Citations

Abstract Purpose: Prostate-specific membrane antigen (PSMA)–directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule. Experimental Design: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc–EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc–EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging. Results: 99mTc–EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc–EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer–like morphology. Conclusions: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.

BACKGROUND: The Commission on Cancer (CoC) implemented 6 operative standards to reduce technical variation in cancer surgery. Although designed to guide surgeons in performing key oncologic techniques, these standards also provide a framework for teaching high-quality cancer surgery to trainees. We assessed surgical trainees’ familiarity with the CoC Operative Standards and the underlying principles of cancer surgery to identify knowledge gaps and opportunities for improved education. STUDY DESIGN: The American College of Surgeons Cancer Surgery Standards Program distributed an anonymous survey to general surgery residents and surgical fellows across the US. Questions addressed the CoC Operative Standards and cancer surgery principles, with scores calculated on the basis of correctness. Univariate logistic regression evaluated associations between trainee or program characteristics and knowledge. Trainees were also asked about their role in procedural documentation, given the synoptic operative report requirements of the standards. RESULTS: A total of 244 surveys were completed by 205 residents and 39 fellows. Fellows reported greater familiarity with the CoC Operative Standards (68% vs 24%, p < 0.001). Only 30% of trainees reported receiving a formal curriculum on the standards. Correct response rates were 30% for CoC Operative Standards questions vs 50% for cancer surgery principles, with minimal association between knowledge and trainee or program characteristics. Most residents (71%) reported contributing to operative documentation. CONCLUSIONS: Surgical trainees demonstrated limited knowledge of the CoC Operative Standards, highlighting the need for multifaceted educational strategies at the national and institutional levels. Incorporating education about the CoC Operative Standards into surgical training can help emphasize the importance of performing and documenting critical elements of cancer operations.

Abstract Early-onset Alzheimer’s disease (EOAD) and Late-onset AD (LOAD) differ in clinical presentations and rates of progression. We aimed to compare baseline and longitudinal tau PET burden, and their relationship with clinical variables in amyloid-PET positive, cognitively impaired participants from the Longitudinal Early-Onset Alzheimer’s Disease Study (EOAD; n=390) and Alzheimer’s Disease Neuroimaging Initiative (LOAD; n=211). Patients with EOAD showed higher baseline tau PET retention, broader neuroanatomical involvement and faster accumulation rates over time compared to LOAD, after adjusting for amyloid load and clinical stage. Tau PET showed stronger correlations with baseline amyloid burden and clinical measures of global cognition and function in EOAD than LOAD. We conclude that earlier age of onset in AD is linked to a more aggressive tauopathy, which in turn is a primary driver of clinical decline. These findings suggest that optimal therapeutic targets and strategies may differ between EOAD and LOAD. One Sentence Summary Younger patients with Alzheimer’s disease show more aggressive tau spread, suggesting age of onset defines distinct disease pathways with key clinical implications.

Abstract Objective Despite being safe and effective, surgery for pediatric epilepsy is underutilized. Social determinants of health (SDoH) are important to consider when examining this treatment gap. This study examined the potential systemic inequities at three different stages in the journey toward epilepsy surgery across the Pediatric Epilepsy Research Consortium (PERC). Methods Any youth in the PERC prospective surgery database (≤18 years) was eligible and included if sociodemographic factors were also available. We examined if there were differences in disparity factors in: (1) referral to Phase I evaluation, (2) offering of surgery, and (3) completion of surgery. Results Of 1309 patients, the majority were male (53%, p = .04), White (82.2%, p < .001), not Hispanic or Latino (84.3%, p < .001), and privately insured (56.3%, p < .001). Of the youth who were offered surgical treatment ( n = 1103, 84.3%), there were no significant differences in race/ethnicity or sex. Those with a structural lesion were more likely to be offered surgery, and historically marginalized youth were more likely to have a lesion. Of patients who completed surgery ( n = 927, 84.0%), White patients were 1.88 times (95% confidence interval [CI]: 1.14–3.04) more likely than Black patients to complete surgery ( p = .01). Significance Youth who began surgery evaluation are not representative of the demographics of those with epilepsy in the United States, with greater representation of White, non‐Hispanic male individuals. In addition, youth who began surgery evaluation disproportionally have private insurance. At the next stage of offering surgery, there were no differences based on SDoH. However, there is evidence that underrepresented youth that were magnetic resonance negative were less likely to be referred for surgical workup and that Black youth were less likely to undergo surgery. Therefore, efforts to provide equitable opportunity for all youth with refractory epilepsy should be concentrated at the referral for surgery evaluation point of care; however, additional efforts are also needed at later stages.

Abstract Generative artificial intelligence (AI) is rapidly populating medical records with synthetic or partially AI-generated content, creating a feedback loop where future models are increasingly at risk of training on uncurated AI-generated data. However, the clinical consequences of this AI-generated data contamination remain unexplored. Here, we show that in the absence of mandatory human verification, this self-referential cycle drives a rapid erosion of pathological variability and diagnostic reliability of medical data at population scale. By analysing more than 800,000 synthetic data points across clinical text generation, vision–language reporting, and medical image synthesis, we find that models progressively converge toward generic phenotypes regardless of the model architectures. Specifically, rare but critical findings, including pneumothorax and effusions, vanish from the synthetic content generated by AI models, while demographic representations skew heavily toward middle-aged male phenotypes. Crucially, this degradation is masked by false diagnostic confidence. Models continue to issue reassuring reports while failing to detect life-threatening pathology, with false reassurance rates tripling to 40%. Blinded physician evaluation confirms that this decoupling of confidence and accuracy renders AI-generated documentation clinically useless after just two generations. We systematically evaluate three mitigation strategies that can be easily integrated into existing clinical workflows, finding that while synthetic volume scaling fails to prevent collapse, mixing real data with quality-aware filtering effectively preserves diversity. Ultimately, our results suggest that without policy-mandated human oversight, the deployment of generative AI threatens to degrade the very healthcare data ecosystems it relies upon.

BACKGROUND Ulnar neuropathy at Guyon’s canal is rare, but when it occurs, it is frequently due to underlying masses, including extraneural and intraneural ganglion cysts, as well as adventitial cysts. The pathogenesis of these cysts, especially at a rare site, remains controversial. The articular theory, which is gaining popularity, posits that a joint connection via a nerve (or vascular) branch to a neighboring joint represents the pathway for their formation and propagation. OBSERVATIONS A recently published case of a patient with an ulnar intraneural ganglion at the wrist with a series of postoperative cystic recurrences was reevaluated, as it challenged the articular theory. No discrete articular branch had been identified on imaging or at surgery. Serial MR images were reinterpreted, which revealed that the original intraneural cyst was treated; new sequential cysts—an adventitial cyst and then a soft tissue ganglion—developed, all arising from the same wrist joint. LESSONS This case strengthens the principles of the articular theory for intraneural ganglion, adventitial, and soft tissue ganglion cysts. A small wrist connection from the ulnar intraneural ganglion was unrecognized and untreated. Scarring disrupted the original nerve pathway and pressure dynamics. New cysts developed through neighboring joint capsular rents along different pathways into other “compartments” (vessel or soft tissues). https://thejns.org/doi/10.3171/CASE25618

ABSTRACT Objective This study compared the effects of phentermine‐topiramate‐ER (mid‐dose 7.5/46 mg) versus placebo on weight loss and cardiovascular disease (CVD) risk outcomes when used as an adjunct to a digitally enhanced lifestyle intervention (DELI). Methods We conducted a 12‐month, randomized, double‐blind, placebo‐controlled trial at a single tertiary academic center in the United States (June 2020–June 2022). Eighty participants with obesity (BMI ≥ 30 kg/m 2 ) were enrolled in the DELI program, consisting of in‐person and telehealth modalities, dietary and physical activity goals, and use of a smartphone application integrated with digital devices (Apple Watch and Bluetooth‐enabled weight scale and blood pressure monitor). Participants were randomized 1:1 to receive either phentermine‐topiramate‐ER ( n = 42) or placebo ( n = 38) in addition to the DELI. Results At 3 months, the phentermine‐topiramate group lost a mean of 10.82 kg versus 4.04 kg in the placebo group (mean difference −6.78 kg; p = 0.002). At 12 months, weight loss was 15.32 kg versus 5.85 kg, respectively (mean difference −9.48 kg; p < 0.001). Participants receiving phentermine‐topiramate‐ER experienced a 3.35% reduction in the estimated atherosclerotic CVD risk compared to baseline ( p = 0.004). Conclusions Phentermine‐topiramate‐ER, when combined with a DELI, produced significant and sustained weight loss and reduced CVD risk in adults with obesity. Trial Registration ClinicalTrials.gov : NCT04408586

Abstract Background Risankizumab (RZB), a high-affinity humanised IgG1 monoclonal antibody targeting interleukin-23 p19, has demonstrated sustained efficacy, with a consistent safety profile supporting long-term use for patients (pts) with ulcerative colitis (UC).1-3 This interim analysis reports efficacy and safety through open-label extension (OLE) week (wks) 96 (3 years [yrs] of total maintenance) from the COMMAND OLE. Methods The OLE enrolled RZB-treated pts who completed the 52-wk maintenance substudies and/or responded to 12/24-wk induction therapy.1 All pts received subcutaneous RZB 180 mg (RZB180) starting at OLE wk 0, except those who received prior OLE RZB rescue therapy (1 RZB 1200 mg intravenous dose then RZB 360 mg [RZB360] every 8 wk) and continued RZB360 for 96 wks. Efficacy endpoints (clinical remission [CR] per Adapted Mayo Score [AMS], CR per Partial AMS [PAMS], corticosteroid-free CR per PAMS, clinical response per AMS, clinical response per PAMS, endoscopic improvement, and endoscopic remission) were assessed at OLE wks 0 and 96 and reported as observed (AO) prior to OLE RZB rescue therapy and nonresponder imputation (NRI), among the overall population and by inadequate response to advanced therapy (AT-IR vs non-AT-IR; data cutoff: 25Aug2025). The safety analysis included pts who received at least 1 dose of OLE RZB, with data presented as events/100 pt-yrs. Results At OLE wk 0, approximately 90% pts (N = 1003) completed the study visit; some differences were observed in the clinical characteristics of RZB180 and RZB360-treated pts, including mean AMS (2.0, 3.4); a numerically higher proportion of RZB360-pts were AT-IR (63.1%, 76.8%), and had an endoscopic score of ≥ 3 (12.1%, 31.1%). A lower proportion of RZB360-treated pts achieved CR per AMS (54.8%, 25.2%) at OLE wk 0, while a higher proportion of RZB360-treated pts received OLE rescue therapy (RZB180, 22.1%; RZB360, 34.5%). Efficacy rates remained stable at OLE wks 0 and 96 for CR per AMS; similar results were observed within each subgroup, AT-IR and non-AT-IR (Table 1). Numerically lower efficacy rates were observed in the AT-IR vs non-AT-IR pts at wk 96; efficacy was sustained through OLE wk 96 for all endpoints (AO, NRI; Table 1). Similar rates were observed for any adverse event (AE), severe AE, and serious AE in RZB180 and RZB360-treated pts. No new safety risks were identified in either treatment group (Table 2). Conclusion In the ongoing COMMAND OLE, sustained clinical and endoscopic benefit was observed in pts receiving up to 3 yrs of long-term RZB maintenance therapy, with numerically lower efficacy rates observed for AT-IR vs non-AT-IR vs pts. The long-term safety of RZB remains consistent with a favorable benefit-risk profile, supporting its long-term use in UC. References: 1.Louis E et al. JAMA. 2024;332:881-97. 2.Atreya R et al. J Crohn’s Colitis. 2025;19(S1):i108-i110. [Abstract]. 3.Panaccione R et. al. J Crohn’s and Colitis. 2025, 19(1):jjaf005. Conflict of interest: Atreya, Raja: RA has served as a speaker, or consultant, or received research grants from AbbVie, Abivax, AlfaSigma, Arena Pharmaceuticals, Astra-Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Galapagos, Gilead, GlaxoSmithKline, InDex Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Merck Sharpe & Dohme, Pfizer, Roche Pharma, Takeda Pharma, Viatris. Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Loftus, Jr, Edward: Grant: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, UCB. Personal Fees: AbbVie, Allergan, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Iterative Scopes, Janssen, Ono Pharma, Pfizer, Sun Pharma, Takeda, UCB. Rubin, David T.: Grant support: Takeda Pharmaceuticals Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx. Dubinsky, Marla C: Personal Fees: Consultant or Advisory Board: Abbvie, Abivax, Astra Zeneca, BMS, Celltrion, Gilead, Genentech, Janssen, Johnson and Johnson, Lilly, Merck, Pfizer, Prometheus Biosciences, Sanofi, Spyre, Target RWE, Takeda Other: Shareholder, Co-founder, Board of Directors of Trellus Health Co-Founder Mi Test Health Hisamatsu, Tadakazu: Grant support: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Takeda, Pfizer., Mochida, Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd. Consulting: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer, Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Abivax, MSD, Chugai. Lecture fee: Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda, Pfizer, Kissei Mambetsariev, Nurbek: Employee of AbbVie and may own stock and/or stock options. Kalabic, Jasmina: Employee of AbbVie and may own stock and/or stock options. Cheng, Peiyao: Employee of AbbVie and may own stock and/or stock options. Chen, Su: Employee of AbbVie and may own stock and/or stock options. O’Brien, Dan: Employee of AbbVie and may own stock and/or options. Morisset, Pierre: Employee of AbbVie and may own stock and/or stock options. Duan, W. Rachel: Employee of AbbVie and may own stock and/or stock options. Panaccione, Remo: Grant: Abbvie, Janssen, Pfizer, Takeda. Other: Consultant for: Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Spyre Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, UCB Speaker’s Fees for: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals Advisory Boards for: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals, Ventyx.