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e18060 Background: Intensity-modulated proton therapy (IMPT) has been gaining popularity as a method of treating locally advanced HPV positive oropharyngeal squamous cell carcinoma (OPSCC) due to the ability to reduce the amount of normal tissue that is exposed to radiation but whether or not it will result in better clinical outcomes when compared to intensity-modulated photon radiotherapy (IMRT), is still unknown. We performed a meta-analysis to evaluate the effects of IMPT on both cancer related toxicities and outcomes in comparison to IMRT for patients diagnosed with locally advanced HPV positive OPSCC. Methods: We evaluated all comparative studies that examined the use of IMPT vs. IMRT in stage III-IV HPV positive OPSCC. Using random-effects models, we estimated pooled relative risks (RRs) with 95% CIs for each study's measure of association. The primary outcomes of interest were: weight loss; gastrostomy tube insertion; xerostomia; dysphagia; mucositis; fatigue; locoregional recurrence; and OS. Statistical heterogeneity was assessed via I². Results: In total, there were 4 studies that involved 912 patients. As per these studies, a greater number of patients experienced clinically relevant weight loss when receiving IMPT than when receiving IMRT (RR 1.63, 95% CI 1.17–2.27; p= .004; I²= 0%). Additionally, a comparison of six studies which included a total of 1143 patients indicated that gastrostomy tubes are inserted more often after IMPT (RR 2.9, 95% CI 1.8 – 4.6; p<.00001; I²= 0%). No statistically or clinically significant differences were found regarding other side effects from treatments. In terms of cancer recurrence, there was a greater rate of loco-regional recurrence for those patients who received IMPT as compared to IMRT (RR 1.58, 95% CI 1.26- 1.97; p< .0001; I²= 0%) in three studies which included a total of 592 patients. However, no statistical difference in overall survival was identified between IMPT and IMRT (RR 1.06, 95% CI 0.87- 1.29; p=.56), even though there was significant variability (I²= 87%) in three studies which included a total of 747 patients. Conclusions: In locally advanced HPV positive OPSCC, there were no differences in toxicity profiles from IMPT compared to IMRT, and there were increased rates of weight loss, gastrostomy tube placement, and locoregional recurrence from IMPT compared to IMRT, without any observed survival advantage. This highlights the need for future prospective randomized trials to clarify the role of IMPT in the management of locally advanced HPV positive OPSCC.

e16443 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with KRAS mutations present in approximately 90% of cases. Patients with advanced or metastatic PDAC who have progressed after standard chemotherapy face limited treatment options, with historical outcomes showing objective response rates (ORR) below 10% and median progression-free survival (PFS) and overall survival (OS) of approximately 2-4 months and 6-8 months, respectively. The development of covalent KRAS G12C inhibitors—including sotorasib, adagrasib, garsorasib, glecirasib, and divarasib—has opened new therapeutic options for this molecularly defined subset of PDAC patients. Methods: We conducted a systematic review and meta-analysis of clinical trials evaluating KRAS G12C inhibitor monotherapy in patients with advanced/metastatic pancreatic ductal adenocarcinoma. Data were extracted from 3 studies (Strickler 2022, Li J 2025, and Tanios 2023) encompassing a total of 91 patients with KRAS G12C-mutant PDAC who had received 1-2 prior lines of chemotherapy. Pooled estimates were calculated using random-effects meta-analysis models (DerSimonian-Laird method). For proportion outcomes (ORR and DCR), standard errors were calculated using binomial distribution, and for continuous outcomes (PFS and OS), inverse-variance weighting was employed. Heterogeneity was assessed using the I² statistic and Cochran's Q test. All confidence intervals were calculated at the 95% level. Results: The pooled analysis revealed clinically meaningful efficacy across all endpoints. The pooled objective response rate (ORR) was 32.9% (95% CI: 17.0% to 48.9%), with moderate heterogeneity (I² = 64.0%). The pooled disease control rate (DCR) was substantially higher at 88.3% (95% CI: 80.5% to 96.1%), with low heterogeneity (I² = 27.7%), indicating consistent disease stabilization across studies. For survival outcomes, the pooled median progression-free survival (PFS) was 4.98 months (95% CI: 3.62 to 6.34 months), with low heterogeneity (I² = 32.3%). The pooled median overall survival (OS) was 8.73 months (95% CI: 6.07 to 11.39 months), though with substantial heterogeneity (I² = 77.0%). Conclusions: KRAS G12C inhibitor monotherapy demonstrates clinically significant and durable efficacy in pretreated adults with advanced/metastatic PDAC harboring the KRAS G12C mutation. The pooled ORR of approximately one-third, together with a DCR near 90%, indicates substantial tumor control in a population with historically poor outcomes. Median PFS of approximately 5 months and OS of nearly 9 months represent clinically relevant improvements over standard salvage therapies, supporting KRAS G12C inhibitors as a viable option after chemotherapy failure.

e13121 Background: Triple-negative breast cancer (TNBC) lacks reliable prognostic biomarkers beyond standard clinical staging, limiting individualized risk stratification and treatment planning. The neutrophil-to-lymphocyte ratio (NLR), a readily available marker of systemic inflammation, has been proposed as a prognostic indicator in TNBC; however, existing evidence remains inconsistent. We performed an updated systematic review and meta-analysis to evaluate the prognostic value of pretreatment NLR in the contemporary treatment era. Methods: PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were systematically searched from database inception through January 1, 2026, for randomized and observational studies reporting associations between pretreatment NLR and survival outcomes in TNBC. Two reviewers independently screened studies and extracted data with discrepancies resolved by consensus. Outcomes included overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Hazard ratios (HRs) were pooled using random-effects models. Risk of bias was assessed using ROBINS-I tool. Prespecified subgroup and sensitivity analyses were performed based on NLR cut-off values, follow-up duration, geographic region, and risk of bias. Results: Twenty-three retrospective studies comprising 4,731 patients with TNBC were included. On multivariate analysis, elevated pretreatment NLR was independently associated with poorer OS (HR 2.21, 95% CI: 1.56–3.13) and DFS (HR 1.97, 95% CI: 1.65–2.37. Similar associations were observed on univariate analysis (OS: HR 1.70, 95% CI: 1.07–2.72; DFS: HR 1.84, 95% CI: 1.14–2.98). No statistically significant or consistent association was observed between NLR and PFS. Associations between high NLR and adverse OS and DFS remained robust across prespecified subgroup and sensitivity analyses, representing the largest contemporary synthesis of multivariable-adjusted outcomes in TNBC. Key pooled outcome associations are summarized in Table 1. Conclusions: Elevated pretreatment NLR is independently associated with worse OS and DFS in patients with TNBC, supporting its potential role as a low-cost tool for clinical risk stratification and treatment planning. Given its availability from routine blood tests, NLR may assist in identifying high-risk patients who could benefit from intensified surveillance or therapeutic strategies. Prospective validation in the modern chemo-immunotherapy era is warranted. Summary of pooled associations between pretreatment NLR and survival outcomes in TNBC. Outcome Studies (n) Interpretation Overall survival 14 Worse survival Disease-free survival 15 Worse survival Progression-free survival 3 Inconclusive

Abstract Aims To characterize global variation in cardiac rehabilitation (CR) staffing, indications, and prescribed dose by country income classification and compare findings with the International Council of Cardiovascular Prevention and Rehabilitation’s 2016 Global Audit. Methods and results Cross-sectional REDCap survey of Phase II/post-discharge CR programmes (May–September 2025). Outcomes were multidisciplinary team size/composition, accepted cardiac and non-cardiac indications, and centre-based CR dose. Comparisons were made across World Bank country income classifications and Audit decade (2016 vs. 2025). Of 7025 programmes identified globally, 1505 (median programme response rate = 62%/country) initiated a survey, from 90/113 (80%) countries with CR. CR was delivered by a multidisciplinary team of 7 (median; P25–P75 = 5–8; nurses, physiotherapists, cardiologists, and dietitians most common); teams were smaller in low-income countries (median = 4; P &lt; 0.001), and physician specialty varied. Non-low-income programmes consistently accepted (≥90%) patients with acute coronary syndrome, with programmes in low-income countries less often accepting related interventions (e.g. surgery: low-income 0% vs. high-income 97%; P &lt; 0.01), but non-cardiac indications were more frequently accepted (e.g. primary prevention, diabetes, and lung disease). Acceptance of heart failure increased compared with the previous Audit (70% vs. 87%; P &lt; 0.001). Centre-based programmes prescribed a median of 20 h (P25–P75 = 12–30), typically two sessions/week over 8 weeks. Globally, 65 (72%) countries prescribed a median ≥12 sessions/programme. Programmes in upper-middle-income countries prescribed more sessions (median = 24, P25–P75 = 12–36; P &lt; 0.001). Dose did not differ meaningfully between Audits (P = 0.07). Conclusion CR programmes globally are offered by small, but multidisciplinary teams. They accept guideline-indicated patients, with applicable variation by context. Insufficient dose in one-quarter of countries underscores investment need.

4514 Background: Maintenance avelumab is a standard of care in patients (pts) with la/mUC who do not progress after first-line PBC. Cabozantinib (CABO) is an oral inhibitor of MET, VEGFR and TAM, active in multiple solid tumors. We hypothesized that an avelumab (Av)-CABO combination would improve outcomes in pts with mUC with an acceptable safety profile compared to avelumab maintenance alone. Methods: MAIN-CAV (NCT05092958) is a phase III randomized, multicenter, international trial for la/mUC pts who did not progress after 4-6 cycles of any PBC (gemcitabine-cisplatin, gemcitabine-carboplatin, MVAC, ddMVAC). Pts were randomized 1:1 to Av 800 mg IV every 2 weeks alone or with CABO 40 mg daily for ≤2 years. Stratification factors were response to first-line PBC (complete response [CR] vs partial response [PR] vs stable disease [SD]) and visceral metastases. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), safety and quality of life. The target accrual was 654 pts; the trial closed early after enrollment of 68 pts following adoption of enfortumab vedotin plus pembrolizumab as the new preferred first-line standard in the US. Results: From 3/2022 to 3/2024, 68 pts were randomized (Av n = 33; CABO-Av n = 35). Median OS was 24.8 months (mo) with Av and 23.0 mo with Avb-CABO (Hazard ratio 1.41; 95% CI 0.66–3.01; p = 0.186). Median PFS was 4.6 mo with Av vs 6.0 mo with Av-CABO (p = 0.343). Objective response rate among pts with PR or SD after first-line PBC was 20.8% with Av vs 11.5% with Av-CABO (p = 0.424). Grade ≥3 treatment-related adverse events occurred in 24.2% pts on the Av arm vs 39.4% of pts on the Av-CABO arm and CABO dose reductions occurred in 63% of pts. Conclusions: Addition of CABO to Av did not improve OS or PFS compared with Av alone in this underpowered, prematurely closed phase III trial; safety was consistent with known profiles. U10CA180821,U10CA180882; U24CA196171, U10CA180863. (CCTG);U10CA180888 (SWOG); https://acknowledgments.alliancefound.org. Clinical trial information: NCT05092958 .

4178 Background: In the CABINET trial, CABO significantly prolonged progression-free survival (PFS) compared to placebo (PB) in patients (pts) with advanced, previously treated extrapancreatic NET (epNET) or pancreatic NET (pNET) (Chan et al., NEJM, 2025). Here we report outcomes according to functional status based on NET hormone secretion. Methods: Pts with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. Eligibility included progression by RECIST within 12 months (mo) before registration, ≥ 1 prior systemic therapy not including somatostatin analogs (SSA). Pts with functional NET due to hormone secretion and non-functional NET were included. In this post hoc subgroup analysis, we analyzed PFS by blinded independent central review and adverse events for pts receiving CABO vs PB based on functional status. Cox regression models were used with stratification on primary tumor site (epNET vs pNET). Subset analyses to evaluate treatment arm differences were conducted in pts with functional and non-functional tumors. Due to small numbers, separate results for those with unknown functional status are not included. Results: Of the total 298 pts enrolled in both cohorts, 74 had a functional NET (CABO, n = 47; PB, n = 27); 179 had a non-functional NET (CABO, n = 123; PB, n = 56); 45 had unknown functional status (CABO, n = 28; PB, n = 17). For functional NET, primary tumor sites were GI tract (n = 50; 68%), pancreas (n = 15; 20%), unknown (n = 4; 5%), lung (n = 3; 4%), and thymus (n = 2; 3%). Secreted hormones that were reported included serotonin (55%), somatostatin (18%), gastrin (16%), glucagon (4%), insulin (4%), ACTH (1%), and vasoactive intestinal peptide (1%). For non-functional NET, primary tumor sites were pancreas (n = 75; 42%), GI tract (n = 42; 23%), lung (n = 30; 17%), unknown (n = 17; 9%), thymus (n = 8; 4%), and other (n = 7; 4%). Concurrent SSA was received by 91% and 53% of pts with functional and non-functional NET, respectively. In both subgroups, CABO was associated with improved PFS compared to PB (for functional NET: stratified hazard ratio [sHR], 0.40; 95% confidence interval [CI]: 0.20-0.82, P = 0.012; for non-functional NET: sHR, 0.26; 95% CI: 0.17-0.41, P < 0.001). The most frequent grade 3/4 adverse events (AEs) attributed to CABO vs PB in pts with functional NET included hypertension (21% vs 11%), diarrhea (9% vs 11%), and fatigue (2% vs 15%); in pts with non-functional NET, grade 3/4 AEs included hypertension (21% vs 4%) and fatigue (18% vs 4%). Conclusions: Subset analyses of the CABINET trial suggest that CABO is an effective treatment option for pts with functional and non-functional epNET or pNET. Efficacy and safety results for pts with functional or non-functional NET treated with CABO are consistent with results for the entire trial. Clinical trial information: NCT03375320 .

SUMMARY Neurodegenerative diseases are often accompanied by systemic comorbidities, including changes in bone health, but the molecular relationship between neurodegeneration, skeletal decline, and cellular senescence remains poorly understood. In this study, we investigated sex-specific changes in circulating bone- and senescence-related proteins across the spectrum of Alzheimer’s disease(AD), Lewbody dementia(LB) and Parkinson’s disease(PD). Plasma proteomic profiling was performed on samples from 408 participants deeply phenotyped for neurodegenerative diseases, followed by differential protein and pathway analyses. This study reveals sex-dependent alterations in bone and senescence-related circulating proteins in AD-related, PD and LB-related neurodegenerative diseases, providing insights into the complex relationship between neurodegeneration and bone health. Several candidate proteins were also associated with established plasma neurodegeneration biomarkers, particularly pTau181. Pathway analyses revealed shared mitochondrial and metabolic dysfunction across neurodegenerative diseases, with disease-specific features including vesicle trafficking disruption in AD and inflammatory-senescence pathways in LB, plus sex-divergent patterns in inflammatory signaling and bone-related pathways.

Introduction Obesity and related cardiometabolic comorbidities, including hypertension, dyslipidaemia, diabetes, metabolic dysfunction-associated steatotic liver disease and atherosclerotic cardiovascular disease, are increasingly prevalent among individuals with inflammatory bowel disease (IBD). These conditions influence disease activity, therapeutic response, surgical outcomes and overall quality of life, yet evidence remains fragmented. The M odulate O besity and relate D metabolic compl I cations F or Y ielding improvements in IBD outcomes (MODIFY-IBD) initiative aims to synthesise evidence and generate consensus recommendations to guide practice and future research in this area. This study describes a protocol for a structured evidence synthesis and Research ANd Development/University of California, Los Angeles (RAND/UCLA) Appropriateness Method (RUAM) consensus process. Methods and analysis We will conduct three systematic reviews and a structured evidence synthesis organised into three domains: (1) the impact of obesity on IBD outcomes, (2) the burden of cardiometabolic complications in IBD and (3) the management of overweight, obesity and cardiometabolic comorbidities in IBD. A multidisciplinary international panel of gastroenterologists, surgeons, endocrinologists, hepatologists, cardiologists and dietitians will assess each statement using the RAND/UCLA appropriateness method. Panellists will rate the appropriateness of each statement (only those that fall within their area of expertise) on a 1–9 scale (1–3=inappropriate, 4–6=uncertain and 7–9=appropriate), with medians rounded up (eg, 6.5=appropriate). Agreement will be assessed using the RAND Disagreement Index (DI<1.0=agreement). Ethics and dissemination This study will not involve direct patient participation, as it is based on evidence synthesis and expert consensus; therefore, formal research ethics committee approval will not be required. Patient representatives will contribute to the consensus process to provide contextual perspectives but no identifiable data will be collected. Findings will be disseminated through publication in peer-reviewed journals, presentation at major gastroenterology and IBD conferences and communication with professional societies. A lay summary and patient-friendly infographic will also be developed to facilitate translation of recommendations into clinical practice. PROSPERO registration numbers CRD420251178843: a systematic review of the impact of obesity on inflammatory bowel disease outcomes. CRD420251178799: a systematic review of cardiometabolic complications in inflammatory bowel disease. CRD420251174653: management of overweight, obesity and cardiometabolic comorbidities in inflammatory bowel disease: a systematic review.

Background/Objectives: White matter (WM) tract detection is critical in the presurgical planning of tumor resection. However, standard-of-care imaging techniques including T1-weighted, T2-weighted, and Diffusion Tensor Imaging (DTI) often fail to identify WM tracts within edematous regions. In T1/T2-weighted imaging, edema increases extracellular water and reduces tissue contrast, and in diffusion-weighted imaging, edema elevates isotropic diffusion, reducing sensitivity to anisotropic diffusion along WM tracts. Advanced biophysical diffusion modeling techniques such as Neurite Orientation Dispersion and Density Imaging (NODDI) and the Standard Model (SM) address this limitation by compartmentalizing the diffusion signal into free-water, intra-neurite, and extra-neurite contributions. Here, we test if biophysical multi-compartment models can robustly identify WM tracts and recover tractography streamlines within edematous regions. Methods: In this study, we use multi-shell diffusion-weighted MRI data obtained from patients with meningiomas—a pathology allowing for isolation of the effects of edema without the confounding effects of tumor cell invasion. We compared FA from standard and free-water-corrected DTI, the orientation dispersion index (ODI) from NODDI, and P2 (a scalar descriptor of fiber orientation coherence) from the SM fODF in edematous and unaffected contralateral WM regions. As a proof of concept, we visually evaluated the tractography performance across models. Results: Our results show that (1 − ODI) and P2 values in edema remained close to within-subject contralateral measurements, contrasting with substantial reductions in FA and FW-FA. (1 − ODI) showed a small but statistically significant increase in edema (~8%, p = 0.02), while P2 was unchanged. Conclusions: These results highlight the potential of biophysical diffusion models for preoperative mapping in edema.

Objective The Accreditation Council for Graduate Medical Education (ACGME) introduced Milestones in 2013 to aid the assessment of residents and fellows within the framework of the six core competencies of practice. Feedback from program directors and trainees, clinical competency committee processes, and milestone reporting identified the need for modification. This study represents a consensus-driven educational quality improvement initiative which describes the development, revision process, and key features of Critical Care Anesthesiology (CCA) Milestones 2.0, and provides lessons learned in adapting competency-based assessment to a one-year subspecialty training program. Methods A Critical Care Anesthesiology (CCA) working group was convened by the ACGME in 2021 to revise the content, enhance relevance to training, clarify goals for program leadership, and develop supplemental resources to aid implementation. The group consisted of a diverse group of experienced educators and clinicians from CCA fellowship programs nationwide. A modified Delphi process, stakeholder feedback, Milestones performance data, and public comment were used to iteratively revise Milestones. In addition, a supplemental guide was developed to provide examples and resources to aid the Milestones assessment. Conclusion The Milestones 2.0 simplify the use, implementation, and interpretation of this competency framework for program directors, trainees, faculty, and the American Board of Anesthesiology. The resulting CCA Milestones 2.0 provide updated specialty-specific, competency-based behavioral anchors to guide the developmental progression of competencies and outcomes for CCA fellows and facilitate the design of curricula and the advancement of CCA training programs. Lessons learned in the development of the CCA Milestones 2.0 include the importance of simplification, behavioral specificity, and supplemental.