Citations

Background: Integrating machine learning (ML) with population pharmacokinetic (PPK) modeling may improve therapeutic drug monitoring predictions. Methods: Tacrolimus trough concentrations from lung transplant patients were split into a training data set (1151 concentrations in 80 patients) and a testing data set (224 concentrations in 20 patients). A PPK model was developed using NONMEM, followed by the development of 10 ML models to fit individual pharmacokinetic parameters from the PPK model with Bayesian forecasting. The best performing ML model was selected as the final model. Both the final PPK and ML models were compared for prediction performance. A web-based dashboard was established with R-shiny to recommend dosing regimens based on patient data. Results: In the PPK model, postoperative days, hematocrit, aspartate aminotransferase, tacrolimus daily dose, coadministered voriconazole or posaconazole, and the CYP3A5*3 genotype were identified significant covariates on the clearance. The Cubist ML model outperformed the PPK model, showing lower root mean squared error for tacrolimus concentrations in the testing data set. An online web-based precision dosing dashboard was created, accessible at (https://tac-dose-ml.shinyapps.io/shiny/). Conclusions: Integrating ML with PPK modeling could yield superior tacrolimus concentration predictions for lung transplant patients, offering an efficient alternative to Bayesian forecasting. The online dashboard provides rapid, individualized dosing recommendations.

Abstract Background The tumor, node, metastasis (TNM) classification at pathological evaluation determines prognosis following cancer treatment. For rectal cancer patients undergoing neoadjuvant therapy, whether ypTNM likely confers different prognosis than pTNM. We compared survival outcomes of patients classified by ypTNM vs pTNM staging. Methods Patients with resected locoregional rectal cancer from the National Cancer Database who underwent upfront surgery (pTNM) and had ≥5 years follow-up (2010-2017) were compared with those receiving neoadjuvant therapy followed by surgery (ypTNM). To address treatment selection bias, analyses were stratified by receipt of guideline-concordant care. Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox regression analyses. Results Of 50 436 patients (median age = 60; 61.4% male), 11 732 (23.3%) underwent upfront surgery and 38 704 (76.7%) received neoadjuvant therapy; 78.8% of the upfront surgery group received guideline-concordant care. In analyses stratified by guideline-concordant care, overall survival was similar for stage 0-I (hazard ratio [HR] = 1.05; 95% CI = 0.96 to 1.15) but significantly worse for ypTNM vs pTNM in stage II (HR = 1.50; 95% CI = 1.27 to 1.77; 5-year OS = 75.6% vs 83.2%) and stage III (HR = 1.60; 95% CI = 1.46 to 1.75; 5-year OS = 67.0% vs 78.2%). Multivariable analysis confirmed ypTNM was associated with worse survival at each stage (stage 0-I: HR = 1.14, P = .004; stage II: HR = 1.49, P < .001; stage III: HR = 1.60, P < .001). Conclusion Stage for stage, ypTNM classification is associated with worse survival than pTNM classification, with increasing difference at higher stages. Future staging systems and management guidelines should account for these differences to optimize prognostication and stratification for clinical trials and surveillance strategies.

Abstract Introduction Despite progress in understanding placebo effects in clinical trials of inflammatory bowel disease (IBD), there is a limited understanding of how socioeconomic factors of recruiting countries impact placebo rates. We investigated the association of socioeconomic factors across recruitment sites on placebo rates in IBD randomized controlled trials. Methods We examined the association of clinical and endoscopic remission and response to the weighted Gross National Index (GNI) per capita, Human Development Index (HDI), and out-of-pocket health expenditures as a percentage of current health expenditures (OOP_CHE) of identified trials using mixed effects linear regression. Results Across 76 trials (Crohn’s disease [CD]: n = 32; ulcerative colitis [UC]: n = 44), placebo response rates over time were largely stable, with a small increase across time in clinical remission for CD trials (β = 0.4% per increase in study year, 95% CI: 0.3%-0.84%, P = .04) and a small decrease across time in endoscopic response for UC trials (β = −1.39% per increase in study year, 95% CI: −1.79, −0.99, P < .001). Clinical response was most susceptible to changes in socioeconomic factors in IBD trials (β = −2.96% per 10 000 USD increase in study GNI, 95% CI: −4.98, −0.95%, P = .004; P < .05 for HDI and OOP_CHE). Across both conditions, decreases in clinical response were associated with increases in HDI and OOP_CHE (CD HDI: β = −1.15% per 0.01 increase in study HDI, 95% CI: −2.24, −0.06%, P = .04; UC HDI: β = −0.66% per 0.01 increase in study HDI, 95% CI: −1.19, −0.12%, P = .02). Discussion We found that placebo clinical response was most susceptible to influences of site-level socioeconomic wellbeing. These findings highlight that estimation of placebo rates in trial planning should account for geographic location of recruiting sites.

Abstract Background Ionizing radiation (IR) accelerates atherosclerosis through induction of cellular senescence, DNA damage, defective efferocytosis, and dysregulation of clonal hematopoiesis (CH) drivers. Although low-dose colchicine reduces ischemic cardiovascular events in coronary artery disease, the precise molecular mechanisms underlying its vasculoprotective effects remain incompletely defined, and whether it mitigates radiation-associated vascular injury is unknown. Methods Bone marrow–derived macrophages (BMDMs) were pretreated with low-dose colchicine and exposed to 2 Gy IR. Molecular effects were assessed by RNA-seq, immunoblotting, and molecular docking. In vivo effects were tested in a partial carotid ligation (PLCL) model using spatial proteomics. Human monocyte-derived macrophages (HMDMs) from thoracic malignancy patients were analyzed before and after radiation therapy (RT). Results Low-dose colchicine suppressed IR-induced macrophage senescence signaling while preserving NRF2 activity. In a cell-free assay, colchicine directly activated aldehyde dehydrogenase 2 (ALDH2) in a dose-dependent manner (EC 50 1–5 nM), identifying ALDH2 as a direct molecular target of colchicine. Following irradiation, colchicine restored ALDH2, reduced mitochondrial (mt)ROS - dependent p90 ribosomal S6 kinase ( p90RSK ) activation and lipid peroxidation, preserved TET2 and DNMT3A expression, and rescued impaired efferocytosis while preventing nicotinamide adenine dinucleotide (NAD⁺) and adenosine triphosphate (ATP) depletion. These protective effects were ALDH2-dependent, as they were lost with ALDH2 inhibition or depletion and were mimicked by pharmacologic ALDH2 activation. In vivo, colchicine attenuated radiation-induced atherosclerosis and macrophage senescence-associated stemness (SAS). Consistently, macrophages from patients after RT showed reduced ALDH2 with increased mtROS, lipid peroxidation, and senescence. Conclusion These findings identify ALDH2 as a previously unrecognized molecular target of colchicine that links mitochondrial redox control to suppression of radiation-induced macrophage senescence and atherosclerosis and may contribute to the efficacy of low-dose colchicine in cardiovascular disease.

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 < 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 < 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 < 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 < 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.

5045 Background: Radioligand therapy with radium-223 (Rad) and lutetium-177 (Plu) demonstrates notable hematologic toxicities in patients (pts) with prostate cancer (PC), including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Delivery of ionizing radiation to the bone microenvironment is a known risk factor for accelerating clonal hematopoiesis, although the incidence of clonal cytopenias with these agents is not well characterized. We hypothesized that pts treated with Rad and/or Plu would have higher risk of clonal cytopenia of undetermined significance (CCUS) vs matched controls in the “real-world”. Methods: We performed a retrospective study using de-identified aggregate data from the TriNetX US Research Collaborative Network from January 2010 to December 2025. Adult males with PC who received ≥1 administration of Plu and/or Rad were included; pts with prior myeloid malignancy were excluded. Primary outcomes were incidence of CCUS and MDS. Propensity score matching (PSM) was performed based on age, race, prior diagnosis of leukopenia, anemia, thrombocytopenia, or pancytopenia. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. Results: We identified 2,569 pts treated with Plu alone and 2,007 treated with Rad alone and compared them with pts with advanced PC without exposure to either agent (unexposed control) (Table 1). After PSM, the incident risk of CCUS was greater in Rad-exposed pts (RR 2.62, 95% CI 1.45 – 4.73, p < 0.001) while Plu was not associated with a significant increase in CCUS or MDS. Direct comparison after PSM (n=1,433) demonstrated lower risk of pancytopenia (RR 0.46, 95% CI 0.37 – 0.56, p <0.001) and CCUS (RR 0.41, 95% CI 0.20 – 0.81, p =0.008) in Plu vs Rad. In unadjusted analysis, pts receiving both Plu and Rad had increased incidence of CCUS vs Plu alone (RR= 3.64, 95% CI 1.87 - 7.07, p <0.001) and higher risk of MDS vs either agent alone. Conclusions: This “real-world” analysis demonstrates that compared with unexposed controls, Rad – but not Plu – is associated with an increased risk of CCUS. Treatment with Plu and Rad portends a higher risk of CCUS than Plu alone, as well higher risk of MDS than either drug alone. Study limitations include its retrospective nature, missing/ unknown data (e.g. bone marrow and mutation analysis), and potential selection and confounding biases. As treatment sequencing evolves for pts with metastatic PC, further evaluation of clonal hematopoiesis, MDS/AML with adequate sample size and follow up in this population is warranted. ¹⁷⁷Lu-PSMA-617 Exposed(n = 2,569) Unexposed(n =2,569 ) Risk Ratio (95% CI) p -value CCUS 1.03% (26) 0.67% (17) 1.54 (0.84 – 2.82) 0.16 MDS 0.94% (24) 0.55% (14) 1.72 (0.89 – 3.32) 0.10 Radium-223 Exposed(n = 2,007) Unexposed(n = 2,007) Risk Ratio (95% CI) p -value CCUS 1.97% (39) 0.75 (15) 2.62 (1.45 – 4.73) <0.001 MDS 0.85% (17) 0.75% (15) 1.13 (0.57 – 2.26) 0.72

4559 Background: Baseline QOL has been linked to survival in mRCC therapy clinical trials (Cella, 2024); however, there is a paucity of prospectively collected real-world QOL data across front-line management strategies. We used data from ODYSSEY to examine the relationship between baseline QOL and early death. Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology); have no prior systemic therapy (ST) or be within 3 months of starting ST; and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Early death was defined as death within 12 months post-enrollment. All pts with non-missing FKSI-19 or FKSI-DRS at enrollment were included. Cumulative event probabilities as a function of time were stratified by either < or ≥ median QoL value and plotted as a step function vs time since enrollment to create cumulative event curves. To determine association between QoL at enrollment and early death, separate Cox proportional hazards models (unadjusted and adjusted) for time-to-first-event as a function of baseline QoL were fit. The adjusted model controlled for the following baseline covariates: IMDC risk (favorable vs intermediate or poor), histology (clear cell vs non). Results: As of 1/5/26, 468 pts were enrolled; 425 had non-missing FKSI-19 or FKSI-DRS at enrollment (329 immediate ST, 96 deferred ST [DST]). ST included 129 IO-IO, 108 IO-TKI, 92 Other. DST included 57 Active Surveillance, 22 Local Therapy Planned, 17 Other/Missing. 209 and 190 pts have < median FKSI-19 (score = 59) and FKSI-DRS (score = 29), respectively; 216 and 235 pts have ≥ median FKSI-19 and FKSI-DRS, respectively. Those below the median have lower rates of nephrectomy, worse IMDC risk and KPS, shorter time since RCC diagnosis, and higher rates of bone metastasis (all p<0.05). Cumulative event probabilities for death at 12 months are 21% and 7% in those < and ≥ median baseline FKSI-19, respectively; and 21% and 7% in those < and ≥ median baseline FKSI-DRS, respectively. For FKSI-19, the unadjusted hazard ratio (HR) for early death is 0.55 (95% CI: 0.43 – 0.70; p<0.001) and adjusted HR is 0.65 (0.49 – 0.85; p = 0.002) per 1 SD higher score. For FKSI-DRS, the unadjusted HR for early death is 0.57 (95% CI: 0.46 – 0.71; p<0.001) and adjusted HR is 0.66 (0.51 – 0.86; p =0.002) per 1 SD higher score (higher score indicates better QOL). Conclusions: Across management strategies in our ODYSSEY cohort of systemic therapy naïve mRCC patients, better baseline QOL was associated with better survival. This is to our knowledge the largest reported real world mRCC cohort with prospectively collected PROs. Future analyses will focus on association of outcomes with longitudinal PROs. Clinical trial information: NCT04919122 .

Introduction Geriatric distal femur fractures are associated with mortality rates exceeding 20%, comparable to hip fractures. Traditional single implant fixation often requires weight-bearing restrictions that delay recovery. This pilot study aims to assess the feasibility of conducting a multicentre randomised controlled trial comparing dual vs single implant fixation for geriatric distal femur fractures. Methods and analysis This multicentre, prospective, randomised controlled pilot trial will enrol 80 participants aged 60 years or older with displaced distal femur fractures at five US level 1 trauma centres. Patients will be randomly allocated 1:1 to receive either single implant (lateral plate or retrograde nail) or dual implant (nail-plate or dual plate) fixation. All patients will be permitted immediate weight-bearing. The primary outcome is feasibility assessed through enrolment rate (80 patients in 12 months), protocol adherence (≥90%) and follow-up retention (≥85% at 12 months). Secondary outcomes include post-surgical mobility (AM-PAC, TUG), patient-reported outcomes (PROMIS-PF, PROMIS-29), mortality (90-day and 1 year) and complication rates. Analyses will be on an intention-to-treat basis. Ethics and dissemination The protocol was approved by the University of Utah Institutional Review Board (IRB_00149119) and IRBs at all participating centres. Written informed consent will be obtained from participants or legally authorised representatives. Findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration number NCT05292313 .