined dependencies for precision degrader therapy. The harmonized pan-tissue atlas and the UbiDash interactive resource that underpin parts of this analysis are reported in our companion paper [1].

OBJECTIVE/UNASSIGNED:Timely use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) is vital for managing type 2 diabetes (T2DM) and preventing cardiovascular and renal complications. However, socioeconomic barriers and prescribing inertia may disproportionately affect disadvantaged populations. We examined racial and ethnic differences in the initiation of SGLT2i among Medicaid patients with T2DM. METHODS/UNASSIGNED:Adult participants 18-64 with T2DM and prescribed with metformin were drawn from MarketScan Multistate Medicaid Database (2015-2022) for this retrospective cohort study. We used a Cox proportional hazards model, adjusted for age, sex, type of Medicaid coverage, and comorbidities, to assess time to SGLT2i initiation. RESULTS/UNASSIGNED:Among 13 744 Medicaid patients, non-Hispanic Black patients had an 18% lower rate of SGLT2i initiation compared with non-Hispanic White patients (hazard ratio [HR] = 0.82; 95%CI: 0.75-0.90). This disparity was most pronounced among patients without pre-existing atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease (HR = 0.79; 95%CI: 0.71-0.87). No significant racial/ethnic differences were observed among patients with these conditions. CONCLUSIONS/UNASSIGNED:Significant delays in SGLT2i initiation among Black Medicaid patients-particularly in early stage of diabetes-may increase their risk for long-term complications. Addressing structural barriers through targeted interventions is essential to promote equity in diabetes care.

OBJECTIVE:Long COVID (LC) remains poorly understood, and there is a critical need for advanced computational tools to better identify and characterize patients. In this study, we use summarized symptom reports by RECOVER-Adult cohort participants linked to EHR data to characterize patients and train a computable phenotype algorithm of LC. MATERIALS AND METHODS/METHODS:The study included adult participants with linked FHIR-sourced EHR data. We characterized EHR diagnoses, procedures, medications, lab tests, and vital sign features associated with LC. A computable phenotyping algorithm was trained and validated against patient-reported symptoms. MAIN OUTCOME AND MEASURES/METHODS:We assessed model discrimination and calibration in a held-out test set. We describe important model features and evaluate model discrimination and calibration. RESULTS:The study included 1,501 RECOVER-Adult cohort participants with linked EHR data. 376 (25%) met criteria for highly symptomatic LC based on the RECOVER Long COVID Research Index (LCRI). EHR features associated with LC included clinician diagnosis of shortness of breath, malaise and fatigue, and cardiac dysrhythmias; documented treatment with albuterol, gabapentin, or duloxetine; or elevated heart rate. The algorithm identifying patients with highly symptomatic LC had an AUROC of 0.80 (95% confidence interval (CI) 0.74-0.85), and AUPRC of 0.58 (95% CI, 0.47-0.69). CONCLUSION AND RELEVANCE/CONCLUSIONS:These findings demonstrate that, using EHR data, a machine-learning model can accurately select patients with sets of self-reported LC symptoms. The model could help identify patients within a health system with the highest probability of the condition and facilitate screening, recruitment for clinical trials, and etiologic studies.