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Importance In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ–positron emission tomography (PET; 18 F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET ( 18 F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET–positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217–negative and Aβ-PET–positive; 7 participants were p-tau217–positive and Aβ-PET–negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Abstract Background Approximately 12,000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA and adult). Results The cohort of 21,099 CNS tumors included 5139 tumors from AYAs (24%), which showed a mixed pattern, with tumors typical of childhood (e.g. medulloblastoma) as well as those common in older adults (e.g. glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Abstract Background TOPAZ-1 demonstrated durvalumab + gemcitabine and cisplatin (GemCis) superiority over GemCis in first-line treatment of advanced biliary tract cancers. Real-world data from US patients and patients excluded from TOPAZ-1 (patients with autoimmune conditions [AICs] who did not receive immunotherapy) are lacking. We report real-world data for patients with cholangiocarcinoma treated with durvalumab + GemCis. Methods This retrospective, observational study enrolled adult patients diagnosed with cholangiocarcinoma in the US from the International Cholangiocarcinoma Patient Registry (ICPR) treated with first-line durvalumab + GemCis between 2021–2023. De-identified medical records from ICPR were obtained directly from consenting patients/caregivers. Patient demographics and tumor characteristics (primary objective; assessed at initial diagnosis), comorbidities, second-line treatment modalities, median real-world overall survival (mrwOS), and median real-world time to next treatment (mrwTTNT; initiation of first-line treatment and last activity in the database or death) are reported. Results Seventy patients received first-line durvalumab + GemCis: 13 (18.6%) had AIC(s) and 57 (81.4%) did not. Patient demographics, clinical characteristics, and comorbidities are shown (Table). Median (quartile 1–3) time from diagnosis to start of first-line treatment was 1.0 (0.7–1.7) months; median follow-up from first dose of first-line treatment was 7.0 (3.7–12.1) months. The mrwOS (95% CI) was 15.5 (15.1–not evaluable [NE]) months. mrwTTNT (95% CI) was 10.8 (10.4–15.7) months overall and was 20.8 (10.4–NE) months in patients who died without receiving subsequent treatment (censored at date of last activity). Among patients with AIC(s), <5 received second-line therapy (all received chemotherapy alone). Among patients with no AICs, 15 received second-line treatment; 11 (73.3%) received targeted therapy alone and <5 received chemotherapy alone. Conclusions This dataset demonstrates patients with AIC(s) are treated with durvalumab + GemCis in clinical practice. The mrwOS for durvalumab + GemCis in this patient population is consistent with TOPAZ-1 and global real-world studies.

Abstract Background & Objectives Based on the TOPAZ-I study, durvalumab combined with gemcitabine and cisplatin (GemCis) is now supported as a standard of care treatment for cholangiocarcinoma. Patients with extrahepatic cholangiocarcinoma (eCCA) often have underlying autoimmune conditions (AICs) which could restrict immunotherapy use. Treatment patterns in patients with eCCA with AICs and non-autoimmune conditions (NAICs) are reported. Method This retrospective observational analysis of adult patients diagnosed with eCCA in the United States enrolled in the International Cholangiocarcinoma Patient Registry between 2019 and 2023, focused on those treated with durvalumab. The registry contains de-identified data from medical records obtained directly from consenting patients and caregivers. Patients were followed from index date (date of eCCA diagnosis) until the last activity in the database or death. Demographics, clinical characteristics, biomarkers, treatment patterns, and adverse events (AEs) are reported. Results Overall, 135 patients with eCCA were enrolled: 24 (17.8%) had 2:1 AICs and 111 (82.2%) had NAICs. Baseline demographics were comparable between groups: the median (quartile [Q]l-Q3) age at diagnosis was 63.0 (55.0-70.0) years, the mean number of comorbidities in the overall population was 10.1, and 50.4% of patients were female. PD-Ll positivity was noted in 12.6% of patients and HER2 positivity in 10.4%. Of 91 patients with eCCA who received first-line therapy, 34 (37.4%) received GemCis alone, 27 (29.7%) chemotherapy alone (non-GemCis +/- nab-paclitaxel), 9 (9.9%) GemCis plus nab-paclitaxel, 7 (7.7%) durvalumab plus GemCis, 7 (7.7%) durvalumab monotherapy or in combination, and 7 (7.7%) other regimens. Treatment patterns by autoimmune comorbidity status are also reported (Table). Overall, 129 patients (95.6%) had ≥1 AE; fatigue was the most common (71.1%). Conclusion More patients with eCCA received a first-line durvalumab-based regimen post-March 2022 vs the full study period. The use of durvalumab as first-line treatment in this subgroup may suggest that AICs do not restrict its use.

Abstract INTRODUCTION Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau‐PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS Cortical regions with lower typical GM MWF showed higher tau‐PET uptake ( β = −0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau‐PET covariance ( β = −0.238, p < 0.001). Higher typical FC was associated with higher tau‐PET covariance ( β = 0.447, p < 0.001). DISCUSSION In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.

Abstract Clinical medical physics is a profession that intersects with various groups as part of a broader healthcare team, including dosimetrists, radiation therapists, radiologic and MRI technologists, IT specialists, and physicians. Success in this field requires academic and technical excellence as well as comprehensive skills for working effectively within an interdisciplinary healthcare team. When hiring medical physics residents, the selection of well‐rounded and highly qualified candidates can be facilitated through a holistic review process that ensures consideration of traditional metrics such as academic performance while also accounting for the importance of various experiences, personal attributes, and intrinsic motivations that impact clinical performance and patient care. The Association of American Medical Colleges (AAMC) emphasizes an overall consideration of Experiences, Attributes, Competencies, and Metrics (EACM) as important for the search process. As part of the healthcare community, medical physics shares the same commitment to high‐quality patient care. By adopting the AAMC's EACM framework, medical physics residency programs can strengthen the fairness, rigor, and overall effectiveness of their application review processes—ultimately benefiting applicants, the medical physics community, and the patients we serve. This Society of Directors of Academic Medical Physics Programs (SDAMPP) task report aims to provide information and resources for applying holistic review to the applicant selection process for medical physics residency programs. Our objective is to enable program directors to reevaluate their selection methods in the context of institutional and program missions and goals and to improve the quality and specificity of recruitment by integrating holistic review concepts into their residency recruitment processes. This initiative can inspire change in recruitment practices, aid programs in hiring well‐rounded and well‐qualified residents, and support the professional growth of our trainees in healthcare. This report provides an overview of holistic reviews and its core principles. We review the current literature and provide evidence from successful implementations of holistic review in other medical fields to illustrate how it can benefit our field. Furthermore, we outline actionable recommendations to facilitate transitioning to a holistic review framework and address potential barriers with practical solutions. A supplemental workbook is provided to guide residency programs in developing their own holistic application review and interview processes. With this report, we aim to provide practical implementation guidelines that will allow residency program directors to implement a selection methodology that comprehensively assesses the full qualifications of individual candidates and ultimately fosters the development of versatile and competent clinical medical physicists who are best equipped to advance the field, meet patient needs, and improve patient care.

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 Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45–74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45–74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen’s d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen’s d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P &lt; 0.00001) and an earlier age of first exposure to tackle football (P &lt; 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P &lt; 0.04) and rotational force (P &lt; 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.