Citations

Abstract Patients with glioblastoma (GBM) face poor outcomes; the 5-year survival rate is 7% with standard of care treatments, which are frequently associated with systemic toxicity. Tumor Treating Fields (TTFields) are electric fields that disrupt critical cancer cell processes. The TTFields therapy device consists of a portable electric field generator and arrays placed on the patient’s scalp, thus delivery is locoregional and noninvasive. Currently, TTFields therapy is approved for recurrent and newly diagnosed GBM, based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz + temozolomide), respectively. These studies confirmed that TTFields therapy had a tolerable safety profile with mild-to-moderate localized skin adverse events (AEs) being the most common related AEs. Here, we present an updated analysis of the largest global real-world evidence dataset of patients with brain tumors receiving TTFields therapy over an 11-year time period. Unsolicited safety data were obtained from routine post-marketing activities, including published literature and interactions with patients, caregivers, and healthcare professionals. Safety data were grouped according to age, diagnosis, and sex. AEs were categorized using MedDRA version 25. Data from 25,898 patients were included in this analysis; median age was 59 years (range: 3-103) for patients with known age. Diagnoses were ndGBM (67.7%), rGBM (26.1%), anaplastic astrocytoma/oligodendroglioma (4.2%) and other (2.1%). Most (n=17,817, 68.8%) patients were 18-65 years of age; n=93 (0.4%) were pediatric/adolescent patients (<18 years), and n=7,808 (30.2%) were elderly patients (>65 years). For 130 patients (0.5%) age was not known. Two-thirds of patients were male, which reflects the preponderance of CNS tumors in males. Most patients were based in North America (72.1%), followed by Europe, the Middle East and Africa (23.3%), and Japan (4.6%). Overall, 72.4% of patients experienced at least one AE, with 55.9% being related to TTFields therapy. The most common AEs (overall and related to TTFields therapy) were skin reactions (42.0%), electric (tingling) sensations (13.5%), and heat (warmth) sensations (11.8%). The percentage of patients experiencing ≥1 AE in the pediatric/adolescent, 18-65, and elderly groups was 63.4%, 74.6%, and 68.4%, respectively. The percentage of females and males experiencing ≥1 AE was 75.2% and 70.9%, respectively. These long-term, real-world data from the largest global dataset of patients with brain tumors using TTFields therapy to date demonstrate a tolerable safety profile consistent with pivotal clinical studies. There were no new safety signals, and most AEs were manageable localized mild-moderate skin events that can be resolved. The distribution of AEs between age and sex was similar, with broad applicability among different patient groups. Citation Format: Maciej M. Mrugala, Wenyin Shi, Fabio Iwamoto, Rimas V. Lukas, Joshua D. Palmer, John H. Suh, Martin Glas. Patients with glioblastoma (GBM) treated with tumor treating fields (TTFields) therapy: post-marketing safety data over the last decade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3221.

Abstract Lung squamous cell carcinoma (LUSC) is a major histological subtype of lung cancer accounting for ~30% of all lung cancer diagnoses. LUSC patients suffer from poor therapeutic response, high relapse rate, and poor prognosis. A major reason for this bleak outcome is the lack of well characterized oncogenic drivers of LUSC. This has stalled the generation of relevant genetic pre-clinical mouse models amenable to studying LUSC tumorigenesis in vivo and developing targeted therapeutics to treat LUSC patients. Our group has identified concomitant 3q26 copy number gain (CNG) and TP53 loss as defining genetic alterations present in ~90% of LUSC tumors. Furthermore, we have identified three 3q26 oncogenes (PRKCI, ECT2 and SOX2) that genetically and biochemically collaborate to drive LUSC tumor formation. Coordinate overexpression of Prkci, Ect2 and Sox2, and loss of Trp53 in ex vivo cultures of lung basal stem cells (LBSCs; a potential cell of origin for LUSC) is both necessary and sufficient to transform these cells into orthotopic LUSC tumors in syngeneic mice. These findings indicate that 3q26 amplification and TP53 loss play a critical role in the initiation and progression of LUSC. Based on these data, we have developed the first autochthonous genetically engineered mouse model (GEMM) to study the role of 3q26 CNG in LUSC tumorigenesis in vivo. Our GEMM allows inducible overexpression of Prkci, Ect2, and Sox2 and knockout of Trp53 (PES/Trp53−/−) in lung tissue. Tumorigenesis will be initiated in PES/Trp53−/− mice using an established protocol to target transgene recombination to LBSCs in vivo. These mice will be assessed for tumor latency, survival, tumor burden, and metastatic potential. In related studies, we used bioinformatics analyses on primary LUSC tumors from the Cancer Genome Atlas’ database to identify 13 genes in addition to PRKCI, ECT2 and SOX2, whose expression is driven by 3q26 amplification. These genes were functionally characterized by assessing the effect of shRNA-mediated gene silencing on soft-agar growth of human H520 LUSC cells, a cell line that harbors 3q26 amplification. Our results revealed that knockdown of each of these genes independently resulted in a significant decrease in soft agar colony formation. We further assessed these genes through RT-qPCR mRNA expression profiling comparing PES/Trp53−/- transformed LBSCs to non-transformed LBSCs. These genes were significantly upregulated in PES/Trp53−/- transformed LBSCs, suggesting that they play important roles in LBSC transformation. Future work will further assess the molecular mechanisms by which these additional 3q26 genes contribute to LUSC cell transformation and assess the role of alternate cells of origin (Club and AT2) in 3q26-driven LUSC tumor formation using our PES/Trp53−/− GEMM. Citation Format: Kayleah M. Meneses, Capella Weems, Yi Liu, Verline Justilien, Nicole R. Murray, Alan P. Fields. Characterizing 3q26 copy number gain in lung squamous cell carcinoma through a novel genetically engineered mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 27.

Young athletes may be at risk for low energy availability (LEA) or dietary habits that are indicative of eating disorders. Thus, the purpose of the current study was to investigate the prevalence of LEA among high school athletes and examine those at risk for eating disorders. A secondary aim was to examine relationships between sport nutrition knowledge, body composition, and LEA. Methods: 94 male (n = 42) and female (n = 52) mean ± SD age: 18.09 ± 2.44 y; height: 172.6 ± 9.8 cm; body mass: 68.7 ± 14.5 kg; BMI: 22.91 ± 3.3 kg·m−2) athletes completed a body composition assessment and electronic versions of the abridged sports nutrition knowledge questionnaire (ASNK-Q), brief eating disorder in athletes questionnaire (BEDA-Q), and the low energy availability for females questionnaire (LEAF-Q; females only). Results: 52.1% of female athletes were classified as being at risk for LEA. Moderate inverse relationships existed for computed LEAF-Q scores and BMI (r = −0.394; p < 0.01). A total of 42.9% of males (n = 18) and 68.6% of females (n = 35) were at risk for eating disorders, with females being at greater risk (p < 0.01). Body fat percentage was a predictor (β = −0.095; p = −0.01) for eating disorder risk status. For every 1 unit increase in body fat percentage, athletes were 0.909 (95% CI: 0.845–0.977) times less likely to be classified as at risk for an eating disorder. Male (46.5 ± 13.9) and female (46.9 ± 11.4) athletes scored poorly on the ASNK-Q, with no differences between sex (p = 0.895). Conclusions: Female athletes were at a greater risk for eating disorders. No relationships existed between sport nutrition knowledge and %BF. Female athletes with a higher %BF had a lower risk for an eating disorder and risk for LEA.

Abstract Background: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research. Methods: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities in participant engagement: (i) a brainstorming exercise to elicit potential priorities; (ii) a 2-day virtual meeting to discuss priorities; (iii) recommendations from the PE-CGS External Advisory Panel to refine priorities; and (iv) a virtual meeting to set priorities. Results: Nearly 150 PE-CGS stakeholders engaged in the process. Five priorities were set: (i) tailor education and communication materials for participants throughout the research process; (ii) identify measures of participant engagement; (iii) identify optimal participant engagement strategies; (iv) understand cancer disparities in the context of cancer genomics research; and (v) personalize the return of genomics findings to participants. Conclusions: PE-CGS is pursuing these priorities to meaningfully engage diverse and underrepresented patients with cancer and posttreatment cancer survivors as participants in cancer genomics research and, subsequently, generate new discoveries. Impact: Data from PE-CGS will be shared with the broader scientific community in a manner consistent with participant informed consent and community agreement.

Abstract Objective Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic‐based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment. Methods Participants ≥18 years of age with overnight polysomnogram‐confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function. Results Outcomes are primarily reported based on sex (361 total: n = 295 male, n = 66 female), and secondarily based on history of antidepressant use ( n = 200 with, n = 154 without; with correction for sex differences) and based on extent of synucleinopathy burden ( n = 56 defined as isolated RBD, n = 305 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Overall, these participants commonly demonstrated abnormalities in global cognition (MoCA; 38%), motor function (alternate tap test; 48%), sensory (BSIT; 57%), autonomic function (orthostatic hypotension, 38.8%), and anxiety/depression (BAI and PHQ‐9; 39.3% and 31%, respectively). Interpretation These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials.

Firefighters often complete air management courses (AMC) to assess the ability to tolerate personal protective equipment, appropriately manage the breathing system and assess occupational performance. Little information is known relative to the physiological demands of AMCs, nor how to assess work efficiency in order to characterize occupational performance and evaluate progress. Purpose: To assess the physiological demands of an AMC and examine differences across BMI categories. A secondary aim was to develop an equation to assess work efficiency in firefighters. Methods: Fifty-seven firefighters (Women, n = 4; age: 37.2 ± 8.4 yr.; height: 182.0 ± 6.9 cm; body mass: 90.8 ± 13.1 kg; BMI: 27.8 ± 3.6 kg·m−2) completed an AMC per routine evaluation while wearing a department issued self-contained breathing apparatus and full protective gear. Course completion time, starting pounds per square inch (PSI) on the air cylinder, changes in PSI, and distance traveled were recorded. All firefighters were equipped with a wearable sensor integrated with a triaxial accelerometer and telemetry to assess movement kinematics, heart rate, energy expenditure, and training impulse. The AMC consisted of an initial section involving a hose line advance, rescue (body drag), stair climb, ladder raise, and forcible entry. This section was followed by a repeating loop, which consisted of a stair climb, search, hoist, and recovery walk. Firefighters repeated the course loop until the self-contained breathing apparatus air supply pressure reached 200 PSI, at which time they were instructed to lay down until the PSI reached zero. Results: Average completion time was 22.8 ± 1.4 min, with a mean distance of 1.4 ± 0.3 km and an average velocity of 2.4 ± 1.2 m·s−1. Throughout the AMC, the mean heart rate was 158.7 ± 11.5 bpm equating to 86.8 ± 6.3% of the age-predicted max heart rate and a training impulse of 55 ± 3 AU. Mean energy expenditure was 464 ± 86 kcals and work efficiency was 49.8 ± 14.9 km·PSI−1·s. Regression analysis determined that fat-free mass index (R2 = 0.315; β = −5.069), body fat percentage (R2 = 0.139; β = −0.853), fat-free mass (R2 = 0.176; β = −0.744), weight (R2 = 0.329; β = −0.681), and age (R2 = 0.096; β = −0.571) were significant predictors of work efficiency. Conclusions: The AMC is a highly aerobic task with near-maximal heart rates reached throughout the course. Smaller and leaner individuals achieved a higher degree of work efficiency during the AMC.

Abstract Fields, JB, Jones, MT, Feit, MK, and Jagim, AR. Athlete external loads across a collegiate men’s lacrosse season. J Strength Cond Res 37(8): e455–e461, 2023—Tracking and quantifying athlete workload may provide insight into best practice periodization strategies and workload management. Limited information exists detailing the external demands associated with collegiate men's lacrosse. Therefore, the purpose of this study was to investigate and compare practice, game, and positional differences across a lacrosse season. Male collegiate lacrosse athletes ( n = 17; body mass: 79.9 kg ± 9.7 kg; body fat %: 14.7 ± 3.8%) wore a global positional system device during practices ( n = 66) and games ( n = 19). External load metrics were total distance (TD), sprint distance (SD), accelerations (>3 m·s −2 ), sprint efforts, player load (PL), PL/min, and top speed. Multiple analysis of variances assessed differences in external loads across session (practice versus game) and sport position (attackers, midfielders, and defenders). A 3 × 4 analysis of variance was used to determine a position-by-time (first quarter [Q1], second quarter [Q2], third quarter [Q3], and fourth quarter [Q4]) interaction ( p < 0.05). Total distance ( p < 0.001, η 2 : 0.047), SD ( p < 0.001, η 2 : 0.093), sprint efforts ( p < 0.001, η 2 : 0.077), PL ( p < 0.001, η 2 : 0.022), and top speeds ( p < 0.001, η 2 : 0.086) were all higher in games compared with practices. Attackers and defenders covered more TD ( p < 0.001, η 2 = 0.0257), accelerations ( p < 0.001, η 2 = 0.126), PL ( p < 0.001, η 2 = 0.233), and PL/min ( p < 0.001, η 2 = 0.193) than midfielders. Attackers and midfielders covered more SD ( p = 0.002 η 2 = 0.043), sprint efforts ( p < 0.001, η 2 = 0.053), and achieved higher top speed ( p < 0.001, η 2 = 0.0063) than defenders. Volume and intensity metrics declined by Q4 in attackers and defenders ( p < 0.05), whereas external load measures did not differ across quarters for midfielders. Monitoring in-game external loads can assist coaches with individualizing training programs and preparing athletes for game demands.

AbstractAlterations of cerebral glucose metabolism can be detected in patients with isolated rapid eye movement sleep behaviour disorder, a prodromal feature of neurodegenerative diseases with α-synuclein pathology. However, metabolic characteristics that determine clinical progression in isolated rapid eye movement sleep behaviour disorder and their association with other biomarkers need to be elucidated. We investigated the pattern of cerebral glucose metabolism on 18F-fluorodeoxyglucose PET in patients with isolated rapid eye movement sleep behaviour disorder, differentiating between those who clinically progressed and those who remained stable over time. Second, we studied the association between 18F-fluorodeoxyglucose PET and lower dopamine transporter availability in the putamen, another hallmark of synucleinopathies. Patients with isolated rapid eye movement sleep behaviour disorder from the Mayo Clinic Alzheimer’s Disease Research Center and Center for Sleep Medicine (n = 22) and age-and sex-matched clinically unimpaired controls (clinically unimpaired; n = 44) from the Mayo Clinic Study of Aging were included. All participants underwent 18F-fluorodeoxyglucose PET and dopamine transporter imaging with iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane on single-photon emission computerized tomography. A subset of patients with isolated rapid eye movement sleep behaviour disorder with follow-up evaluations (n = 17) was classified as isolated rapid eye movement sleep behaviour disorder progressors (n = 7) if they developed mild cognitive impairment or Parkinson’s disease; or isolated rapid eye movement sleep behaviour disorder stables (n = 10) if they remained with a diagnosis of isolated rapid eye movement sleep behaviour disorder with no cognitive impairment. Glucose metabolic abnormalities in isolated rapid eye movement sleep behaviour disorder were determined by comparing atlas-based regional 18F-fluorodeoxyglucose PET uptake between isolated rapid eye movement sleep behaviour disorder and clinically unimpaired. Associations between 18F-fluorodeoxyglucose PET and dopamine transporter availability in the putamen were analyzed with Pearson’s correlation within the nigrostriatal pathway structures and with voxel-based analysis in the cortex. Patients with isolated rapid eye movement sleep behaviour disorder had lower glucose metabolism in the substantia nigra, retrosplenial cortex, angular cortex, and thalamus, and higher metabolism in the amygdala and entorhinal cortex compared with clinically unimpaired. Patients with isolated rapid eye movement sleep behaviour disorder who clinically progressed over time were characterized by higher glucose metabolism in the amygdala and entorhinal cortex, and lower glucose metabolism in the cerebellum compared with clinically unimpaired. Lower dopamine transporter availability in the putamen was associated with higher glucose metabolism in the pallidum within the nigrostriatal pathway; and with higher 18F-fluorodeoxyglucose uptake in the amygdala, insula, and temporal pole on a voxel-based analysis, although these associations did not survive after correcting for multiple comparisons. Our findings suggest that cerebral glucose metabolism in isolated rapid eye movement sleep behaviour disorder is characterized by hypometabolism in regions frequently affected during the prodromal stage of synucleinopathies, potentially reflecting synaptic dysfunction. Hypermetabolism is also seen in isolated rapid eye movement sleep behaviour disorder, suggesting that synaptic metabolic disruptions may be leading to a lack of inhibition, compensatory mechanisms, or microglial activation, especially in regions associated with nigrostriatal degeneration.