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Introduction: Flipped classroom models, which use active, case-based discussion, have shown promise across graduate medical education. Previous literature demonstrates that transitioning to a flipped classroom model resulted in significant increases in overall Orthopaedic In-Training Examination (OITE) scores. This observational study retrospectively compares foot and ankle OITE scores for orthopaedic surgery residents before and after implementation of a flipped classroom curriculum. Methods: This retrospective study reviewed OITE scores for orthopaedic residents, comparing a lecture-based curriculum (n = 49) to a flipped classroom curriculum (n = 61). Residents who started their second year in July 2020 or later were defined as treated. The curriculum is given to the postgraduate year-2 (PGY2) residents only. Percentage of correct foot and ankle questions (F&A) were analyzed via mixed-effects models using random-subject intercepts. Fixed effects included PGY, overall performance on other sections, and flipped classroom status. All statistical analyses were performed in R version 4.4.1. Results: Residents in the flipped classroom cohort demonstrated a statistically significant increase in F&A questions answered correctly. The average increase was 7% (95% confidence interval: 4%, 10%; p < 0.001). This improvement trend became clearly visible in PGY3 and grew stronger in senior residents. Specifically, PGY3 residents improved their mean percentage correct from 62.26% to 66.07% (p = 0.16). PGY4 residents improved from 69.16% to 74.83% (p = 0.013), and PGY5 residents improved from 69.03% to 75.53% (p = 0.006). Historically, approximately 75% of traditional PGY5 residents scored lower on the F&A section than on the rest of the examination. Conversely, in the flipped classroom group, approximately 75% of PGY4 and PGY5 residents scored higher on the F&A section compared with other sections Discussion: The implementation of a flipped classroom model was associated with a statistically significant improvement in resident performance on the F&A section of the OITE. The educational benefits of this curriculum appear cumulative over the course of residency, with the most substantial performance gains realized by senior residents in their fourth and fifth years of training. Level of Evidence: Level III , Observational Study. See Instructions for Authors for a complete description of levels of evidence.

Importance The NRG Oncology research organization and NSABP B-35 randomized clinical trial prospectively collected margin width data on postmenopausal women with hormone receptor (HR)–positive ductal carcinoma in situ (DCIS) who underwent lumpectomy, whole-breast irradiation (WBI), and randomly assigned adjuvant anastrozole or tamoxifen therapy. This permitted analysis of outcomes per margin width. Objective To analyze the effect of margin width on ipsilateral breast tumor recurrence (IBTR). Design, Setting, and Participants NSABP B-35 was a phase 3, double-blind, randomized clinical trial in which patients were randomized to either 5 years of tamoxifen or anastrozole. Postmenopausal women with HR-positive DCIS and tumor-free margins were eligible. Enrollment was from January 6, 2003, to June 15, 2006, in academic and community hospital members of the NSABP. Study data were analyzed from July 2024 to April 2025. Interventions There were no specific interventions based on lumpectomy margin width. Main Outcomes and Measures Lumpectomy margin width data were prospectively collected within 3 months of randomization. A pathology form classified margins as positive (ink on tumor), close (&amp;lt;1 mm), or negative (≥1 mm). For the negative margin subgroup, closest margin width was stated separately. Thus, an ancillary analysis using 1-mm and 2-mm margin width partitions was performed. Results A total of 3104 postmenopausal women (mean [SD] age, 61 [7.8] years) were enrolled in NSABP B-35. In an ancillary analysis, 2707 patients were included in the 1-mm margin width partition group, and 2546 patients were included in the 2-mm margin width partition group. IBTR was the most common first event, occurring in 90 of 2707 patients (3.3%): 24 of 502 patients (4.8%) with a margin width less than 1 mm and 66 of 2205 patients (3.0%) with a margin width greater than or equal to 1 mm. Ten-year unadjusted cumulative incidence of IBTR events was 5.6% vs 4.0% for margins less than 1 mm vs margins greater than or equal to 1 mm ( P = .04). Using 2 mm as the discriminant threshold for margin width, 39 of 879 patients (4.4%) with margins less than 2 mm and 49 of 1667 patients (2.9%) with margins greater than or equal to 2 mm experienced an IBTR first. Ten-year unadjusted cumulative incidence of IBTR events with margins less than or equal to 2 mm was 5.3% vs 3.8% for those with margins greater than 2 mm ( P = .05). In models adjusting for other patient and tumor factors, margin width was not a significant predictor of IBTR risk (2-mm threshold hazard ratio, 1.33; 95% CI, 0.86-2.06). Conclusions and Relevance Results of this ancillary analysis of the NSABP B-35 trial show that absolute differences in IBTR rates using margin width groupings of less than 1 mm or greater than or equal to 1 mm and margin width groupings of less than 2 mm or greater than or equal to 2 mm in postmenopausal women with HR-positive DCIS receiving lumpectomy, WBI, and adjuvant endocrine therapy were small. Omission of reexcision lumpectomies based on margin widths of less than 1 mm or less than 2 mm can be reconsidered in appropriate patients. Trial Registration ClinicalTrials.gov Identifier: NCT00053898

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.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

TPS650 Background: The TAILORx and RxPONDER trials showed that recurrence score (RS) identifies many postmenopausal pts who do not benefit from addition of ACT to endocrine therapy (ET); however, RS also identifies subsets who do benefit (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25). Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2– BC in SOFT/TEXT, we question whether the ACT benefit in TAILORx/RxPONDER was due to chemotherapy-induced OFS. To address this, we developed OFSET, a phase III clinical trial comparing OFS+ET to ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal pts with early-stage HR+/HER2– tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25; pN1 RS 0-15; pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39; ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI) per physician discretion; or tamoxifen if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per protocol guidelines. An HRQOL sub-study will assess severe menopausal symptoms (measured by FACT ESS-19) and pain severity (PROMIS) between arms. Blood and tumor specimens will be collected for future research. We anticipate accrual of 3,960 pts in 7 yrs, 7 mos. Per NSABP B-28/RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Per TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with 1-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ~11 yrs after study initiation. Accrual is 496/3,960 (from 8/2023 to 1/2026). NCT #: NCT05879926. Clinical trial information: NCT05879926 .

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 .

Introduction/Aim: Heart failure (HF) is a complex clinical syndrome, characterised by reduced exercise capacity (VO 2 peak) and quality of life leading to premature death. The reduction in VO 2 peak is a key prognostic indicator, and improving exercise capacity remains a critical therapeutic target. In athletes, the use of intermittent hypoxia training to improve VO 2 peak and performance is well established. Changes in VO 2 peak are typically accompanied by improved oxygen carrying capacity with increased haemoglobin (Hb) concentration mediated through increased erythropoietin (EPO) production in the kidney. The purpose of this pilot study was to examine the feasibility of using intermittent hypoxia training in individuals with HF, and examine changes in VO 2 peak, EPO and Hb. We hypothesised that intermittent hypoxia training would be feasible, well tolerated, and improve VO 2 peak, EPO production, Hb concentration in HF with reduced ejection fraction (HFrEF). Methods: Ten male participants with stable, optimally managed HFrEF (Age: 73 ± 5 yr; Ejection Fraction: 37 ± 11%) participated in the study. The training stimulus consisted of 12 x 60-minute sessions of intermittent hypoxia over a 2-week period. During each 60-minute session participants received 6 x 5 minutes of pulsed, reduced FIO 2 exposures interspersed with 5 min of normoxia (total of 30 min hypoxic exposure per session). All participants commenced at 18% FIO 2 , which was decreased to 12% by the 3-4th sesion, as tolerated. Throughout each exposure, oxygen saturation (SpO 2 ), heart rate, blood pressure and dyspnoea (modified Borg scale) were monitored every 5 min. Changes in VO 2 peak were measured using a cycle ergometry, cardiopulmonary exercise test. Changes in VO 2 peak, N-terminal pro B-type natriuretic peptide (NT-proBNP), EPO and Hb concentration were measured pre and immediately post intermittent hypoxic training. Results: All participants completed between 10-12 (median n=12) sessions over the 2-week period. Intermittent hypoxia was well-tolerated with no adverse events. The mean SpO 2 during the hypoxic exposure was 88 ± 4%, and median reported dyspnoea 0 (range 0-1). Following 2 weeks of intermittent hypoxic training, there were significant increases in VO 2 peak (mean difference[MD]: +1.18 mL·kg - ¹·min - ¹, 95% CI 0.47 to 1.89, p = 0.010); EPO (MD: +3.33 IU/L, 95% CI 1.35 to 5.32, p = 0.011); with a modest increase in Hb concentration that approached significance (MD: +4.00 g/L, 95% CI 0.51 to 7.49, p = 0.055). NT-proBNP remained unchanged (MD: –107 pg/mL, 95% CI –356 to 142, p = 0.424). Conclusion The results of this pilot study suggest that in clinically stable HFrEF, 2 weeks of intermittent hypoxic training results in a significant improvement in VO 2 peak, accompanied by increases in EPO and potentially levels of Hb. In our participants, this 60-minute pulsed intermittent hypoxic protocol was extremely well tolerated without any adverse effects, and may improve oxygen carrying capacity of the blood in HFrEF. Further research on the mechanisms of adaptation and the translation of the response into different HF phenotypes is warranted. Supported By: The Prince Charles Hospital Foundation Innovation Grant INN202-049 and Griffith University. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Background Lung cancer is the leading cause of cancer-related death, and the most common cancer diagnosed globally. Approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). After initial surgical treatment, adjuvant therapy with conventional or targeted chemotherapy can help optimize survival. These treatments, however, must be tailored to each patients’ problematic situation, including cancer characteristics and goals of care. Shared decision making (SDM) is a method of care by which patients and clinicians work together to form plans of care that advance the patient’s problematic human situation. This method often requires evaluating alternative options, “trying them on” for fit given their practical demands and favorable and unfavorable effects. Tools used within the encounter can facilitate and support SDM conversations, yet none exist for considering care post-surgical treatment of NSCLC. Therefore, we aimed to evaluate the effectiveness of a novel encounter tool for SDM, NSCLC Choice, compared to usual care at improving SDM and reducing decisional conflict for patients with resected early-stage NSCLC considering adjuvant treatment. Methods We will conduct a parallel, patient-level randomized trial comparing NSCLC Choice with usual care. Patients will be eligible if they are adults with stage >1B NSCLC eligible for postsurgical adjuvant chemotherapy. Allocation will be central and post-consent. Patients will be blinded to our trial hypothesis, instead of being invited to evaluate an educational intervention. Our primary outcome is SDM quality, which we will assess using participant reported measures (patient SDM-Q-9) obtained immediately post-encounter and an observer measure estimated from video recording of trial encounters in both arms (OPTION12). With resources to conduct a 100-patient trial, we will have >80% power to detect a 12-point medium difference between arms in patient-reported SDM-Q-9. We will also assess the secondary outcomes of knowledge about the disease and the features of treatment options using an ad hoc questionnaire, decisional conflict using the Decisional Conflict Scale, and patient and clinician satisfaction using the metrics used in prior SDM intervention trials. We will also determine encounter length using video recordings. Discussion In testing NSCLC Choice, we seek to determine the extent to which this intervention can improve care for patients with NSCLC considering adjuvant therapy after surgery. In addition, we expect to determine whether this intervention is satisfactory to participants and feasible in practice. If successful, this study will result in an evidence-based tool for promoting patient-centered conversations around NSCLC and cancer care those fits. Trial Registration: NCT06122064 ClinicalTrials.gov