Conditioned pain modulation (CPM) is a behavioral measure of diffuse noxious inhibitory control (DNIC), an endogenous central pain modulatory mechanism in which one pain stimulus suppresses the perception of another. CPM efficiency is reduced in individuals with chronic pain and serves as a potential predictor for the development of chronic pain conditions. Current research indicates that CPM, traditionally viewed as a static metric, may exhibit protocol-dependent variability in its effects on pain sensitivity, potentially through neuroplastic mechanisms and central pain processing pathways. This randomized controlled trial (NCT05783362) investigated whether repeated activation of central pain modulatory systems enhances CPM efficiency. The secondary aim examined associations between repeated CPM exposure and pain-related psychological factors. Sixty healthy participants (52% female; ages 18–75) were randomly allocated to High Exposure (HE), Low Exposure (LE), or No Exposure (NE) CPM intervention groups. Pre- and post-intervention measures included CPM efficiency and pain sensitivity across thermal and pressure pain tests. Two-way ANOVA analyses revealed significant main effects for both time (p < 0.001, η2 = 0.23) and intervention (p = 0.030, η2 = 0.107) on CPM efficiency when comparing HE and LE groups from pre- to post-intervention. One-way ANOVA analysis at the final visit showed that HE demonstrated significantly higher CPM efficiency compared to LE (p = 0.02, Cohen's d = 0.73), while comparisons between HE and NE approached but did not reach statistical significance (p = 0.053–0.060; medium-to-large effect sizes, Cohen's d > 0.70). This was supported by increased heat threshold pain intensity ratings (p < 0.001, η2 = 0.13), suggesting broader adaptations in pain processing that strengthen descending pain control mechanisms. Other QST measures and psychological variables remained unchanged, suggesting the specificity of the modulatory enhancement. Results support the plasticity of endogenous pain modulation and suggest potential therapeutic applications for pain management interventions.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT05783362, identifier NCT05783362.

12085 Background: Sarcomas are a rare heterogeneous malignancy group affecting both sexes and all ages. Treatment is often intensive, resulting in long-term toxicities. Given the rarity of sarcoma, there is a paucity of data defining physical and emotional outcomes. The Cohort to Augment the Understanding of Sarcoma Survivorship Across the Lifespan (CAUSAL) was constructed at Vanderbilt University Medical Center (VUMC) to evaluate health-related outcomes. Methods: Sarcoma patients treated at VUMC from 2012 – present are enrolled into CAUSAL. Patient demographics, tumor and treatment data are abstracted from the electronic medical record. Participants complete surveys including PROMIS-57 consisting of seven domains including physical function, sleep disturbance, fatigue, and satisfaction with participation in social roles, which are reported here. Participants who have completed treatment are given a FitBit to track activity level and sleep over 12 weeks. Data are synced to an online platform, Fitabase. Body mass index (BMI) is assessed at study entry. For each participant, FitBit data were summarized using medians. To estimate the association between PROMIS-57 scores and activity and sleep data (FitBit), linear regression models were fit controlling for age, sex, and BMI of participants. Results: Of 306 CAUSAL participants who completed the PROMIS-57, 193 were post completion of sarcoma therapy. Of these, 76 also had FitBit data and are included in this analysis. Median step count was 5826 (quartiles: 3668, 7967), which was lower than average Fit Bit step count data for the US population (8170). Median daily active minutes was 252 minutes (quartiles: 174, 307). Median duration of sleep was 447 minutes (quartiles:381, 474) which was greater than the average reported by FitBit for the general US population (436 min). Step count was correlated with higher physical function score (p < 0.001). A 10-point increase in physical function led to an average increase of 1291 (95% CI: 609,1973) steps when adjusting for age and sex. Compared with participants receiving treatment within 30 days prior to CAUSAL enrollment, participants not receiving treatment had 4.50 (95% CI: 1.53, 7.47) higher physical function score and 6.26 (95% CI: 1.87, 10.65) higher satisfaction in their social roles. There was no correlation between minutes of sleep recorded by FitBit and PROMIS responses. Conclusions: Using PROMIS-57, and FitBits, we demonstrated an association between higher step counts and self-reported higher physical function but did not find a correlation between FitBit recorded activity level/sleep and self-reported sleep disturbance or fatigue scores. Further, our data suggests patients with sarcoma sleep more and walk less than the general US population. As enrollment continues in CAUSAL, we will focus on PROMIS scores over time and their association with activity level and sleep.

11548 Background: Sarcomas are a rare and heterogenous group of cancers that arise from bone or soft tissue, and two thirds have poorly defined mutational profiles. Given their rarity, few comprehensive studies have fully characterized mutations and gene expression across sarcoma histologies correlated with clinical outcomes. Further studies are needed to determine the presence of targetable mutations that may improve patient outcomes. In this study, we explored the genomic landscape and clinical actionability of sarcoma mutations from patients enrolled in our CAUSAL (Cohort to Augment the Understanding of Sarcoma survivorship Across the Lifespan) study. Methods: Between 04/01/2022 and 01/01/2023, 481 participants, treated from 2012 – present with multiple sarcoma histologies were enrolled on CAUSAL. Next Generation Sequencing (NGS) was performed on primary or metastatic tumors from 76 patients to determine DNA mutations within a 648 gene panel. Whole transcriptome RNA sequencing (seq) provided expression profiles and RNA fusion products. Further analysis was performed using principal components analysis of RNA seq data to explore correlates amongst sarcoma subtypes. Tumor mutations were queried in ClinVar for relevance to known variants and were assigned to tiers I-IV based on the ESMO scale for clinical actionability of molecular targets (ESCAT). Tier I mutations have drug-mutation matched evidence of actionability while tier IV have only pre-clinical evidence. Results: NGS has been completed on 76 tumor samples. Sequenced tumors represented 19 histologies, with the most common ones as follows: undifferentiated pleomorphic sarcoma (15.8%), liposarcoma (9.2%), gastrointestinal stromal tumor (9.2%), osteosarcoma (7.9%), and leiomyosarcoma (7.9%). Of 76 patients, 66 (87%) had at least one mutation detected with an mean frequency of 2.74. TP53 (20/66), RB1 (14/66), and ATRX (9/66) were most commonly mutated genes. Mean (std) tumor mutation burden (TMB) was 3.4 m/MB (3.5m/MB) and one tumor had TMB of 25.3 m/MB. Of the 76 samples, 68 had RNA expression and fusion data available, of which 42 (62%) had anomalous expression changes and 11 had RNA fusions. The most overexpressed genes were NY-ESO-1 (13), LAGE-1 (9), and RET (7); the most under-expressed genes were SMARCB1 (9) and MGMT (6). 30.2% (23 of 76) of patients had potentially actionable DNA mutations, 9 had ESCAT tier I DNA mutations, 3 had tier II, 10 had tier III, and 1 had tier IV. 29.4% (20/68) of patients had potential targets based on RNA expression. 51.3% (39/76) patients had either a potential DNA or RNA target, and 6.6% (5/76) had multiple RNA or DNA targets. Conclusions: NGS revealed potentially actionable targets in over half of sarcoma patients based on ESCAT criteria. With ongoing accrual and sequencing of additional tumor specimens future analysis of CAUSAL will focus on assessing the correlation between targetable mutations and clinical outcomes.

OBJECTIVE:The objective was to examine the 22 variables from the Sport Concussion Assessment Tool's 5th Edition Symptom Evaluation using a decision tree analysis to identify those most likely to predict prolonged recovery after a sport-related concussion.DESIGN:A cross-sectional design was used in this study. A total of 273 patients (52% men; mean age, 21 ± 7.6 yrs) initially assessed by either an emergency medicine or sport medicine physician within 14 days of concussion (mean, 6 ± 4 days) were included. The 22 symptoms from the Sport Concussion Assessment Tool's 5th Edition were included in a decision tree analysis performed using RStudio and the R package rpart. The decision tree was generated using a complexity parameter of 0.045, post hoc pruning was conducted with rpart, and the package carat was used to assess the final decision tree's accuracy, sensitivity and specificity.RESULTS:Of the 22 variables, only 2 contributed toward the predictive splits: Feeling like "in a fog" and Sadness. The confusion matrix yielded a statistically significant accuracy of 0.7636 (P [accuracy > no information rate] = 0.00009678), sensitivity of 0.6429, specificity of 0.8889, positive predictive value of 0.8571, and negative predictive value of 0.7059.CONCLUSIONS:Decision tree analysis yielded a statistically significant decision tree model that can be used clinically to identify patients at initial presentation who are at a higher risk of having prolonged symptoms lasting 28 days or more postconcussion.

Background: MT1-MMP plays an important role in pericellular proteolysis and is implicated in cancer cell migration, growth, invasion and angiogenesis. Limited evidence suggests that MT1-MMP overexpression is associated with a poor prognosis in numerous solid tumours. Using data from immunohistochemical pre-screening for a Phase 1/2 clinical trial targeting MT1-MMP (clinicaltrials.gov identifier: NCT03486730), we determined if MT1-MMP over-expression was a prognostic biomarker in selected solid tumours. Methods: An analytically validated MT1-MMP immunohistochemistry assay using a commercially available antibody was developed by NovoPath (Newcastle upon Tyne) in collaboration with Cancer Research UK and Bicycle Therapeutics® and was used for clinical trial pre-screening. All patients (pts) from 5 UK sites pre-screened between 2/2020 and 2/2022 were included. Pts were considered positive (+ve) for MT1-MMP overexpression if the cancer cell membrane H score on their archival tumours was ≥ 150. Overall survival (OS) was evaluated using Kaplan Meier methodology from 3 timepoints (T): date of diagnosis (T1), date of archival tissue (T2) and date of MT1-MMP testing consent (T3). Log rank analysis was used to assess for survival differences between groups. Results: 284 pts were included; 26% (N = 74) MT1-MMP +ve and 74% (N = 210) MT1-MMP -ve. Pts characteristics are outlined in Table 1. At a median follow up time of 8.9 months (mos), 55% (N = 41) MT1-MMP1 +ve pts and 52% (N = 108) MT1-MMP -ve pts had died (p = 0.58). There was no statistically significant difference in median OS between MT1-MMP +ve and – ve pts at T1 (43.4 mos vs 49.8 mos p = 0.71), T2 (27.3 mos vs 33.1 mos p 0.32) or T3 (6.5 mos vs 7.2 mos p = 0.84). Subgroup analysis based on tumour or histological subgroups did not reveal a significant difference in OS at any time point for MT1-MMP +ve and -ve tumours.Table 1Demographic factors of pts who tested +ve and -ve for MT1-MMP overexpression.MT1-MMP +veMT1-MMP −vep Value*Comparison between MT1-MMP overexpression +ve and −ve pts.Median Age59 years59.6 yearsp = 0.93ap value calculated using Independent T test,Genderp = 0.56bp value calculated using Pearson’s chi squared test.Male30%(22)33%(70)Female70%(52)67%(140)ECOGp = 0.95bp value calculated using Pearson’s chi squared test.0-197% (72)98% (206)21.5% (1)2% (4)Unknown1.5% (1)Tumour Groupp = 0.20bp value calculated using Pearson’s chi squared test.Breast20% (15)11.5%(24)Lung22% (16)17% (35)Gynaecological16% (12)27%(57)Head and Neck12%(9)11% (23)Genitourinary8% (6)3% (7)Sarcoma12% (9)11.5% (24)Gastrointestinal5.5% (4)9% (19)Melanoma3% (2)3% (7)Other1.5%(1)7% (14)Histological subtypep = 0.66bp value calculated using Pearson’s chi squared test.Adenocarcinoma34%(25)38%(80)Squamous cell carcinoma40%(30)31%(66)Melanoma3% (2)3% (7)Sarcoma12% (9)11.5%(24)Small cell carcinoma1.5%(1)4.5%(9)Adenosquamous carcinoma1.5%(1)0.5%(1)Other/Unknown8%(6)11%(23)* Comparison between MT1-MMP overexpression +ve and −ve pts.a p value calculated using Independent T test,b p value calculated using Pearson’s chi squared test. Open table in a new tab Conclusion: In this study of heavily pre-treated pts, MT1-MMP expression was shown not to be a prognostic biomarker. Conflict of interest: Advisory Board: Jeff Evans has received honoraria from Bicycle Therapeutics (payable to employing institution) for advisory boards on a different compound, and support from Bicycle Therapeutics for commercial clinical trials (different compound – payable to employing institution). B.Basu Consulting or Advisory Role - Eisai GenMab Roche Corporate-sponsored Research: Jeff Evans holds the research grant (payable to the employing institution) from CRUK’s CDD for the Glasgow Biomarkers Hub which supports biomarker studies for this, and other, CDD clinical trials. B.Basu Research Funding – Celgene N.Cook Research funding/educational research grants have been received by Cook’s research team from AstraZeneca, Bayer, Pfizer, Orion, Taiho, Oncology, Roche, Starpharma, Eisai, RedX, UCB, Boeringher, Merck, Stemline Tarveda and Avacta. Other Substantive Relationships: B.Basu: Speakers’ Bureau - Eisai Europe

Sport concussions can be difficult to diagnose and if missed, they can expose athletes to greater injury risk and long-lasting neurological disabilities. Discovery of objective biomarkers to aid concussion diagnosis is critical to protecting athlete brain health. To this end, we performed targeted proteomics on plasma obtained from adolescent athletes suffering a sports concussion. A total of 11 concussed male athletes were enrolled at our academic Sport Medicine Concussion Clinic, as well as 24 sex-, age- and activity-matched healthy control subjects. Clinical evaluation was performed and blood was drawn within 72 h of injury. Proximity extension assays were performed for 1,472 plasma proteins; a total of six proteins were considered significantly different between cohorts (P < 0.01; five proteins decreased and one protein increased). Receiver operating characteristic curves on the six individual protein biomarkers identified had areas-under-the-curves (AUCs) for concussion diagnosis ≥0.78; antioxidant 1 copper chaperone (ATOX1; AUC 0.81, P = 0.003), secreted protein acidic and rich in cysteine (SPARC; AUC 0.81, P = 0.004), cluster of differentiation 34 (CD34; AUC 0.79, P = 0.006), polyglutamine binding protein 1 (PQBP1; AUC 0.78, P = 0.008), insulin-like growth factor-binding protein-like 1 (IGFBPL1; AUC 0.78, P = 0.008) and cytosolic 5'-nucleotidase 3A (NT5C3A; AUC 0.78, P = 0.009). Combining three of the protein biomarkers (ATOX1, SPARC and NT5C3A), produced an AUC of 0.98 for concussion diagnoses (P < 0.001; 95% CI: 0.95, 1.00). Despite a paucity of studies on these three identified proteins, the available evidence points to their roles in modulating tissue inflammation and regulating integrity of the cerebral microvasculature. Taken together, our exploratory data suggest that three or less novel proteins, which are amenable to a point-of-care immunoassay, may be future candidate biomarkers for screening adolescent sport concussion. Validation with protein assays is required in larger cohorts.

Abstract Chronic low back pain is the leading cause of disability among older adults. The impact of psychological factors, including high levels of stress, are associated with increased risk for pain. Despite the growing evidence suggesting that psychological well-being is associated with better health outcomes, limited research has examined positive psychological factors in the context of pain among older adults. In this secondary data analyses of we examined the association of perceived stress on pain and physical functioning, and the moderating role of positive affect and well-being (PAW) on these relationships. A total of 60 adults over the age of 60 completed completed questionnaires assessing perceived stress (Perceived Stress Scale) and positive affect and well-being (Neuro-QOL PAW). The Back Performance Scale measured back-related physical functioning and movement-evoked pain. We hypothesized that PAW would be inversely associated with pain outcomes and would moderate the relationship between perceived stress and pain. Bivariate correlations assessed the association between study variables, while the interaction of PAW and perceived stress was examined via linear regression. Age (r=.30), income (r=.28), and being married (r=.32) were associated with higher PAW scores, while there was an inverse association with movement-evoked pain (r=-.28). After controlling for demographic covariates, moderation analysis revealed that higher levels of perceived stress were associated with poorer physical functioning, but only among those with lower positive affect and well-being (b=0.14). As seen, examining the influence of positive psychological functioning on pain-related outcomes has important clinical implications that may promote positive pain adaptation in this population.

Objective: The goal of this study was to determine whether the acute analgesic effects of alcohol intake are moderated by acute alcohol tolerance, characterized by differing subjective and neurobehavioral effects of a given blood alcohol concentration (BAC) depending on whether BAC is rising or falling. Method: Twenty-nine healthy drinkers (20 women) completed two laboratory sessions in which they consumed a study beverage: active alcohol (target BAC= .08 g/dl) and placebo. Acute alcohol tolerance was assessed by examining the main and interactive effects of beverage condition and assessment limb (ascending vs. descending) on quantitative sensory testing measures collected using slowly ramping heat stimuli and perceived relief ratings at comparable breath alcohol concentrations on the ascending and descending limbs. Results: BAC limb moderated the effect of condition on pain threshold, such that the threshold was significantly elevated in the alcohol condition on the ascending limb. The alcohol condition produced greater ratings of perceived pain relief than the placebo condition, and pain relief ratings were greater on the ascending versus descending limb of the BAC curve. Alcohol intake did not significantly affect pain tolerance or aftersensation ratings on either BAC limb. Conclusions: This study provides initial experimental evidence that alcohol's analgesic and pain-relieving effects are subject to acute tolerance following acute alcohol intake. These findings suggest that self-medicating pain via alcohol intake may be associated with high-risk drinking topography, increasing the risk for alcohol-related consequences. Further research is needed to determine if these effects extend to the context of clinical and chronic pain.

Concussions are frequent in sports and can contribute to significant and long-lasting neurological disability. Adolescents are particularly susceptible to concussions, with accurate determination of the injury challenging. Our previous study demonstrated that concussion diagnoses could be aided by metabolomics profiling and machine learning, with particular weighting on changes in plasma glycerophospholipids (PCs). Here, our aim was to report directional change of PCs after concussion and to develop a diagnostic concussion panel utilizing a minimum number of plasma PCs. To this end, we enrolled 12 concussed male athletes at our academic Sport Medicine Concussion Clinic, as well as 17 sex-, age- and activity-matched healthy controls. Blood was drawn and 71 plasma PCs were measured for statistically significant changes within 72 hours of injury, and individual PCs were further analyzed with receiver operating characteristic (ROC) curves. Our data demonstrate that 26 of 71 PCs measured were significantly decreased after sports related concussion (P<0.01). None of the PCs increased in plasma after concussion. ROC curve analyses identified the top 4 PCs with areas-under-the curves (AUCs) ≥ 0.86 for concussion diagnosis; PCaeC36:0 (0.92, P<0.001); PCaaC42:6 (0.90, P<0.001); PCaeC36:2 (0.86, P=0.001) and PCaaC32:0 (0.86, P=0.001). Cut off values in M were ≤ to 0.31, 0.22, 5.07 and 4.63, respectively. Importantly, combining these 4 PCs produced an AUC of 0.96 for concussion diagnoses (P<0.001; 95% CI 0.89, 1.00). Our data suggest that as few as 4 circulating PCs may provide excellent diagnostic potential for adolescent concussion. External validation is required in larger cohorts.

Distant soft-tissue metastases (subcutaneous tissues and skeletal muscle) are extremely rare, specially in esophageal carcinoma. We describe a patient who was treated for oesophageal adenocarcinoma 2.5 years before. A PET/CT was performed showing metastatic spread because of a solitary focus of increased tracer uptake corresponding one subcutaneous node in the upper abdomen. An excisional biopsy proved to be a metastasis from the carcinoma. Restaging 18F-FDG PET/CT study was performed 2 years later demonstrating some focus of increased uptake within several muscles as isolated distant hematogenous spread of metastases, as they were histopathologically confirmed.As most of soft-tissue metastases are asymptomatic, the physicians should recommend histopathological study of focus of FDG uptake at subcutaneous tissues and/or skeletal muscles, because they may be the first sign of disease expansion so therapeutic management of these patients could be changed.Las metástasis en partes blandas (tejido celular subcutáneo y músculo esquelético) son extremadamente raras, especialmente en cáncer de esófago. Presentamos un varón con antecedente de adenocarcinoma de esófago tratado 2,5 años antes, con hallazgo en 18F-FDG PET/TC de afectación metastásica a distancia exclusiva en un nódulo subcutáneo en pared abdominal, con confirmación anatomopatológica tras su resección. En nuevo PET-TAC 18F-FDG realizado 2 años después se objetivó nueva afectación a distancia pero exclusiva en musculatura esquelética, también confirmada histológicamente.Como las lesiones en partes blandas frecuentemente son asintomáticas, ante el hallazgo en un estudio PET de lesiones subcutáneas y/o musculares hipermetabólicas debemos recomendar su estudio histológico, ya que pueden tratarse del primer signo de una metastatización a distancia cambiando radicalmente el manejo terapéutico del paciente.

In this paper, we want to explore which verbal and non-verbal communication behaviors health professions trainees will employ during the training of interpersonal skills through the interaction experience with virtual patients. We investigated participants' eye gaze position, nodding gesture, speeches, interaction distance, and questions participants asked in a pilot study. We compared the results of verbal behaviors and non-verbal behaviors observed in the pilot study with what we would expect to find given prior research from real-world interactions. Then we tried to explore the potential reasons if our results are different from what we expect.

Background Acute alcohol intoxication has wide‐ranging neurobehavioral effects on psychomotor, attentional, inhibitory, and memory‐related cognitive processes. These effects are mirrored in disruption of neural metabolism, functional activation, and functional network coherence. Metrics of intraregional neural dynamics such as regional signal variability (RSV) and brain entropy (BEN) may capture unique aspects of neural functional capacity in healthy and clinical populations; however, alcohol’s influence on these metrics is unclear. The present study aimed to elucidate the influence of acute alcohol intoxication on RSV and to clarify these effects with subsequent BEN analyses. Methods 26 healthy adults between 25 and 45 years of age (65.4% women) participated in 2 counterbalanced sessions. In one, participants consumed a beverage containing alcohol sufficient to produce a breath alcohol concentration of 0.08 g/dl. In the other, they consumed a placebo beverage. Approximately 35 minutes after beverage consumption, participants completed a 9‐minute resting‐state fMRI scan. Whole‐brain, voxel‐wise standard deviation was used to assess RSV, which was compared between sessions. Within clusters displaying alterations in RSV, sample entropy was calculated to assess BEN. Results Compared to the placebo, alcohol intake resulted in widespread reductions in RSV in the bilateral middle frontal, right inferior frontal, right superior frontal, bilateral posterior cingulate, bilateral middle temporal, right supramarginal gyri, and bilateral inferior parietal lobule. Within these clusters, significant reductions in BEN were found in the bilateral middle frontal and right superior frontal gyri. No effects were noted in subcortical or cerebellar areas. Conclusions Findings indicate that alcohol intake produces diffuse reductions in RSV among structures associated with attentional processes. Within these structures, signal complexity was also reduced in a subset of frontal regions. Neurobehavioral effects of acute alcohol consumption may be partially driven by disruption of intraregional neural dynamics among regions involved in higher‐order cognitive and attentional processes.