The peri-operative period surrounding esophagectomy is challenging for patients to navigate. In this study, we describe the implementation of a digital health pathway to provide peri-operative education and track patient reported outcomes (PRO) after esophagectomy. This single-center study involved adults who underwent esophagectomy between 2021 and 2024. Educational emails, PRO surveys, and quality of life (QOL) questionnaires were delivered via a mobile health (mHealth) platform (CareSense; MedTrak Inc). Pathway data were combined with outcome data. Primary outcome was the rate of post-operative complications. Secondary outcomes included enrollment rate, PRO, and QOL scores. Fisher's exact test, Pearson Chi-square test, Kruskal-Wallis test, and logistic regressions were utilized for statistical analyses. Of 168 eligible patients, 136 (80.9%) enrolled in the pathway. There were no significant differences in demographic characteristics between patients who enrolled and those who did not. Enrollment was not associated with post-operative complication rate. Patients activated the pathway a median of 26 days (19-36) before their operation. They received a median of 23 emails (22, 30), 14 surveys, and 6 questionnaires; only 8 patients did not complete any of the daily surveys (5.9%). Median pre-operative anxiety score was 51 (43-56) after peri-operative education, indicating little to no anxiety. Median score change in global QOL at the 2-year time-point was +17 (0, 21). The majority of eligible patients enrolled in the pathway and patient satisfaction was high. There were no differences in post-operative complications based on enrollment. Enrolled patients had low pre-operative anxiety following peri-operative education and clinically significant QOL improvement at 2 years.

OBJECTIVE:The study objective was to develop a novel wearables-based sleep index that can quantify sleep disruption after lung resection and to apply machine learning analysis to these indices to identify patients exhibiting distinct postoperative sleep patterns. METHODS:This prospective observational cohort study analyzed patients undergoing lung resection who wore wearable devices preoperatively and at least 90 days postoperatively. To capture patient-level deviations in sleep-wake states postoperatively, we developed the Circadian Sleep Recovery Index. We used K-means clustering to identify patient groups exhibiting distinct sleep patterns based on principal component analysis-reduced Circadian Sleep Recovery Index features from postoperative days 2 to 7. Associations between these groups and long-term sleep quality and patient-reported quality of life were evaluated. RESULTS:Among 113 patients, the median Circadian Sleep Recovery Index decreased sharply on postoperative day 0 and remained lower during the first 2 postoperative weeks than observed preoperatively, indicating significant sleep disruptions. Unsupervised analysis of the Circadian Sleep Recovery Index revealed 2 groups: one that experienced minimal sleep disruptions ("Fast Sleep Recovery Group") and one that experienced significant sleep disruptions ("Slow Sleep Recovery Group"). Compared with the Fast Sleep Recovery Group, the Slow Sleep Recovery Group experienced greater reductions in quality of life at 30 days postoperatively and greater sleep disruptions during the 3 months after surgery. CONCLUSIONS:Machine learning analysis of a novel wearable-based sleep index identified patients experiencing significant early postoperative sleep disruptions; these sleep disruptions were associated with long-term sleep disruptions and greater reductions in quality of life.

Objectives: Treatment of esophageal adenocarcinoma has historically involved trimodality therapy. Recently, perioperative chemotherapy has become standard of care due to improved survival. We investigated the implications of this change on surgical and pathologic outcomes. Methods: This multicenter retrospective analysis included adults who underwent esophagogastrectomy for esophageal/gastroesophageal junction adenocarcinoma between 2023 and 2025. The primary outcome was any positive margin on final pathology. Secondary outcomes included rates of nodal upstage and posttreatment tumor characteristics. Fisher exact and Kruskal-Wallis tests were used for comparisons. Results: In total, 110 patients were included; 22 received perioperative chemotherapy (20.0%), 48 chemoradiation (chemoRT, 43.6%), and 40 induction chemotherapy followed by chemoRT (chemo + chemoRT, 36.3%). On final pathology, 36.4% of patients experienced nodal upstaging in the chemotherapy group (n = 8) relative to 16.7% (n = 8) and 7.5% (n = 3) in the chemoRT and chemo + chemoRT groups (P = .030). Similarly, more patients had tumors exhibiting poor treatment response (tumor regression grade 3) in the chemotherapy group (n = 7, 33.3%) compared with the other 2 groups (n = 2 [4.5%] and n = 4 [10.5%]; P = .007). More patients in the chemotherapy group had any positive final margin (n = 8, 36.4%), as compared with the chemoRT (n = 5, 10.4%) or chemo + chemoRT groups (n = 4, 10.0%; P = .017). Early data suggest greater rates of frozen-to-final esophageal margin discrepancies in the chemotherapy cohort (n = 2 [16.6%] vs n = 1 [2.8%] chemoRT vs n = 2 [6.6%] chemo + chemoRT; P = .232). Conclusions: In this small multi-institutional study, chemotherapy-only preoperative regimens seemed to be associated with increased rates of nodal upstage and margin positivity after esophagectomy relative to radiotherapy-inclusive protocols.

CD38, an ecto-enzyme involved in NAD+ catabolism, is highly expressed in exhausted CD8+ T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However, the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here, we show that CD38+CD8+ T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD+ pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support further preclinical and clinical evaluation of CD38-directed therapies in melanoma and underscore the importance of NAD+ as a vital metabolite to enhance those therapies.

Targeted CCR5 inhibition replicates CCL5 loss with reduced tumor cell proliferation in vitro and in vivo.

The rarity of thymic epithelial tumors and absence of targetable alterations present significant challenges for identifying improved systemic therapies. Recent advances in single-cell sequencing have enhanced our understanding of normal thymus development and the factors underlying malignant transformation. During medullary epithelial differentiation in adulthood, anti-apoptotic factors are expressed, potentially increasing resistance to cell death and thus facilitating tumorigenic processes. We hypothesized that this resistance to apoptotic cell death might be a hallmark of thymic epithelial tumorigenesis and could generate therapeutic vulnerabilities. To investigate this possibility, we measured apoptotic priming and dependencies on anti-apoptotic proteins in metastatic, surgically-resected thymic epithelial tumors. We utilize dynamic BH3 profiling, a functional assay that detects induction of apoptosis in response to titrated doses of pro-apoptotic signals in viable cancer cells freshly isolated from resection specimens. Our interim results show that advanced, WHO B-subtype thymomas are highly primed for apoptotic cell death, even in chemotherapy-resistant tumors, supporting the notion that thymomas may be more radiosensitive than chemosensitive. Furthermore, we find that thymomas consistently exhibit dependence on anti-apoptotic proteins, which may be targeted by recently-developed BH3 mimetics that inhibit these proteins. Apoptotic priming and dependencies are further enhanced by co-treated with clinically-relevant, targeted anti-cancer agents. To understand the basis for these findings, we evaluate the role of apoptotic priming during normal thymic epithelial development to determine how apoptotic resistance aligns with other molecular features of medullary epithelial biology, including the transcription of non-thymic tissue antigens and DNA damage response. These findings have significant therapeutic implications for further clinical investigation and deepen the foundational knowledge of molecular factors contributing to tumorigenesis, revealing new opportunities for preclinical modeling. Citation Format: Christopher Nabel, Yin P. Hung, Brian Do, Xingping Qin, Cameron Fraser, Yolonda Colson, Michael Lanuti, Uma Sachdeva, Cameron Wright, Kris Sarosiek. Assessment of apoptotic priming in thymic epithelial tumors to define hallmarks of pathogenesis and novel therapeutic strategies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B015.

With the publication of CALGB 140503, an increase in wedge resections for small, peripheral non-small cell lung cancer is expected; however, a relative paucity of data exists as to what defines a high quality oncologic wedge resection. The Thoracic Surgery Outcomes Research Network (ThORN), through expert discussion, guided by review of what limited data does exist, and through use of a modified Delphi process, provides these consensus statements defining an oncologically sound, high quality wedge resection. The statements are classified into five categories: 1) Preoperative Considerations 2) Technical Aspects 3) Lymph Node Assessment 4) Margin Assessment and 5) Tissue Handling by Pathology.

Confirmation of CCL5 knockout clones.

Introduction: Endobronchial optical coherence tomography (EB-OCT) imaging has unique potential to diagnose and quantify early, microscopic disease changes and assess therapeutic responsivity in interstitial lung disease (ILD). However, training and time requirements for interpretation and quantitative evaluation of large volumetric EB-OCT datasets need to be optimized to facilitate clinical adoption. We develop and validate a computationally-efficient, rapid EB-OCT quantitative image analysis framework using artificial intelligence (AI) with deep learning architecture for 2D feature segmentation, 3D feature burden and spatial distribution mapping, and computer-aided diagnosis in early ILD subjects. Methods: Volumetric EB-OCT datasets, consisting of 2D cross-sectional images, were acquired from multiple locations in the bilateral lungs of ILD and healthy control subjects. EB-OCT features were manually segmented from cross-sectional images by an expert EB-OCT reader, including fibrosis, microscopic honeycombing, traction bronchiolectasis, normal parenchyma, and emphysema. EB-OCT images with corresponding feature segmentations were used to train and validate a multiclass convolutional neural network. The 2D AI-based segmentation model was subsequently evaluated against manual ‘ground truth’ segmentations for each feature in a de novo ‘test’ dataset of independent subjects using dice similarity score, precision, recall/sensitivity, specificity, and balanced accuracy. To generate 3D AI-based quantitative feature burden and spatial distribution maps, AI-based feature segmentation was performed on each EB-OCT 2D cross-sectional image within a volumetric imaging site. Three external pathologist readers independently interpreted 3D AI-based features maps for each EB-OCT imaging site acquired for a subject (without access to EB-OCT images) and provided a single diagnosis of usual interstitial pneumonia (UIP) or non-UIP ILD. Performance of computer-aided ILD diagnosis was compared against independently evaluated histopathology, clinical diagnosis, and prior EB-OCT image interpretation. Results: EB-OCT was acquired in 51 subjects: 30 in vivo early ILD, 5 in vivo non-ILD controls, and 16 ex vivo end-stage ILD. Overall pixel similarity between 2D manual and AI-based segmentation demonstrated high accuracy for each ILD feature (mean balanced accuracy 0.9). 3D quantitative AI-based feature maps demonstrated strong agreement (Spearman ρ0.87, p<0.001) between manual and AI-based segmentation. AI-based computer-aided diagnosis demonstrated 100% sensitivity/specificity for histologic UIP and clinical IPF for all pathologist readers, with improved diagnostic accuracy and significantly reduced training (45-minute training, 75% reduction) and interpretation time (<1 minute per subject for computer-aided diagnosis, 88% reduction) compared to EB-OCT image interpretation. Conclusion: The AI-based EB-OCT image analysis framework could expedite computer-aided diagnosis of early ILD and robust, quantitative assessment of microscopic disease burden, progression, and therapeutic responsivity.

Loss of tumor-derived CCL5 reduces tumor cell proliferation in TE-1 cells.

e16065 Background: Gastrointestinal cancer remains a significant challenge due to limited effectiveness of current therapies. Clinical and molecular tumor features provide some prognostic and predictive value but apply to a limited number of patients. Novel approaches to predict therapeutic response in a timely manner may improve treatment selection and clinical outcomes. Methods: We performed drug screening with mass response testing (MRT) analysis on fresh gastrointestinal adenocarcinoma samples. Samples were shipped to Travera Inc. (Medford, MA) and underwent CLIA-certified MRT with results returned within 48 hours. Drug response profiles were generated by comparing the cell mass distributions of vehicle-treated replicates (baseline heterogeneity) and drug-treated cells (drug effect). A bootstrapping procedure produced a P-value which was mapped to a 0–100 mass response score (MRS). An MRS ≥ 50 indicated a statistically significant effect for a given drug. This study was an exploratory analysis and did not include formal statistical testing. Results: From February to September 2024, 13 samples containing viable tumor cells of adenocarcinoma histological subtype were collected. Three samples were excluded from MRT analysis —one sample did not have sufficient tumor cell purity and two samples demonstrated unsuitable mass change observed in replicate controls. Median age was 68 years (range 54-89), and 9 samples (69%) were from males. Biopsy locations included the esophagus (N = 3), gastroesophageal junction (N = 6), stomach (N = 3), and liver (N = 1). Six patients (46%) were locally advanced upon collection, with the remaining subjects (54%) presenting with advanced disease. The majority of biopsies (N = 12) were collected during a routine esophagogastroduodenoscopy (EGD) prior to start of therapy. Collections yielded a median of 313,000 cells (range: 0.49-38 x10^6 ). Tumor cell enrichment was confirmed via cytometric EpCAM readout with Coulter Counter measurements where indicated. Median purity was 38% (range 6-91%) and median viability was 96% (range 80-100%) at time of analysis. Clinical responders were defined as having exhibited a radiographic response on subsequent clinical imaging. Response status was utilized to assess concordance of clinical response with MRT-based predictions. MRT analysis guided second line treatment-selection for one patient with advanced gastric cancer and reported clinically actionable results in a second patient with advanced rectal cancer. Conclusions: Rapid zero-passage ex-vivo drug predictions from routine clinical samples in a cohort of gastrointestinal adenocarcinomas were feasible across both core needle biopsy and endoscopic samples. If validated in a larger cohort, mass response testing (MRT) may represent a complement to current clinical tools for response prediction and further study is warranted.

T cell exhaustion is a major driver of immune checkpoint blockade (ICB) resistance and clinically effective strategies to prevent or reverse T cell exhaustion to restore ICB sensitivity are lacking. CD38, an ecto-enzyme involved in NAD+ catabolism, is highly expressed in exhausted CD8+ T cells in human melanoma, yet its role in T cell exhaustion remains to be elucidated. Here we show that CD38+CD8+ T cells are enriched during tumor progression and following unsuccessful ICB treatment and are strongly associated with ICB resistance in melanoma. Chronic TCR activation and type I interferon stimulation upregulate CD38 in human T cells, leading to mitochondrial dysfunction and reduced anti-tumor activity. Disrupting CD38 restored cellular NAD+ pools and T cell bioenergetics, leading to improved T cell proliferation, enhanced effector function and elevation in T cells “stemness” markers that are associated with increased response to ICB in human melanoma. Importantly, targeting CD38 in a cohort of patient-derived organotypic tumor spheroid (PDOTS), human living tumor explants, with intact immune compartment, demonstrates that CD38-directed therapies can overcome ICB resistance in clinically resistant human melanoma, an effect that is furthered enhanced by supplementation with NAD+. These results emphasize the need for further preclinical and clinical evaluation of CD38 directed therapies in melanoma and underscore the importance of NAD+ as a vital metabolite to enhance those therapies. Citation Format: Or-Yam Revach, Angelina Cicerchia, Ofir Shorer, Boryana Petrova, Seth Anderson, Joshua Park, Chen Lee, Arnav Mehta, Samuel Wright, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Payal Tiwari, Hongyan Xie, Johanna Sweere, Li-Chun Cheng, Natalia Sigal, Elizabeth Enrico, Marisa Miljkovic, Shane Evans, Ngan Nguyen, Mark Whidden, Ramji Srinivasan, Matthew Spitzer, Yi Sun, Tatyana Sharova, Aleigha Lawless, William Michaud, Martin Rasmussen, Jacy Fang, Claire Palin, Feng Chen, Xinhui Wang, Cristina Ferrone, Donald Lawrence, Ryan Sullivan, David Liu, Uma Sachdeva, Debattama Sen, Keith Flaherty, Robert Manguso, Lloyd Bod, Manolis Kellis, Genevieve Boland, Keren Yizhak, Jiekun Yang, Naama Kanarek, Moshe Sade-Feldman, Nir Hacohen, Russell Jenkins. Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B034.

OBJECTIVE:To evaluate differences in patient-reported quality of life after lobectomy versus sublobar resection. METHODS:This was a retrospective analysis of patients enrolled in a prospective trial evaluating recovery after thoracic surgery using wearable devices and patient-reported outcome measures. Patients who underwent elective lobectomy or sublobar resection were included. Patients wore a wearable device preoperatively to postoperative day 90 and completed the 36-Item Short Form Survey (SF-36) preoperatively and on postoperative days 30 and 90. SF-36 total, Physical Component Summary (PCS), and Mental Component Summary (MCS) scores at each timepoint were compared between patients who underwent lobectomy and those who underwent sublobar resection in both the overall cohort and a propensity score-matched cohort. Changes in SF-36 scores from baseline to postoperative day 30 and day 90 were compared in the lobectomy and sublobar resection groups using multivariable-adjusted linear regression models. RESULTS:A total of 30 patients undergoing lobectomy and 55 undergoing sublobar resection were included. In both groups, overall quality of life was significantly lower at 30 days postoperatively compared to preoperatively but recovered to baseline levels by 90 days postoperatively. There were no significant differences in quality-of-life scores preoperatively and at 30 days and 90 days postoperatively between the 2 groups in unadjusted analysis or propensity score-matched analysis. There were also no statistically significant differences in changes in the SF-36, PCS, or MCS scores from baseline to postoperative day 30 and 90 between the 2 groups. CONCLUSIONS:In this retrospective analysis, patients undergoing lobectomy and those undergoing sublobar resection reported similar changes in quality of life after surgery.

Rationale: HRCT and PFT are major cornerstones in the current standard of care for chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis assessment. However, in the setting of combined pulmonary fibrosis and emphysema (CPFE), restrictive defects caused by pulmonary fibrosis and obstructive defects caused by COPD can negate one another, giving an inaccurate appearance of stable physiology on PFTs, despite both diseases progressing. Due to resolution limitations of HRCT, microscopic (< 2mm) emphysema can be difficult to visualize in COPD, as well as to distinguish from honeycomb cysts in CPFE. Endobronchial optical coherence tomography (EB-OCT) is a bronchoscope-compatible, high-resolution, volumetric imaging modality that can detect microscopic features of emphysema and pulmonary fibrosis. Here, we assess the ability of EB-OCT to detect microscopic emphysema in patients with pulmonary fibrosis as compared with HRCT. Methods: EB-OCT was performed in two cohorts with matched smoking history: 12 subjects with idiopathic pulmonary fibrosis (IPF) and 5 subjects with no known interstitial lung disease (ILD). EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct lung locations bilaterally, including the upper lobes. For each subject, the presence or absence of emphysema and severity was visually assessed by consensus amongst three experts in EB-OCT, one with additional expertise in pulmonary pathology. Emphysema presence and severity was also independently evaluated on corresponding HRCT and histopathology for each subject. Results: Average FEV1/FVC in the IPF and non-ILD cohorts was 0.80 and 0.69, respectively. Average smoking pack-year history in the IPF and non-ILD cohorts was 21.5 (range: 0-84) and 22.3 (range: 0-40), respectively. Emphysema was detected by EB-OCT in 11 IPF subjects (92%), which was confirmed in all cases on histopathology from concurrent surgical lung biopsy. EB-OCT also successfully distinguished emphysema from honeycomb cysts. On HRCT, only 2 IPF subjects had radiologically identifiable emphysema (16.6%). In the non-ILD cohort, EB-OCT detected emphysema in all 5 subjects (100%), which was confirmed on histopathology, while CT detected emphysema only in 4 non-ILD subjects (80%). Conclusion: EB-OCT detected microscopic emphysema with high accuracy, as compared with histopathology, both in the setting of IPF and in non-ILD subjects with similar smoking history. In conclusion, EB-OCT allows for accurate visualization of microscopic COPD features that are beyond the resolution capabilities of HRCT, even in the setting of pulmonary fibrosis. With further, larger-scale studies, EB-OCT may aid in diagnosis, monitoring and clinical decision-making regarding treatment of patients with combined pulmonary fibrosis and emphysema.

Mucormycosis is a fungal infection typically affecting persons with immunocompromise. Gastrointestinal infection of immunocompetent hosts is exceedingly rare. We report a case of gastroesophageal mucormycosis in an immunocompetent host that manifested as gastric necrosis within an incarcerated paraesophageal hernia. The patient was managed with resection, requiring subtotal gastrectomy and esophagectomy, and prompt antifungal treatment, resulting in full recovery.

ERK1/2 signaling pathway in CCL5 knockout cells.

452 Background: We performed a single-arm phase II study of neoadjuvant NALIRIFOX and chemoradiation (CRT) with concurrent carboplatin/taxol (C/T) followed by surgery in patients with locally advanced gastroesophageal (GE) cancer. Methods: Patients were enrolled on an NCI sponsored, prospective, single arm study (NCT04656041). Key eligibility criteria included: histologically confirmed T3/4 or lymph node (LN) positive GE junction or esophageal cancer, ECOG PS ≤1, age 18+, and life expectancy > 3 months. Exclusion criteria included: metastatic disease, prior chemotherapy or RT, or prior targeted therapy for diagnosis. Extensive LN disease beyond the surgical field (supraclavicular or para-aortic) was permitted if deemed feasible to be encompassed within a RT field. Laparoscopy was not required. Pts were treated with neoadjuvant NALIRIFOX x 4-8 cycles pending patient tolerance and physician discretion, restaging, CRT (50.4 Gy in 28 fractions) with concurrent C/T, restaging, followed by surgical resection. Dose reductions were at discretion of the treating physician. The primary study endpoint was the pathologic complete response rate following neoadjuvant treatment with NALIRIFOX and CRT with concurrent C/T. Major pathologic response (mPR) was defined as Tumor Regression Grade 0 and 1. Secondary endpoints included: 1) acute toxicity; 2) clinical response per RECIST criteria; 3) PFS and 4) OS. Results: From June 2021 to October 2023, 40 patients were enrolled. Median age was 64 (range: 47-82), and 31 patients were male (78%). All patients started NALIRIFOX, and the median number of NALIRIFOX received was 5 (range: 1-8). Reasons for discontinuation of NALIRIFOX were: physician discretion (n=29), subject withdrew from treatment (n=2), progressive disease (n=1), death (n=1). Rates of grade 3+ toxicity for overall, gastrointestinal, and hematologic attributed to NALIRIFOX were 55%, 35%, and 13% respectively. 35 patients started chemoRT (88%) and 33 patients completed chemoRT (83%). Rates of grade 3+ toxicity for overall, gastrointestinal, and hematologic attributed to chemoRT were 86%, 11%, and 9% respectively. Of 33 who completed chemoRT, two patients declined surgery (including 1 with clinical CR), and 31 (78%) patients went for surgical exploration. No patients were found with intraoperative metastases. Therefore, 31 (78%) patients underwent surgical resection. In total, 9 patients had pCR (29% in resected cohort, 23% in ITT cohort) and 15 had a major PR (48% in resected cohort, 38% in ITT cohort). In total, 10 (25% in ITT) patients had pCR or clinically CR at 1 year. Conclusions: Neoadjuvant NALIRIFOX followed by CRT is feasible with acceptable rates of treatment completion and grade 3+ toxicity. In our phase II trial, the rate of pCR is promising and further studies incorporating this regimen should be considered. Clinical trial information: NCT04656041 .