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Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

TPS4199 Background: Biliary tract cancer (BTC) is a rare but aggressive heterogenous group of gastrointestinal cancers that arise from the intra- or extrahepatic bile ducts (cholangiocarcinoma [CCA]) or the gallbladder (GBC). In early-stage disease following curative resection, adjuvant chemotherapy with a fluoropyrimidine- or gemcitabine-based regimen is usually recommended, however, recurrence rates remain high (e.g. in the BILCAP study, 5-year recurrence-free survival with adjuvant capecitabine was 34%). Immunotherapy is efficacious as adjuvant therapy in other cancer types. Results from the TOPAZ-1 and KEYNOTE-966 studies support combining immunotherapy and chemotherapy in advanced BTC, including in locally advanced non-metastatic disease. Furthermore, dual inhibition of programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) and the novel immune checkpoint, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), has shown promising results across multiple tumor types without major increases in high-grade toxicity compared with PD-1 or PD-L1 inhibition alone. Rilvegostomig is an anti-PD-1/-TIGIT bi-specific monoclonal antibody that appears active and well tolerated in non-small-cell lung cancer. ARTEMIDE-Biliary01 will investigate the efficacy of rilvegostomig plus standard of care adjuvant chemotherapy in patients with BTC after curative intent resection. Methods: ARTEMIDE-Biliary01 (NCT06109779) is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study to assess the efficacy and tolerability of rilvegostomig IV every three weeks versus placebo in combination with investigator's choice of chemotherapy (capecitabine, S-1 [tegafur/gimeracil/oteracil] or gemcitabine/cisplatin) as adjuvant treatment in patients with BTC after curative intent resection. This study will enroll approximately 750 adults with histologically confirmed adenocarcinoma of the biliary tract (intrahepatic or extrahepatic CCA or muscle-invasive GBC) after macroscopically complete resection (R0 or R1) and an ECOG PS of 0–1. Key exclusion criteria include locally advanced, unresectable, or metastatic disease at initial diagnosis and any anti-cancer therapy for BTC prior to surgery. The primary endpoint is recurrence-free survival, and the key secondary endpoint is overall survival. Additional endpoints include progression-free survival following recurrence, patient-reported tolerability, and safety. Enrollment has begun, and approximately 200 sites will be recruiting globally across Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT06109779 .

Abstract Generative artificial intelligence (AI) holds immense potential for medical applications, but the lack of a comprehensive evaluation framework and methodological deficiencies in existing studies hinder its effective implementation. Standardized assessment guidelines are crucial for ensuring reliable and consistent evaluation of generative AI in healthcare. Our objective is to develop robust, standardized guidelines tailored for evaluating generative AI performance in medical contexts. Through a rigorous literature review utilizing the Web of Sciences, Cochrane Library, PubMed, and Google Scholar, we focused on research testing generative AI capabilities in medicine. Our multidisciplinary team of experts conducted discussion sessions to develop a comprehensive 32‐item checklist. This checklist encompasses critical evaluation aspects of generative AI in medical applications, addressing key dimensions such as question collection, querying methodologies, and assessment techniques. The checklist and its broader assessment framework provide a holistic evaluation of AI systems, delineating a clear pathway from question gathering to result assessment. It guides researchers through potential challenges and pitfalls, enhancing research quality and reporting and aiding the evolution of generative AI in medicine and life sciences. Our framework furnishes a standardized, systematic approach for testing generative AI's applicability in medicine. For a concise checklist, please refer to Table S or visit GenAIMed.org .

Abstract BACKGROUND Medulloblastoma (MB) is a highly malignant childhood cerebellar tumor comprising a collection of molecularly and clinically distinct entities. Group 3 and Group 4-MB subgroups originate from overlapping progenitor pools of the developing rhombic lip when neuronal differentiation hierarchies are subverted through somatic alterations. Mutations suspected to deregulate the activity of chromatin-modifying genes are pervasive in Group 3 and Group 4-MB. However, the molecular consequences of these alterations remain largely undefined. METHODS We characterized the chromatin landscape of fifty-two primary MBs using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for six histone modifications and performed multi-modal integration with sample-matched somatic lesions, genome-wide DNA methylation, and transcriptomic profiles. RESULTS Analysis of differential chromatin states across MB subgroups using a Hidden Markov Model revealed a significant enrichment of the bivalent enhancer state (EnhBiv; marked by coincident H3K4me1 and H3K27me3) in Group 4-MB which localized to promoters of neurodevelopmental genes and transcription factors. To functionally dissect the pathogenetic significance of the enriched EnhBiv state in Group 4-MB, we sought to identify key regulators that confer this state. Integrative bioinformatics coupled with CUT&RUN analysis revealed significant enrichment of KDM2B, a histone lysine demethylase overexpressed in Group 4-MB, in gene promoters marked by the EnhBiv state. CRISPR gene targeting or targeted protein degradation of KDM2B selectively suppressed growth of Group 3 and Group 4-MB models in vitro and in vivo. Mechanistically, inhibition of KDM2B disrupted chromatin bivalency by blocking PRC2 complex recruitment and reducing H3K27me3 deposition, profoundly derepressing PRC2 targets involved in neuronal differentiation. CONCLUSIONS Our comprehensive characterization of the MB chromatin landscape in a large cohort of primary tumors provides unprecedented insights into the epigenetic basis of MB subgroups, implicating novel mechanisms of tumorigenesis, and nominating KDM2B as a selective dependency in Group 3/4-MB that should be prioritized as an attractive therapeutic target.

7531 Background: MM eventually becomes refractory to current treatments, and new therapeutic options with convenient dosing and improved safety are needed to enhance patient (pt) adherence, access, and outcomes. ABBV-383 is a distinctive next-generation BCMA x CD3 bispecific antibody composed of 2 high-affinity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS) risk, and a silenced Fc tail for an extended half-life allowing convenient dosing. ABBV-383 monotherapy has shown promising activity in the ongoing first-in-human phase 1 trial in RRMM (Vij et al. Blood 2023;142[suppl 1]:3378). Here, safety and efficacy results are reported that support the RP2D of 60mg Q4W as the optimal therapeutic ABBV-383 monotherapy dose. Methods: This phase 1 open-label, dose-escalation/expansion trial (NCT03933735) enrolled pts with RRMM who received ≥3 prior lines of therapy with exposure to PI, IMiD, and anti-CD38 mAb. ABBV-383 regimens explored in the expansion phase included 60mg Q4W and 40 or 60mg Q3W. A modified dexamethasone premedication schedule and shortened CRS monitoring period were implemented in the 60mg Q4W cohort for cycle 1. IV ABBV-383 was administered as a flat dose with no step-up schedule. Treatment was continued until disease progression/unacceptable toxicity. Primary objectives were to assess safety, tolerability, PK, PD, and determine the RP2D. Efficacy evaluation was a secondary objective. TEAEs were assessed per CTCAE v5.0 and tumor response per IMWG 2016 criteria. Results: As of May 2023, 220 pts received ABBV-383 (median age: 68 yr [35–92]; median prior therapy lines: 5 [3‒23]). Median FU was 4.1 mo (0.8–5.2) at 60mg Q4W (n=21), 12.2 mo (1.3–34.4) at 40mg Q3W (n=55), and 24.2 mo (0.6–33.4) at 60mg Q3W (n=61). At 60mg Q4W, with the modified premedication regimen, CRS was reported in 43% of pts (38% G1, 5% G2), and ICANS in 5% of pts (G2). In Q3W cohorts, CRS was reported in 71% (40mg; 45% G1, 25% G2) and 70% (60mg; 51% G1, 18% G2, 2% G3) of pts. The incidence of G3/4 neutropenia, anemia, and thrombocytopenia was 14/24/10% at 60mg Q4W, 31/31/16% at 40mg Q3W, and 34/13/13% at 60mg Q3W. G3/4 infections occurred in 10/24/34% of pts at 60mg Q4W, 40mg and 60mg Q3W, respectively. ORR and ≥VGPR were 65/50% at 60mg Q4W, 64/53% at 40mg Q3W, and 60/52% at 60mg Q3W. Corresponding exposure-response (ER) analyses and correlative analyses further supported RP2D determination (separate abstract submissions). Conclusions: The optimal therapeutic dose of 60mg Q4W ABBV-383 monotherapy was selected on the basis of safety, efficacy, and ER analyses. The extended interval of Q4W, with a shortened CRS monitoring period in cycle 1 and no step-up dosing, will improve convenience and reduce the treatment burden for pts. ABBV-383 at 60mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM. Clinical trial information: NCT03933735 .

The development and performance of two mass spectrometry (MS) workflows for the intraoperative diagnosis of isocitrate dehydrogenase (IDH) mutations in glioma is implemented by independent teams at Mayo Clinic, Jacksonville, and Huashan Hospital, Shanghai. The infiltrative nature of gliomas makes rapid diagnosis necessary to guide the extent of surgical resection of central nervous system (CNS) tumors. The combination of tissue biopsy and MS analysis used here satisfies this requirement. The key feature of both described methods is the use of tandem MS to measure the oncometabolite 2-hydroxyglutarate (2HG) relative to endogenous glutamate (Glu) to characterize the presence of mutant tumor. The experiments i) provide IDH mutation status for individual patients and ii) demonstrate a strong correlation of 2HG signals with tumor infiltration. The measured ratio of 2HG to Glu correlates with IDH-mutant (IDH-mut) glioma ( P < 0.0001) in the tumor core data of both teams. Despite using different ionization methods and different mass spectrometers, comparable performance in determining IDH mutations from core tumor biopsies was achieved with sensitivities, specificities, and accuracies all at 100%. None of the 31 patients at Mayo Clinic or the 74 patients at Huashan Hospital were misclassified when analyzing tumor core biopsies. Robustness of the methodology was evaluated by postoperative re-examination of samples. Both teams noted the presence of high concentrations of 2HG at surgical margins, supporting future use of intraoperative MS to monitor for clean surgical margins. The power of MS diagnostics is shown in resolving contradictory clinical features, e.g., in distinguishing gliosis from IDH-mut glioma.

DNA replication is a vulnerable cellular process, and its deregulation leads to genomic instability. Here, we demonstrate that chromobox protein homolog 3 (CBX3) binds replication protein A 32-kDa subunit (RPA2) and regulates RPA2 retention at stalled replication forks. CBX3 is recruited to stalled replication forks by RPA2 and inhibits ring finger and WD repeat domain 3 (RFWD3)–facilitated replication restart. Phosphorylation of CBX3 at serine-95 by casein kinase 2 (CK2) kinase augments cadherin 1 (CDH1)–mediated CBX3 degradation and RPA2 dynamics at stalled replication forks, which permits replication fork restart. Increased expression of CBX3 due to gene amplification or CK2 inhibitor treatment sensitizes prostate cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors while inducing replication stress and DNA damage. Our work reveals CBX3 as a key regulator of RPA2 function and DNA replication, suggesting that CBX3 could serve as an indicator for targeted therapy of cancer using PARP inhibitors.

Abstract This retrospective study from Jiangsu Province Hospital elucidates the prevalence and impact of pediatric androgenetic alopecia (AGA). Over a period of 14 years, 133 patients under the age of 18 were studied, with manifestations appearing as early as 8 years of age. Of note, 39.8% had an overweight/obese and 78.2% reported a family history of AGA. Comorbidities included seborrhoeic dermatitis (51.9%), acne (42.9%) and sleep disorders (28.6%). In addition, 4.5% had polycystic ovarian syndrome. Hormonal imbalances such as low sex hormone-binding globulin (47.1%) and vitamin D deficiency (61%) were common, as was low ferritin (23.6%). Male AGA patterns were characterised by crown thinning and temporal variations, whereas females showed crown thinning with frontal hair retention. Trichoscopic differences were observed between genders and age groups. This study highlights the importance of individualised, stepwise and comprehensive treatment, prioritising hormonal disorders and comorbidities when treating hair loss with topical minoxidil. Encouraging patients to adhere to regular medication and follow-up appointments can lead to favourable outcomes.