Citations

Abstract Severe neuropathies with predominant involvement of motor fibres can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibres. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n = 86, Guillain–Barré syndrome n = 37, multifocal motor neuropathy n = 18, diabetic neuropathy n = 30, other inflammatory neuropathies n = 10), amyotrophic lateral sclerosis (n = 50), multiple sclerosis (n = 50) and healthy controls (n = 50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and the sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over 4 years. Among 3543 total samples tested, three patients (two male, one female)—diagnosed with the LMND variant of amyotrophic lateral sclerosis (aged 65, 72 and 79 years, respectively)—showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt–Lanterman incisures (SLIs), paranodes and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs (‘incisuropathy’). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over 3 years. The other two patients died of rapid disease progression: one of them received no immunotherapy while the other had ineffective treatments with single administrations of intravenous immunoglobulin and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor-predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome and responses to immunotherapy in larger cohorts.

e22006 Background: Metastasectomy is recommended for select pediatric patients with osteosarcoma with resectable pulmonary parenchymal metastases. It is unclear whether pulmonary metastasectomy confers the same benefit to patients with hilar or mediastinal lymph node metastases (LNM). This study aims to characterize pediatric patients with osteosarcoma with thoracic LNM and their outcomes compared to those with only pulmonary parenchymal metastasis. Methods: This is a retrospective cohort study of patients aged 0-21 with osteosarcoma metastatic to the lung who underwent pulmonary metastasectomy between 2000-2024. Patients were categorized into groups based on the presence or absence of LNM on imaging reviewed by pediatric surgeons and radiologists. Descriptive statistics and Wilcoxon rank sum, chi-square or Fisher’s exact tests evaluated differences between patients with and without LNM. Kaplan-Meier survival curves with log-rank tests evaluated the relationship between the presence of LNM and outcomes. The primary outcome was overall survival (OS) with secondary outcomes of recurrence-free survival (RFS) and disease-free survival (DFS). Results: 39 patients met inclusion criteria for this study, of which 13 (33%) had LNM (Table). Of the 13 patients with LNM, 8 (62%) had a pulmonary metastasectomy after their LNM diagnosis. Patients with LNM had poorer OS after first metastasectomy (log-rank p = .027), DFS after first metastasectomy (p = .018), and RFS after diagnosis (p = .039) than patients with pulmonary parenchymal metastasis without LNM. Patients who underwent metastasectomy after their LNM diagnosis had improved OS after LNM diagnosis than patients who did not undergo metastasectomy (pairwise log-rank test with Bonferroni correction p = .015). Conclusions: Pediatric patients with osteosarcoma metastatic to the lung with LNM had poorer OS, DFS, and RFS compared to patients without LNM. These results confirm the importance of attention to the presence of nodal involvement in patients with pulmonary metastatic osteosarcoma. Despite their poor prognosis, these results suggest a persistent survival benefit to surgical intervention. Total N = 39 No LMN N = 26 LMNN = 13 p Age 13.7 (9.5, 16.1) 13.9 (9.0, 15.9) 13.7 (10.7, 16.5) .777 Female 15 (38%) 10 (38%) 5 (38%) > .999 Histology Chondroblastic Osteoblastic Telangiectatic 11 (39%)16 (57%)1 (3.6%) 9 (50%)8 (44%)1 (5.6%) 2 (20%)8 (80%)0 (0%) .162 Primary tumor site Chest wall Femur Humerus Pelvis Radius Tibia 2 (5.1%)24 (62%)5 (13%)2 (5.1%)1 (2.6%)5 (13%) 2 (7.7%)14 (54%)3 (12%)2 (7.7%)1 (3.8%)4 (15%) 0 (0%)10 (77%)2 (15%)0 (0%)0 (0%)1 (7.7%) .821 Lung metastases present at time of diagnosis 20 (51%) 13 (50%) 7 (54%) .821 Treatment protocol AOST0331 AOST06P1 CCG 7921 P9754 30 (81%)2 (5.4%)4 (11%)1 (2.7%) 19 (79%)1 (4.2%)3 (13%)1 (4.2%) 11 (85%)1 (7.7%)1 (7.7%)0 (0%) > .999 Lung nodules removed during first metastasectomy 3 (2, 6) 3 (2, 5) 6 (1, 20) .567

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 .

7546 Background: MRD assessment informs relapse risk in MM but is typically bone marrow-based and invasive. We therefore compared two minimally invasive MRD assays: BM-informed cfDNA whole-genome sequencing (cfWGS) and plasma proteomic MRD (EasyM). Methods: 71 longitudinal plasma samples (22 diagnosis, 49 follow-up) from 22 newly diagnosed MM patients across 8 Canadian sites (TFRIM4) had paired cfWGS and EasyM (Rapid Novor Inc). cfWGS MRD used patient-specific mutation lists from diagnostic BM WGS (Abelman et al., medRxiv 2025). EasyM used mass spectrometry to quantify residual M-protein from baseline. The primary endpoint was progression-free survival (PFS). Results: Among 22 MM patients (8 male, 14 female; median age at diagnosis 62 years), 8 progressed at a median follow-up of 52.6 months (range: 10-79 months). At 1-year maintenance (n = 18 available), cfWGS MRD+ (6/18) predicted inferior PFS (HR 20.12, 95% CI 2.23-181.60, p = 0.007). EasyM any-detect positivity was frequent (16/18, reflecting delayed clearance) and not prognostic (p = 0.99), with poor agreement vs cfWGS (44.4%, κ = 0.118). An exploratory EasyM clearance threshold of 0.93% (hypothesis-generating) classified 5/18 patients as MRD+ and stratified PFS (HR 8.78, 95% CI 1.55-49.82, p = 0.004), improving agreement with cfWGS (17/18, 94.4%, κ = 0.870). Progression clustered in cfWGS+/EasyM-high patients (EasyM >0.93%; 4/5; median 11.9 months post-collection [1.9–22.8]) and occurred once in cfWGS−/EasyM-low patients (1/12, 27.6 months). The only discordant case (cfWGS+/EasyM−) progressed 8.7 months after collection. Higher quantitative MRD burden was associated with inferior PFS (cfWGS: HR 2.92 per 1 SD, 95% CI 1.29-6.59, p = 0.01; EasyM: HR 5.48 per 1 SD, 95% CI 0.79-37.90, p = 0.085). At ~100 days post-autologous stem cell transplantation (ASCT; n = 16 available), EasyM was uniformly MRD+ (16/16) while cfWGS was MRD+ in 7/16 patients. Applying an EasyM clearance threshold (2.13%; 9 cleared vs 7 residual) improved agreement with cfWGS (14/16; 87.5%; κ = 0.746). Of two discordant cases, one cfWGS+/EasyM-cleared patient relapsed 38.6 months post-collection and one cfWGS−/EasyM-residual patient remained progression-free at last follow-up. At post-ASCT, both assays showed consistent but underpowered associations with PFS (cfWGS HR 6.32, 95% CI 0.70–56.76, p = 0.100; EasyM-clearance HR 2.36, 95% CI 0.39–14.18, p = 0.335). Across all post-treatment samples (n = 49), continuous cfWGS burden correlated with EasyM residual M-protein (rho = 0.535, p < 0.001). Conclusions: BM-informed cfWGS MRD strongly stratified PFS, whereas EasyM required a clearance definition due to near-universal early positivity. Concordant plasma burdens support complementary MRD information. Future work will validate these findings in larger cohorts and quantify the incremental value of combined cfWGS and proteomic MRD for early relapse prediction.

10043 Background: Tumor resection is a cornerstone of therapy for neuroblastoma (NB) and Wilms tumor (WT). Minimally invasive surgical approaches such as laparoscopic or robotic tumor resection hold promise to reduce surgical morbidity while maintaining excellent oncologic outcomes. This study aims to determine the utilization and outcomes of laparoscopic and robotic resection of NB and WT among children in a national cohort, hypothesizing that utilization is increasing over time and outcomes are not inferior to open resection. Methods: A retrospective cohort analysis of patients <18 years old in the 2020-2023 National Cancer Database who underwent resection of NB or WT was performed. Surgical approach trends were assessed via Cochran-Armitage tests. Conversions to open surgery, length of stay (LOS), and readmissions were compared between approaches using Kruskal-Wallis, Chi-square, and Fisher’s exact tests. Results: Among 1,262 children who underwent resection of NB (n=581) or WT (n=681), open procedures were most common (83.4%), followed by laparoscopic (13.9%), and robotic (2.7%). Utilization of each approach was stable over time aside from increased robotic resection of NB from 0% to 4% (p=.024). Approach did not vary by patient age (Table 1). Median WT size and lymph node yield were similar between approaches (both p>.05). In NB, laparoscopic procedures were performed on smaller tumors than open or robotic (p<.001). There were no robotic conversions to open; 11.4% of laparoscopic procedures were converted without change over time or difference between NB and WT (both p>.05). Median LOS was greater for open procedures than laparoscopic or robotic (p<.001). Readmission rates (p=.64) and margin status (p=.63) were similar between approaches. Outcomes did not vary by diagnosis. Conclusions: Utilization of minimally invasive approaches for NB or WT resection remains low despite noninferior or improved outcomes. Efforts to safely increase utilization are needed, especially for robotics, so that survivorship can be improved through reduced surgical morbidity. Differences in patient characteristics and outcomes by surgical approach. Characteristic or Outcome Open Laparoscopic Robotic p value Age in years (median, IQR) 3 (1, 4) 3 (1, 5) 3 (1, 7) 0.08 % female 53% 53% 44% 0.59 NB tumor size in mm (median, IQR) 72 (50, 101) 47 (35, 71) 70 (51, 86) <0.001 WT tumor size in mm (median, IQR) 110 (75, 140) 115 (93, 150) 93 (54, 125) 0.10 % metastatic disease 33% 30% 15% 0.07 % neoadjuvant therapy 35% 27% 22% 0.014 % conversion to open n/a 11% 0% 0.05 Negative margins 86% 83% 96% 0.63 # Lymph nodes assessed in WT (median, IQR) 5 (3, 8) 6 (3, 10) 4 (3, 9) 0.62 LOS in days (median, IQR) 5 (4, 7) 4 (2, 6) 4 (1, 5) <0.001 % readmission 15% 14% 9% 0.64

OBJECTIVE Frailty is a known predictor of adverse outcomes in pituitary surgery, yet its impact regarding craniopharyngioma remains unclear. The authors assessed preoperative frailty, measured by the 11-factor modified frailty index (mFI-11), and its association with perioperative morbidity among adult patients undergoing craniopharyngioma surgery. METHODS Using the Registry for Adenomas of the Pituitary and Related Disorders (RAPID) database, the authors performed a retrospective cohort study of the records of patients ≥ 18 years of age who underwent craniopharyngioma surgery between June 2007 and November 2024. Patients were stratified into the following categories according to their numeric mFI-11 score: fit (scores 0 and 1), managing well (scores 2 and 3), and mildly frail (scores 4–6). Primary outcomes included hospital length of stay (LOS) and discharge disposition. Secondary outcomes included 90-day readmission, surgical outcomes, and complications. Multivariable analyses were performed to identify independent predictors of hospital LOS and non-home discharge, adjusting for age, surgeon experience, American Society of Anesthesiologists class, complications, and surgical approach. RESULTS Among 278 patients (221 fit, 43 managing well, 14 mildly frail), higher-frailty patients were older (mean age 47.8 ± 16.1 years in fit vs 60.1 ± 12.5 years in managing well vs 67.6 ± 8 years in mildly frail, p < 0.001) and more likely to present urgently (24.2% vs 36.4% vs 78.6%, p = 0.001). Gross-total resection was achieved less frequently in frail patients (44.8% vs 24.3% vs 23.1%, p = 0.030). Overall complication rates were similar; however, increasing frailty was associated with higher rates of postoperative mortality (0% vs 2.8% [1/36] vs 7.7% [1/13], p = 0.018), pneumonia (0.5% [1/195] vs 2.8% [1/36] vs 15.4% [2/13], p = 0.006), and reintubation (2.6% [5/195] vs 2.8% [1/36] vs 30.8% [4/13], p = 0.002). Higher frailty was associated with a stepwise rise in median [IQR] LOS (5 [3–8] days vs 7 [4–12] days vs 13 [6.5–21.8] days, p < 0.001) and remained an independent predictor of extended LOS on multivariable analysis (β = 1.729 per point, p = 0.006). Rates of non-home discharge showed a similar pattern (9.2% vs 30.0% vs 64.3%, p < 0.001), with frailty independently predicting non-home discharge (OR 2.352, 95% CI 1.527–3.822). Unplanned 90-day readmission rates were significantly higher in the mildly frail cohorts (22.5% vs 45.7% vs 53.8%, p = 0.002). CONCLUSIONS The mFI-11 scores independently predicted perioperative morbidity following craniopharyngioma resection. Incorporating frailty screening into preoperative screening may improve risk stratification, family and patient counseling, and discharge planning.

OBJECTIVE Craniopharyngiomas are benign intracranial tumors that can be difficult to manage operatively and often result in postoperative complications and prolonged recovery. Understanding the factors that influence length of stay (LOS), discharge disposition, and readmission can guide perioperative planning and patient counseling. The authors examined the clinical, radiographic, and surgical predictors of extended LOS (eLOS), nonhome discharge, 90-day readmission, and hospitalization ratio (HR) after craniopharyngioma resection using a large, multicenter cohort. METHODS A retrospective analysis was conducted using the Registry of Adenomas of the Pituitary and Related Disorders database, encompassing 469 patients who underwent craniopharyngioma resection at 14 US academic centers from 2011 to 2025. Patients were stratified by 4 outcomes: eLOS (> 75th percentile), discharge to home versus skilled nursing facility/rehabilitation, 90-day hospital readmission, and hospitalization ratio (i.e., integration of initial and readmission LOS). Multivariable logistic regression models identified independent predictors for each outcome among patient and surgical variables. RESULTS An eLOS (> 10 days) was independently associated with preoperative memory loss (OR 3.75, 95% CI 1.95–7.21), gait imbalance (OR 5.90, 95% CI 1.53–22.70), and postoperative complications (OR 4.07, 95% CI 2.34–7.06). The use of a nasoseptal flap was protective against an eLOS (OR 0.52, 95% CI 0.28–0.93). Discharge to home was predicted by an endoscopic approach (OR 3.87, 95% CI 1.78–8.44) and postoperative intact thirst (OR 2.22, 95% CI 1.05–4.66) and negatively predicted by preoperative diabetes mellitus (OR 0.21, 95% CI 0.09–0.50), LOS (OR 0.87, 95% CI 0.84–0.91), and postoperative cognitive dysfunction (OR 0.30, 95% CI 0.13–0.72). Among 385 patients with follow-up data, a 90-day readmission was independently associated with postoperative complications (OR 5.62, 95% CI 3.12–10.13), preexisting coronary artery disease (OR 4.30, 95% CI 1.46–12.69), and postoperative cognitive dysfunction (OR 3.33, 95% CI 1.76–6.44). A higher HR was associated with diabetes mellitus (unstandardized B 0.059, 95% CI 0.010–0.108, p = 0.02), postoperative complications (unstandardized B 0.054, 95% CI 0.021–0.086, p = 0.001), and postoperative cognitive dysfunction (unstandardized B 0.049, 95% CI 0.006–0.092, p = 0.02). Tumor pathologic subtype and size, prior treatment, extent of resection, and surgeon experience were not directly predictive of outcomes. CONCLUSIONS Cognitive and functional status, systemic comorbidities, and postoperative complications, in addition to surgical approach, are important predictors of the early clinical course after craniopharyngioma surgery. Early identification of high-risk patients may help to guide treatment decisions, improve discharge planning, and reduce healthcare utilization.