Citations

Abstract Disclosure: R. Castaneda: None. D. Bechenati: None. R.D. Rivera Gutierrez: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. J.L. Meek: None. P. Bennett: None. A. Acosta: Novo Nordisk, Gila Therapeutics, Amgen Inc, Regeneron Pharmaceuticals, Boehringer Ingelheim, Rhythm Pharmaceuticals, General Mills, Currax, Nestle, Phenomix Sciences, Busch Health, RareDiseases, National Institute of Health, Vivus Pharmaceuticals, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical. S. Faubion: Era Women’s Health Platform, PriMed, MedAll, AiCME, Medscape, Weight Watchers. C. Shufelt: Bayer Advisory Board. M.D. Hurtado: Novo Nordisk, National Institute of Health, Phenomix. Introduction: Tirzepatide, a dual GIP and GLP-1 receptor agonist, is an FDA-approved medication demonstrating the highest efficacy for weight loss among currently available treatments. However, the influence of sex and age on weight loss outcomes with tirzepatide remains unclear. Objective: To investigate the influence of sex and age on weight loss outcomes in patients treated with tirzepatide. Methods: This retrospective study evaluated weight loss outcomes associated with tirzepatide across sex and age groups. Patients with active malignancy, prior bariatric surgery, or concurrent anti-obesity medication were excluded. The primary endpoint was total body weight loss percentage (TBWL%) at 15 months by sex and age. The influence of age was analyzed as a categorical (≤45, 46-59, ≥60 years) and continuous variable. Secondary outcomes included TBWL% at 3, 6, 9, and 12 months by sex and age. Data were analyzed using independent t-tests, one-way ANOVA, and multivariate regression; results are reported as mean ± standard deviation. Results: The study included 1033 patients (57.1% female; mean age 56 ± 11 years; mean BMI, 37.7 ± 8 kg/m2). By age category, 18.8% (196) were ≤45 years (35.7% males, 64.3% females), 45.9% (473) were 46-59 years (42.7% males, 57.3% females), and 35.3% (364) were ≥60 years (54.7% males, 45.3% females). At all timepoints, TBWL was significantly greater in females compared to males at all timepoints. At 15 months females had a higher TBWL than males: 15.3% ± 10, n=340, vs. 10.2% ± 8, n=244, (p < 0.001). Among females, premenopausal women achieved a higher TBWL than postmenopausal women: 16.9% ± 10 vs 14.4% ± 9, p = 0.04. Analysis by age groups revealed a trend toward higher TBWL in younger patients that did not reach statistical significance (p = 0.152): ≤45 years (14.7% ± 10%), 46-59 years (12.9% ± 10%), and ≥60 years (12.7% ± 9%). After adjusting for baseline age, BMI, and diabetes status, sex remained a strong predictor for weight loss outcomes (PE= 4.5, 95% CI [2.96, 5.97], p < 0.001), following type 2 diabetes status (PE= 4.8, 95% CI [3.0, 6.7], p < 0.001). Conclusion: Sex but not age was a strong predictor of weight loss with tirzepatide. Female sex was associated with greater weight loss than male sex. These results emphasize the importance of considering sex-specific factors in weight loss strategies and warrant further investigation into the underlying biological mechanisms. Differential weight loss by menopause, underscores the role of sex hormones. Presentation: Monday, July 14, 2025

Abstract Disclosure: R.D. Rivera Gutierrez: None. D. Bechenati: None. R. Castaneda: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. J.L. Meek: None. T.M. Taaffe: None. P.K. Bennett: None. A.J. Acosta: Novo Nordisk, Gila Therapeutics, Rhythm Pharmaceuticals, Amgen Inc, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Currax, Nestle, Phenomix Sciences, Busch Health, RareDiseases, National Institute of Health, Vivus Pharmaceuticals, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical. S. Faubion: Era Women’s Health Platform, PriMed, AiCME, MedAll, Medscape, Weight Watchers. C. Shufelt: Bayer Advisory Board. M.D. Hurtado: Novo Nordisk, National Institute of Health, Phenomix Sciences. Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular (CV) benefits. Tirzepatide (TZP), a dual GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonist approved for weight management and glycemic control, currently lacks evidence on CV outcomes. This study evaluates TZP’s impact on cardiometabolic parameters and atherosclerotic cardiovascular disease (ASCVD) risk scores. Methods: We conducted a multicenter retrospective study of adults prescribed TZP from June 1, 2022, to November 1, 2024. Inclusion criteria included 12 months of TZP use and age >18 years. Exclusion criteria were pregnancy, active malignancy, concurrent FDA-approved antiobesity medications, and prior bariatric surgery. Endpoints included changes in blood pressure, lipid profiles, liver enzymes, glucose control parameters, medication use (statins, aspirin, antihypertensives), and ASCVD risk scores from baseline to 12 months, stratified by sex. Data were obtained from electronic medical records. We present data as mean differences [95% CI]. We used T-tests and multivariate regression analyses for analyses. Results: Among 831 participants (59.4% female; 91.2% White; mean age: 58 ± 12 years), 12-month weight loss was -12% [-13, -11], p<0.001. We observed significant improvement in systolic blood pressure (SBP) (-4 [-5, -3] mmHg, p<0.001), triglycerides (TG) (-38 [-52, -23] mg/dL, p<0.001), total cholesterol (TC) (-7 [-10, -4] mg/dL, p<0.001), LDL cholesterol (LDL) (-6 [-9, -4] mg/dL, p<0.001), fasting glucose (FG) (-39 [-48, -29] mg/dL, p<0.001), ALT (-10 [-15, -5] U/L, p<0.001), HbA1c (-1.3% [-1.5, -1.2], p<0.001), and HDL cholesterol (HDL) (+4 [+3, +5] mg/dL, p<0.001). The Lifetime and 10-year ASCVD scores did not significantly change after 12 months (p>0.05), underscoring TZP’s potential in mitigating the aging-associated increase in CV risk. Considering sex, females had greater weight loss (-13% [-14, -12] vs. -10% [-11, -9], p<0.001), and greater improvements in TC (-5% [-8, -2] vs -3% [-6, 0.1], p<0.001) and LDL (-10% [-14, -6] vs -4% [-8, 1], p<0.001). Males had a greater reduction in DBP (-2% [-4, -1] vs (-1% [-6, 3], p=0.006). Both males and females demonstrated similar improvements in FG and HbA1c. Conclusion: TZP significantly improved CV and metabolic parameters after 12 months, with greater benefits observed in females. These improvements effectively mitigated the age-related rise in ASCVD risk scores. Larger, prospective studies are warranted to confirm these findings and further investigate TZP’s long-term CV effects. Presentation: Monday, July 14, 2025

ABSTRACT Precision medicine approaches have gained attention for their potential to more effectively manage obesity by tailoring diagnosis and treatment strategies to individual characteristics, including genetic background, phenotypes, metabolic profiles, and environmental exposures. The current review evaluates the evidence for precision medicine in weight management by summarizing the proceedings of a Pennington Biomedical Scientific Symposium titled “Precision Prevention, Diagnostics, and Treatment of Obesity: Pipedream or Reality?” This review discusses the extent to which we can classify and predict obesity risk based on individual‐level factors; whether we have the diagnostic capability to prospectively identify people who will benefit most from specific interventions; whether prospective trials demonstrate superior prevention and treatment of obesity when precision approaches are applied; and whether evidence is sufficient to guide policy decisions. Expert opinions were presented on the current evidence of precision medicine for obesity to collectively evaluate key barriers and opportunities for implementation of precision approaches in clinical and public health settings.

Purpose of review The rising prevalence of obesity, now affecting over 40% of U.S. adults, poses critical implications for colorectal cancer screening, as obesity increases the risk of both colorectal adenomas and cancer. Despite these elevated risks, patients with obesity have lower colonoscopy screening participation and face unique barriers that compromise procedural quality. This review aims to highlight the challenges encountered during colonoscopy in obese patients and examine emerging solutions that may enhance screening effectiveness and patient outcomes. Recent findings Obesity is associated with suboptimal bowel preparation, prolonged cecal intubation times, lower adenoma detection rates, and increased sedation-related complications. These challenges stem from altered gastrointestinal physiology, body habitus, and comorbid conditions. Recent innovations in bowel preparation strategies, sedation protocols, and endoscopic technologies—such as robotic-assisted colonoscopy and artificial intelligence-enhanced visualization—have demonstrated promise in addressing these limitations. Institutional initiatives, including tailored protocols and endoscopy team training, are also contributing to improved outcomes. Summary As obesity rates climb, adapting colonoscopy practices to meet the needs of this population is essential. Incorporating evidence-based strategies and emerging technologies can help overcome procedural barriers, improve detection rates, and reduce disparities in colorectal cancer screening. Continued research and guideline refinement are needed to optimize care delivery for patients with obesity.

Pelvicalyceal invasion (PCI) is a relatively novel pT3a staging parameter for renal cell carcinoma (RCC) nephrectomies. While interobserver reproducibility staging studies of sinus/vascular invasion in RCC exist, a similar evaluation for PCI has not been performed. Moreover, in our experience, there is also diagnostic variability in how pathologists interpret PCI. Herein, we explore interobserver reproducibility among genitourinary (GU) pathologists. Twenty hematoxylin and eosin-stained digitized slides from RCCs (all grossly approaching the renal pelvis) were distributed to 31 GU pathologists to classify each as PCI or not PCI based on their respective clinical practices; slides with concomitant sinus/fat/vascular invasion were excluded. Slides were then evaluated for the following 4 morphologic features: tumor abutting renal pelvis, tumor pushing/indenting into the renal pelvis, polypoid configuration of tumor into the renal pelvis, and tumor eroding through renal pelvic urothelium. Interobserver reproducibility was assessed, and the morphologic features were correlated with PCI. Relationships between pathologists’ interpretations, morphologic features, and PCI were evaluated using hierarchical clustering. Although the diagnosis of PCI was relatively uniform with a majority agreement (>67%) reached in 16/20 slides, overall interobserver reproducibility was only moderate (kappa=0.601). While all 4 morphologic features were sensitive for PCI, polypoid configuration of the tumor into the renal pelvis and the tumor eroding through the renal pelvic urothelium were most specific (90%, 100%, respectively). Although we show general consensus among genitourinary pathologists on PCI assessment, clarifying the diagnostic guidelines with specific criteria should be included in pathologic staging systems.

AimsCompared to lymphovascular invasion (LVI), hilar soft tissue invasion (HSTI) is a relatively novel pT2 staging parameter in testicular germ cell tumours (GCT), associated with metastasis at the time of diagnosis and a risk factor for disease relapse. Given diagnostic variability in how pathologists interpret HSTI, herein we explore interobserver reproducibility among genitourinary (GU) pathologists.MethodsTwenty haematoxylin and eosin‐stained digitized slides from testicular GCTs were distributed to 30 GU pathologists to classify each as HSTI or not HSTI based on their respective clinical practices; slides with concomitant LVI were excluded. Slides were then evaluated for the following morphologic features: tumour invasion beyond prominent hilar vessels, tumour invasion beyond the rete, tumour invasion beyond the level parallel to hilar adipose tissue and tumour within (directly touching) hilar adipose tissue. Interobserver reproducibility was assessed, and the morphological features were correlated with HSTI. Relationships between pathologists' interpretations, morphological features and HSTI were evaluated using hierarchical clustering.ResultsAlthough the diagnosis of HSTI was relatively uniform with a majority agreement (>67%) reached in 17/20 slides, overall interobserver reproducibility was only moderate (kappa = 0.50). Morphological features such as invasion beyond the level parallel to hilar adipose tissue and invasion into fat were more sensitive and specific for HSTI, while features such as invasion beyond hilar vessels and invasion beyond rete were less useful.ConclusionsThese findings suggest that more specific defined diagnostic criteria for testicular GCT HSTI are needed.

Aims Testicular sex cord‐stromal tumours (TSCSTs) are relatively rare, accounting for ~5% of all testicular neoplasms. They were historically classified into Leydig cell tumour, Sertoli cell tumour, granulosa cell tumour, and unclassified sex cord‐stromal tumour. More recently, classification was expanded to incorporate additional histologic types, including some associated with inherited cancer predisposition syndromes. However, the classification of TSCSTs still relies entirely on morphology, with some tumour types being defined based on their resemblance to ovarian counterparts. In recent years, molecular studies have identified drivers and genomic alterations associated with aggressive behaviour and progression; however, these findings have not yet impacted classification and management. Methods and results Under sponsorship of the International Society of Urological Pathology (ISUP) and the Genitourinary Pathology Society (GUPS), a group of genitourinary pathologists was assembled in 2023 with the aim of assessing how to use these new data to improve the classification and management of TSCSTs. Conclusions This paper summarizes the recommendations derived from the consensus activities and the first meeting of the te sticular s ex cord‐ s tromal t umour (TESST) group (held at Johns Hopkins Hospital, Baltimore, USA, 3/23/2024).

Abstract Obesity is a chronic, heterogeneous, and complex disease associated with increased morbidity, mortality, and health-care costs. By 2030, 1 in 2 people in the United States will have obesity. Lifestyle interventions are the cornerstone of obesity management. However, they often fail to achieve clinically significant weight loss, necessitating additional treatments involving pharmacotherapy or procedures. Advancements in obesity pharmacotherapy have improved weight-loss outcomes and reduced associated comorbidities. Despite these advances, variability in response to treatment between individuals is still considerable. This variability reflects limitations in the current “one-size-fits-all” approach to obesity management. A precision medicine approach aims to address this gap by incorporating genetic, physiological, and behavioral characteristics to guide treatment selection and improve outcomes. Advances in multi-omics technologies, such as genomics, proteomics, metabolomics, and microbiome profiling, offer new opportunities to refine patient stratification and identify novel therapeutic targets. These tools may help move obesity care toward a more individualized and mechanism-based approach.

Context.— Distinguishing between renal oncocytic tumors, such as renal oncocytoma (RO), and a subset of tumors with overlapping characteristics, including the recently identified low-grade oncocytic tumor (LOT), can present a diagnostic challenge for pathologists owing to shared histopathologic features. Objective.— To develop an automatic computational classifier for stratifying whole slide images of biopsy and resection specimens into 2 distinct groups: RO and LOT. Design.— A total of 269 whole slide images from 125 cases across 6 institutions were collected. A weakly supervised attention-based multiple-instance–learning deep learning (DL) model was trained and initially evaluated through 5-fold cross validation with case-level stratification, followed by validation using an independent holdout data set. Quantitative performance evaluation was based on accuracy and the area under the receiver operating characteristic curve (AUC). Results.— The developed model data set yielded generalizable performance, with a 5-fold average testing accuracy of 84% (AUC = 0.78), and a closely aligning accuracy of 83% (AUC = 0.92) on the independent holdout data set. Conclusions.— The proposed artificial intelligence approach contributes toward a comprehensive solution for addressing commonly encountered renal oncocytic neoplasms, encompassing well-established entities like RO along with the challenging “gray zone” LOT, thereby proving applicable in clinical practice.

Objective: To develop and validate 2 predictive models, the Diabetes Remission Index (DRI) and the Weight loss–adjusted DRI (W-DRI), for assessing type 2 diabetes (T2D) remission following metabolic and bariatric surgery (MBS). Background: MBS, including Roux-en-Y gastric bypass and sleeve gastrectomy, is highly effective in achieving T2D remission, but outcomes vary across populations. Predicting remission remains critical for individualized patient care and optimizing surgical outcomes. Existing tools focus on general outcomes, and a specific model incorporating weight loss data has been lacking. Methods: This multicenter, retrospective cohort study included patients with T2D and overweight/obesity (body mass index: ≥27 kg/m 2 ) who underwent Roux-en-Y gastric bypass or sleeve gastrectomy between 2008 and 2018. Institution 1 (I-1) data (n = 503) were used to develop and internally validate the models, whereas Institution 2 (I-2) data (n = 409) were used for external validation. The DRI model incorporated preoperative variables, and the W-DRI model, in addition, included postsurgical weight loss. Predictive accuracy was assessed using area under the Receiver Operating Characteristic curve [area under the curve (AUC)], calibration plots, and stratified analyses. Results: In I-1, 44.7% of patients achieved T2D remission, with a DRI model AUC of 0.80. In I-2, 52.6% achieved remission, with a model AUC of 0.78. Incorporating weight loss improved W-DRI predictive accuracy (AUC: 0.82 in I-1, 0.79 in I-2). Calibration plots demonstrated strong agreement between predicted and observed remission rates. An online DRI and W-DRI calculator is available through the Mayo Clinic webpage (https://newsnetwork.mayoclinic.org/dri-calculator/). Conclusions: The DRI and W-DRI models accurately predict T2D remission post-MBS, enabling personalized patient care and informed decision-making. Further validation across diverse populations is warranted.