Harmsen, William S.

Abstract Rationale Mechanically ventilated intensive care unit patients receive sedatives based on clinician observations of arousal and motor activity with potential for negative consequences and poor mitigation of symptoms. Objectives To test the preliminary efficacy of patient self-managed sedative therapy compared to usual care of nurse-administered sedation on self-reported anxiety, duration of mechanical ventilation, and delirium incidence (CAM-ICU). Methods A two-group, open-label, randomized, multicenter clinical trial in 5 Midwestern hospitals enrolled 161 patients receiving invasive mechanical ventilation who were willing and able to use a push-button device to self-administer sedation for up to 7 days. Patients were randomized 1:1 using center-stratified blocks to usual care (n = 81) or intervention (n = 80) with self-administered dexmedetomidine. Intervention patients were allowed 3 self-administered dexmedetomidine boluses per hour (0.25 mcg/kg) with 20-minute lock-outs. The initial basal infusion (0.2 mcg/kg/hr) was adjusted by nurses between 0.1-0.7 mcg/kg/hr based on patient-delivered boluses in the prior 2 hours. Analysis consisted of linear mixed-effects model for comparisons of anxiety ratings over time and duration of mechanical ventilation. Incidence of delirium was analyzed using generalized estimating equations. Measurement and Main Results Sample characteristics had a female (54.7%) and Caucasian preponderance (92.5%) with a median age of 62 years on protocol for a median of 88 hours. Nine intervention patients were extubated prior to protocol initiation. Patient self-reported three times daily anxiety ratings with a visual analog scale (VAS) ranged from 0-100 over time but were not significantly different between groups in either an intention-to-treat (ITT) or per protocol (PP) analysis (p = 0.94, p = 0.30 respectively). While intervention patients had shorter duration of MV [(mean 50.8(52.8) vs. usual care 68.7(58.2) hours), p = 0.02 ITT], PP analysis resulted in no difference between groups (mean 56.4 (53.0) vs. 68.7(58.2), p = 0.23). 10.2% of intervention patients developed new incidence of delirium vs. 8.5% of usual care which was not significantly different between groups by either ITT (p = 0.65) or PP analyses (p = 0.58). Conclusions Intervention patients had similar outcomes compared to usual care patients. Self-administration of sedative therapy is a safe, novel patient-centered intervention warranting further rigorous investigation for anxiety self-management.

Objective: This single institutional analysis explored outcomes and factors associated with local control and survival in pediatric patients with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Methods: Patients 18 years of age or younger diagnosed between October 1990 and November 2021 who received external beam radiotherapy (EBRT) were retrospectively identified. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier methods and univariate Cox models. Results: Among 51 included patients, there were 33 extremity tumors (65%), with 80% T1/T2 and 90% M0. Surgery in 49/51 (96%) resulted in 32 (65%) R0 resections. All received EBRT, with brachytherapy or intraoperative radiotherapy boosts in 21/51 (41%). Thirty-four (66.7%) received chemotherapy. With 5.7 years median follow-up, 5-year OS and DFS were 70.7% and 67.9%, respectively. Positive margins were significantly associated with worse OS. Two-year local failure incidence was 18.1% for EBRT versus 5.3% for EBRT+boost (HR 3.67, P =0.24). Among 6 local failures, 5 received EBRT alone, including 3 with positive margins. Two treated with EBRT+boost had positive margins, neither with local recurrence. Conclusion: Multimodality treatment of pediatric NRSTS results in 5-year OS and DFS around 70%. Although complete resection remains essential, and the modern incidence of R1 resection has declined, IORT/brachytherapy boost may continue to have a role in selected patients with a high local recurrence risk.

Abstract Introduction: Detectable circulating tumor DNA (ctDNA) is associated with inferior outcomes in Ewing sarcoma (ES); however, ctDNA clears in nearly all patients within 2 of the 6 chemotherapy cycles before radiotherapy (RT) or surgery. Given a 3-year EFS of 37% on AEWS 1221 (metastatic) and 5-year EFS of 78% on AEWS 1031 (localized), current ctDNA testing fails to predict most relapses. Extracellular vesicles (EVs) are microscopic particles studied as a biomarker in multiple cancer types. We hope to improve the sensitivity of ctDNA in ES and provide the first application of EVs in ES. Methods: cfDNA was isolated from 1mL plasma, quantified by Qubit, and sequenced as NEBNext Enzymatic Methyl-seq v2 libraries. We performed a systematic unsupervised clustering analysis of 27 ES plasma cfDNA profiles using 4 differentially methylated regions (DMR) subsets (63 strong DMRs, top 30, top 15, and 10 promoter-proximal loci), 3 clustering algorithms (k-means, Ward hierarchical, PAM), and k=2-5 clusters, testing associations with tumor burden and progression. EV analysis involved antibody detection against ES surface markers, including LINGO1, ENPP1, CDH11, and CD99. Concentrations of EVs were determined by standardized and calibrated high-resolution flow cytometry then analyzed with custom-built software to automatically determine and apply gates. Samples were de-identified, randomly coded, and run in triplicates. The senior research technologist responsible for EV analysis was blinded to patient information and clinical data. Results: EV analysis included 36 pre-RT samples from 16 metastatic and 20 localized ES patients from a prospectively maintained biobank, with 27 pre-RT samples in the cfDNA analysis and 19 healthy donor (HD) samples. 35 of 36 patients had chemotherapy before sample collection. cfDNA concentrations were markedly elevated in ES patients compared with HD (24.4 vs 4.6 ng/mL, p<0.0001), and 74% of ES samples exceeded the HD 95th-percentile detectability threshold (7.0 ng/mL). Across clustering configurations, ES cfDNA profiles consistently exhibited reproducible methylation substructure. One configuration (PAM clustering, k = 5, 63 strong DMRs) showed a modest but permutation-supported association with primary tumor size (nominal p ≈ 0.04; empirical p ≈ 0.03-0.04). ES samples had increased EV concentration compared to HD (p<0.001), with AUC 0.988 for distinguishing between ES and HD ENPP1 (p<0.0001). The highest ENPP1 EV values were in patients with large primary tumors (>8 cm vs. ≤ 8cm) and metastatic disease (p=0.066). Conclusions: cfDNA- and EV-based liquid biopsy provide encouraging signals for high ES detectability pre-RT. We also show the first study of EVs as a novel biomarker in ES, which may provide complementary information to ctDNA. Multimodal liquid biopsy in ES may identify candidate patients for systemic or local therapy escalation and facilitate personalized care. Citation Format: Roman O. Kowalchuk, Lilli J. Greiner, Yohan Kim, Rubia Noori, Jeffrey Szymanski, William S. Harmsen, Pradeep S. Chauhan, Adam C. Amundson, Andrea M. McMahon, Peter J. Schoettler, Wendy A. Allen-Rhoades, Stephanie F. Polites, Peter S. Rose, Kelly M. Bailey, Linda M. McAllister-Lucas, Anita Mahajan, Fabrice Lucien-Matteoni, Nadia N. Laack, Aadel A. Chaudhuri. Multimodal liquid biopsy of Ewing sarcoma reveals high sensitivity prior to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1149.

334 Background: Sarcopenia, or decreased skeletal muscle mass, has been associated with worse surgical and oncologic outcomes across multiple malignancies. This study investigates the impact of sarcopenia on outcomes after multimodal therapy for esophageal cancer. Methods: Retrospective observational cohort study including adult patients who underwent neoadjuvant therapy followed by esophagectomy for primary esophageal cancer from January 2000 - December 2021. A fully automated abdominal segmentation using deep convolutional neural network was utilized to calculate skeletal muscle index (SMI) from preoperative CT scans performed at our institution. Males with SMI <52.4 cm 2 /m 2 and females with SMI <38.5 cm 2 /m 2 at any point before surgery were classified as sarcopenic. The relationship between sarcopenia and patient demographics, operative details, and complications were explored using chi-square tests. The relationship between sarcopenia and disease-free survival and overall survival were investigated using parsimonious multivariable analysis retaining variables with p-value <0.05 using backward selection method. Results: We identified 200 patients meeting the study criteria with 142 (71%) having sarcopenia at any time prior to surgery. Patients with sarcopenia were significantly older [65.2 (59.6, 71.2) vs 63 (53.6, 67.5), p = .023] and more likely to have had open surgery [129 (90.8%) vs 46 (79.3%), p = .034]. There were no significant differences in sex, history of diabetes, coronary artery disease, renal disease, smoking, cancer type, cancer stage, tumor size, tumor location, or margin status between sarcopenic groups ( p > .05). Sarcopenic patients were significantly more likely to require blood transfusion ≥3 units after esophagectomy [79 (55.6%) vs 8 (13.8%), p < .001] or to experience complications requiring surgical intervention [36 (24.6%) vs 7 (12.1%), p = .048]. Multivariate analysis revealed that sarcopenia was associated with disease-free and overall survival (Table). Conclusions: Sarcopenia is a prognostic factor in patients undergoing multimodal therapy for esophageal cancer. Interventions that aim to prevent decreases in SMI after initiating neoadjuvant therapy should be investigated. Multivariate analysis with sarcopenia predicting outcomes. Disease free survivalHR (95% CI) p-value Overall survivalHR (95% CI) p-value Age 1.04 (1.02, 1.06) < .001 1.04 (1.02, 1.07) < .001 Epicenter Middle Upper 1.88 (1.21, 2.86)3.16 (1.67, 5.98) .001.005< .001 1.96 (1.26, 3.04)4.00 (1.90, 8.44) < .001.003< .001 Stage Stage II Stage III Stage IV 1.88 (0.95, 3.71)2.90 (1.46, 5.75)16.02 (6.12, 41.93) < .001.069.002< .001 1.65 (0.83, 3.25)2.76 (1.37, 5.55)10.14 (4.03, 25.53) < .001.151.005< .001 Cancer type - - 1.76 (1.03, 3.02) .039 Transfusion > 3 pRBC - - 1.54 (0.99, 2.40) .057 BMI prior to cancer diagnosis - - 0.98 (0.94, 1.01 .208 Sarcopenic 1.76 (1.16, 2.67) .007 1.64 (1.04, 2.60) .033

Abstract Background Deep learning auto segmentation (DLAS) tools are widely used for radiation therapy planning, yet limited information exists on how patient positioning impacts their performance, particularly in head and neck (HN) computed tomography (CT) imaging. Purpose This study investigates the impact of abnormal neck tilt on the accuracy of DLAS‐generated contours in HN CT scans. We hypothesize that abnormal positioning degrades auto segmentation performance, particularly for organs at risk (OARs) influenced by cervical spine orientation. Methods A total of 35 HN CT scans were retrospectively analyzed. Neck tilt was quantified using principal component analysis of the spinal cord contours from C1 to C4, with patients stratified into normal and abnormal tilt groups based on percentile thresholds. Seven FDA‐cleared DLAS tools were evaluated for OAR segmentation accuracy across brainstem, parotid glands, submandibular glands, brachial plexus, and optic nerves. Gold‐standard contours were curated from manually created clinical contours and compared to DLAS output using Sorenson's volumetric dice similarity coefficient (DSC), surface Dice similarity coefficient with a 2 mm threshold (sDSC), mean distance to agreement (MDA) and difference in mean dose. Statistical differences were assessed using Wilcoxon rank‐sum tests ( p < 0.05). Results Among the evaluated OARs, the parotid glands showed consistent and statistically significant degradation in contouring accuracy for patients with abnormal neck tilt across all metrics (DSC, sDSC, MDA) and across all seven DLAS tools. Changes in contouring accuracy resulted in significant differences in both absolute and signed difference in mean dose. No consistent differences were observed for other structures across multiple DLAS tools. Conclusions Abnormal neck tilt is associated with reduced DLAS accuracy and greater dose variability for parotid gland segmentation in HN radiotherapy planning. These findings underscore the need for enhanced patient quality assurance strategies for patients with abnormal positioning when using clinical DLAS workflows. Future work should explore automated detection of anatomical outliers and site‐specific model retraining to ensure accurate contouring delineation for patients with atypical positioning or anatomy.

ABSTRACT Objectives Patients requiring long‐term enteral nutrition or continuous infusion of carbidopa/levodopa can benefit from jejunostomy tube placement. Recently, directly placed percutaneous transgastric jejunal tubes (TGJs) have been used instead of gastrostomy tubes with jejunal extensions (PEG‐Js) for enteral access. We aim to compare patient characteristics and outcomes after placement of TGJs placed via the introducer technique compared to PEG‐Js. Methods We performed a retrospective study of 141 patients (TGJ = 58, PEG‐J = 83) assessed at Mayo Clinic between 2010 and 2024. Patients were identified using a prospectively maintained procedure data registry. Demographic data, patient characteristics, procedural indications, complications, and first‐replacement date were gathered. Statistical analysis included the Wilcoxon rank sum test, chi‐square test, Fisher's exact test, and Kaplan‐Meier estimates. Patients receiving carbidopa/levodopa were excluded from complications analysis due to the carbidopa/levodopa tube's proprietary structure. A p ‐value of <0.05 was set as a threshold for significance. Results Our results demonstrated no difference in cumulative incidence of complications within 1 year for TGJs and PEG‐Js, p ‐value 0.48. Regarding time to first replacement, treating death as a competing risk factor, there was no statistically significant difference in cumulative incidence of replacement within 1 year for TGJs and PEG‐Js, p ‐value 0.389. Conclusions Our study demonstrates that both direct TGJs and PEG‐Js are safe options for long‐term jejunal feeding. More studies are needed to compare endoscopic to radiologically placed percutaneous transgastric jejunal feeding tubes.

Objective: To evaluate treatment trends and compare outcomes following fenestrated-branched endovascular aortic repair (FB-EVAR) versus open surgical repair (OSR) of thoracoabdominal aortic aneurysms (TAAA). Background: FB-EVAR has been increasingly utilized as a less invasive alternative to OSR for treatment of TAAAs. Methods: We studied patients who underwent elective FB-EVAR or OSR of TAAAs (2008-2020), since the initiation of an Advanced Endovascular Aortic Program. Primary endpoints were early major adverse events (MAE) and early and late all-cause mortality. Propensity score overlap weighting analysis was performed to adjust for measured confounders between groups. Results: There were 357 (70.8%) patients treated by FB-EVAR and 147 (29.2%) with OSR. The use of FB-EVAR increased from 16.7% in 2008 to >80% since 2017 ( P <0.001). Incidences of early MAEs were 25.8% and 49.0%, respectively; early mortality rates for FB-EVAR and OSR were 2.5% and 6.8%, respectively. In the weighted cohort, FB-EVAR patients had decreased early MAEs (weight-adjusted odds ratio [aOR], 0.28; 95% confidence interval [CI], 0.18-0.41; P <0.001) and mortality (aOR, 0.35; 95% CI, 0.17-0.73; P =0.005) versus OSR patients. Five-year survival estimates were 52.2% (95% CI, 45.2-60.4%) and 78.0% (95% CI, 70.6-86.2%), respectively. In the weighted cohort, there was no significant difference in late survival between groups (weight-adjusted hazard ratio, 1.33; 95% CI, 0.74-2.39; P =0.34). Conclusions: This study confirmed the change in practice from OSR to FB-EVAR for treatment of TAAAs over the past decade. Incidences of early MAEs and mortality were lower with FB-EVAR, with no significant difference in late survival in the weighted cohort.

Abstract Background We retrospectively assessed volumetric response of myxoid liposarcoma (MLPS) with preoperative radiotherapy (RT) and sought to identify disease and treatment characteristics associated with response. Patients and methods We identified all patients with a histologic diagnosis of MLPS who received preoperative RT from 2013 to 2021 at our institution. We used cone beam computed tomography (CBCT) to assess changes in tumor volume and greatest dimension during treatment. Tumors were contoured on CBCT images prior to treatment and at the end of each week of RT. Percentage change in tumor volume and greatest dimension were calculated based on pre-treatment and final week contours. Patients with tumors incompletely visualized on CBCT were excluded from volume analysis but included on greatest dimension analysis. Magnetic resonance imaging (MRI) was used to evaluate pre- and post-RT radiographic features. Surgical pathology was reviewed to record pathologic characteristics. Results Twenty patients met inclusion criteria. Most tumors (18/20) were low grade. The most frequent dose/fractionation scheme was 50 Gy in 25 fractions (16/20), with 3 patients receiving 36 Gy in 18 fractions. Median pre-RT volume and greatest dimension were 120 cc (interquartile range [IQR]: 56–399) and 11.2 cm (IQR: 8.4–14.1), respectively. Median percentage change in volume and greatest dimension were -37% (IQR: -57 to -29) and -10% (IQR: -20 to -7). All evaluable tumors decreased in volume during RT. Between pre- and post-RT MRI, most patients had a decrease in intratumoral (16/20) and peritumoral edema (11/20). Sixteen patients exhibited extensive pathologic response. There were no significant associations between radiographic and pathologic features and volumetric change. Local failure at 3 years was 9% (95% confidence interval: 1–59). Conclusions We report significant decreases in MLPS tumor size during preoperative RT. There may be a role for adaptive RT planning to reduce target volumes and minimize RT-associated morbidity.

e14551 Background: Extracellular vesicles (EVs) are microscopic particles released by all cell types with a distinct fingerprint reflecting the cell of origin. In patients with prostate cancer, PSMA+EVs have been associated with clinical outcomes. In this study, we investigated tumor-derived EVs (tdEVs) using the tumor-specific CD326 marker as a novel biomarker for pancreas ductal adenocarcinoma (PDAC). Methods: The study included patients with localized PDAC treated on a prospective phase 2 clinical trial evaluating a 15-fraction chemoradiation (CRT) regimen. Blood samples were obtained after induction chemotherapy (C) (prior to CRT) and in follow-up. 20 healthy controls were included. High-resolution flow cytometry enumerated levels of fluorescent antibody labelled tumor-specific CD326 (EpCAM)-positive EVs. All samples were de-identified and randomly coded. The technologist responsible for EV analysis was blinded to patient information and clinical data. Each sample was run in triplicate. Flow cytometry data was analyzed with custom-built software to automatically determine and apply gates and generate reports with scatter plots and EV concentrations for each combination of markers and data summaries. Results: tdEV data were analyzed from 70 patients with pre-CRT samples. Patients had mean age 66 years (9.0 standard deviation), with 60% ECOG 0, 43% borderline resectable and 48% locally advanced. Patients had a median 8 cycles of C prior to CRT, and 70% proceeded to surgery after CRT. 2-year overall survival (OS) was 54%. Patient samples showed elevated total CD326 EVs compared to the healthy controls (p = 0.0005). Furthermore, patient CD326 EVs revealed two distinct subpopulations: small (120-1,000nm) and large (1,000-3,000nm) size CD326 EVs. No large CD326 subpopulation was found in healthy donor samples. Higher pre-CRT levels of total CD326 and large CD326 EVs were associated with decreased progression-free survival (PFS) (hazard ratio (HR) = 2.38, p = 0.013 and HR = 2.017, p = 0.021) on multivariable models with surgical resection. Resection was associated with increased PFS (p < 0.0001), and the interaction terms did not meet significance (p = 0.083 and p = 0.21). No differences in pre-CRT total or large CD326 EVs were identified between patients with or without surgical resection (p = 0.72 and p = 0.83). CA19-9 levels were not predictive of clinical outcomes in this trial and showed no association with EV levels. Conclusions: We present an association between clinical outcomes and tdEVs in PDAC, highlighting their potential as a novel, independent biomarker. If validated, tdEVs may offer an opportunity to personalize care and improve risk stratification.

ABSTRACT Pneumonia may be caused by a diverse group of microorganisms; however, a microbiologic diagnosis is not universally made. Molecular tests such as the BIOFIRE FILMARRAY Pneumonia Panel (BF-PP) offer the possibility of rapid identification of potential pneumonia pathogens. This retrospective analysis was conducted as a sub-study of a recently published randomized controlled trial. Specimens from patients with suspected pneumonia were tested by the BF-PP, with results compared to cultures. The overall BF-PP positivity rate was 44.8% (252/563), and was higher [64.6% (164/254)] in specimens from patients ultimately diagnosed with pneumonia. Discrepancies between the BF-PP and cultures were most common for Streptococcus pneumoniae , Haemophilus influenzae , Moraxella catarrhalis, and Streptococcus agalactiae . Positive percent agreement (PPA) and negative percent agreement (NPA) between the BF-PP and culture were 91.4% (CI 86.3%–94.9%) and 83.6% (CI 79.5%–87.2%), respectively. For most bacteria, a correlation between high genomic abundance (genomic copies/mL) reported from the BF-PP and culture growth abundance was found. In specimens from patients ultimately diagnosed with pneumonia, clinical consistency—assessed based on whether BF-PP results aligned with associated culture results—was 79.9% and was highest for bronchoalveolar lavage fluid specimens. The BF-PP has reliable analytical performance and offers the potential advantage over conventional cultures of providing higher detection rates and more rapid results. Interestingly, despite the use of this advanced molecular diagnostic tool, one-third of pneumonia cases remained without a microbiologic etiology. IMPORTANCE This study evaluates the BIOFIRE FILMARRAY Pneumonia Panel by comparing its performance to conventional cultures in a real-world patient population (including patients ultimately diagnosed as not having pneumonia) using different types of specimens. Findings show a higher detection rate of microorganisms with the panel compared to cultures, suggesting that this test could aid in tailoring treatments for pneumonia. However, challenges remain and require further study, including distinguishing true pathogens from colonizing microorganisms and determinig why one-third of patients diagnosed with pneumonia still lacked a microbiologic etiology.