Citations

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

Background/Objectives: Bowel resection may be necessary during cytoreductive surgery (CS) in advanced epithelial ovarian cancer to achieve complete tumor removal. However, concerns about increased perioperative risks and unclear survival benefits have led to ongoing debate. This study aimed to evaluate the impact of bowel resection on perioperative mortality and overall survival (OS) in patients undergoing CS. Methods: We retrospectively reviewed 127 patients with FIGO stage IIB–IV epithelial ovarian cancer who underwent primary or interval CS between 2007 and 2021. Patients were stratified based on the performance of bowel resection. Clinical, surgical, and survival data were analyzed using Kaplan–Meier survival analysis and Cox proportional hazards modeling. Primary outcomes were 90-day mortality and OS. Results: Bowel resection was performed in 58 patients (46%) with more extensive disease and poorer ECOG performance scores. Although the resection group had increased perioperative risks (e.g., higher transfusion rates and ICU use), OS was similar between groups (log-rank p = 0.122). Multivariate analysis identified that increasing age (HR = 1.042, p = 0.005) was independently associated with poorer OS, whereas lymph node dissection (HR = 0.450, p = 0.003) and undergoing primary CS (HR = 0.540, p = 0.047) were associated with improved survival. Bowel resection was not independently associated with OS. Conclusions: Bowel resection does not adversely affect OS when optimal cytoreduction is achieved. Although it increases perioperative complexity, it can be safely incorporated into CS in selected patients. These findings support its use as part of an individualized surgical strategy for advanced ovarian cancer.

SUMMARY Tau aggregates propagate through the brain in a prion-like manner in Alzheimer’s disease (AD) and other tauopathies, but the molecular identity and functional partners of the seeding-competent Tau species remain poorly defined. Here, we present an unbiased proteomic profiling of a high-molecular-weight (HMW) Tau-seed isolated from AD patient brains. We contrast this interactome with that of a biochemically similar, seeding-incompetent HMW-Tau species from age-matched healthy controls. Despite comprising less than 5% of total Tau in the brain, Tau-seed associates with a distinct set of proteins enriched in synaptic, mitochondrial, and vesicle-trafficking functions. Cross-species functional screening in Drosophila and mouse models identifies interactors that modulate Tau toxicity and seeding. Spatially resolved analysis of postmortem AD brains reveals heterogenous co-deposition of these proteins with Tau aggregates, suggesting functionally distinct Tau-seed complexes. Together, this dataset provides a framework for understanding selective Tau-seed toxicity and identifies candidate regulators of Tau propagation with therapeutic potential.

ABSTRACT Background Despite the classic Kraepelinian dichotomy between bipolar disorder (BD) and schizophrenia (SZ), contemporary evidence suggests shared antecedent risk factors and similarities in the early course. This study aimed to identify distinct trajectories leading to first‐episode mania (FEM) and first‐episode psychosis (FEP) by examining antecedent psychopathology, including psychiatric diagnoses, symptoms, substance use, and psychotropic medication exposure. Methods Individuals born after 1985 who resided in Olmsted County, Minnesota, USA, and had FEM/FEP were identified through the Rochester Epidemiology Project. Latent class analysis (LCA) was used to identify subgroups based on antecedent psychopathology incorporating 57 dichotomous antecedent measures before FEM/FEP. Results A total of 202 individuals ( BD n = 73, SZ n = 129; 26.7% female, mean age 20.8 ± 3.7 years) were included. A 3‐class LCA model optimally fits the data. Class 1 (Neurodevelopmental, 29.7%) had a high prevalence of neurodevelopmental disorders, behavioral symptoms, and ADHD medication use. Class 2 (Depressive‐Anxious, 31.2%) included depressive and anxiety disorders, mood‐related symptoms, and SSRI / SNRI use. Class 3 (Minimal Psychiatric Morbidity, 39.1%) had a low prevalence of antecedent diagnoses and symptoms, with comparable substance use to other classes. There were significant diagnostic differences, with SZ being more common in the Neurodevelopmental (71.7%) and Minimal Psychiatric Morbidity (70.9%) classes, while BD was more common in the Depressive‐Anxious class ( p = 0.007). Neurodevelopmental and Minimal Psychiatric Morbidity classes had higher proportions of males (85.0% and 82.3%, respectively) compared to the Depressive‐Anxious class (50.8%, p < 0.001). The Neurodevelopmental class showed an earlier age at first mental health visit (9.5 ± 5.5 years) and a longer antecedent illness duration (10.8 ± 6.1 years) than the other classes ( p < 0.001). Conclusion This study identified three distinct pathways to FEM and FEP, offering a transdiagnostic perspective on the antecedent illness trajectories of BD and SZ. Future research should validate these categories that are more inclusive than the classic BD versus SZ dichotomy and explore their potential for predicting illness course and guiding personalized early interventions.

LBA4005 Background: To date, no phase 3 clinical trial has demonstrated an overall survival (OS) benefit in patients with locally advanced pancreatic adenocarcinoma (LA-PAC). TTFields are electric fields that disrupt cancer cell division. TTFields therapy is approved for glioblastoma, pleural mesothelioma, and metastatic non-small cell lung cancer. A phase 2 trial in PAC demonstrated the safety and preliminary efficacy of TTFields therapy with gemcitabine with or without nab-paclitaxel. We report final data from PANOVA-3 (NCT03377491), the largest global, phase 3, randomized, open-label trial in LA-PAC to date. Methods: Adult patients with newly diagnosed unresectable LA-PAC were randomized 1:1 to receive TTFields therapy (150 kHz) with gemcitabine/nab-paclitaxel (GnP) or GnP. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), local PFS, objective response rate (ORR), and pain-free survival. Distant PFS (metastases beyond the pancreas and regional lymph nodes) was assessed post hoc. Survival data were compared using the Kaplan-Meier method and a log-rank test. Results: 571 patients were randomized. Baseline characteristics were generally well balanced between the study arms. OS was significantly longer with TTFields/GnP than with GnP (median 16.2 [95% CI: 15.0, 18.0] vs 14.2 months [95% CI: 12.8, 15.4]; HR 0.82 [95% CI: 0.68, 0.99], p=0.039). One-year survival rate was also significantly improved with TTFields/GnP vs GnP (68.1% [95% CI: 62.0-73.5] vs 60.2% [95% CI: 54.2-65.7], p=0.029). There was no significant difference in PFS or local PFS between arms. Pain-free survival was significantly longer with TTFields/GnP vs GnP (median 15.2 [95% CI: 10.3, 22.8] vs 9.1 months [95% CI: 7.4, 12.7]; HR 0.74 [95% CI: 0.56, 0.97], p=0.027). Post-hoc analysis showed significant distant PFS benefit (median 13.9 [95% CI: 12.2, 16.8] vs 11.5 months [95% CI: 10.4, 12.9], HR 0.74 [95% CI: 0.57, 0.96], p=0.022) with TTFields/GnP vs GnP. ORR was similar between arms (36.1% [95% CI: 30.0, 42.4] vs 30.0% [95% CI: 24.3, 36.2], p=0.094). 97.8% and 98.9% of patients who received TTFields/GnP and GnP, respectively, had adverse events (AEs) and 88.6% and 84.3% had grade ≥3 AEs. The most frequent grade ≥3 AEs were neutropenia (47.8% and 47.6%) and anemia (21.9% and 22.3). 81% of patients receiving TTFields/GnP had device-related AEs, mostly grade 1/2 skin AEs, e.g., dermatitis (27.7%), rash (17.5%), and pruritus (15.0%); grade 3 and grade 4 device-related AEs occurred in 9.1% and 0.4% of patients, respectively. Conclusions: PANOVA-3 is the largest phase 3 trial exclusively performed in patients with LA-PAC and the first to show a statistically significant OS benefit. With no additive systemic toxicity and a statistically significant pain-free survival benefit, TTFields therapy is a potential new standard treatment for LA-PAC. Clinical trial information: NCT03377491 .