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Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

AimsCeramic-on-ceramic (CoC) articulations in total hip arthroplasty (THA) have the advantage of low wear but the unique risk of fracture. After revision for CoC-bearing fracture, third-body ceramic particles can lead to massive wear of cobalt-chrome (CoCr) bearings, causing extremely elevated blood cobalt. We present a multicentre series of five cases where patients sustained fractures of ceramic liners, were revised using a CoCr articulation, and rapidly developed severe cobalt toxicity.MethodsWe identified five cases of cobalt toxicity after fractured CoC THA treated with revision to CoCr on polyethylene bearings. Mean follow-up was three years (5 to 72 months) after re-revision to remove the CoCr bearing.ResultsSymptoms of cobalt toxicity occurred at a mean ten months (6 to 12) after revision for ceramic fracture. All patients developed vision and hearing loss, balance difficulties, and peripheral neuropathy. Several had cardiomyopathy, endocrine abnormalities, and local skin discolouration. Only two reported hip pain. Repeat revision for recognized cobalt toxicity occurred at a mean 22 months after revision for ceramic fracture. Mean serum cobalt level at re-revision was 991 ng/ml (normal value < 1 ng/ml; 734 to 1,302). All CoCr femoral heads exhibited massive wear, and deep tissues showed prominent metal staining. Treatment consisted of debridement and revision to a ceramic femoral head with highly cross-linked polyethylene (HXLPE) liner. Serum cobalt improved to a mean 25 μg/l (1 to 76) at final follow-up. All patients reported partial improvement in vision and hearing, however their peripheral neuropathy and balance difficulties did not recover.ConclusionSystemic cobalt toxicity is a devastating complication of ceramic-bearing fracture in THA treated with CoCr bearings, which may not present with hip symptoms. The diagnosis of this syndrome of systemic cobalt toxicity was significantly delayed following systemic symptoms in this series. Debridement and re-revision to a ceramic-on-HXLPE bearing leads to improvement, but not full resolution, of cobalt toxicity complications.Cite this article: Bone Joint J 2025;107-B(6 Supple B):92–100.

e13637 Background: Large language models (LLMs) like GPT-4 (OpenAI) and Claude Opus (Anthropic) showed high accuracy in medical multiple-choice exams, but data on their oncology-specific clinical reasoning and performance is limited. This study evaluates their accuracy and clinical reasoning on breast oncology multiple-choice questions (MCQs) from the American Society of Clinical Oncology (ASCO) question bank. Methods: Using OpenAI and Anthropic Application Programming Interface (APIs), questions were tested without additional prompts under consistent settings (GPT-4 and Claude Opus; Temperature = 0, Tokens = Max). Each question was tested three times to assess precision. Then, Chain-of-thought (COT) prompting was applied to promote LLMs stepwise reasoning to increase their accuracy. Accuracy before and after COT prompting was compared. Incorrect responses were reviewed by board-certified medical oncologists speclized in breast cancer, who scored reasoning clarity, bias, and clinical relevance. Qualitative feedback was descriptively analyzed. Results: A total of 273 breast oncology MCQs were evaluated across the two LLMs. GPT-4 achieved an initial accuracy of 81.3% (222/273; 95% CI: 76.3%-85.5%), compared to Claude Opus, which achieved an accuracy of 79.5% (217/273; 95% CI: 74.3%-83.9%). The Chi-squared test for difference between the models before chain-of-thought (COT) prompting yielded a p-value of 0.59, indicating no statistically significant difference in accuracy between GPT-4 and Claude Opus prior to COT prompting. After COT prompting, the performance of the two models diverged significantly. GPT-4 saw a net decline in accuracy, decreasing by a net of 1 correct answer, resulting in an overall accuracy of 80.95% (221/273). In contrast, Claude Opus experienced a notable improvement, with a net of 19 additional correct answers, leading to an accuracy of 86.4% (236/273). A statistical analysis using a Chi-squared test revealed a difference in accuracy between the two models of 5.5% (p = 0.08), demonstrating that the improvement in accuracy for Claude Opus after COT prompting was borderline statistically significant compared to GPT-4. Thematic analysis of oncologists' feedback revealed that the most common reasons for incorrect answers were reliance on outdated guidelines, misinterpretation of clinical trial data, and failure to consider multidisciplinary or patient-specific approaches in clinical decision-making. Conclusions: Although AI models can achieve high scores on multiple-choice exams, they still require human supervision. These models rely on potentially outdated training data and lack the ability to individualize patient care or apply data from clinical trials. especially in unique or unconventional/non textbook scenarios.

TPS3171 Background: Genetic alterations in fibroblast growth factor receptors 2 and 3 ( FGFR2/3 ) occur in nearly all cancer types. FGFR2 fusions and rearrangements occur in up to 10-15% of intrahepatic cholangiocarcinomas (iCCA) and alterations in FGFR3 occur in 15-30% of urothelial cancers. The clinical benefit from currently approved FGFR inhibitors (FGFRi) is often curtailed by development of acquired resistance, which may arise through on-target mutations in the FGFR2/3 kinase domain. Additionally, off-tumor effects on FGFR1 by pan-FGFRi can lead to hyperphosphatemia and consequently to dose reductions or dose holds. Thus, there is an unmet clinical need for a selective FGFR2/3 inhibitor that has clinical efficacy against activating alterations and resistance mutations without causing FGFR1-mediated hyperphosphatemia. CGT4859 is an orally bioavailable, ATP-competitive, reversible inhibitor of FGFR2/3, with potency against clinically relevant FGFR2/3 kinase domain mutations. In addition, CGT4859 demonstrates >140 fold selectivity over FGFR1, and shows robust efficacy in target altered in vivo tumor models without increases in serum phosphorus. Nonclinical pharmacokinetics (PK) and safety data support evaluating CGT4859 in a first-in-human, open-label, dose-escalation and signal-seeking Phase I/II study (NCT06777316). Safety, tolerability, PK, pharmacodynamics, and antitumor activity of CGT4859 will be assessed in adults with histologically confirmed unresectable or metastatic iCCA or other solid tumors with FGFR2/3 alterations. Methods: CGT4859 will be administered orally continuously in 28-day cycles to patients (N=~50) at a starting dose of 1 mg QD, and dose escalation will not exceed 40 mg QD as determined using a Bayesian optimal interval design with backfill (BF-BOIN). This approach will be used to guide dose escalation and establish the maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D). BF-BOIN enables backfilling of participants to doses that are cleared for safety during the dose escalation, generating additional data on safety and tolerability below the MTD. Objective response rate (ORR) and disease control rate will be determined based on investigator assessment using RECIST v1.1. Phase II will enroll up to 4 cohorts, each enrolling ~15 patients. Proposed cohorts will include participants who have iCCA and are either FGFRi-naïve or FGFRi-exposed. Two additional cohorts with other advanced solid tumors harboring FGFR2/3 alterations may be included based on signals detected in dose escalation. The primary efficacy endpoint for Phase II is ORR per RECIST v1.1. The preclinical data support the study of CGT4859 in this patient population with solid tumors harboring FGFR2 and/or FGFR3 genetic alterations. The phase I dose escalation study is currently enrolling at sites in the United States. Clinical trial information: NCT06777316 .

Abstract Celiac disease (CeD) is an immune-mediated condition driven by dietary gluten resulting in small intestinal mucosal inflammation and injury, along with myriads of symptoms. The only treatment is a lifelong gluten-free diet (GFD) and although most patients improve, the restriction can lead to nutrient deficiencies including fiber. While duodenal microbiota is altered in CeD, its fiber metabolic capacity is unknown. Here we show that both active and GFD-treated CeD patients had impaired microbial fiber metabolism in the small intestine which associates with depletion of the carbolytic taxa Prevotella spp. Colonization of germ-free mice with Prevotella spp increased small intestinal short chain fatty acids (SCFA). In gluten-sensitized mice expressing the celiac risk gene, HLA-DQ8, an inulin-supplemented diet facilitated microbial carbolytic function, SCFAs production and accelerated mucosal healing in the small intestine during GFD. The results support clinical investigations of dietary fiber supplementation and microbial carbolytic function to enhance responses to GFD in CeD.

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol &gt;1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI &lt;30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P &lt; 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

Abstract Immune checkpoint inhibitors (ICIs) block immunoregulatory receptor-ligand interactions and robustly increase survival of cancer patients but frequently result in immune-related adverse events (irAEs). While rheumatologic toxicities are commonly reported as irAEs, the effect of immune checkpoint blockade on the underlying mechanisms of ICI-induced fractures and bone loss is controversial, with reports of both positive and negative effects on bone mass in preclinical models. However, no previous reports have investigated the impact of ICIs on females or aged mice, or on fracture risk in either sex. We report that global deletion of programmed cell death protein 1 (PD-1) broadly results in bone loss in skeletally mature male and female PD-1−/− mice, with a sexually divergent phenotype in adolescent mice, decreased bone strength in adult males and young females, and expansion of multiple T cell subsets in the bone marrow. In a model of pharmacologic PD-1 blockade, administration of α-PD-1 reduced bone mass, expanded multiple T cell subsets in the bone marrow, and increased osteoclast activity and resorptive capacity. T cell deficient mice were resistant to osteoclast-mediated bone loss following α-PD-1 therapy, suggesting that T cells in the bone marrow are necessary for bone loss in the setting of ICI therapy. These findings may be leveraged to identify patients at greater fracture risk following ICI therapy due to enrichment of effector T cell populations in the bone marrow.

AbstractINTRODUCTIONHigher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.METHODSWe included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex.RESULTSFemales with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe.DISCUSSIONFemales with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.Highlights Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.