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4545 Background: The treatment landscape of front-line nccRCC has evolved with recent trials demonstrating the efficacy of combination systemic therapy. However, the efficacy of treatment after combination therapy is unknown. This study evaluates the efficacy of VEGF-based regimens in nccRCC patients (pts) previously treated with combination regimens. Methods: ORACLE is a real-world, multi-center, retrospective database that includes nccRCC patients that received combination systemic therapies (IO+IO, IO+VEGF and VEGF+ mTOR) in any line. Subsequent treatments were categorized as VEGF only regimens (cabozantinib vs other VEGF), IO+ VEGF and VEGF+ mTOR. The primary endpoint was objective response rate (ORR) assessed by investigator review using RECIST 1.1. Secondary endpoints included disease control rate (DCR), defined as the proportion of patients achieving complete or partial responses or stable disease, time to treatment progression (TTP), calculated from the date of VEGF-based initiation to progression or last follow-up using the Kaplan-Meier method. Differences between groups were estimated with the log-rank test, and categorical outcomes were compared with the chi-square test. Results: 105 pts who received VEGF – based regimens after combination therapy were included in the analysis. Baseline characteristics: median age: 59years, 71 % male, 58% white, 25% black, 87% ECOG 0-2. IMDC-risk categories included:21% favorable, 59% intermediate and 20% poor risk. Histology included papillary (40%), unclassified (32%), chromophobe (16%) and other rare subtypes (12%). Prior combination therapies included IO+IO: 62%, IO+ VEGF: 34% and VEGF+ mTORi:4%. 70% pts received combination therapy in the first line setting while the remainder received combination therapy in a second or later line. Outcomes with subsequent treatments are described in Table1. IMDC risk score correlated with TTP. Conclusions: Modest antitumor activity was observed with VEGF- based approaches in combination therapy refractory nccRCC. Optimal management of nccRCC remains an unmet need. Outcomes of nccRCC patients by treatment and histologic type. Outcomes per Treatment n ORR (%) DCR (%) mTTP (mo.) Cabozantinib 56 18 47 3.6 VEGF/mTOR 19 16 42 9.3 IO+VEGF 17 29 47 5.6 Other VEGF 13 15 46 5.5 Outcomes per Histology Papillary 42 19 43 6.5 Unclassified 33 21 42 6.1 Chromophobe 17 29 59 8.9 Other * 13 0 46 NR

Abstract Nearly half of premature deaths can be prevented with healthy lifestyle behaviours. However, most older adults do not adhere to established guidelines to promote a healthy lifestyle. We propose a tailored framework of lifestyle medicine that acknowledges the complex contexts and care needs of older adults. The proposed framework of lifestyle medicine for older adults integrates their lived experiences (e.g. social determinants of health, built environment), the 5 M framework of geriatric medicine (i.e. Mind, Mobility, Medications, Multicomplexity, Matters Most) and the six pillars of lifestyle medicine (i.e. nutrition/diet, physical activity/exercise, restorative sleep, stress management, avoidance of risky substances, positive social connections) through a novel transdisciplinary approach. Guided by the updated framework, key gaps and opportunities are presented to advance lifestyle medicine practice, research and policy with the goal of promoting sustained behaviour change and improving the healthspan of older adults.

AbstractObjectiveThe effects of brain stimulation for diseases like epilepsy are delayed, making stimulation optimization difficult. The parameters for anterior thalamic nuclei (ANT) deep brain stimulation (DBS) for focal drug‐resistant epilepsy management are often restricted to those used in the SANTE landmark trial. There is little evidence regarding effective alternatives, and low‐frequency stimulation is typically neglected. We prospectively compare a widely differing stimulation parameter set to typical settings.MethodsThis randomized, modified crossover, open trial compares the efficacy and safety of an alternative set of parameters using continuous low‐frequency stimulation (cLFS) with a longer pulse width (7 Hz, 200 μs, continuous) compared to SANTE's intermittent high‐frequency stimulation (iHFS) with a short pulse width (145 Hz, 90 μs, cycling 1 min on/5 min off). After 3 months on a randomly assigned first set, patients are switched to the other settings, unless seizure‐free. Patients are re‐evaluated after 3 more months, which marks the completion of the trial. After that, they can either remain on the same settings or switch back.ResultsSixteen patients with a median baseline seizure frequency of 13.8 seizures/month (interquartile range [IQR] = 2.7–22.8) were included in the analysis. At trial completion (median follow‐up = 30 weeks, IQR = 26–35), ANT‐DBS significantly reduced median seizure frequency (62%, IQR = 18–81, Wilcoxon test statistic [W] = 99, p = .008). Both iHFS (33%, IQR = 0–65, W = 81, p = .02) and cLFS (73%, IQR = 30–79, W = 105, p = .001) significantly reduced median seizure frequency. cLFS showed improved median seizure frequency reduction compared to iHFS (W = 63, p = .03) and was not associated with any moderate or severe adverse effects.SignificanceResults support cLFS for ANT‐DBS as a safe and effective alternative to typical iHFS parameters. Stimulation with widely differing parameter sets may be as effective as or, in some situations, more effective than typical stimulation parameters.

AbstractBackgroundImmune thrombotic thrombocytopenic purpura (iTTP) is a hematologic disorder characterized by severe acquired deficiency in ADAMTS13, resulting in thrombotic microangiopathy and death if untreated. Plasma exchange (PLEX) is the backbone of iTTP management and has improved survival in this disorder. Guidelines suggest initiation of PLEX within 4–8 h of presentation; however, there is little evidence to guide the precise timing of PLEX, and barriers exist to its timely deployment.Study design and methodsWe examined determinants of time between symptom onset to PLEX initiation (S2P) and hospital presentation to PLEX initiation (door to PLEX, D2P) in a large iTTP research cohort at an academic medical center.ResultsIn 225 cases occurring in 143 unique patients, the median (IQR) S2P time was 4.28 (1.92–7.47) days. In linear mixed effects regression analysis, increased S2P was associated with greater distance from a participating apheresis center (p = .01) and higher presenting platelet count (p = .046), while relapse presentation was associated with shorter S2P (p = .036). The median (IQR) D2P time was 8.4 (5.03–15.63) h. Longer D2P time was associated with a higher presenting platelet count (p = .002) and trended towards association with male sex (p = .057). Increased S2P and D2P times were not associated with hospital length of stay, mortality, or the composite of mortality and ICU stay.ConclusionOur data show that different factors contribute to the interval between symptom onset and presentation versus the time between presentation and initiation of therapy in iTTP.

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.

Introduction Infectious intracranial aneurysms (IIAs) are rare but serious complications of systemic infections, particularly infective endocarditis. These aneurysms are prone to rupture, leading to significant morbidity and mortality. Management strategies lack consensus due to the rarity of the condition and reliance on small case series. This study examines the clinical management of IIAs using data from a large multicenter cohort. Methods A retrospective registry-based cohort study was conducted across 11 tertiary care centers in the USA between 2018 and 2023. Patients with IIAs were identified based on clinical and radiographic criteria. The primary outcome was treatment failure defined as persistence, growth, or rupture of the aneurysm. Secondary outcomes were mortality and the modified Rankin Scale (mRS) score at 90 days and 1 year. Multivariate logistic regressions were used to identify outcome predictors. Results A total of 104 patients with 166 aneurysms were included, with a median age of 43 years. Medical management was successful in 56% of cases, with failure often within 18 days of initiation. Predictors of failure included younger age, larger aneurysm size, and rupture at presentation. Surgical and endovascular interventions achieved higher success rates with better outcomes. At 90 days, 57% of patients achieved functional independence (mRS 0–2), while the mortality rate was 24%. Conclusion This study highlights the limitations of medical management for IIAs and underscores the need for early surgical or endovascular intervention in high-risk patients. Outcome predictors aid clinical decision-making, optimizing patient management. Further research is needed to standardize management guidelines for IIAs.

ABSTRACTBackgroundRenal medullary carcinoma (RMC) is an aggressive tumor associated with sickle cell trait. Despite treatment advances for other rare renal tumors, RMC survival remains poor. We aimed to describe the contemporary management and survival of children and adults with RMC.ProcedureIn this multicenter retrospective cohort study, Pediatric Surgical Oncology Research Collaborative sites searched their databases for patients diagnosed with RMC (2000–2022). Descriptive statistics were calculated and survival analyses performed using Kaplan–Meier and Cox regression.ResultsThirty‐four patients with RMC were identified. Median age was 19 years (IQR: 15–28; range: 7–52). Most were male (24/34; 71%), Black (27/32; 84%), had sickle cell trait or disease (30/33; 91%), presented with metastatic disease (27/34; 79%), and were symptomatic at presentation (32/34; 94%). Median overall survival (OS) was 24 months from diagnosis (16 months for children, 28 months for adults, p = 0.6). Receipt of platinum‐based chemotherapy (23/34; 68%) was associated with significantly higher OS than other regimens (35 vs. 5 months, p < 0.001). Nephrectomy (24/34; 71%) was associated with significantly improved OS compared with non‐operative management (34 vs. 7 months, p = 0.001). Immunotherapy, targeted therapy, or radiation therapy were not associated with significant differences in OS, nor were age, sex, race, sickle cell status, SMARCB1/INI‐1, stage, nephrectomy approach, retroperitoneal lymph node dissection, gross residual disease, margins, or tumor size.ConclusionsRMC survival remains poor despite newer therapies. Nephrectomy and platinum‐based chemotherapy should be considered in locally advanced and metastatic disease. Coordinated international cooperative group studies are needed to meaningfully improve RMC survival.

Objective: To establish benchmark cutoffs for robotic liver resection (R-LR), encompassing both major and minor resections, and to determine the impact of patient selection on outcomes. Background: R-LR is a key advancement in minimally invasive liver surgery but lacks standardized benchmarks, especially for minor resections. While guidelines endorse R-LR, its role in optimizing outcomes remains unclear. This study establishes the first benchmarks for R-LR, enabling comparisons across surgical modalities and refining patient selection. Methods: This retrospective, multicenter study analyzed consecutive adult patients undergoing R-LR at 30 international centers (2020–2023). Benchmark centers had an annual case volume of ≥15 R-LR. Benchmark criteria included ASA ≤2, no major comorbidities, no prior liver resections, and Child-Pugh A status. Benchmark cutoffs for 14 key outcomes were set at the 50th and 75th percentiles of median values across benchmark centers. Multivariable logistic regression identified predictors of textbook outcomes. Results: Eighteen high-volume centers contributed 4028 cases with 2632 (65.3%) meeting benchmark criteria. Malignancy was the indication in 29.6%, most commonly hepatocellular carcinoma followed by colorectal liver metastases. Major liver resection was performed in 42.6%. The distribution of Iwate difficulty scores was low (25.4%), intermediate (53.9%), advanced (15.9%), and expert (4.9%). Benchmark cutoffs were established for minor and major resection, and stratified by Iwate low (0-3), intermediate (4-6) and high (7-12): Open conversion (≤6.5% minor, ≤10.5% major), major complications within 90 days (≤5.2% minor, ≤16.7% major), R1 resection (≤9.2% minor, ≤6.7% major). Benchmark cases performed at low-volume centers were able to achieve outcomes within the corresponding benchmark cutoffs. In fact, patient selection reflected by the proportion of benchmark patients, rather than case volume, was associated with textbook outcomes. Conclusions: This study defines R-LR benchmarks, emphasizing patient selection over center volume for optimal outcomes. Benchmark cutoffs guide training and support the expansion of R-LR.

ABSTRACT Mass spectrometry-based metaproteomics, the identification and quantification of thousands of proteins expressed by complex microbial communities, has become pivotal for unraveling functional interactions within microbiomes. However, metaproteomics data analysis encounters many challenges, including the search of tandem mass spectra against a protein sequence database using proteomics database search algorithms. We used a ground-truth dataset to assess a spectral library searching method against established database searching approaches. Mass spectrometry data collected by data-dependent acquisition (DDA-MS) was analyzed using database searching approaches (MaxQuant and FragPipe), as well as using Scribe with Prosit predicted spectral libraries. We used FASTA databases that included protein sequences from microbial species present in the ground-truth dataset along with background protein sequences, to estimate error rates and assess the effects on detection, peptide-spectral match quality, and quantification. Using the Scribe search engine resulted in more proteins detected at a 1% false discovery rate (FDR) compared to MaxQuant or FragPipe, while FragPipe detected more peptides verified by PepQuery. Scribe was able to detect more low-abundance proteins in the microbiome dataset and was more accurate in quantifying the microbial community composition. This research provides insights and guidance for metaproteomics researchers aiming to optimize results in their analysis of DDA-MS data.

Abstract The establishment of guidelines and curriculum standards for medical physics residency training is a critical component of setting expectations and competencies for the profession. Since the last publication of these standards, residency training has become integrated into the eligibility criteria for most medical physics certification bodies. The rapid growth of medical physics requires periodic review of the curriculum to remove outdated approaches, update established knowledge, and add emerging technologies. The goal of this document is to provide a reference standard for residency training program directors, training mentors, and residents to guide creation and/or optimization of their program's curriculum. The document is intentionally forward‐looking to capture emerging technological advances including hybrid diagnostic and therapeutic delivery systems and applications of image processing. This document is an update of the current residency training curriculum. Version history of residency training guidelines Publication Title Date 2013 Essentials and Guidelines for Clinical Medical Physics Residency Training Programs—AAPM Report No. 249 2006 Essentials and Guidelines for Hospital‐Based Medical Physics Residency Training Programs—Report No. 90 1992 Essentials and Guidelines for Hospital‐Based Medical Physics Residency Training Programs—Report No. 36 The Work Group on Periodic Review of Medical Physics Residency Training (WGMPRT) would like to acknowledge the authors of past versions of this document as they form the basis for this update. It is the sincere hope of the WGMPRT that this report will continue to be used by the medical physics community to guide training in the profession.