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476 Background: Lack of standardized reporting and collection of patient-reported outcomes (PROs) limits cross-trial comparisons of first-line IO-based regimens for mRCC. Prospectively collected real world data may fill this important knowledge gap. Pts with stable/improved QoL at 3 mo versus baseline have longer median OS than pts with worse/unobserved HRQoL versus baseline (Cella, 2024). Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology), no prior systemic therapy (ST), and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. Descriptive statistics are used to show PRO score changes from baseline. We evaluate longitudinal change from baseline in PRO scores using least squares mean (LSM). Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Higher score indicates better QOL. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Results: As of 10/1/25, 360 pts were managed with ST, including 266 pts on IO-based combinations: 35 cabozantinib + nivolumab (C+N), 49 lenvatinib + pembrolizumab (L+P), 40 axitinib + pembrolizumab (A+P), and 142 ipilimumab + nivolumab (I+N). Overall median follow-up is 12.1 mos (IQR 6, 24). Age, sex and race were similar across regimens. Prior nephrectomy (50%) was lower than in trials. C+N and L+P pts had less clear cell (56 and 65%) versus A+P and I+N pts (94 and 82%). A+P pts had more favorable IMDC risk (19%) and less poor risk (14%). Baseline QOL was variable across regimens, with L+P generally the lowest. Absolute changes in PROs from enrollment to mo 3 (early change) by regimen are shown in the Table. LSM change from baseline in FKSI-19 and FKSI-DRS favored IO-IO versus IO-TKI at 3 mos but not at 6 mos (not shown). Conclusions: While early change in PROs did not meet the MID threshold between the IO-TKI and I+N cohorts, different patterns of early change are apparent among specific IO-TKI regimens. IO-TKI regimens exhibited higher variation in early PRO change vs I+N. As the data matures, we will associate baseline PROs and early PRO changes with early death and other outcomes. Clinical trial information: NCT04919122 . 3 month change. Instrument C+N (N=35) L+P (N=49) A+P (N=40) All IO-TKI(N=124) I+N(N=142) FKSI-19, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.3 (11) 2.8 (13) -3.2 (12) -0.2 (12) 0.7 (10) Median (IQR) 1.4 (-7, 6) 5.0 (-7, 11) -1.0 (-14, 5) 1.4 (-10, 8) -0.3 (-5, 6) FKSI-DRS, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.8 (5) 1.5 (7) -1.8 (6) -0.3 (6) 0.8 (5) Median (IQR) -0.5 (-5, 3) 2.0 (-5, 5) -1.0 (-5, 3) 0.0 (-5, 4) 0.0 (-2, 4) FACT-G, N (%) 27 (77) 32 (65) 29 (73) 88 (71) 102 (72) Mean (SD) 2.1 (14) 5.2 (16) -3.5 (15) 1.4 (15) 0.3 (13) Median (IQR) 4.0 (-4, 10) 1.2 (-6, 13) -6.4 (-11, 4) 1.6 (-8, 10) 1.6 (-7, 8)

Importance Total thyroidectomy is the established surgical standard for hereditary and sporadic medullary thyroid cancer (sMTC). However, for unilateral sporadic tumors, its benefit over lobectomy remains uncertain. Objective To compare oncologic outcomes between total thyroidectomy and lobectomy in patients with sMTC. Data Sources and Study Selection MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials were searched from inception to December 2025 to identify comparative studies on patients with sMTC who underwent total thyroidectomy or lobectomy. Data Extraction and Synthesis Reviewers working independently and in duplicate screened titles, abstracts, and full-text articles for eligibility using standardized instructions. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses ( PRISMA ) and Meta-Analysis of Observational Studies in Epidemiology ( MOOSE ) guidelines were used for reporting. Main Outcomes and Measures Primary outcomes were mortality, overall survival, structural recurrence, biochemical cure, and distant metastasis development. The secondary outcome was postoperative complications. Effect measures were calculated as odds ratios (ORs) or relative risks (RRs) with 95% CIs using a random-effects model. The risk of bias was assessed using the Newcastle-Ottawa Scale. Results Nine retrospective studies met inclusion criteria and comprised 1371 patients (295 of 397 patients [74.3%] with documented sex were female, and median age ranged from 45.0 to 58.2 years). A total of 531 patients (38.7%) underwent lobectomy and 840 (61.3%) underwent total thyroidectomy. Of 341 tumors, 280 (82.1%) lacked extrathyroidal extension, 284 of 401 tumors (70.8%) measured smaller than 2 cm (70.8%), and 197 of 343 tumors (57.4%) were node negative; central neck dissection was performed in 445 of 492 patients (90.4%). Multifocal disease was uncommon and reported in 30 of 330 patients (9.1%). Mortality did not differ at 5 years (RR, 0.30; 95% CI, 0.07-1.35) or beyond (RR, 1.00; 95% CI, 0.40-2.47). Overall survival at 5 years was similar (RR, 1.02; 95% CI, 0.94-1.11). Total thyroidectomy was not associated with lower structural recurrence rates at 5 years (OR, 0.45; 95% CI, 0.14-1.49), but it was associated beyond 5 years (OR, 7.26; 95% CI, 1.07-49.21). No differences were observed for biochemical cure at 5 years (OR, 0.86; 95% CI, 0.47-1.56) or beyond 5 years (OR, 0.87; 95% CI, 0.26-2.89). Distant metastasis development did not differ at 5 years (OR, 1.64; 95% CI, 0.09-31.52). Sensitivity analyses revealed no differences across any outcomes. Postoperative complications were more common in total thyroidectomy. Risk of bias was high in 4 studies, moderate in 4, and low in 1. Conclusions and Relevance Findings in this systematic review and meta-analysis, based on data from retrospective studies, suggest that thyroid lobectomy may be associated with oncologic outcomes comparable to total thyroidectomy in selected patients with sMTC.

Abstract Objectives Sarcomatoid urothelial carcinoma (sUC) is associated with poor clinical outcomes. Herein, we evaluated clinicopathologic features (including PD-L1 expression) for institutional cases. Methods Sixty-five patients with sUC treated by radical cystectomy were matched for age, sex, and pathologic stage to 190 patients with pure urothelial carcinoma (UC). Outcomes were evaluated using the Kaplan-Meier method. Immunohistochemistry (IHC) results for tumor-specific PD-L1 expression in sUC were quantified using H-scores (range, 0-300). Cases with constitutive PD-L1 expression (cPD-L1; H-score ≥240) were evaluated for amplification events using fluorescence in situ hybridization (n = 28), mate-pair sequencing (Mpseq; n = 6), RNA sequencing (n = 5), and targeted next-generation sequencing (n = 8). PD-L1 regulatory pathways were evaluated using gene set enrichment analysis in the Cancer Hallmark dataset. Results Most patients with sUC had advanced disease (≥pT2, 62/65, 95%), without significant differences in overall and cancer-specific survival, when matched to pure UC. Median PD-L1 H-scores using different clones were 100 (SP142), 120 (SP263), and 195 (22C3). cPD-L1 was seen in 43% (28/65) of cases of sUC that were enriched for TP53, TERT, and CDKN2A/B alterations. PD-L1 amplification was identified in 7 (of 28, 25%) of these cases. Bionformatics analysis consistently identified IL6-JAK-STAT3 and interferon α/γ signaling in sUC with cPD-L1 expression. Conclusions Our results suggest that cPD-L1 expression in most sUC occurs secondary to IL6-JAK-STAT3 and interferon α/γ signaling. This provides a biologic rationale for evaluating response to immunotherapy in this patient population.

Abstract Objective: Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. Method: Former American football players ( n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ 1-42 , p-tau 181 , t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. Results: Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. Conclusions: SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

Abstract Context Evidence on the etiology and function of adrenal masses in younger adults is scarce. Objective This work aimed to characterize the clinical, imaging, and biochemical presentation of adrenal masses in 18- to 40-year-olds. Methods A retrospective cohort study was conducted January 2016 to December 2021 at a tertiary academic medical center. Participants included young adults (age 18-40 years) with adrenal masses identified through radiologic registry. Exclusion criteria included preexisting adrenal masses before 2016, hyperplasia, or masses smaller than 1 cm. Outcomes included adrenal mass diagnosis, as determined by reference standard of histopathology, radiologic surveillance, and biochemical evaluation. Results A total of 255 patients (women 142 [56%]; White 156 [61%]; median age 35 years [interquartile range 30-39 years]) were included. Comorbidities included genetic predisposition syndromes (16, 6.3%), preexisting malignancy (70, 27%), obesity (100, 48%), hypertension (89, 35%), and diabetes (25, 10%). The majority of adrenal masses were incidentally found (184, 72%) and median size was 1.9 cm (IQR 1.4-2.7 cm) on detection. Among adrenal masses in young adults, prevalence of malignancy and pheochromocytoma was 16% and 4%, respectively; among adrenal incidentalomas, 5% were malignant. Factors associated with malignancy or pheochromocytoma in multivariable analysis included nonincidental mechanism of discovery (odds ratio [OR] 15.5; 95% CI, 7.2-35.7; P < .001), and larger size (OR 1.5; 95% CI, 1.2-2.0; P < .001). Hormonal evaluation was performed in only 57 (22%) patients and was positive for hormone hypersecretion in 16 (28%) of tested individuals. Conclusion We demonstrated a high prevalence of malignancy and pheochromocytoma in our cohort of young adults with adrenal masses. Completion of appropriate hormonal work-up was infrequent, potentially missing patients with functioning adrenal adenomas.

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Abstract Guideline-concordant breast cancer treatment selection is increasingly complex due to rapid evolution in biomarker-driven therapies. Large language models (LLMs), such as GPT-4, offer a potential tool to support clinical decision-making. However, hallucinations and deviation from evidence-based guidelines remain significant concerns. This study evaluated whether retrieval-augmented generation (RAG) using National Comprehensive Cancer Network (NCCN) guidelines improves GPT-4 performance in treatment recommendation tasks. We developed a retrieval-augmented GPT-4 agent (RAG-GPT) by indexing 2025 NCCN Breast Cancer Guidelines into a vector database using sentence embeddings. Forty clinical vignettes were created from published case reports to reflect diverse scenarios, including HER2-low, triple-negative, and BRCA-mutated disease across all stages. Two models—a baseline GPT-4 (without augmentation) and the RAG-GPT—were prompted with structured templates requesting treatment plans, rationale, clinical trial options, and citations.Outputs were independently scored by two blinded oncology-trained reviewers using the modified Generative AI Performance Score (mG-PS). The mG-PS scored outputs for 2 categories, guideline concordance (Gold standard = 1.0, Acceptable = 0.5, Non-concordant = 0.0) and hallucination errors (Severe = -1.0, Moderate = -0.5, Mild = -0.25, None = 0.0). Guideline Concordance was deemed based on NCCN guidelines and what an oncologist would due based on using the guidelines for each case. Hallucinations are a term used for falsehoods in Artificial Intelligence, like made-up facts or studies, incorrect information, improper doses, or inappropriate or wrong treatments. To ensure consistency and minimize inter-rater variability, reviewers were provided with comprehensive scoring guidelines and detailed instructions for each evaluation metric. Scores were normalized between -1.0 and 1.0 for improved evaluation of tools. Readability and rationale clarity were rated on a 5-point Likert scale. Inter-rater reliability was assessed using Cohen’s kappa. The RAG-GPT demonstrated a significantly higher mean mG-PS score (0.599 ± 0.102, 95% CI: 0.498-0.702) compared to the baseline GPT-4, which not only scored lower but had a negative mean (-0.21 ± 0.143, 95% CI: -0.353 to -0.067). For the mG-PS Cohen’s Kappa test resulted in a score of .69 with substantial aggreament. An independent sample t-test showed a difference (t(78) = 29.1, p < 0.0001). Severe hallucinations were also absent in RAG-GPT outputs (0/40) but occurred in 8/40 baseline GPT-4 outputs. The evaluation of readability and rationality also showed notable differences, with the augmented LLM scoring significantly higher (M = 4.35, SD = 0.66) compared to the naïve LLM (M = 3.05, SD = 1.06). An independent samples t-test confirmed this difference t(65.3) = 6.58, p < 0.0001, further supporting the benefit of augmented Large Language models. Cohen’s Kappa test resulted in a score of .76 for a substantial agreement for readability and rational clarity scale. Limitations include small sample size; further fine-tuning and larger real-world validation studies remain necessary. Linking GPT-4 to NCCN guidelines via retrieval-augmented generation significantly improves treatment accuracy and reduces hallucination severity in breast cancer care scenarios. While further refinement is needed, the reduced incidence of severe hallucinations, increase in guideline-concordant recommendations, and enhanced readability findings support further development and prospective validation of guideline-anchored LLMs for clinical use. Citation Format: C. Yost, A. Aseem, B. Callas, S. Monick, L. Bonilla, R. Nguyen, R. Galamaga, S. Osborn, Y. Kumar, N. Ertz-Archambault. Retrieval-augmented GPT-4 improves NCCN-concordant breast cancer treatment recommendations [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-06-29.

ABSTRACT Interactions between clinical pharmacists and industry partners continue to evolve as health care increases in complexity and technology assumes a more dominant role. To address the corresponding ethical challenges, the 2025 Industry Relations Committee of the American College of Clinical Pharmacy (ACCP) was charged with updating the 2008 ACCP position statement, Pharmacists and Industry: Guidelines for Ethical Interactions . This update expands its perspective, reflecting the broader and more influential roles pharmacists play across the health care ecosystem. All clinical pharmacist–industry interactions should be grounded in improving patient care. Through this lens, six recommendations are provided: (1) Pharmacists should not engage in industry partnerships or collaborations that might unduly influence objectivity, independence, or fairness in clinical and professional judgments; (2) Pharmacists should disclose and mitigate financial, consulting, or other relationships that constitute potential conflicts of interest and should not participate in activities where an existing conflict cannot be resolved; (3) Pharmacists who participate in industry‐sponsored research should follow accepted ethical, regulatory, and scientific standards; (4) Pharmacists providing continuing education programs or developing drug information materials should maintain control of content; ensure their content is fair, balanced, and free from bias; and disclose and mitigate any conflicts; (5) Formal instruction on ethical interactions with industry professionals should begin early and continue through all stages of pharmacist education, training, and professional development; (6) Pharmacists should maintain the confidentiality and privacy of patients and other health care professionals when working with industry partners. Questions to guide personal industry interactions are provided. This paper does not detail every emerging area (e.g., artificial intelligence, social media), but recommendations are applicable wherever clinical pharmacists leverage their professional expertise. By maintaining a critical, discerning, and ethical approach to industry collaborations, clinical pharmacists can uphold professional obligations while contributing to the advancement of evidence‐based practice, ultimately prioritizing patient welfare.