Citations

Objective: To develop a predictive model for pathological complete response (pCR) after total neoadjuvant therapy (TNT) to inform selection for watch-and-wait (W/W). Summary Background Data: Patient selection for W/W after TNT for locally advanced rectal cancer remains challenging. Methods: An ensemble of tabular foundation models was fine-tuned in adults with clinical stage II or III microsatellite stable primary rectal adenocarcinoma undergoing TNT and total mesorectal excision (TNT+TME) from 2018-2023 to predict pCR, using pre-TNT, post-TNT and pre-TME variables. This model was externally validated on patients having TNT and W/W (TNT+W/W) to predict persistent clinical complete response (pcCR; the absence of local regrowth, distant metastases, or persistent near-cCR). Area under the receiver operator curve (AUROC), area under the precision-recall curve (AUPRC), and Brier score were calculated with 95% confidence intervals (CI). Results: Among 308 patients that underwent TNT+TME (median age 56; 40% female), the model predicted pCR with an AUROC 0.71 (95% CI 0.65-0.77), AUPRC 0.44 (95% CI 0.35-0.57), and was well calibrated with a Brier score of 0.17 (95% CI 0.15-0.20). At external validation in a cohort of 83 patients that are being managed with TNT+W/W (median age 57; 37% female), the model predicted pcCR with an AUROC 0.69 (95% CI 0.57-0.82), AUPRC 0.90 (95% CI 0.82-0.96), and Brier score of 0.30 (95% CI 0.26-0.33), improving to 0.17 with recalibration. Conclusions: This novel predictive model demonstrated good discrimination and calibration for pCR after TNT+TME with utility in TNT+W/W for pcCR after appropriate recalibration, supporting its application for W/W patient selection.

PURPOSE EGFR alterations occur in a subset of biliary tract cancers (BTCs) and are often linked to disease progression and poor prognosis, yet targeted approaches remain underexplored. ERRFI1 , encoding the epidermal growth factor receptor (EGFR) inhibitor MIG6, is mutated in various cancers, including BTC, representing a potential predictive biomarker. We investigated whether loss of ERRFI1 function may enhance sensitivity to EGFR-targeted tyrosine kinase inhibitors (TKIs), presenting a potential therapeutic opportunity. METHODS This is a retrospective multicenter study of patients with BTC harboring ERRFI1 alterations. Data were extracted from electronic health records following institutional approval. ERRFI1 alterations were classified based on the alteration type, variant allele frequencies were documented, and coalterations were analyzed. Treatment outcomes including response, time to progression (TTP), overall survival (OS), safety profiles, and tumor marker kinetics were noted. RESULTS Fourteen BTC patients with ERRFI1 mutations were identified in our database; the median age was 50 years, 64% were males; all cases were intrahepatic cholangiocarcinomas. Common coalterations included IDH1 (36%), TP53 (29%), and ARID1A (29%). All patients received gemcitabine-cisplatin as first-line treatment, and 79% received immune checkpoint inhibitors. Eight patients (57%) received EGFR TKIs. Best responses to EGFR therapy included three partial responses (2 responses lasting >20 months), four stable diseases, and one progressive disease. The median TTP was 7 months (95% CI, 6 to 21 months). Treatment was well-tolerated: toxicities included rash (n = 2), transaminitis (n = 1), and diarrhea (n = 1). The median OS was 20 months (95% CI: 8-36 months); 50% remained alive at last follow-up. CONCLUSION ERRFI1 mutations represent actionable biomarkers in BTC, with EGFR-targeted therapy demonstrating meaningful clinical benefit in this heavily pretreated population. These findings support integration of ERRFI1 testing into routine molecular profiling of BTC and other EGFR-driven malignancies.

Abstract Objective This study was undertaken to evaluate the safety and effectiveness of responsive thalamic stimulation as adjunctive therapy for drug‐resistant idiopathic generalized epilepsy (IGE) with generalized tonic–clonic seizures (GTCSs). Methods NAUTILUS is a prospective, multicenter, single‐blind, randomized sham‐controlled pivotal trial. Patients were ≥12 years of age with drug‐resistant IGE and ≥2 GTCSs over a 3‐month baseline. Bilateral depth leads were targeted to the centromedian thalamus. One month later, patients were randomized to Active (responsive stimulation, n = 44) or Sham (no stimulation, n = 43). The effectiveness evaluation period (EEP) began 3 months postimplant through 1 year. After a second GTCS in the EEP, patients transitioned to open‐label active stimulation. The primary safety endpoint was the serious adverse device‐related event (SADE) rate at 84 days postimplant. The primary effectiveness endpoint was time‐to‐second‐GTCS during the EEP. Additional endpoints included median percent change in days with any generalized seizure, GTCS frequency, and responder rate (RR). Results Eighty‐seven patients were implanted across 23 US centers. The SADE rate was significantly below the performance goal (6.9%, p < .0001), with no adverse effects on cognition, mood, or sleep. The prespecified primary effectiveness endpoint was not significant. However, a post hoc mixed‐effects model considering all EEP days demonstrated greater GTCS reduction in the originally randomized Active group (61%) compared to patients originally randomized to Sham (49%, p = .030). Eighteen‐month outcomes included 76.8% median GTCS reduction, 62.5% RR, 40% GTCS‐free at that timepoint, and 77.8% median reduction in days with any generalized seizure. More than 90% of patients and 86% of physicians reported improvement on Global Impression of Change scales. Significance NAUTILUS is the first randomized controlled neuromodulation trial in IGE. Responsive thalamic stimulation provided a clinically meaningful and durable reduction in seizures with an acceptable safety profile, offering a much‐needed option for drug‐resistant IGE.

LBA7000 Background: ~40% of DLBCL pts are not cured with first-line (1L) R-CHOP, underscoring a significant unmet need for more effective 1L regimens. Tafa (anti-CD19 mAb) + Len-R-CHOP in the phase 1b First-MIND study demonstrated safety and efficacy in pts with newly diagnosed disease. frontMIND, a phase 3, double-blind, placebo-controlled study, compared Tafa-Len-R-CHOP vs R-CHOP in pts with high-risk aggressive BCLs. Methods: Pts aged 18–80 y with newly diagnosed, high-intermediate/high-risk DLBCL or HGBL (IPI 3–5, aaIPI 2–3 if ≤60 y) and ECOG PS 0–2 were randomized 1:1 to Tafa-Len-R-CHOP or R-CHOP. Primary endpoint was investigator-assessed PFS; secondary endpoints included: EFS, OS, CR, ORR, safety. Results: At primary analysis (data cutoff Oct 20, 2025), 899 pts were randomized to Tafa-Len-R-CHOP (n=448) or R-CHOP (n=451); baseline characteristics were similar between arms. With a median follow-up of 35.2 mo, Tafa-Len-R-CHOP achieved a statistically significant improvement in PFS vs R-CHOP (HR 0.75 [95% CI: 0.59, 0.96]; P =0.019) in the overall population; in pts with centrally confirmed lymphoma subtypes (n=773), PFS HR was 0.68 (95% CI: 0.52, 0.88) and 24-mo PFS was 72.7% vs 62.2%. PFS benefit was observed with Tafa-Len-R-CHOP in both molecular COO subtypes, ABC and GCB (data will be presented). Tafa-Len-R-CHOP significantly improved EFS vs R-CHOP; CR and ORR were similar between arms and HR for OS was 0.85 (final OS planned at 5y) (Table). Any-grade TEAEs were similar in treatment arms (98.6% vs 97.1%); more grade ≥3 TEAEs occurred with Tafa-Len-R-CHOP vs R-CHOP (86.7% vs 76.1%). Discontinuations due to TEAEs occurred in 25.7% vs 17.9% and deaths due to TEAEs in 5.9% vs 3.8% of pts for Tafa-Len-R-CHOP vs R-CHOP. Overall, there were fewer deaths with Tafa-Len-R-CHOP vs R-CHOP (18.5% vs 21.7%). Conclusions: The primary endpoint of frontMIND was met; Tafa-Len-R-CHOP resulted in a significant 25% reduction in risk of disease progression or death compared with R-CHOP, with an 8.2% difference in 24-month PFS rate in the overall population and 10.5% difference in pts with centrally confirmed lymphoma subtypes. TEAEs were manageable and consistent with the expected safety profile. Tafa-Len-R-CHOP represents a potential new 1L standard of care for pts with both COO subtypes of high-risk DLBCL or HGBL. Clinical trial information: NCT04824092 . Efficacy outcomes by treatment arm.* Variable Tafa-Len-R-CHOP(n=448) R-CHOP(n=451) HR or OR(95% CI) P value PFS, # events (%) † 121 (27.0) 155 (34.4) 0.75 (0.59, 0.96) 0.019 PFS rate at 24 mo, % 71.1 62.9 − − PFS rate at 36 mo, % 67.3 60.7 − − EFS, # events (%) 154 (34.4) 191 (42.4) 0.79 (0.64, 0.97) 0.026 OS, # events (%) 82 (18.3) 95 (21.1) 0.85 (0.63, 1.14) 0.270 CR at EOT, n (%) 292 (65.2) 294 (65.2) 0.998 (0.76, 1.31) 0.987 ‡ ORR at EOT, n (%) 360 (80.4) 343 (76.1) 1.290 (0.94, 1.78) 0.120 ‡ *Investigator-assessed. † Progressive disease or death from any cause. ‡ Nominal P value.

LBA5012 Background: There is a critical evidence gap on the relative benefits and harms of proton therapy (PT) compared with photon-based intensity-modulated radiation therapy (IMRT) in prostate cancer. Herein we report early results from COMPPARE, a non-randomized comparative study of outcomes with PT and IMRT in prostate cancer. Methods: Between 2018-2022, 2524 patients from 51 facilities (28 PT and 23 IMRT) enrolled in COMPPARE, including 1501 treated with PT and 1023 treated with IMRT, and were followed prospectively. Treatment naïve patients with localized prostate cancer except those with very high-risk disease were eligible. Treatment was pragmatic with daily standard fractionation (1.8-2.1 Gy) and moderate hypofractionation (2.4-3.1 Gy) permitted. Use of rectal spacers and androgen deprivation were at physician discretion. Patient-reported quality of life data and treatment team-reported toxicity and disease control outcomes were collected at baseline and pre-specified time intervals via VisionTreeOptimalCare; treatment planning and delivery data were collected via the Advanced Treatment Consortium. We analyzed 1404 PT patients and 939 IMRT patients. We report the early primary endpoint of the study, a comparison of patient reported bowel urgency and bowel frequency at 2-years using the EPIC tool, and the secondary endpoints of 2-year CTCAE v5 ≥ grade 2 gastrointestinal toxicity outcomes and 3-year freedom from biochemical progression (FFBP) results reported by the study teams. Results: Study sample size was targeted at 1,500 PT patients and 1,000 IMRT patients, and median follow-up time was 4.0 years. The primary endpoint and secondary toxicity 2-year endpoints focused on the alternative hypothesis of PT superiority. All results include inverse probability of treatment weighting. Using generalized linear mixed effects models, we found there to be no significant difference in EPIC bowel urgency scores (p = 0.324) or bowel frequency scores (p = 0.514) between PT and IMRT cohorts over time up to the 2-year endpoint. For grade 2 gastrointestinal toxicity, the 2-year cumulative incidence was 5.2% for PT and 5.6% for IMRT. Gray’s Test for competing risks showed a hazard ratio (HR) of 0.91 [95% confidence interval (CI): 0.65-1.28, p = 0.6] for PT versus IMRT. The exploratory non-inferiority endpoint of 3-year FFBP was 98.0% for PT and 97.9% for IMRT, and Gray’s Test showed a HR of 0.95 (95% CI: 0.52-1.71, p = 0.90). Conclusions: Analysis of early results of COMPPARE show no significant differences between PT and IMRT in patient reported bowel frequency and urgency, grade ≥2 gastrointestinal toxicity, or FFBP. Assessment of long-term disease control, late toxicity and secondary malignancy will require longer follow-up. Clinical trial information: NCT03561220 .

BACKGROUND: The EARLY TAVR trial (Evaluation of TAVR Compared to Surveillance for Patients with Asymptomatic Severe Aortic Stenosis) demonstrated that early transcatheter aortic valve replacement (TAVR) was superior to clinical surveillance (CS) in asymptomatic severe aortic stenosis. The relative impact of early TAVR versus CS strategy by age is unknown. METHODS: The study population of the EARLY TAVR trial was stratified into 4 age groups: 65 to 69 years (n=141), 70 to 74 years (n=263), 75 to 79 years (n=250), and ≥80 years (n=247). Associations between age and the trial primary end point of death, stroke, or unplanned cardiovascular hospitalization; the composite end point of death, stroke, or heart failure hospitalization; and its individual components were examined. Interaction tests evaluated whether the treatment effect of early TAVR versus CS differed by age. RESULTS: No interaction was detected between age and the treatment effect of early TAVR versus CS for the composites or individual outcomes. We observed lower stroke rates with early TAVR compared with CS in the youngest (65–69 years, absolute risk reduction, 13%; P =0.008) and oldest (≥80 years; absolute risk reduction, 12.3%; P =0.029) age groups. The absolute difference in heart failure hospitalization rates between the early TAVR and CS arms at 2 years was greatest in the oldest patients (≥80 years, 9.1%; 75–79 years, 5.9%; 70–74 years, 5.1%; 65–69 years, 4.4%). In the CS group, time to conversion to AVR was similar across all age groups (median, 11 months; P =0.73). Approximately one-third of younger patients (65–69 years) in the CS arm presented with acute valve syndrome at the time of conversion, the frequency of which tended to increase with age ( P =0.06). CONCLUSIONS: In the EARLY TAVR trial, the relative benefit of early TAVR over CS was consistent among all age groups. The greatest absolute reduction in stroke rate with early TAVR compared with CS appeared in the youngest and oldest groups, whereas reduction in heart failure hospitalization was most pronounced in the oldest patients. These data suggest that early TAVR should be considered in all age groups above 65 years. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03042104.

Abstract Objective Pediatric epilepsy surgery is well established, but contemporary global data on referral and presurgical evaluation practices are lacking. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Task Force study provides an updated overview of current trends and regional differences. Methods Group‐level data were collected from 61 epilepsy surgery programs (49 pediatric‐only) across 29 countries and six continents, identified through ILAE networks, and included all children and adolescents treated in 2023 who underwent presurgical evaluation/epilepsy surgery. Results Group‐level data were available for 2427 patients. Mean age at surgery was 9.1 ± 4.9 years; mean epilepsy duration was 5.3. At surgery, 3.2% were <1 year old (highest in Oceania: 5.1%), and 6.1% were nonpharmacoresistant (highest in Europe: 15.0%). Prior neurosurgery was reported in 14.2% (highest in North America: 28.8%), including 8.0% resections (6.1% for epilepsy, 1.5% for tumors; highest in Oceania: 16.5%), 2.3% disconnections (1.3% corpus callosotomy; highest in South America: 4.7%), and 4.2% neuromodulation (3.7% vagal nerve stimulation, .2% responsive neurostimulation, one deep brain stimulation; highest in North America: 12.2%). Developmental and epileptic encephalopathies (DEEs) at surgery included Lennox–Gastaut syndrome (7.4%), infantile epileptic spasms syndrome (5.1%), and DEE with spike–wave activation in sleep (1.5%). Presurgical investigations included fluorodeoxyglucose positron emission tomography (52.6%; highest in Oceania: 79.7%), genetic testing (46.8%; highest in Asia: 54.3%), magnetic resonance imaging (MRI) postprocessing (32.4%; highest in South America: 53.0%), functional MRI (fMRI; 15.2%; highest in North America: 40.3%), magnetoencephalography (11.9%; highest in North America: 39.3%), single photon emission computed tomography (9.6%; highest in North America: 22.2%), high‐density electroencephalography (EEG; 1.9%; highest in Europe: 4.7%), source localization (1.6%; highest in Oceania: 7.6%), Wada test (1.2%; highest in North America: 3.5%), and EEG‐fMRI (.5%; highest in Europe: 1.1%). Significance Despite some early surgeries, including in infancy and before pharmacoresistance, mean epilepsy duration before surgery remains >5 years. Reoperations are common, with resection more frequent than neuromodulation. Genetic testing in nearly half of patients reflects its growing relevance, and the high rate of DEEs underscores the complexity of surgical candidates.

As machine learning (ML)-based decision support tools proliferate in clinical practice, understanding how clinicians integrate personalized ML predictions alongside randomized controlled trial (RCT) evidence is critical. We designed a web-based clinical decision support system (CDSS) presenting survival and adverse event data from a simulated RCT and ML model across 12 synthetic multiple myeloma scenarios. In a within-subjects study with 32 physicians, we evaluated how clinicians synthesize competing evidence sources to make treatment decisions. When ML and RCT outputs were concordant, physicians reported greater confidence than with RCT data alone. When results were discordant, most physicians shifted toward the ML-supported treatment, often before reviewing any information about model training or validation, suggesting a tendency toward automation bias rather than algorithm avoidance. Despite reporting higher perceived reliability after viewing model quality disclosures, physicians were largely unable to describe the validation procedures they had reviewed. Taken together, these findings reveal that clinicians may over-rely on ML recommendations even when equipped with tools designed to support critical appraisal. We discuss implications for CDSS design, clinician training, and the institutional safeguards needed before ML-based systems are deployed in high-stakes oncology settings.

Importance Preoperative and perioperative nivolumab improve event-free survival in resectable non–small cell lung cancer. The role of adjuvant nivolumab after upfront surgery is unknown. Objective To determine whether adjuvant nivolumab improves disease-free survival and overall survival in patients with resected non–small cell lung cancer with any tumor programmed death-ligand 1 (PD-L1) expression and in those with at least 50% PD-L1 expression. Design, Setting, and Participants This open-label, randomized phase 3 study enrolled participants from May 2016 through September 2019, with median follow-up of 72.6 months at the data cutoff in December 2025. The study was conducted at 378 centers in the US National Clinical Trials Network. Patients were identified through a screening trial. Those with resected tumors at least 4 cm and/or who were lymph node positive (N1/N2) were eligible for inclusion after completion of planned standard adjuvant therapy if the tumor was adenocarcinoma without sensitizing sequence variants in EGFR and ALK or squamous cell carcinoma. Intervention Patients were randomized in a 1:1 ratio to receive nivolumab 480 mg intravenously every 4 weeks for up to 1 year or standard care observation. Main Outcomes and Measures Co–primary end points were disease-free survival in the intention-to-treat population and in those with tumoral PD-L1 expression at least 50%. Overall survival was examined if the corresponding test of disease-free survival was statistically significant. Results A total of 466 patients (median age, 66 years; 241 [52%] male) were assigned to receive nivolumab and 469 (median age, 67 years; 245 [52%] male) to undergo standard care observation. The median duration of follow-up was 72.6 months. The trial was stopped for futility at 75% information. In the intention-to-treat population, median disease-free survival was 71.3 months with nivolumab and 68.8 months with observation (hazard ratio for progression or death, 0.97 [97% CI, 0.79-1.20]; [95% CI, 0.81-1.17]; 1-sided P = .39). In the subset of participants with PD-L1 of at least 50%, median disease-free survival was 89.8 months with nivolumab and 78.5 months with observation (hazard ratio for progression or death, 0.86 [98% CI, 0.55-1.34]; [95% CI, 0.59-1.25]; 1-sided P = .22). Conclusions and Relevance Adjuvant nivolumab was not associated with improved disease-free survival in patients with resected non–small cell lung cancer without sensitizing EGFR and ALK alterations when given after planned adjuvant chemotherapy and/or radiotherapy. Trial Registration Clinicaltrials.gov Identifier: NCT02595944

The spinal cord plays a central role in the pathophysiology and clinical manifestations of multiple sclerosis (MS), yet remains under-studied compared with the brain. This review summarizes key insights from the 2025 North American Imaging in MS Spinal Cord Imaging Workshop, highlighting recent advances, ongoing challenges, and future opportunities in MS spinal cord imaging. We review pathological studies and outline the clinical relevance of spinal cord lesions and atrophy for diagnosis, prognosis, and disease monitoring, highlighting emerging biomarkers of progression independent of relapse activity. Correlations between magnetic resonance imaging, histopathology, and clinical outcomes support the validation and translational potential of advanced spinal cord imaging techniques. Finally, we discuss spinal cord–specific processing pipelines and reproducibility challenges. Collectively, these insights underscore the need to integrate advanced and quantitative spinal cord imaging into clinical trials, research studies, and—when feasible—clinical care, to fully capture the extent of MS pathology, and ultimately improve patient outcomes.