Citations

Abstract Objective Margin distance is a significant prognosticator in oral cavity cancer but its role in HPV‐related oropharyngeal squamous cell carcinoma [HPV(+)OPSCC] remains unclear. Here, we investigate the impact of margin distance on locoregional recurrence in HPV(+)OPSCC. Study Design This is a retrospective cohort study of surgically treated HPV(+)OPSCC patients. Patients received either standard of care (at least 60 Gy with or without cisplatin) or de‐escalated adjuvant therapy (30‐36 Gy with concurrent docetaxel). Margin distance was measured in mm from the primary specimen or in combination with separately submitted margins. Kaplan‐Meier survival analysis with univariate and multivariable Cox regressions were conducted to determine the impact of margin distance on risk of local and locoregional recurrence. Setting Setting for this is 3 tertiary centers between January 2010 and February 2024. Results Among 1102 included patients, 33 (3.0%) had positive final margins. 374 patients had adequate margin distance data available. Margin distance was >3 mm in 73.4%, 1 to 3 mm in 24.5%, and <1 mm in 2.2% of patients. Positive final margins, pT4 disease, pN2 disease, and surgery alone as a treatment modality ( P < .02 for all) was associated with higher risk of 5‐year locoregional recurrence. Margin distance did not significantly impact risk of local or locoregional recurrence even after adjusting for de‐escalated adjuvant therapy ( P > .05). Conclusion Positive final margins after TORS without adjuvant radiotherapy for HPV(+)OPSCC carries a high risk of local recurrence. Margin distance does not appear to significantly impact risk of local or locoregional recurrence, even after de‐escalated adjuvant radiotherapy.

Abstract Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a rare and aggressive lymphoma with molecular heterogeneity not well characterize. In this study, we performed next-generation sequencing analysis for a large number of DNA and RNA samples from patients with PT-DLBCL. DNA sequencing analysis identified ≥ 3 chromosomes with copy number variations (CNVs) and microsatellite instability as prognostic biomarkers, rather than MYD88 mutations and genetic subtypes. Remarkably, targeted RNA-seq analysis in 195 patients revealed that TP53 mutations with a ≥ 40% variant allele frequency had significantly adverse prognostic impact, and that a 150-gene expression signature subdivided PT-DLBCL into two distinct clusters, termed as testicular lymphoma tumor (TLT) and microenvironment (ME) subtypes. The TLT subtype featured upregulation of genes involved in B-cell receptor signaling, cell cycle, DNA damage and repair, higher frequencies of CNVs and MYD88 mutations, elder ages, larger tumor sizes, and significantly poorer survival. Genomic microRNA profiling analysis identified significantly differentially expressed microRNAs between 113 PT-DLBCL and 180 systemic DLBCL patients, and further subdivided the PT-DLBCL cohort by microRNA signatures. The subcohort with upregulation of 16 microRNAs associated with PT-DLBCL and testicular tissue expression had significantly better survival. This study revealed characteristic genetic, gene expression, and microRNA profiles and heterogeneity in PT-DLBCL.

AbstractBackgroundAutosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.MethodUtilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity.ResultNfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers.ConclusionIn presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

AbstractBackgroundClinically meaningful cognitive impairment has typically been defined as a single impaired test score, but this approach is prone to false‐positive errors. Examining two test scores at a lower threshold (i.e., using neuropsychological criteria) can improve diagnostic reliability and has shown stronger associations with biomarkers of Alzheimer’s disease. Cognitive impairment in episodic memory and/or executive functioning is a core feature of traumatic encephalopathy syndrome (TES). However, there remains a need to improve the specificity of TES criteria. We applied 1‐ vs. 2‐test criteria for cognitive impairment in former American football players to examine whether 2‐test criteria showed stronger associations with biomarkers of tau, axonal injury, and neurodegeneration.Method169 male former American football players from the DIAGNOSE CTE Research Project completed neuropsychological assessment, lumbar puncture, and MRI (see Table). Episodic memory measures were delayed recall from Craft Story, Brief Visuospatial Memory Test, and NAB List Learning. Executive functioning measures were FAS, Stroop Interference, NAB Mazes, and Trails B. Cerebrospinal fluid (CSF) was measured using Lumipulse technology (p‐tau, t‐tau) and an in‐house ELISA (neurofilament light [NfL]). Hippocampal volumes were extracted from structural MRI using Freesurfer 7.1. Cognitive impairment was identified by 1‐test criteria (≥1.5 SD below norms on one test in either domain) and 2‐test criteria (>1 SD below norms on two tests within a domain). Regressions adjusting for age, race, education, and APOE ε4 status assessed whether meeting 1‐ or 2‐test criteria, separately, predicted log‐transformed CSF p‐tau181, p‐tau231, t‐tau, and NfL, and hippocampal volumes.Result37 of the 99 football players that were impaired by 1‐test criteria did not meet 2‐test criteria, and four uniquely met 2‐test but not 1‐test criteria (see Figure). Cognitive impairment by 2‐test but not 1‐test criteria predicted higher log‐CSF NfL (2‐test: B = 0.24, p = .007; 1‐test: B = 0.06, p = .53), smaller left hippocampal volume (2‐test: B = ‐195.84, p = .01; 1‐test: B = ‐131.52, p = .08), and smaller right hippocampal volume (2‐test: B = ‐161.19, p = .045; 1‐test: B = ‐134.88, p = .08). Neither criterion predicted p‐tau181, p‐tau231, or t‐tau.Conclusion2‐test criteria demonstrated stronger associations between cognitive impairment and markers of axonal injury and neurodegeneration. Incorporating multiple test scores to identify cognitive impairment could improve diagnostic specificity in TES.

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impacts in contact/collision sports. A core clinical feature of TES is cognitive impairment, particularly in memory and executive functions. Cognitive intraindividual variability (IIV) is the extent of variability in neuropsychological test performance (i.e., dispersion of test scores) and is believed to be an indicator of disruption in executive control, linked to altered fronto‐subcortical circuits. Here, we examined cognitive IIV as a method to detect subtle executive dysfunction in TES that may not be captured by traditional neuropsychological measures.MethodThe sample included former American football players (120 professional, 60 college); participants were males, aged 45‐74. Participants completed a baseline neuropsychological test battery (n = 8 excluded for suboptimal performance validity). A multidisciplinary diagnostic consensus conference classified participants using the 2021 NINDS Consensus Diagnostic Criteria for TES (see Table‐1): (1) No‐TES (n = 62); (2) TES‐CTE Suggestive (n = 35); (3) TES‐CTE Possible (n = 21); (4) TES‐CTE Probable (n = 54). TES‐CTE Possible and Probable were combined. The coefficient of variation (CoV) was used to measure cognitive IIV (CoV = iSD/iOTBM, iOTBM = average T‐score across neuropsychological tests; iSD = standard deviation of iOTBM). A higher CoV indicates greater score dispersion. To avoid circularity, memory and executive tests used for classifying TES groups were intentionally excluded from the CoV calculation. Analysis of covariance compared the TES groups on CoV, controlling for age, education, and race.ResultResults showed a significant difference in CoV between TES groups, F(2, 165) = 8.20 p<.001, partial η2 = .09. The TES‐CTE Possible/Probable group had the highest CoV (M = .226, SE = .007), compared with the TES‐no (M = .192, SE = .008, p<.001) and TES‐CTE Suggestive groups (M = .178, SE = .011, p<.001). CoV did not significantly differ between the TES‐no and TES‐CTE suggestive groups (Mdiff = 0.014, SE = .013, p = .293).ConclusionThe TES‐CTE possible/probable group had the highest cognitive IIV with ∼23% dispersion (vs. ∼18‐19% in TES‐no and TES‐CTE suggestive groups), suggesting greater cognitive variability in those with the greatest likelihood for having underlying CTE (based on TES criteria). This finding emphasizes the potential utility of exploring cognitive IIV as a method for detecting nuanced executive dysfunction in TES.

AbstractBackgroundLewy body (LB) diseases can present with overlapping prodromal, cognitive, motor, autonomic or neuropsychiatric symptoms. Intuitively, greater symptom severity should correlate with greater pathological burden, but this has not been consistently shown. LB pathology does not translate to clinical expression in Incidental LB disease. While several composite scores/toolkits utilize overlapping schemes for diagnosis, a composite data‐derived score to predict LB pathologic burden is lacking. We aimed to utilize an autopsy‐confirmed cohort, and validated, brief, and standardized clinical, functional, pathologic assessments, and machine learning (ML)/quantitative modeling techniques to identify clusters and importance rankings among assessments/measures to predict LB pathologic severity and density.MethodA total of 234 subjects with neuropathological finding of LB at autopsy in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) who were classified as Cognitively Unimpaired or Mild Cognitive Impairment after their first study clinical evaluation were included. Of these, 145 subjects had complete scores for 32 of 46 measures (clinical, cognitive, behavioral and functional) that were utilized as predictors of LB pathology. Olfactory function was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). LB severity was assessed by the Unified Staging System for Lewy Body Disorders (USSLB). Several ML algorithms and quantitative prediction models were explored and compared: artificial neural network (ANN), partial least square regression (PLSR), support vector regression (SVR), relevance vector regression (RVR) and ensemble forest regression (EFR) with leave‐one‐out (LOO) scheme. Game‐theory based Shapley methods assessed the impact, including rankings, consistency and magnitude, of model predictors.ResultRVR predicted aggregate LB density with large effect size (R2 = 0.691, p<0.00001). ANN predicted USSLB severity stage with large effect size (R2 = 0.74, p<2.5e‐43). All other ML algorithms/models provided substantial prediction. Across all models, UPSIT was the most influential predictor (>65%), followed by Controlled Oral Word Association Test (COWAT) and age.ConclusionThese preliminary and exploratory results support the utilization of ML techniques/models to assess LB pathologic burden with key measures collected in relatively small samples. UPSIT was consistently ranked highest impactful among clinical and functional measures/predictors. Integrated together in ML/data‐derived composites, UPSIT, COWAT and other clinical characteristics may be of antemortem utility to predict USSLB stages.

PURPOSE In light of evolving evidence that some patients with node-positive estrogen receptor–positive (ER+) disease may receive less benefit from chemotherapy, this study reports 12-year outcomes of the C9741 trial overall, and by the sensitivity to endocrine therapy (SET2,3) test index, a biomarker measuring endocrine transcriptional activity, to identify patients most likely to benefit from dose-dense chemotherapy. METHODS In all, 1,973 patients were randomly assigned to dose-dense versus conventional chemotherapy. Hazard ratios (HRs) for prognosis and for predictive interaction with chemotherapy schedule were estimated from Cox models of long-term disease-free survival (DFS) and overall survival (OS). SET2,3 was tested on the 682 banked RNA samples from ER+ cancers. RESULTS Dose-dense chemotherapy improved DFS in the overall study population by 23% (HR, 0.77 [95% CI, 0.66 to 0.90]) and OS by 20% (HR, 0.80 [95% CI, 0.67 to 0.95]); the benefits of dose-dense therapy were seen for ER+ and ER-negative subsets, without significant interaction between treatment arm and ER status. Low SET2,3 status was highly prognostic, but also predicted improved outcomes from dose-dense chemotherapy (interaction P = .0998 for DFS; 0.027 for OS), independent of menopausal status. Specifically, low endocrine transcriptional activity predicted benefit from dose-dense chemotherapy, whereas tumor burden and proliferation-driven signatures for molecular subtype classification did not. CONCLUSION At 12-year follow-up, C9741 confirmed the sustained long-term benefit of adjuvant dose-dense chemotherapy for node-positive breast cancer. SET2,3 identified patients with ER+ breast cancer who benefited from dose-dense chemotherapy, and specifically, this benefit was predicted by low endocrine activity in the cancer, rather than tumor burden, molecular subtype, or menopausal status.

Background: Previous research has reported higher rates of both injury and illness among Paralympic athletes compared with Olympic athletes during the Winter Olympic and Paralympic Games, but no studies have directly compared injury and illness incidence between Olympic and Paralympic athletes competing in a Summer Games. Purpose: To compare injury and illness rates between Olympic and Paralympic Team USA athletes competing in the Tokyo 2020 Olympic and Paralympic Games. Study Design: Descriptive epidemiology study. Methods: All injuries and illnesses that occurred among the Team USA athletes competing in the Tokyo 2020 Summer Olympic or Paralympic Games were documented. A total of 701 Team USA athletes (53.6% female) competed in the Tokyo 2020 Summer Olympic Games, across 34 different sports. For the Tokyo 2020 Summer Paralympic Games, a total of 245 athletes (51.6% female) competed across 20 sports. Incidence rates (IRs) per 1000 athlete-days were calculated according to sex, sport, anatomic location, and illness type. IR ratios (IRRs) were calculated to compare IRs between male and female athletes and between Olympic and Paralympic athletes. Results: Overall, there were no differences in injury incidence (IRR, 1.18; 95% CI, 0.84-1.68) or illness incidence (IRR, 0.68; 95% CI, 0.41-1.15) between Olympic and Paralympic athletes. Male Paralympic athletes were less likely to sustain an illness compared with female Paralympic athletes (IRR, 0.35; 95% CI, 0.11-0.90). Conclusion: There were no differences in injury or illness rates between Olympic and Paralympic Team USA athletes competing at the Tokyo 2020 Summer Games, contrary to previous comparisons among winter sport athletes. These results challenge the prevailing notion that Summer Paralympic athletes are at greater injury and illness risk, suggesting that factors beyond Olympic or Paralympic Games participation influence health concerns.

Abstract The prevalence of clonal hematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. We previously reported gene specific fitness effects in two longitudinal cohorts of aging. We now set out to define fitness effects across three longitudinal cohorts of aging in a total of 713 participants. We found that fitness correlates with timing of mutations, which needs to be taken into account when predicting health outcomes. We show that fitness and the time of mutations are superior predictors of outcomes such as all-cause mortality compared to the commonly used clone size (variant allele frequency). Our new predictor even outperforms age, the most important predictor for the onset of age-related disease thus far. In conclusion, the fitness landscape of mutations and their context in terms of clonal composition and timing of mutation acquisition are important parameters to bring CH predictors into the clinic.