Citations

Abstract Accurate assessment of left-ventricular ejection fraction (EF) is a critical metric in diagnosing and managing heart failure; however, methods of assessment remain resource intensive, not widely available in low-acuity or remote settings and are intermittent in nature. This study explores the potential of a novel framework, cardiac electromechanical fingerprinting (cEMF) using synchronized electrocardiography (ECG) and seismocardiography (SCG) collected from a wearable sensing patch as a low-cost, non-invasive, continuous estimate of EF that can be used for rapid point of care screening. A machine learning pipeline was developed to process raw ECG and SCG data to derive EF. Signals were cleaned using band-pass filtering, NeuroKit2-based ECG cleaning and fiducial detection of critical electromechanical events. We extracted an ECG-SCG feature space consisting of heart-rate variability metrics, ECG morphological characterization, SCG timing intervals, spectral and entropy-based features. The top thirty most important features for EF were used to train and evaluate several regressor models. The best performing model was the Gaussian Process Regressor with an MAE of 5.43. Our findings demonstrate the promise of producing clinically relevant cardiac function measures, such as EF, from wearable electromechanical signals. Future work using larger datasets and complementary physiological signals such as phonocardiogram (PCG) may significantly strengthen EF% estimation and other cardiac functions for clinical applicability.

Abstract Darier disease (DD) is a rare autosomal dominant genodermatosis. This comprehensive review, developed by the Darier Disease International Task Force (DDITF), consolidates current knowledge on the genetic basis, molecular pathophysiology, clinical presentation, diagnosis and management of DD, offering a global perspective that unites shared expertise. The disease arises from pathogenic variants in the ATP2A2 gene, which encodes sarco/endoplasmic reticulum Ca 2+ ‐ATPase isoform 2 (SERCA2), leading to disrupted calcium homeostasis and impaired desmosomal integrity. Clinically, DD is classified based on lesion type (classic vs. non‐classic) and is often accompanied by significant extracutaneous manifestations. Management remains challenging and requires a multifaceted approach, including topical therapies, systemic retinoids and lifestyle modifications. Emerging treatments that target the underlying molecular mechanisms offer promise for improved outcomes. This review aims to provide an updated reference and practical guidance for clinicians involved in the care and study of DD.

PURPOSE Cholangiocarcinoma is a rare cancer associated with poor prognosis. Pemigatinib was the first FGFR1-3 inhibitor approved for second-line therapy and beyond, on the basis of the phase II FIGHT-202 trial. Here, we assess efficacy and safety of first-line pemigatinib. METHODS FIGHT-302 is a phase III, randomized, global trial evaluating pemigatinib as first-line therapy (ClinicalTrials.gov identifier: NCT03656536 ). Adults with advanced cholangiocarcinoma with FGFR2 rearrangement were randomized 1:1 to receive pemigatinib (13.5 mg once daily) or chemotherapy (1,000 mg/m 2 gemcitabine plus 25 mg/m 2 cisplatin once per day on days 1 and 8 of every 3-week cycle for ≤8 cycles) and were stratified by prior receipt of chemotherapy, geographic region, and tumor burden. Pemigatinib crossover was allowed for patients progressing on chemotherapy. The primary end point was progression-free survival (PFS). Secondary efficacy, safety, and exploratory end points were also analyzed. RESULTS Overall, 4,563 patients were prescreened, 196 were screened, and 167 randomly assigned to receive pemigatinib (n = 83) or chemotherapy (n = 84) before early closure of the study because of a change in standard of care. The median PFS was 8.3 months in the pemigatinib group versus 6.8 months in the chemotherapy group (hazard ratio, 0.58 [95% CI, 0.39 to 0.87]; nominal P = .0078); objective response rate was 47% versus 15%, and the median duration of response was 14.2 versus 6.3 months. Median overall survival was similar (24.4 v 25.0 months, respectively). In the crossover group (n = 42, second-line pemigatinib), the median PFS was 8.1 months. Safety was consistent with the known profile of pemigatinib. CONCLUSION To our knowledge, this was the largest, first-line, randomized, phase III trial of a targeted therapy for advanced FGFR2- rearranged cholangiocarcinoma. Pemigatinib demonstrated prolonged median PFS compared with chemotherapy, with no new safety findings.

Background: Epstein–Barr virus (EBV) is a key environmental risk factor for multiple sclerosis (MS), and tonsils and adenoids serve as a primary viral reservoir. This study investigates the potential role of adenotonsillectomy in pediatric-onset multiple sclerosis (POMS) risk and relapse rate. Objectives: POMS participants and controls were recruited from 16 pediatric MS clinics between 1 November 2011 and 1 July 2017. Clinical and demographic information, including history of adenotonsillectomy, EBV serostatus, and HLA-DRB1*15:01:01 status, were collected. Multivariable logistic regression assessed the association between adenotonsillectomy and MS risk. In addition, negative binomial regression offset by follow-up time was used to assess the relationship between adenotonsillectomy and relapse rate in POMS participants with available follow-up data. Results: The case-control analysis included 359 POMS participants and 560 pediatric controls. Individuals with a history of adenotonsillectomy had a 63% increased odds of MS (adjusted odds ratio (OR) = 1.63, 95% confidence interval (CI) = 1.01–2.64, p = 0.046). Among the 239 POMS participants with available follow-up data, adenotonsillectomy was associated with a twofold increase in annualized relapse rate (adjusted incidence rate ratio (IRR) = 2.00, 95% CI = 1.15–3.48, p = 0.013). Conclusions: Prior adenotonsillectomy was associated with increased risk of MS and greater relapse rate in pediatric patients, suggesting a potential interplay between EBV, immune regulation, and MS pathogenesis.

TPS3686 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA–) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA– (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Accrual is 1,123/1,912 (as of 1/20/2026). *Drs. Dasari and Lieu contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

TPS3184 Background: Replication stress (RS) creates cancer cell vulnerability to which the critical DNA damage response kinase, ATR (Ataxia-Telangiectasia and Rad3-related) responds. ATR senses the stress, halts the cell cycle, and promotes DNA repair to allow proliferation. Alnodesertib is an ATR inhibitor developed to prevent cancer cells from successfully repairing RS and proliferating further. In earlier stages of alnodesertib development, preclinical and translational research demonstrated that tumor cells experience three combined biological insults: irinotecan-induced RS, endogenous RS via ataxia-telangiectasia mutated (ATM) loss, and RS rescue prevention by ATR inhibition. Data from the dose escalation and initial dose expansion cohorts of this trial in a tumor agnostic population showed encouraging results in ATM-negative cancers (confirmed Overall Response Rate of 50% in 20 patients with ATM negative cancers and responses across 8 cancer types including complete responses, Ulahannan et al, AACR 2025). Tumor-specific dose expansion cohorts are now enrolling, including colorectal cancer (CRC) and pancreas ductal adenocarcinoma (PDAC). Methods: Two tumor-specific cohorts are now open, each enrolling approximately 50 patients (pts): ATM-negative CRC and ATM-negative PDAC. Pts will receive the recommended dose of alnodesertib 200mg orally on days 1-3 and 8-10 combined with low-dose irinotecan 60mg/m 2 IV on days 1 and 8, of each 21-day cycle. Tumor tissue is prescreened by immunohistochemistry for ATM protein loss (H score 0) for enrollment eligibility. Pts with CRC must have received a maximum of 2 prior chemotherapies excluding prior trifluridine/tipiracil, fruquintinib, or regorafenib, and pts with PDAC must have received a maximum of 1 prior chemotherapy for advanced disease. Prior targeted agents are allowed and do not count as prior lines of therapy. Key objectives include safety, tolerability, and preliminary efficacy. Clinical trial information: NCT04657068 .

TPS11592 Background: Epithelioid hemangioendothelioma (EHE) is an ultra-rare vascular sarcoma with about 120 cases diagnosed in the US per year. Although it is commonly considered an indolent disease, in its aggressive form clinical outcomes are poor. Molecularly, EHE is characterized by the presence of oncogenic fusions with HIPPO pathway effectors TAZ or YAP; TAZ-CAMTA1 or YAP-TFE3. YAP/TAZ are modulators of mTORC1 in preclinical models, suggesting that mTOR inhibition may be an effective treatment mechanism for EHE. Nab-sirolimus is albumin bound sirolimus, which achieves higher intratumoral accumulation compared to oral sirolimus and has demonstrated increased antitumor activity in preclinical cancer models compared to the oral mTOR inhibitors sirolimus and everolimus. This is an open label, multi-center, single arm, phase II clinical trial with a two-stage design, testing nab-sirolimus for progressing or symptomatic EHE. The primary objective is to determine ORR of nab-sirolimus in patients with EHE who require systemic treatment. We hypothesize that nab-sirolimus will have significant clinical efficacy for EHE as measured by the primary endpoint of objective response rate, as well as by secondary outcomes including progression free survival benefit over historical controls and by improvement in patient reported outcomes (PROs). If positive, this trial could lead to a new standard of care for treating EHE. Methods: This is a single arm, multi-center, phase 2 study with a two-stage design. Key inclusion criteria include histologically or cytologically confirmed EHE that is either progressing or clinically symptomatic, not a candidate for curative intent surgery, and requires systemic therapy in the opinion of the investigator, radiographically evaluable disease by RECIST v1.1, age ≥18 years, ECOG performance status ≤ 2, and adequate end organ function. With a Simon two-stage optimal design with one sided alpha 0.10, power 90%, assuming a historical control ORR 5% to detect an ORR of 20% (alternative hypothesis), 12 patients will be included in the first stage. If there is ≥ 1 response, an additional 25 patients will be enrolled to a total of 37 patients. ≥ 4 responses are needed for a significant result. The total planned accrual is 41 patients to account for unevaluable patients who may be enrolled, 10% above the required evaluable patients. Planned post hoc subgroup analyses will include outcomes by fusion type and presence of serosal effusions at the time of study enrollment. The trial is registered at clinicaltrials.gov NCT07104331. Clinical trial information: NCT07104331 .

e20731 Background: Selective RET (REarranged during Transfection) inhibitors (RETi) have become standard treatment for RET fusion-positive non-small cell lung cancer ( RET + NSCLC), which represent 1–2% of NSCLC cases. Clinical factors that drive front-line versus later-line RETi use and outcomes are not well understood. This retrospective chart review evaluates physician decision drivers alongside real-world effectiveness and safety for pralsetinib (PRAL) in RET + NSCLC. Methods: A retrospective chart review was conducted via a standardized web-based form among US oncologists treating advanced RET + NSCLC. Eligible patients initiated PRAL for RET + NSCLC between October 2020 and December 2024. Data gathered included physician treatment considerations, patient baseline characteristics, and efficacy outcomes. Results: Eighty-two charts from patients who received PRAL as their first (index) RETi were collected from 43 physicians across both academic (41.9%) and community (58.1%) sites. Of the 82 patients, 51.2% received PRAL front line (1L) and 31.7% in the second line (2L). From a predefined list, physicians most often cited comorbidities (36.6%) and ECOG performance status (31.7%) as clinical factors when considering index PRAL therapy and efficacy profile (56.1%), followed by intracranial activity (24.4%) and hypersensitivity to immuno-oncology agents (24.4%) as therapy-related considerations. Although not a primary therapy selection driver, in 13 patients with safety as a consideration, 6 (46.2%) had myelosuppression noted as a concern for index PRAL treatment. RET + NSCLC patients treated in the 1L setting with PRAL had an overall response rate (ORR) of 73.8% (14 CR; 17 PR). For 2L line PRAL, the ORR was 61.5% (1 CR; 15 PR). Anemia (17.1%), diarrhea (13.4%), and constipation (13.4%) were the most frequently reported adverse events (AE). Discontinuation was mainly due to loss of/no response (80.6%), insurance (16.1%), and AEs (3.2%). The single PRAL patient that discontinued due to an AE had edema. There were an additional 7 patients that switched to PRAL due to an AE on a different RETi. The post-switch ORR was 57.1% (4/7); of these patients, 3 maintained their previous response and 1 improved their response. Conclusions: In this retrospective chart review, pralsetinib was used across treatment lines with high real-world response rates, consistent with results from the ARROW trial. Treatment selection was influenced by specific clinical factors including patient comorbidities, ECOG performance status, and safety concerns, with AE-driven switching uncommon yet associated with continued responses.

e15708 Background: AFTT is characterized by physical, nutritional, and psychosocial decline. In GIC, AFTT arises from malnutrition, disease progression, or treatment-related toxicity resulting in poor quality of life. We evaluated the association between AFTT and IM, length of stay (LOS), and hospital charges (HC) in hospitalized GIC patients. Methods: The National Inpatient Sample (2016-21) was used to identify adult hospitalizations with GIC using ICD-10 codes, which were stratified as primary or secondary diagnoses by AFTT. Clinical characteristics and primary outcomes including IM, LOS, and HC were extracted. Multivariable regression models adjusting for demographics, insurance, comorbidity burden, census tract income, and hospital teaching status were evaluated. Results: Among 2,732,505 GIC hospitalizations, colorectal (46.9%) and pancreatic (20.4%) cancer predominated; 121,035 (4.4%) had AFTT. Patients with AFTT vs non-AFTT, were older (mean = 69.3 vs 66.5 yrs), more often male (58.1% vs 57%), and from the lowest income quartile (27.7% vs 26%). AFTT cohort had higher comorbidity burden (mean CCI = 7.24 vs 6.26), more Black patients (19.1% vs 12.8%), higher Medicare use (62.7% vs 56.0%), increased palliative care consultation (37.4% vs 13.6%), risk of malnutrition, AKI, and dementia (all p< 0.001). AFTT was associated with higher IM, longer LOS, and lower HC. Higher age, males, and self-pay were associated with increased IM and HC, but shorter LOS. Lower CCI was associated with reduced IM, LOS, HC, whereas urban hospitals showed lower IM but higher LOS and HC. Black patients had higher IM and LOS but lower HC, contrary to Hispanic patients. Conclusions: The grave impact of AFTT and variability in survival and practice patterns is driven multifactorially, raising concerns about inequitable care access and differences in healthcare utilization. Standardized guidelines and multidisciplinary interventions are urgently needed to combat AFTT in GIC. Predictor IM aOR (95% CI) LOS Adj. Ratio (95% CI) HC Adj. Ratio (95% CI) AFTT Status (vs. Non-AFTT) 1.96 (1.93-2.00) 1.13 (1.12-1.14) 0.86 (0.85-0.86) Age (/year increase) 1.02 (1.02-1.02) 1.00 (1.00-1.00) 1.00 (1.00-1.00) Sex (vs. Female) Male 1.18 (1.17-1.19) 0.99 (0.98-0.99) 1.05 (1.05-1.06) CCI Score (vs. High, ≥5) Low (≤2) Mid (3-4) 0.33 (0.32-0.33) 0.48 (0.47 - 0.48) 0.87 (0.87 - 0.88) 0.93 (0.93 - 0.94) 0.93 (0.93 - 0.94) 1.02 (1.02 - 1.02) Insurance (vs. Medicare) Private Medicaid Self-Pay 1.03 (1.01 - 1.05) Ref in model 1.29 (1.24 - 1.33) 0.92 (0.91 - 0.92) 0.96 (0.95 - 0.97) 0.98 (0.97 - 1.00) 1.03 (1.02 - 1.03) 1.06 (1.05 - 1.06) 0.96 (0.95 - 0.97) Race (vs. White) Black 1.03 (1.00 - 1.06) 1.07 (1.06 - 1.08) 0.95 (0.94 - 0.96) Facility Status (vs. Rural) Urban Non-Teaching Urban Teaching 0.87 (0.85 - 0.89) 0.78 (0.77 - 0.80) 1.10 (1.09 - 1.11) 1.18 (1.17 - 1.19) 1.64 (1.63 - 1.65) 1.86 (1.84 - 1.87)

e13615 Background: Bacillus Calmette-Guérin (BCG) remains the standard intravesical therapy for high-risk non-muscle-invasive bladder cancer (NMIBC), but weekly clinic-based instillations create substantial travel, time, and indirect costs that may threaten adherence. Therefore, we proposed a pilot trial of delivering BCG at Home as a prospective, single-center pilot testing a pharmacy-to-home pathway with digital patient-reported outcome (PRO) monitoring. Methods: BCG at Home is a prospective, single-center pilot evaluating feasibility and safety of home delivery of induction BCG for treatment-naïve, high-grade T1 and/or carcinoma in situ NMIBC. Dose 1 is administered in clinic to confirm tolerability and catheterization feasibility; doses 2-6 are administered at home by Penn Medicine at Home nurses after a 3 month training and proctorship program in intravesical therapy and exposure precautions. To enable transport beyond conventional short post-preparation windows, the pharmacy prepares BCG using a closed system transfer device (CSTD); bench testing demonstrated stability and sterility for 24 hours after connection. A medical courier delivers the prepared medication to the patient’s home, where the nurse receives the delivery and performs the instillation. The primary endpoint is induction adherence (completion of all recommended doses). Secondary endpoints include PROs (EORTC QLQ-C30/QLQ-NMIBC24), satisfaction, and acute care utilization. PROs are captured before and after treatment using a conversational chatbot; domain summaries are assessed at baseline, 6 weeks, and 12 weeks. Results: The pilot began enrollment in June 2025 (planned sample size: 20). To date, eight participants have enrolled and completed induction. Median age was 76 years (range 41-88); 50% were female and 25% were Black/African American. Participants lived a mean of 30 miles from the treating facility. Forty home instillations were delivered, and all participants completed all recommended induction doses (100% adherence). Median nurse time in the home was 40 minutes. Five episodes of hematuria were self-limited; one urinary tract infection resolved with antibiotics. Self-efficacy improved from a median of 3 pre-treatment to 7 post-treatment. The median COST-FACIT score was 30 (scale 1-44). Mean EORTC QLQ-C30 global health status was 71 (0-100). EORTC QLQ-NMIBC24 averages showed urinary symptoms rising during induction (23 at baseline to 30 at 6 weeks) with improvement by 12 weeks (18) and future worries decreasing (33 to 25); intravesical treatment issues remained low (5 to 2). Conclusions: BCG at Home is, to our knowledge, the first prospective trial to administer intravesical BCG in the home setting using a standardized pharmacy-to-home pathway. Early results support feasibility, complete adherence, and an acceptable short-term safety profile. Clinical trial information: 07048496 .