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OBJECTIVE Deep brain stimulation (DBS) is emerging as an additional surgical option for refractory, multifocal epilepsy. Four-lead DBS systems can be used when seizure onset is poorly localized, generalized, or involves multiple targetable circuits. The goal of this study was to assess preliminary outcomes and complication rates in 4-lead DBS systems for treating epilepsy. METHODS A consecutive series of 32 patients with 4-lead DBS implants who had at least 6 months of follow-up was reviewed, and demographics, outcomes, and complications were abstracted. RESULTS Thirty-two patients implanted with 4 DBS leads (including off-label use) were included. The median age at surgery was 28.5 years, the median age at epilepsy diagnosis was 7.5 years, and 18 patients (56%) were women. The median epilepsy duration prior to implantation was 21 years. The most common seizure localization was frontotemporal (53%), followed by generalized (28%) and parietoccipital (13%). Prior vagus nerve stimulation had been trialed in 20 patients (63%), and an invasive stereotactic EEG recording was performed in 17 patients (59%). Eight patients had prior epilepsy surgery (25%). DBS targets included the anterior thalamic nucleus in combination with the centromedian thalamic nucleus, hippocampus, pulvinar nucleus, cingulate, insula, and globus pallidus. The median surgical duration was 5 hours 22 minutes, with a median operating room time of 8 hours 21 minutes. The median postoperative follow-up was 27 (interquartile range 17–41) months. Three patients experienced transient neurological deficits and 2 patients required intraoperative lead repositioning. There were no infections or hemorrhages. Most patients benefited from stimulation (22% Engel class I, 22% class II, 28% class III, and 28% class IV). The median patient-reported seizure reduction rate was 70%, with a responder rate of 72%. One patient elected to have the system explanted. CONCLUSIONS Four-lead DBS is safe and can achieve meaningful improvement in challenging cases of multifocal epilepsy with a low complication rate.

OBJECTIVE The aim of this study was to determine predictors of the minimum clinically important difference (MCID) in the Neck Disability Index (NDI) following cervical spinal deformity surgery. METHODS A retrospective review was performed of a prospective, multicenter adult cervical spinal deformity database. All patients had baseline and 1-year NDI scores. Patients met MCID with an improvement of NDI by 7 points between baseline and 1 year, as previously established. Baseline demographics, comorbidities, and both baseline and 1-year spinopelvic parameters were evaluated for statistical significance in a univariate logistic regression analysis. Significant variables, in addition to baseline NDI, were analyzed in a multivariable logistic regression model by backward selection with Akaike information criterion minimization. RESULTS A total of 122 patients were included with a median age of 62 (IQR 56, 69) years; 62% of patients were female. Of the 122 patients, 72 (59%) achieved NDI MCID at 1 year. Predictors of achieving MCID on univariate analysis included a lower Charlson Comorbidity Index (CCI) total score (OR 0.70, p = 0.03), depression as a comorbidity (OR 2.9, p = 0.02), lower C2 tilt at the 1-year follow-up (OR 0.92, p = 0.02), and a greater difference between 1-year postoperative C2–7 sagittal vertical axis (SVA) and preoperative C2–7 SVA (OR 0.98, p = 0.0495). On multivariable logistic regression analysis, predictors of achieving MCID included a lower CCI (OR 0.62, p = 0.03), depression as a comorbidity (OR 3.1, p = 0.059), a greater change in C2–7 SVA at the 1-year follow-up compared with baseline (OR 0.97, p = 0.055), and baseline NDI (OR 1.02, p = 0.24) with an area under the curve of 0.74. CONCLUSIONS The best-fit multivariable model included higher baseline NDI, a greater change in C2–7 SVA, patient-reported baseline depression, and lower CCI as important factors in predicting NDI MCID.

Abstract Background: As with most Sub-Saharan African countries, Nigeria has a rising incidence of cancer, with disproportionate mortality rates. The financial burden of cancer care often results in catastrophic healthcare spending, leading to treatment refusal, disruption, and discontinuation. This is particularly significant in Nigeria, where nearly all patients are uninsured, and out-of-pocket costs often exceed households’ ability to pay. Financial Navigation Programs (FNPs) have been shown to mitigate treatment-related financial toxicity in cancer care and reduce treatment abandonment, but there is a paucity of high-quality data on this intervention in resource-constrained settings. Here, we present a randomized controlled trial to evaluate the impact of a novel FNP in Nigeria. Methods: We designed the COST-FIN trial, a multi-site pragmatic single-blinded randomized controlled trial of newly diagnosed (<6 weeks from diagnosis) adults (≥18 years) with breast, colorectal, or prostate cancer at two tertiary cancer centers in Nigeria. Participants (n=200) will be randomized (1:1) to either the intervention (FNP) or the control arm and followed for 12 months. Data on key individual, treatment, and financial parameters will be collected via structured interviews and chart abstraction at baseline, 3, 6, and 12-month follow-up. In addition, participants randomized to the FNP will receive a tailored financial literacy assessment, financial planning support, and enhanced access to resources by trained financial navigators. Primary and secondary outcomes are Financial Catastrophe (FC) and Financial Distress (FD), respectively. Exploratory outcomes will include cost-related non-adherence and cost-effectiveness of the program. An interim analysis will be conducted when 50% of the estimated accruals reach 6 months of follow-up, with crossover if compelling evidence of benefit is demonstrated at that time point. All participants will be followed for 12 months from recruitment. Discussion: This first-of-its-kind study will provide evidence on the role of FNP in potentially eliminating financial barriers to cancer care in Nigeria. Given the country’s renewed interest in cancer control through the passage of the National Cancer Control Plan, findings from this study have the potential to influence policy reform and set the stage for further studies to evaluate the scalability and implementation of similar interventions in resource-limited settings. Trial registration : ClinicalTrials.gov NCT06630962. Oct 8, 2024 (https://clinicaltrials.gov/study/NCT06630962)

Abstract Objective High-frequency oscillations (HFOs) are highly specific biomarkers of epileptogenic tissue, yet their noninvasive localization remains challenging due to their brief duration, low amplitude, and poor signal-to-noise ratio. Here, we introduce TH-DeepSIF, a transformer-based deep learning framework trained on biologically realistic neural mass model simulations, to robustly perform HFO source imaging from scalp EEG. Methods TH-DeepSIF was evaluated in simulated single- and dual-source HFO scenarios, where it was tasked with recovering both the spatial location and temporal dynamics of HFO generators under increasing spatiotemporal complexity. We further validated TH-DeepSIF in 25 patients with drug-resistant epilepsy by comparing EEG source imaged HFO sources against surgical resection regions. Results TH-DeepSIF accurately recovered both the spatial location and temporal dynamics of simulated HFO generators, achieving low localization error and strong waveform correspondence with ground truth. TH-DeepSIF localization for pathological HFOs (pHFOs, or spike ripples) demonstrated strong agreement with surgical resection regions, achieving a median localization error of 11.9 mm and specificity of 0.896. Compared with all HFOs (aHFOs), pHFO-based source imaging showed significantly stronger spatial correspondence with resection regions, significantly smaller localization error, and higher precision, sensitivity, geometric mean, and F1 score. Significance These findings demonstrate that TH-DeepSIF provides a robust, data-driven framework for noninvasive HFO source imaging with improved anatomical specificity and enhanced clinical utility for presurgical evaluation using scalp EEG. Moreover, they show that pathological HFOs (spike ripples )—rather than general HFOs—serve as robust EEG biomarkers for accurate localization of the epileptogenic zone. Key Points A fully data-driven, parameter-free framework for noninvasive HFO source imaging using scalp EEG. Pathological HFO source maps exhibit strong spatial concordance with both the surgical resection region and the seizure onset zone. Source imaging based on pathological HFOs consistently outperforms imaging based on all detected HFOs.

Abstract INTRODUCTION The genetic basis of sporadic early‐onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late‐onset Alzheimer's disease (LOAD) polygenic risk in EOAD. METHODS A LOAD polygenic score (PGS) was calculated in the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. RESULTS Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset ( p = 0.106) or with cognitive performance ( p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal‐associated protein 25 (SNAP‐25) ( p = 2.3 × 10 −5 ). DISCUSSION While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. Highlights LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal‐associated protein 25 (SNAP‐25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

Abstract Despite promising results, it remains unclear how to optimally target and personalize closed-loop stimulation to ameliorate deficits in memory and other cognitive functions. We hypothesized that evoked connectivity – the measurement of neural pathway activation using single pulses of electrical stimulation – can guide patient-specific selection of stimulation location and parameters for memory. We characterized brain-wide evoked connectivity profiles of stimulation in memory-related brain regions recorded from 81 patients undergoing intracranial monitoring for epilepsy, showing that greater evoked connectivity between the lateral temporal cortex and the broader memory network (including the mesial temporal lobe, limbic regions and prefrontal cortex) corroborates observations of memory improvement by lateral temporal cortex stimulation. We first found that the lateral temporal cortex, compared to other stimulated regions, evokes the greatest and most distributed connectivity response throughout other memory-related regions. Evoked connectivity in downstream regions is greatest when stimulating a previously identified optimal target for memory improvement, bordering white matter at the rostrocaudal center of the middle temporal gyrus. Evoked connectivity corroborates other biomarkers of memory improvement by closed-loop stimulation, including increased resting-state functional connectivity between stimulated and recorded sites and increased modulation of oscillatory power. These results provide insight into the network mechanisms of stimulation for memory and suggest that evoked connectivity can more broadly predict the functional effects of closed-loop stimulation to prospectively guide targeting and parameter selection.

Cholangiocarcinoma (CCA) represents a biologically and clinically heterogeneous group of biliary tract malignancies. Growing evidence underscores that the 3 major anatomic subtypes—intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA)—are distinct tumor entities rather than a single disease. Each subtype differs in embryologic origin, carcinogenesis mechanisms, molecular landscape, and immunogenic profile, all of which contribute to variability in diagnosis, treatment responsiveness, and prognosis. The importance of understanding these distinctions is reinforced by the rising global incidence of CCA, which highlights the need for precision medicine approaches based on these subtypes. Recent advances have deepened our insight into subtype-specific risk factors, including chronic biliary diseases and metabolic conditions, while artificial intelligence–driven tools are improving diagnostic accuracy and risk stratification. Surgical innovations now allow for more tailored resections and perioperative care, and therapeutic strategies are increasingly guided by molecular and immune profiling. Emerging strategies for early diagnosis and chemoprevention in high-risk populations further emphasize the significance of recognizing the unique biology of each subtype. In this review, we provide a comprehensive overview of the distinct anatomic subsets of CCA, integrating their molecular and biological foundations with clinical management to inform practice and guide future research.

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 .

561 Background: For patients with aHCC, second-line treatment options are not well established. The primary aim of this study was to evaluate the efficacy of Futi, an FGFR 1-4 inhibitor, in combination with Pem as a second line therapy in patients with FGF19-expressing aHCC. Methods: Patients aged ≥ 18 years, with histological/cytological diagnosis or radiological diagnosis of HCC, Child-Pugh (CP) class A-B7, Barcelona Clinic Liver Cancer (BCLC) A, B or C, ECOG performance status of 0-2, and FGF19+, by in-situ hybridization or immunohistochemistry, received Futi 20 mg once daily plus i.v. Pem 200mg every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints include overall survival (OS). The study was designed to enroll 22 evaluable patients to detect PFS6 from 25% (historical control) to 47%, assuming a 1-sided alpha of 0.1 with 80% power. All patients provided written consent. Eligible patients with consent who started treatment are considered evaluable. Results: The study was closed to enrollment early at the request of funding agency due to poor accrual. Between 8/2021 and 3/2024, 14 patients enrolled with 1 patient withdrawing consent before beginning protocol treatment. Among 13 evaluable patients, median age was 72 (range: 60-87) years, 7 (53.8%) were male, 12 CP A (92.3%), 7 BCLC C (53.8%), with 7 (53.8%) having received prior liver directed therapy. Median PFS was 15 weeks (95% confidence interval [CI]: 9.0-Not Estimable) and PFS6 was 23.1% (95% CI: 8.6%, 62.3%). Objective response rate was 0% (95% CI: 0%, 24.71%) and stable disease occurred in 7 (53.9%) of patients. Median OS was 55.7 weeks (95% CI: 47.3-NE). Nine (69.2%) patients experienced at least 1 grade 3+ adverse event (AE), and 2 (15.4%) patients experienced at least a grade 4+ AE. One patient had a grade 5 AE unrelated to study treatment (acute kidney injury). Most commonly reported AEs (occurring in more than 31% of patients) were hyperphosphatemia (76.9%), fatigue (69.3%), diarrhea (61.6%), AST (53.9%) and ALT (46.2%), dry eye (38.5%), nail changes (38.5%), rash-maculo-papular (38.5%), and mucositis oral (38.5%). Conclusions: This prospective study evaluated the use of a targeted treatment in combination with immunotherapy following first line immune-based therapy. This combination had modest activity as a second line therapy for patients with aHCC but did not meet the primary endpoint. The safety profile was acceptable and consistent with prior reports. An optimal second-line regimen remains a critical need. Clinical trial information: NCT04828486 .

Abstract Background Tau‐PET neuroimaging is increasingly applied to diagnose and stage, track progression, and assess response to putative disease‐modifying treatments in individuals with Alzheimer disease. However, it remains to be seen whether findings established in predominantly non‐Hispanic White (nHW) cohorts will generalize to Black and Latino participants who are underrepresented in dementia research. Method Community‐dwelling Black ( n = 83) and Latino participants ( n = 27) completed MRI (with quantification of white matter hyperintensity volumes), and amyloid‐ (PiB or florbetapir) and tau‐ (flortaucipir) PET brain imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Global and regional tau‐PET standardized uptake value ratios (normalized to the cerebellar crus) were determined in Black and Latino participants and compared with findings from an independent cohort of nHW participants ( n = 110), 1:1‐matched for age, sex, education, and global Clinical Dementia Rating®. Conditional logistic modeling compared 47 regions of interest, adjusted for false discovery rate. Relevant associations between flortaucipir retention and clinical outcomes were assessed using Spearman rank correlations. Result Eighty‐three Black (mean 72±10.8‐years‐old, 63% female, 33% cognitively impaired) and 27 Latino participants (mean 65.8‐years‐old, 56% female, 11% cognitively impaired) completed neuroimaging. Data were compared with findings in 110 matched nHW individuals. Global tau‐PET burden was similar between matched cohorts (Black and nHW participants, mean SUVR: 1.34±0.39 vs 1.36±0.37, p = 0.71; Latino and nHW participants, mean SUVR: 1.17±0.09 vs 1.20±0.11, p = 0.66). Lower flortaucipir uptake was noted in the caudate ( p = 0.005) and putamen ( p = 0.022) of Black/Latino participants (vs nHW), although differences attenuated following adjustment for white matter hyperintensity volume. Global flortaucipir retention increased with age (Black: Rho=0.31; Latino: Rho=0.46; nHW: Rho=0.27; p <0.05), amyloid Centiloids (Black: Rho=0.65; Latino: Rho=0.41; nHW: Rho=0.58; p <0.05), and cognitive impairment (i.e., Clinical Dementia Rating® Sum‐of‐Box scores, Black/Latino: Rho=0.31, p = 0.07; nHW: 0.76, p <0.001). Conclusion Tau‐PET patterns were similar across ethnoracial groups after adjusting for white matter hyperintensity volumes—a biomarker of small vessel disease. Flortaucipir retention increased with age, amyloid accumulation, and cognitive impairment across all cohorts. These findings affirm the clinical and research applications of tau PET in diverse cohorts. Acknowledgements : Flortaucipir precursor and technology was supported by Avid Radiopharmaceuticals.