Citations

INTRODUCTION: Ongoing surveillance after successful endoscopic eradication therapy for Barrett's esophagus (BE)-related neoplasia is essential to detect and manage recurrence. Despite established surveillance interval recommendations after complete eradication of intestinal metaplasia (CE-IM), patient compliance with repeat endoscopy is frequently suboptimal. Understanding patient drivers to adherence is essential to inform interventions that address the high rates of overdue surveillance and loss to follow-up. METHODS: Patients with BE-related neoplasia who achieved CE-IM were eligible for inclusion and classified as delayed or on-time for endoscopic surveillance. Patients were prospectively enrolled and participated in structured virtual interviews designed to explore barriers and facilitators to on-time care. A rapid qualitative analysis approach was applied, continuing until thematic saturation was reached. RESULTS: Thirty-nine patients were interviewed: 22 (56.4%) were delayed, and 17 (43.6%) were on-time for surveillance. Patients in the delayed group had longer mean BE segment lengths and a higher prevalence of tobacco use. Geographic distance from the treatment center was the most frequently cited barrier to follow-up (n = 17; 43.5%). Other common barriers were access limitations, financial concerns, misunderstanding of disease course, and test-related anxiety. DISCUSSION: Patient-related drivers of delay in postendoscopic eradication therapy surveillance are largely logistical, socioeconomical, and psychological in nature. Solutions to reduce the significant burden on the patient and achieve timely surveillance may include transitioning patients back to their local endoscopists after CE-IM or incorporating nonendoscopic surveillance methods through patient centered approaches.

Introduction People most likely to be affected by Alzheimer’s disease and related dementias (ADRD) are underrepresented in clinical research. Identifying and addressing factors which may influence their research participation is important to advance science and promote diversity. We examined the influence of social determinants of health (SDOH) on research participation among people living with ADRD. Methods We included those age 55 years and older living with ADRD, followed in our community practice in Rochester, Minnesota, who completed a questionnaire assessing SDOH and had at least one clinic visit between June 1, 2019 and June 1, 2020. Demographic and SDOH factors were examined by research participation. Results Among 3273 people included, research participation was low overall (265/3273; 8.1%). People participating in research were more likely to be socially integrated and of higher educational attainment (p < 0.05). Conclusion Promoting social interaction is a potential area for focus to increase research participation in at risk populations.

Background Increased chronological age correlates with reduced relapse rates and increased disability in multiple sclerosis (MS). Biological age may better capture ageing’s impact on MS and might accelerate due to MS itself. Establishing accelerated biological ageing in adults is complicated by normal ageing and comorbidities. Telomere length, a well-recognised biological ageing marker, is shortened in adults with MS and associated with disability. Demonstrating accelerated biological ageing in paediatric-onset MS (POMS) would strengthen the hypothesis that MS drives premature biological ageing. This study aimed to determine if telomere length differs in POMS compared to age-similar healthy controls. Methods We performed a cross-sectional case-control study of whole blood samples and clinical data from The US Network of Pediatric MS Centers. Real-time quantitative PCR measured telomere length, expressed as a telomere to somatic DNA ratio (T/S ratio). T/S ratio was compared between cases and age-similar healthy controls using multivariate regression analysis adjusting for chronological age, sex, race, ethnicity, tobacco exposure, socioeconomic status and body mass index. Results We analysed 300 POMS cases and 200 controls. The unadjusted mean T/S ratios were 1.66 (SD 0.32) for cases and 1.71 (SD 0.29) for controls (mean difference –0.05, 95% CI –0.10 to 0.01, p=0.08). After adjusting for key covariables with face validity, POMS participants had a mean 0.086 shorter T/S ratio than controls (95% CI 0.015 to 0.157, p=0.018). Conclusions POMS participants demonstrated shorter telomeres than age-similar controls in a multivariable model adjusting for sociodemographic variables, suggesting that MS may contribute to accelerated biological ageing.

Abstract Background: Two years of adjuvant abemaciclib plus endocrine therapy is approved and guideline-recommended in patients (pts) with HR+, HER2-, node-positive, early breast cancer (EBC) at high risk of recurrence. In initial real-world studies, the high rate (&gt;85%) of treatment (tx) persistence beyond 3 months suggests that adjuvant abemaciclib is well-tolerated in routine clinical practice.1,2 Dose reductions were associated with higher persistence in prior studies and clinical trial data have shown that efficacy of abemaciclib was maintained with dose reductions. This study describes 6-month tx persistence and dosing patterns in pts with HR+, HER2-, node-positive EBC initiating abemaciclib 150 mg twice daily (BID). Methods: Retrospective data were accessed from the US de-identified Flatiron Health Research Database. Adults with HR+, HER2-, node-positive, EBC, who initiated abemaciclib 150 mg BID from Jan 2022-Jun 2024 were eligible and further characterized by ≥1 vs no dose reduction. Data cut-off was Dec 2024. Persistence rate was the proportion of pts on abemaciclib &gt;6 months, allowing for ≤60-day medication gap within this period. Time to dose modifications and reasons for discontinuation (DC) were summarized. Subgroup analyses were conducted in pts confirmed as meeting the monarchE high-risk criteria (N2, N3, or N1 plus Grade 3 and/or tumor &gt;5 cm). All analyses were descriptive. Results: Of 1063 eligible pts, median age was 56 years (IQR 47, 65). Most had N1 (48%) or N2 (34%) disease. Median follow-up was 17.5 months (IQR 11, 25). Tx persistence at 6 months was 75%. DC was mostly due to adverse events (AEs; 19%) and &lt;1% due to recurrence. Approximately 50% of pts had ≥1 dose reduction. Persistence was 85% in pts with ≥1 dose reduction and 64% in pts with no dose reductions. 70% of pts who DC’d by 6 months did not have a dose reduction. Median time from start of abemaciclib to first dose change and/or hold was 49 days (IQR 23, 111). During the first 30 days of tx and Days 31-90, DCs due to AEs were lower in pts with dose reductions vs pts with no dose reductions (Table). Persistence and use of dose reductions were similar in pts confirmed as meeting the monarchE high-risk criteria. Conclusion: In US clinical practice, a majority (75%) who initiated adjuvant abemaciclib continued abemaciclib beyond 6 months. Tx persistence was higher among pts with dose reductions relative to those with no dose reductions, and rates of early DCs due to AEs were low in pts with dose reductions. Given that dose reductions in monarchE were not associated with reduced efficacy, these additional real-world data support the use of early dose modifications to improve tolerability and tx persistence for adjuvant abemaciclib in pts with high risk of recurrence. Citation Format: H. Soliman, S. Dent, A. Liepa, V. Stefaniak, M. Huang, T. Sugihara, K. Moreira, K. Hudson, M. Goetz. Treatment Persistence and Dose Modifications in US Patients with HR+, HER2-, Node-Positive, Early Breast Cancer Treated with Adjuvant Abemaciclib [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-09.

Abstract Background PARP inhibitors (PARPi) are active in patients (pts) with germline BRCA1/2 or PALB2 mutated (gBRCA1/2; gPALB2m) breast cancer (BC). Preclinical data suggest PARPi leads to intratumoral activation of the proinflammatory cGAS/STING pathway, recruiting CD8+ T cells, and sensitizing gBRCAm cancers to immune-targeted therapy. Prolonged preoperative treatment with PARPi monotherapy has demonstrated notable pathologic complete response (pCR) rates. The randomized phase II TBCRC 056 study evaluates the PARPi niraparib (N) with the anti-PD-1 antibody dostarlimab (D) as neoadjuvant treatment of gBRCAm or gPALB2mHER2-negative BC, with cohorts for both triple negative BC (TNBC, Arms A and B) and estrogen receptor positive (ER+) BC (Arm C). Results from Arms A and B are being presented. Methods Eligible pts (gBRCA1/2m/gPALB2m BC, T &gt;1.0 cm, ER- (&lt;10%), HER2-) were randomized to either Arm A: upfront combination N 200 mg orally QD and D 500 mg IV every 3 weeks (wks) for 18 wks (1 cycle = 3 wks), or Arm B: N monotherapy for 3 wks, followed by combination N plus D for 15 wks, with baseline (BL) and wk 3 tumor biopsies. After 18 wks, pts either underwent surgery or received additional preoperative systemic therapy (per MD choice) after an end of treatment biopsy if residual disease present. The primary study objectives are to evaluate pCR in Arms A and B combined, as well as change in stromal tumor infiltrating lymphocytes (sTILs) from BL to 3 wks in each Arm separately; 46 pts and a target pCR rate of 50% provides 85% power to reject the null hypothesis of pCR &lt; 30%. Results A total of 46 pts with TNBC enrolled to Arms A and B (38 gBRCA1m (82.6%), 8 gBRCA2m (17.4%), 0 gPALB2m). Median age was 39.3 years (range 24.8-72.8); 84.8% self-reported White, 6.5% Black, 4.3% Asian, and 8.7% Hispanic. Clinical stage distribution was 37.0% stage I, 45.7% stage II, and 17.4% stage III; most had ER- BC (42 ER &lt;1%, and 4 ER 1-10%). Among all pts, 38 (82.6%) completed the target number of cycles of D, with mean cycles received 5.1. Five pts discontinued D early (3 inadequate response/progression, 2 unacceptable AE: LFTs, rash). A total of 38 pts (82.6%) completed 6 cycles of N, with mean cycles received 5.7. Seven pts discontinued N early (3 inadequate response/progression, 4 unacceptable AE: LFTs, anemia, rash (2)). Most common AEs (&gt; grade 2) with D+N were anemia (26.1%), fatigue (21.7%), hypertension (15.2%), hypothyroidism (15.2%), and neutropenia (15.2%). Most common Grade &gt;3 AEs with D+N were anemia (17%) and neutropenia (6.5%). Among all pts, 23 (50%) had a pCR at surgery (90% CI 37.1% - 62.9%), 12 (26.1%) had residual disease (4 RCB-I, 5 RCB-II, 2 RCB-III, 1 RCB not calculable), and 11 (23.9%) crossed over to additional preoperative therapy. The pCR rate exceeded the protocol efficacy criterion of &gt;43%, a significant increase over null hypothesis. pCR rates were the same on Arms A (50%, 90% CI 31.1% - 68.9%) and B (50%, 90% CI 31.9% - 68.1%). Among 15 pts on Arm A with evaluable sTILs at BL and 3 wks, mean sTILs at BL was 16% (range 1% - 40%), and at 3 wks was 27.4% (range 0.5% - 60%), for an average increase of 11.4% (p=0.009). Among 22 pts on Arm B with evaluable sTILs at BL and 3 wks, mean sTILs at BL was 19.5% (range 1% - 75%), and at 3 wks was 42.1% (range 1% - 85%), for an average increase of 22.7% (p=0.0003). Among all pts, BL sTILs (continuous) were significantly higher among those who achieved pCR than those who did not (median 15% vs. 5%, p=0.03). There was no relationship between pCR and BL PD-L1 score, or pCR and ER-0 vs. ER-low. Conclusions In pts with gBRCAm early TNBC, 18 wks of targeted therapy using PARPi and anti-PD1 agents, with or without 3-week PARPi lead-in, resulted in a pCR rate of 50%, and a statistically significant increase in sTILs from BL to 3 wks. Further ongoing correlative work may identify best candidates for this non-chemotherapy-based approach. Citation Format: E. L. Mayer, N. Graham, R. A. Leon-Ferre, M. Rozenblit, C. A. Santa-Maria, S. Isakoff, J. Specht, N. Tung, V. Abramson, J. Desrosiers, A. Schubert, B. Koca, S. M. Tolaney, E. P. Winer, I. E. Krop, A. C. Wolff, G. I. Shapiro, N. Tayob, J. L. Guerriero. Tbcrc 056: a phase 2 study of neoadjuvant niraparib with dostarlimab for patients with BRCA- or PALB2-mutated breast cancer: results from the TNBC cohorts [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF5-02.

Abstract Background: Despite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in breast cancer and other solid tumors due to lack of targets that distinguish tumor from normal cells. Epithelial growth factor receptor (EGFR) plays a critical role in oncogenesis across several cancers and is often upregulated [1]. While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin and gastrointestinal toxicity, which constrains dose escalation and efficacy [2]. A2B395 is an allogeneic, logic-gated, EGFR-targeted, TmodTM CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR and a blocker targeting human leukocyte antigen (HLA)-A*02. The activator recognizes EGFR on both tumor and normal cells, whereas the blocker inhibits CAR T activity against normal cells (with preserved HLA expression) while allowing activation against tumor cells (with HLA-A*02 loss of heterozygosity [LOH]). This approach is designed to avoid on-target, off-tumor toxicity, a significant limitation to CAR T treatment of solid tumors [3]. To address potential graft-vs-host response, a short-hairpin RNA expression module targeting beta-2 microglobulin is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response [4]. Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy [5]. A2B395 represents a novel approach for targeting EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity. Methods: DENALI-1 is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA loss of heterozygosity at any time in the course of their disease via next-generation sequencing. Key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including triple-negative breast, colorectal, non-small cell lung, squamous cell head and neck, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of the phase 1 portion is to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D) using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm the RP2D and collect and analyze biomarker data. The Phase 2 portion will assess overall response rate per RECIST v1.1. As of 03 July 2025, the first patient dosed with A2B395, who has breast cancer, completed the 28-day safety review period. Dose-escalation is ongoing. Citation Format: J. M. Specht, S. R. Punekar, M. Ulrickson, D. J. Wong, J. R. Hecht, M. Maus, P. M. Grierson, J. B. Sunwoo, J. R. Molina, D. G. Maloney, K. Spencer, H. E. Fuentes Bayne, M. Davila, S. P. Patel, B. Creelan, D. B. Zhen, J. Niu, D. C. Prasad, R. L. Marar, N. A. Bagegni, G. Palluconi, J. Lee, A. Mardiros, W. Bretzlaff, W. J. Langeberg, J. S. Welch, E. Ng, W. Y. Go, K. Kirtane, R. A. Shatsky. Denali-1: a seamless phase 1/2 study of A2B395, a logic-gated, allogeneic, Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with triple-negative breast cancer and other EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity (LOH) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-03.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Abstract This publication represents the first part of an update to the clinical practice guideline on the diagnosis and management of group A streptococcal (GAS) pharyngitis, developed by the Infectious Diseases Society of America (IDSA). Diagnosis of GAS pharyngitis by clinician judgment alone is unreliable, and universal testing incurs cost and inconvenience for individuals at low risk of having GAS infection. Clinical scoring systems have been used to quantify the probability of a positive GAS throat culture based on standardized criteria such as the presence of fever, tonsillar enlargement or exudate, tender and enlarged anterior cervical lymph nodes, and the absence of cough. The goal of this manuscript is to review the evidence and provide a recommendation as to whether a scoring system should be used to decide which patients should have a GAS diagnostic test (ie, rapid antigen test [RADT], molecular method, and/or throat culture) performed. We performed a systematic review of randomized and nonrandomized studies that compared the use of a clinical scoring system to clinician judgment alone in predicting the result of a throat culture. Evidence from studies in children and adults suggests the diagnostic accuracy is comparable or slightly higher using a scoring system compared to clinician judgment alone. Although the studies are limited due to small size, lack of uniformity in outcome measures, and incomplete data, the consensus of the panel is that the balance of benefits and harms favors incorporation of a clinical scoring system as part of the evaluation of patients with sore throat and suspected GAS pharyngitis.

Abstract Objective To test the effectiveness of a surgical web‐based decision aid (DA) in improving knowledge. Summary of Background Data DAs support decision making by providing information about the options. Methods A stepped wedge trial was conducted in 10 National Cancer Institute Community Oncology Research Program clinics (Alliance for Clinical Trials in Oncology). Clinics were randomized to time of transition from usual care (UC) to delivery of a web‐based DA. Patients with stage 0 through 3 breast cancer being considered for surgery were enrolled. Knowledge (primary outcome) was measured using the Breast Cancer Surgery Decision Quality Instrument and patients were asked, “How informed do you feel?” Intervention effects were tested with linear mixed‐effects models, accounting for surgeon and clinic‐level clustering, time, and enrollment after COVID. Additional models controlled for demographics. Results A total of 44% of DA arm patients reviewed the DA and 58% in UC arm reported reviewing “any information.” Being in the DA arm versus UC was not associated with knowledge. However, “review of information” was associated with higher knowledge. In addition, non‐White race and lower education were associated with lower knowledge. The DA arm was associated with higher perceptions of feeling informed (parameter estimate 1.36; 95% CI, 0.18–2.55; p = .02); this persisted even when controlling for review of information or demographics. Conclusion Improved knowledge was not demonstrate with a web‐based DA versus UC. Interestingly, the DA was associated with a higher likelihood of feeling informed. Future research will explore the discrepancy between patients feeling informed but having low knowledge, especially for disadvantaged patients. Trial Registration ClinicalTrials.gov Identifier: NCT0376600