Citations

ABSTRACT Objective Despite the availability of approved treatments, a substantial proportion of patients with bipolar disorder experience treatment‐resistant bipolar depression (TRBD), characterized by persistent depressive symptoms unresponsive to standard therapies. However, a universally accepted definition of TRBD is lacking. This consensus document, developed by the International Society for Bipolar Disorders (ISBD) Task Force on TRBD, aims to provide a standardized definition of TRBD to facilitate clinical trials, research, and treatment strategies. Methods The Task Force employed a literature review, clinical trials analysis, and expert consensus meetings to define TRBD. Results TRBD was defined as the failure to achieve a significant and sustained clinical response after at least two approved and adequately dosed pharmacological treatments, administered for a sufficient duration with treatment adherence. For bipolar I (BD‐I) depression, approved treatments included quetiapine (300–600 mg/day for ≥ 8 weeks), lurasidone (20–120 mg/day for ≥ 6 weeks), the combination of olanzapine (6–12 mg/day) and fluoxetine (25–75 mg/day for ≥ 8 weeks), cariprazine (1.5–3 mg/day for ≥ 6 weeks), and lumateperone (42 mg/day for ≥ 6 weeks). For bipolar II (BD‐II) depression, approved treatments included quetiapine (300–600 mg/day for ≥ 8 weeks) and lumateperone (42 mg/day for ≥ 6 weeks). Conclusion This consensus definition aims to provide clarity for clinical trials, improve consistency in research, and guide treatment approaches and inform regulatory pathways. It represents a foundational step in addressing the unmet needs in TRBD and promoting the development of innovative therapeutic strategies. Future efforts will focus on adapting the definition to better align with real‐world clinical challenges and optimize patient care.

AimThe aim of this study was to compare the histopathologic features of MMF‐induced colitis and colonic GVHD and develop a digital tool using deep learning convolutional neural networks (CNNs) to semi‐automate the quantification of eosinophils.MethodsMMF and GVHD colitis cases were retrieved. A cohort of transplant patients who were at risk for developing GVHD and were on MMF at the time of biopsy was also identified. Cases were reviewed for histologic features and a deep learning CNN was trained to quantify lamina propria eosinophils. Clinical history was collected.ResultsNinety‐five patients were included in the study group: GVHD (n = 37), MMF (n = 25) and GVHD vs. MMF (n = 33). Within the GVHD vs. MMF group, one patient was thought to have definitive MMF colitis and one possible MMF colitis. The GVHD group had a significantly higher apoptotic count compared to the MMF group (median: 7 vs. 2, P = 0.03). Neuroendocrine aggregates were present in the GVHD (N = 12) and GVHD vs. MMF (N = 4) groups while absent in the MMF group. The MMF group had a higher semi‐quantitative eosinophil score and a higher automated eosinophil count as detected by the deep learning CNN (median eos/HPF: MMF 19.2, GVHD vs. MMF 3.6, GVHD 3.4, P < 0.001).ConclusionsLower eosinophil counts, higher apoptotic counts and neuroendocrine cell aggregates favour the diagnosis of GVHD. AI models for eosinophil quantification may serve as an ancillary tool for assessing this differential diagnosis. Given the rarity of MMF‐induced colitis in SCT patients, pathologists should have a high threshold for making this diagnosis in this population.

BACKGROUND: Heart failure (HF) is a heterogeneous syndrome with high mortality. The need for a new taxonomy of HF is recognized; up to now, such phenomapping efforts have primarily used clinical data. Proteomics offers potential for more precise phenotypic identification and mechanistic insights. However, few phenomapping studies have used this approach, and all have focused on targeted cardiovascular proteomics panels and a restricted HF ejection fraction group. METHODS: We measured over 7000 plasma proteins in a population-based cohort of 1351 patients with HF, used k-means clustering to identify distinct phenogroups, and compared their clinical characteristics and all-cause mortality. RESULTS: Three proteomics-defined phenogroups were identified, with substantial differences in survival (phenogroup 1 5-year survival probability, 65% [95% CI, 61%–68%]; phenogroup 2, 45% [40%–51%]; phenogroup 3, 26% [22%–30%]), independent of clinical characteristics. Phenogroups also exhibited differences in several measures suggesting poorer health, including NT-proBNP (N-terminal pro-B-type natriuretic peptide), kidney function, and Meta-Analysis Global Group in Chronic Heart Failure scores, but did not differ by ejection fraction or New York Heart Association class. CONCLUSIONS: Our study demonstrates that molecular phenomapping can stratify patients with HF into distinct subgroups that go beyond predefined clinical classifications.

Abstract Anti-IgLON5 disease is an autoimmune encephalitis that presents with a heterogenous clinical phenotype, including sleep disorders, movement abnormalities and bulbar involvement. It is characterized by autoantibodies against IgLON5, 85% association with HLA-DQB1*05:∼ and a brainstem-dominant tauopathy. Cellular and murine models report pathogenic effects of the autoantibodies, and neurodegenerative factors suggest progressive atrophy as a common sequela. However, evidence from in vivo patient data and long-term follow-up is limited, and the degree of progression remains elusive. In this multicentre study, clinical and brain MRI data were collected from 127 patients across 12 countries to investigate the relationships between clinical presentations and the development of distinct brain atrophy patterns. Our data show that most patients develop a complex multisystem phenotype as the disease progresses; however, neuromuscular manifestations rarely emerge at later disease stages. By comparison to healthy controls, this disease presents with severe substructure-specific atrophy, especially affecting the hypothalamus, brainstem, accumbens and basal ganglia, which, in age-independent analyses, show significant ventricular enlargement and also suggest progression of brainstem atrophy over the disease course. Moreover, the focality of atrophy was functionally linked to specific symptoms, with more severe involvement of the basal ganglia in patients with movement disorders, and greater atrophy in the hippocampus and thalamus in patients with cognitive impairment. Taken together, our results provide evidence of distinct atrophy patterns in anti-IgLON5 disease, which closely mirror sites of pathophysiologic processes, including autoantibody binding and tau deposition. Our data emphasize the brainstem as the pathophysiological hub of the disease and provide normative data for the incorporation of atrophy measurements into routine clinical assessments and future treatment studies to monitor disease trajectory and evaluate future treatment strategies.

ImportanceEtiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood.ObjectiveTo examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes.Design, Setting, and ParticipantsThis study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024.ExposureMHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use).Main Outcomes and MeasuresBreast cancer intrinsic-like subtypes (luminal A–like, luminal B–like, luminal B–ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched–like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-&amp;lt;25; overweight, 25-&amp;lt;30; or obesity, ≥30).ResultsThis study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A–like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B–ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B–like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A–like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B–ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched–like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P &amp;lt; .04 for heterogeneity) tumors.Conclusions and RelevanceIn this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.

Pediatric central nervous system tumors are the leading cause of cancer-related deaths in children. The five-year survival rate for high-grade glioma in children is less than 20%. The development of new treatments is dependent upon multi-institutional collaborative clinical trials requiring reproducible and accurate centralized response assessment. We present the results of the BraTS-PEDs 2023 challenge, the first Brain Tumor Segmentation (BraTS) challenge focused on pediatric brain tumors. This challenge utilized data acquired from multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. BraTS-PEDs 2023 aimed to evaluate volumetric segmentation algorithms for pediatric brain gliomas from magnetic resonance imaging using standardized quantitative performance evaluation metrics employed across the BraTS 2023 challenges. The top-performing AI approaches for pediatric tumor analysis included ensembles of nnU-Net and Swin UNETR, Auto3DSeg, or nnU-Net with a self-supervised framework. The BraTS-PEDs 2023 challenge fostered collaboration between clinicians (neuro-oncologists, neuroradiologists) and AI/imaging scientists, promoting faster data sharing and the development of automated volumetric analysis techniques. These advancements could significantly benefit clinical trials and improve the care of children with brain tumors.

e18017 Background: Head and neck (H&N) cancers affect the oral cavity, pharynx, larynx, salivary glands, nasal cavity, and sinuses. In Sub-Saharan Africa (SSA), the true burden of H&N cancers remains unclear, with available estimates suggesting approximately 47,000 new cases and 26,000 deaths annually. Limited cancer datasets hinder understanding of disease patterns and outcomes. This study explores patient characteristics, treatments, and outcomes to guide regional cancer control efforts. Methods: A cancer dataset was created and implemented at 4 leading teaching hospitals in Ghana, Kenya, Ethiopia, and Rwanda to systematically collect data on patient demographics, disease characteristics, and treatment patterns. Established through competitive grant funding, the primary objective of the database was to assess the indirect impact of the COVID-19 pandemic on cancer care. The dataset includes all cancer patients seen in consultation and/or treated between 2016 and 2023. In this study, a subset of patients diagnosed with H&N cancers was analyzed using descriptive statistics to assess clinical characteristics, treatments modalities, and patients' outcomes. Results: A total of 1,023 patients with H&N cancer were included in the analysis. The median age at diagnosis was 54 yrs (IQR 41-66), with 37% (n= 374) of the cohort being female. A total of 55% (n= 549) had no health insurance coverage. Of those with staging data, majority presented with advanced disease (89%) on presentation. Regarding treatment modality, 16% (n= 157) underwent surgery, 27% (n=279) received radiotherapy (RT), 14% (n= 143) received chemotherapy (CT), and 56% (n= 572) received no cancer therapy. Of those who received CT the timing was neoadjuvant (12%), concurrent with RT (22%), adjuvant after surgery (8.9%) or as palliative treatment (57%). Platinum-based agents (94%) were the most common CT, followed by Taxol-based (31%), and 5FU-based agents (27%). Regarding RT, planning was performed using 2D (55%) and 3D (45%) techniques. The median delivered dose was 60 Gy in 30 fractions. At a median follow up of 43 months, 1.6% were disease free, 10% (n= 103) were alive, 5.9% (n= 60) were confirmed dead, and 84% (n= 848) were lost to follow up. Conclusions: This study identifies key challenges in managing H&N cancers in SSA, including late-stage presentation, limited access to advanced treatment modalities, and a high lost to follow-up rate (84%). The reliance on older RT techniques such as 2D planning and the limited use of surgery highlight gaps in infrastructure and resource availability. Limited health insurance coverage suggests potential financial barriers to care and disparities in treatment access. Addressing these challenges will require greater investment in cancer care, expansion of the oncology workforce, and improvements in healthcare infrastructure to support better patient outcomes in the region.

e17511 Background: Cervical cancer is a significant public health concern in Sub-Saharan Africa (SSA), where it remains the leading cause of cancer-related mortality among women. SSA has the highest global incidence and mortality rates, with an estimated 110,300 new cases and 76,700 deaths in 2020. Despite this burden, data on patient characteristics and treatment outcomes remain limited. This study aims to address these gaps by analyzing current treatment patterns and outcomes for cervical cancer in SSA. Methods: A cancer dataset was established at 4 major teaching hospitals in Ghana, Kenya, Ethiopia, and Rwanda to capture data on patient demographics, disease characteristics, and treatment modalities. The dataset encompasses all cancer patients seen between 2016-2023, with over 9,000 cases collected to date. The primary objective of the dataset was to assess impact of COVID-19 pandemic on cancer care in SSA. This study conducted a retrospective analysis of cervical cancer cases within the dataset utilizing descriptive metrics. Results: A total of 2,326 patients were analyzed, with a median age at diagnosis of 56 y (48–65) and 53% having health insurance. The majority had squamous cell carcinoma (87%) and presented with locally advanced disease (FIGO stages IIB–IVA, 88%). Treatment primarily consisted of concurrent chemoradiotherapy (CRT, 34%) or radiotherapy (RT) alone (30%), while smaller proportions received chemotherapy (CT) alone (1.2%) or surgery (1.3%). A total of 33% of patients received no cancer therapy. Among 1,524 patients treated with RT, 1,180 received external beam RT with a median dose of 46 Gy in 23 fractions, using 2D planning in 60% and 3D planning in 40% of cases. Additionally, 25 patients underwent brachytherapy, with 58% receiving low-dose-rate and 42% high-dose-rate treatments. Of 1,011 patients treated with CT, 85% (n=844) completed the intended course, with a median of 4 cycles, primarily delivered concurrently with RT (95%). Only a few received CT as adjuvant (4.8%), neoadjuvant (1.6%), or palliative (3.4%) therapy. Platinum-based regimens were most common, with 43% receiving platinum monotherapy and 5% receiving platinum-taxane combinations. By the end of treatment, 27% (n=633) achieved disease-free status. After a median follow-up of 47 months (range,37–55), 42% were alive, 7% had died, and 53% were lost to follow-up with unknown vital status. Conclusions: This study reveals significant challenges in management and follow-up of cervical cancer in SSA. Most patients were diagnosed at advanced stages, with 32% receiving no treatment and 53% of treated patients lost to follow-up. These findings highlight barriers to early diagnosis, treatment access, and continuity of care. Addressing these issues requires expanding early diagnostic services, increasing vaccination coverage, strengthening healthcare infrastructure, and improving patient retention.