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707 Background: Due to insufficient data, therapy for unresectable, locally advanced pancreatic adenocarcinoma (LAPAC) is based on trials in metastatic disease, and outcomes remain poor. TTFields disrupt cancer cell division using alternating low-frequency electric fields delivered externally by a portable device. In the phase 3 PANOVA-3 trial (NCT03377491), TTFields with gemcitabine/nab-paclitaxel (GnP) significantly improved overall survival (OS; HR 0.82) and pain-free survival (HR 0.74) vs GnP in patients with unresectable LAPAC. Methods: In PANOVA-3, patients with newly diagnosed LAPAC were randomized 1:1 to receive GnP with or without concomitant TTFields. Kaplan-Meier methodology was used for time-to-event analyses. Response evaluations were based on RECIST V1.1. OS, pain-free survival, and safety were analyzed post-hoc in subgroups based on sex (male, female), age ( < 65, ≥65 years), and BMI (<25, ≥25 kg/m 2 for efficacy; ≤20, 20–25, 25–30, ≥30 kg/m 2 for safety). Differences between treatment arms were compared using the log-rank test. Results: Efficacy outcomes are shown in the table. TTFields significantly extended pain-free survival in females and patients ≥65 years. Device-related adverse events (AEs) were comparable between sexes, older and younger patients, and across BMI ranges. Some device-related skin adverse events occurred more frequently in females (e.g. dermatitis, 33.1% vs 22.7%; rash 21.8% vs 13.5%, females vs males, respectively); others occurred more often in males (e.g. maculo-papular rash, 9.8% vs 14.2%; erythema, 9% vs 12.1%, females vs males, respectively). Dermatitis and pruritus had a higher incidence in the BMI ≥30 kg/m 2 subgroup (38.5%), whereas patients with BMI <30 kg/m 2 did not show noticeable differences in device-related AEs. Skin irritation (11.5% vs 5.5%) and skin reactions (8.5% vs 2.8%) were more common in patients ≥65 years than patients <65 years. Conclusions: Median OS and pain-free survival in these post-hoc subgroup analyses are generally consistent with the overall analysis, supporting use of TTFields with GnP in unresectable LAPAC. No new safety concerns were noted; observations were consistent with the general PANOVA-3 population. Clinical trial information: NCT03377491 . Survival outcomes for the subgroup analyses. Median OS, months TTFields + GnP GnP P value Age<65 years≥65 years 18.6 (n=113)15.4 (n=172) 16.0 (n=114)12.9 (n=172) 0.2060.061 SexFemaleMale 16.8 (n=138)15.7 (n=147) 14.5 (n=161)13.4 (n=125) 0.1140.145 BMI<25≥25 16.7 (n=166)16.2 (n=117) 14.2 (n=174)14.5 (n=108) 0.1550.105 Median pain-free survival, months Age<65 years≥65 years 16.5 (n=113)13.1 (n=172) 9.2 (n=114)8.3 (n=172) 0.4070.035 SexFemaleMale 16.5 (n=138)15.2 (n=147) 8.3 (n=161)9.3 (n=125) 0.0260.478 BMI<25≥25 16.6 (n=166)14.7 (n=117) 9.1 (n=174)8.3 (n=108) 0.1170.088

635 Background: [ 212 Pb]VMT-a-NET is an alpha therapy agent targeting somatostatin receptor subtype 2 (SSTR2)-expressing tumors. Here, we report the results of a prospective, open-label, Phase I/IIa trial (NCT05636618), assessing safety, tolerability, pharmacokinetics, and preliminary efficacy of [ 212 Pb]VMT-a-NET in patients with advanced neuroendocrine tumors (NETs). Methods: Adults with well-differentiated unresectable or metastatic SSTR2-expressing NETs, who are peptide receptor radionuclide therapy (PRRT) naïve, and who progressed on at least one prior line of systemic therapy, are eligible. Participants can receive up to four cycles of [ 212 Pb]VMT-a-NET at the assigned dose level. Participants are followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Results: As of 16-Aug-2025 (data cut-off [DCO]) a total of 48 participants were enrolled into cohorts 1 and 2 and received at least one dose of [ 212 Pb]VMT-a-NET (n=2 in Cohort 1, and n=46 in Cohort 2 at a dose level of 92.5 MBq and 185 MBq, respectively). Among all participants treated with at least one dose of [ 212 Pb]VMT-a-NET (n=48), no DLTs, no grade 4 or 5 adverse events (AEs), and no treatment-related discontinuations, were observed. Median follow-up time was 28 weeks (range: 6-93). Nine participants were followed for DLT observation (n=2 in cohort 1 and n=7 in cohort 2).Seven of these patients were with no progression as of the DCO. Three out of the seven participants enrolled at the dose level of 185 MBq achieved a confirmed partial response (PR). Median follow-up time for participants included in the efficacy group was 72 weeks (range: 6-93). Cohort 3, at a dose level of 222 MBq, has recently been opened for enrollment. At the DCO, 4 participants were enrolled in this cohort. Updated safety outcome for all participants along with updated efficacy findings for participants in Cohort 1 and 2 with sufficient maturity, will be presented during the congress. Conclusions: [ 212 Pb]VMT-a-NET showed a favorable safety profile and promising clinical benefit for patients with advanced SSTR2-expressing NETs treated at the dose levels of 92.5 MBq and 185 MBq. The study is ongoing with Cohort 3 (222 MBq) currently open for enrollment. Clinical trial information: NCT05636618 .

373 Background: Recent studies have demonstrated encouraging outcomes with neoadjuvant ICIs in pts with localized deficient mismatch repair (dMMR) and/or microsatellite instability-high (MSI-H) GEC, prompting discussions around the feasibility of nonoperative management (NOM). However, current evidence is largely from phase 1 and 2 clinical trials with limited sample sizes. Thus, the efficacy and safety of neoadjuvant ICI in this pt population remain subject to ongoing debate. Methods: We conducted a systematic review and meta-analysis of prospective and retrospective studies evaluating neoadjuvant ICIs in pts with localized dMMR/MSI-H GEC according to the PRISMA guidelines. The primary outcomes were pathological complete response (pCR) and complete clinical response (cCR) rates. cCR was defined as no evidence of residual disease on tumor-specific imaging and on endoscopy with biopsy. Secondary outcomes included major pathologic response (MPR) rates and the incidence of grade 3–4 immune-related adverse events (irAEs). Proportions with 95% confidence intervals (CI) were used to pool event rates for occurrence of cCR, pCR, MPR and grade 3-4 irAEs. The DerSimonian and Laird random-effects model was used. NOM was assessed as part of the qualitative analysis. Results: 20 studies comprising 396 pts treated with neoadjuvant ICIs were included. Three studies utilized double ICI blockade (PD-1/ PD-L1 inhibitor plus CTLA-4 inhibitor), while the remaining studies primarily utilized monotherapy with a PD-1 inhibitor, with or without chemotherapy. Overall, 320 (81.0%) underwent surgical resection. The pooled pCR rate was 41.6% (95% CI, 33.1%–50.8%), cCR 63.8% (95% CI, 45.6%–78.8%), and MPR 64.2% (95% CI, 49.1%–76.9%). The pooled incidence of grade 3–4 irAEs was 5.1% (95% CI, 0.6%–12.2%). Subgroup analysis showed higher pCR with ≥3 months versus <3 months of ICI (50.2% [95% CI 42.2–58.3] vs 28.4% [18.9–40.2]; χ²=8.69, p=0.003). Forty-four pts were managed with NOM, two experienced early local regrowth over median follow-up ranging from 11.5 to 28 months. Conclusions: Neoadjuvant ICI therapy appears to be a safe and effective therapeutic strategy for pts with localized dMMR/MSI-H GEC. Neoadjuvant ICI exposure for ≥3 months seems to yield higher pCR rates than <3 months. The high and prolonged cCR rates support the nonoperative strategy in selected patients with dMMR/MSI-H GEC.

BACKGROUND: Patients with cervical artery dissection (CeAD) may experience a recurrent dissection, but its frequency, risk factors, and clinical implications are not well defined. We aimed to determine the risk, associated factors, and clinical impact of recurrent CeAD. METHODS: The STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection) was a multicenter international retrospective observational study of patients with CeAD treated between January 2015 and June 2022. Recurrent dissection was defined as a CeAD occurring at least 7 days after the diagnosis of the index event that affects a different artery or a different segment of the same artery. Patients were followed from day 7 up to 2 years. The absolute risk of recurrent CeAD over time was calculated using Kaplan-Meier survival estimates. Multivariable logistic and Cox regression models were used to assess predictors of CeAD recurrence. RESULTS: Of the 4023 patients included in STOP-CAD, 3836 (median age 46 years, 45% women) were eligible for this analysis. During a median (interquartile range) follow-up of 295 (97–720) days, 88 (2.29%) patients had a CeAD recurrence. Median time-to-recurrent CeAD was 53 (interquartile range, 18–157) days. The estimated risk of recurrent CeAD at 2 years was 3.22% (95% CI, 2.59%–4.00%). In multivariable analyses, younger age (adjusted odds ratios, 0.98 [95% CI, 0.96–0.99]), migraine (adjusted odds ratio, 1.88 [95% CI, 1.14–3.07]), and fibromuscular dysplasia (adjusted odds ratio, 2.90 [95% CI, 1.66–5.06]) were associated with CeAD recurrence, while presenting with an ischemic stroke was associated with a lower likelihood of recurrence (adjusted odds ratio, 0.47 [95% CI, 0.29–0.75]). These associations with CeAD recurrence over time were confirmed by Cox regression analyses. Among the 88 patients with recurrent CeAD, only 5 had accompanying ischemic events (3 strokes, 2 transient ischemic attacks). CONCLUSIONS: In this retrospective study, recurrent CeAD was uncommon, approximately half of the events were diagnosed within the first 2 months of the index event, and recurrent events rarely caused new ischemic events. Younger age, migraine, absence of ischemic stroke at presentation, and signs of fibromuscular dysplasia may help identify high-risk patients.

Abstract Background Stigma associated with tuberculosis (TB) and TB diagnosis is a major social factor in delay of diagnosis and non-adherence to TB treatment among Asian American and Pacific Islander (AAPI) populations. Main sources of stigma include misconceptions regarding TB transmission and lack of knowledge about symptoms or treatment.Figure 1.Respondent demographicsBreakdown of respondent demographics by age, gender, and AAPI subgroup.Figure 2.Demographic breakdown of TB awarenessTB awareness by AAPI subgroup, age, and gender. Methods A cross-sectional survey of 666 AAPI individuals analyzed TB symptom recognition, transmission misconceptions, and awareness in two AAPI community centers. Data were segmented by AAPI subgroup, metropolitan area (Seattle/Tacoma vs. Las Vegas), age, and gender.Figure 3.TB transmission beliefs.Figure 4.TB treatment, curability, and latent TB infection awareness. Results Overall, 76.6% of respondents reported TB awareness, varying by AAPI subgroup. Awareness was highest among Korean (95%) and Filipino (91%) participants, and lowest among Vietnamese (52%) and Cambodian (50%) respondents. Regionally, TB awareness was similar between Tacoma (76%) and Las Vegas (79%). Age and gender significantly impacted awareness. Respondents under 18 had the lowest TB awareness (59%), while those aged 18-34 had the highest (84%). Females reported higher TB awareness (79%) and symptom recognition (61%) than males (74% and 46%, respectively). Symptom knowledge varied. 55% were aware of TB symptoms, but only 16% were able to recognize five common TB symptoms. Misconceptions about transmission also persisted broadly. Out of the 71% of respondents who were aware that TB is transmissible, many incorrectly believed TB spread via shaking hands (35%), sharing food/drinks (50%), or touching items in public areas (37%). The 45-64 and 65+ age groups were most prone to misconceptions about transmission. While 72% of respondents were aware that TB could be treated, only 57% knew TB could be cured. 30% of respondents were aware of latent TB infection. Conclusion Significant disparities in TB awareness exist in AAPI communities. Females demonstrated greater TB awareness perhaps due to cultural differences (“caretaker role”), while TB transmission misconceptions were prevalent among older individuals. Limited knowledge on LTBI and TB treatment represent significant barriers to effective TB control. Tailored educational efforts will be required to improve TB awareness and reduce misconceptions within AAPI communities. Disclosures All Authors: No reported disclosures

Abstract Background The COVID-19 pandemic saw a worrisome rise in mucormycosis cases in India, especially among those receiving corticosteroid therapy. While corticosteroids are essential for managing severe COVID-19 cases, their immunosuppressive action appears to augment infection risk. Clinically, prolonged steroid use may result in severe forms of mucormycosis; however, this requires rigorous systematic evaluation. Methods We conducted an exhaustive analysis of 327 mucormycosis cases and 596 COVID-19 controls, all of whom were treated during the second wave in India. Exposure to steroids was carefully categorized by duration into three groups: short-term (1-5 days), standard-term (5-10 days), and long-term ( &gt; 10 days). Each case was biopsy-proven, with further radiographic confirmation of disease extent. Special emphasis was laid on intracranial extension as a marker of severity, along with tracking treatment outcomes and survival. Statistical modeling was used to correct for important confounders, including diabetes status, glycemic control, and concurrent use of other immunomodulators. Results The results were striking. Those receiving steroid treatment for more than ten days of duration had a nearly fourfold higher incidence of intracranial mucormycosis compared with short-term-treated patients (38.2% vs. 12.5%, p&lt; 0.001). Each day of steroid use accounted for a 12% increase in associated risk. While mortality rates were equal, patients receiving prolonged treatment had a considerably increased number of surgical procedures (35.3% vs. 16.7%, p=0.02) as well as more complicated hospitalization. Those with diabetes were especially sensitive to such effects of prolonged treatment. Conclusion The study highlights the role of cautious use of corticosteroids in the management of COVID-19. Our work gives strong evidence for the importance of compliance with guideline-based recommendations for corticosteroid duration, especially for high-risk populations. This study empowers healthcare practitioners with unequivocal evidence to provide optimal COVID-19 treatments while avoiding the risk of severe fungal infection. Disclosures All Authors: No reported disclosures

Abstract Background Previous studies demonstrate that certain asymptomatic MAPT variant carriers (Asymp‐ MAPT ) exhibit altered baseline gray matter volume (GMV) and functional connectivity (FC) profiles. It remains unclear whether these imaging measures may herald risk for earlier conversion to the symptomatic phase. To address this, we stratified Asymp‐ MAPT based on baseline GMV and longitudinal FC changes to assess whether any Asymp‐ MAPT subgroups showed signs of longitudinal neurodegeneration or cognitive decline. Method We studied 25 Asymp‐ MAPT recruited from the UCSF Memory and Aging Center and ALLFTD Consortia. Using a median split, we divided Asymp‐ MAPT into groups with smaller (LowGMV; n = 12) and larger baseline GMV (HighGMV; n = 13) within regions atrophied in symptomatic MAPT carriers ( n = 20). Next, we stratified Asymp‐ MAPT based on longitudinal FC changes using k‐means clustering on rates of change in FC for four intrinsic connectivity networks associated with common MAPT ‐related syndromes: salience (SN), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and default mode (DMN) networks. We compared Asymp‐ MAPT subgroups from each stratification on baseline and longitudinal changes in demographics, plasma neurofilament light (NfL) concentration, GMV within 246 Brainnetome regions, and neuropsychological test scores. Result Stratification of Asymp‐ MAPT based on baseline GMV showed that LowGMV had higher education levels compared to HighGMV, with no other demographic differences. Though LowGMV and HighGMV did not differ in baseline NfL, LowGMV showed greater longitudinal NfL increases. These groups did not differ in baseline or longitudinal GMV changes. LowGMV had lower baseline attention and working memory scores, and greater longitudinal decline in set‐shifting and visuospatial performance. Stratification based on FC changes yielded one group (DecFC; n = 17) exhibiting longitudinal decreases in the SN, PSP, and DMN and another (IncFC; n = 8) showing increases in each network. DecFC and IncFC did not differ in demographics, baseline or longitudinal NfL, or baseline GMV. Longitudinally, DecFC showed greater decline in posterior superior temporal and inferior parietal cortices. DecFC showed lower baseline attention and semantic fluency scores, and greater longitudinal decline in set‐shifting and visuospatial memory performance. Conclusion Lower baseline GMV within regions atrophied during the symptomatic phase and longitudinal FC declines within MAPT ‐relevant networks may signal earlier symptomatic conversion in Asymp‐ MAPT .

BACKGROUND AND OBJECTIVES: Minimum clinically important differences (MCIDs) for patient-reported outcome metrics (PROMs) in patients with cervical spondylotic myelopathy (CSM) lack consensus on the most appropriate calculation method. This retrospective study aimed to identify the optimal MCIDs for commonly used PROMs in CSM. METHODS: The CSM database from the Quality Outcomes Database SpineCORe Study Group was analyzed. Baseline, 3-month, and 24-month PROM values for Neck Disability Index (NDI), 5-dimension Euro-quality of life (EQ-5D) in quality-adjusted life years, modified Japanese Orthopaedic Association (mJOA) score, and neck/arm pain numeric rating scale (NRS) were collected. MCIDs were calculated for each PROM using previously validated techniques. MCID values were compared using the area under the curve (AUC) with the North American Spine Society satisfaction scale as an anchor. RESULTS: A total of 1141 patients with CSM undergoing surgery were included in this analysis. Improvement of ≥30% from baseline was the optimal MCID for NDI and neck/arm NRS. At 24 months, the optimal percentage cutoff MCID for these instruments resulted in AUCs of 0.76, 0.72, and 0.67, similar to the 30% improvement method, with AUCs of 0.73, 0.71, and 0.67, respectively. Numeric cutoffs (0.065 at 3 months; 0.149 at 24 months) were the superior MCIDs for EQ-5D. For mJOA score, a severity-adjusted MCID outperformed other methods, yielding an AUC of 0.67 at 24 months. MCIDs were achieved in 63% of patients for NDI, 59% for neck pain NRS, 61% for arm pain NRS, 52% for EQ-5D, and 59% for mJOA score at 24 months. CONCLUSION: Using the Quality Outcomes Database SpineCORe data set, we defined optimal MCIDs for key PROMs in CSM. A ≥30% improvement from baseline was optimal in NDI and arm/neck NRS. An absolute numeric cutoff was superior for EQ-5D (0.149 at the 24-month follow-up). A severity-adjusted MCID performed best for mJOA score. These redefined benchmarks better capture the treatment impact and guide care decisions for patients with CSM.

ABSTRACT Musculoskeletal infection (MSKI) remains a major problem after trauma and elective orthopedic surgery. Chronic MSKI is related to the formation of biofilm, which impairs diagnosis and effective treatments. Therefore, to understand and communicate global standards and best practices, the 2025 International Consensus Meeting (ICM) on MSKI created a Biofilm Section to address crucial aspects of biofilm biology pertaining to its mechanisms of drug resistance and immune evasion, and potential approaches to overcome them. This featured a 2‐year process, with final voting and discussion on May 8–10, 2025, in Istanbul, Turkey. This Consensus Article is the effort of the Biofilm Basic Mechanisms Workgroup, which interpreted the results on ICM questions related to (1) the infectious microenvironment; (2) appropriate inocula in preclinical research; (3) biofilm behavior in infected tissues; and (4) synergy within biofilms and with other comorbidities. Collectively, we find that this field has the necessary research tools to discover the pathophysiology of orthopedic implant‐associated biofilm development and maturation, perform clinically relevant studies in animal models, and elucidate mechanisms that allow opportunistic infections in compromised tissues and patients with other health issues.

Objective Cervical artery dissection (CeAD) may be limited to the extracranial extradural space or extend to the intradural space. Intradural extension can potentially increase the risk of stroke and subarachnoid hemorrhage. However, the factors associated with intradural extension and its impact on clinical outcome remain unclear. Methods This was a secondary analysis of the STOP‐CAD observational, multi‐center study. Patients with CeAD and intradural extension (CeADid) were compared with those with pure CeAD extradural dissections (CeADed) using multiple regression analyses. Results Of 4,023 patients with CeAD, 534 (13.3%) had CeADid. In comparison to patients with CeADed, those with CeADid more often had clinical overt stroke or transient ischemic attack (TIA) at presentation, acute infarcts on imaging, a vertebral artery affected, and severe stenosis of the involved vessel ( p < 0.001 for all). In contrast, carotid involvement and complete occlusions were more frequent in patients with CeADed ( p < 0.001 for both). CeADid was associated with a shift in the distribution of scores on the modified Rankin Scale (mRS) toward worse functional outcome (odds ratio [OR] = 0.76, 95% confidence interval [CI] = 0.62–0.92) but the odds for favorable outcomes (mRS = 0–2) did not differ between the groups after appropriate adjustments on multivariate analysis. CeADid was independently associated with higher mortality at 180 days on multivariate analysis (adjusted OR = 2.84, 95% CI = 1.50–5.38). Interpretation CeADid is associated with more severe clinical presentation, a shift toward less favorable outcomes, and higher mortality rates. These findings suggest that CeADid may represent a high‐risk type of CeAD. ANN NEUROL 2026;99:1189–1197