Introduction:Recruitment for rare disease studies is challenging due to small eligible populations. Traditional clinical research management systems often lack tools to track recruitment contacts prior to enrollment. The NET-PRO study, focused on neuroendocrine tumors (NETs), implemented a participation monitoring system to enhance recruitment efficiency and representativeness. Methods:NET-PRO is a multicenter cohort study of 2538 adults diagnosed with gastroenteropancreatic (GEP) or lung NETs between January 2018 and September 2024. Recruitment occurred from January 2022 to February 2025 across 14 U.S. medical centers. Sites used flexible recruitment methods (email, mail, phone, in-clinic) and tracked contacts using REDCap-based tools. Participant characteristics were analyzed by enrollment mode (online or mail) and recruitment difficulty (number of contacts required prior to enrollment) using standardized mean differences, chi-square tests, and ANOVA. Results:Of 9279 contacted patients, 2675 consented (28.8%) and 2538 enrolled (27.4%). Most enrolled online (83.2%), while 16.8% enrolled by mail. Mail respondents were older, had lower education and income, and more comorbidities. Among those enrolled, recruitment difficulty was associated with older age, lower education and income, but not comorbidity. Over half of the most difficult-to-recruit participants enrolled online. Contact methods varied by attempt, with email dominating early contacts and phone/mail used more in later attempts. Conclusions:A participation monitoring tool supported flexible, multimodal recruitment and improved sample representativeness in a rare cancer study. Tracking recruitment contacts enabled adaptive strategies and may reduce bias in observational research by enabling better outreach to harder-to-reach populations.

Abstract Background and Objectives The distinction between benign and neoplastic bile duct strictures remains challenging. Pathologic assessment of ERCP-obtained specimens has limited sensitivity, particularly among patients with primary sclerosing cholangitis (PSC). Next-generation sequencing (NGS) of bile duct specimens provides a promising diagnostic approach; but a prospective, multi-institutional, and comprehensive DNA/RNA analysis is lacking. Method A 6-year, prospective, multi-institutional study was conducted using BiliSeqV2 (28 cancer-associated genes and 167 fusion genes) and BiliSeqV3 (161 cancer-associated genes and 763 fusion genes) for 2908 ERCP-obtained brushings, biopsies, and bile from 2116 patients at 28 medical institutions across the United States. Molecular results were compared to clinical, imaging, and pathologic parameters including diagnostic pathology and/or at least 1-year follow-up. Results BiliSeqV2N3 testing was performed for 2865 (99%) specimens from 2080 (98%) patients. Based on follow-up from 1979 (95%) patients, BiliSeqV2N3 demonstrated 82% sensitivity and 98% specificity for a neoplastic stricture. In comparison, pathologic assessment had a sensitivity of 44% and a specificity of 99%. Combining BiliSeqV2N3 testing with pathologic assessment improved the sensitivity to 88% and maintained a high specificity of 97%. High-risk populations, such as Hispanic, germline carrier, and PSC patients, also showed improvement in sensitivity with BiliSeqV2N3 (74% to 86%) compared to pathologic assessment (26% to 50%). Further, actionable molecular alterations were identified in 20% of BiliSeqV3-positive neoplasms and modified patient management in 30% of these cases. Conclusions Applying BiliSeqV2N3 testing to ERCP-obtained specimens improved the diagnostic evaluation of bile duct strictures, achieving higher sensitivity, especially for PSC, and maintained high specificity compared to traditional methods. This study highlights the importance of NGS for precise diagnosis and therapeutic intervention.

Background Colorectal liver metastases are common, and the degree of liver tumor often determines overall prognosis. Advances in systemic therapy, surgical technique, locoregional therapies, and transplant oncology have expanded the curative-intent treatment options for patients with upfront unresectable colorectal liver metastases (uCRLM). Study Design This narrative review synthesizes the contemporary evidence regarding the management of unresectable or borderline resectable CRLM, with a focus on microsatellite-stable disease. Results The modern management of uCRLM requires integration of systemic therapy with liver-directed strategies, including ablation, transarterial therapies, hepatic artery infusion chemotherapy, staged hepatectomy techniques, and liver transplantation. Patient selection increasingly emphasizes tumor biology, response to therapy, and adequacy of future liver remnant rather than strict anatomic criteria. Emerging strategies such as combined portal and hepatic vein embolization, multimodal cytoreduction, and transplant-based approaches have further expanded treatment options. Conclusions The management of unresectable CRLM has evolved into a dynamic, multidisciplinary field. This review provides a practical, evidence-informed framework to guide treatment sequencing and patient selection, emphasizing the importance of multidisciplinary evaluation and early referral to experienced centers.

BACKGROUND & AIMS:The distinction between benign and neoplastic bile duct strictures remains challenging. Pathologic assessment of endoscopic retrograde cholangiopancreatography (ERCP)-obtained specimens has limited sensitivity, particularly among patients with primary sclerosing cholangitis (PSC). Next-generation sequencing of bile duct specimens provides a promising diagnostic approach, but a prospective, multi-institutional, and comprehensive DNA/RNA analysis is lacking. METHODS:A 6-year, prospective, multi-institutional study was conducted using BiliSeq version 2 (28 cancer-associated genes and 167 fusion genes) and BiliSeq version 3 (161 cancer-associated genes and 763 fusion genes) for 2908 ERCP-obtained brushings, biopsies, and bile from 2116 patients at 28 medical institutions. Molecular results were compared with clinical, imaging, and pathologic parameters including diagnostic pathology and/or at least 1-year follow-up. RESULTS:BiliSeqV2/V3 testing was performed for 2865 (99%) specimens from 2080 (98%) patients. Based on follow-up from 1979 (95%) patients, BiliSeq version 2/version 3 demonstrated 82% sensitivity and 98% specificity for a neoplastic stricture. In comparison, pathologic assessment had a sensitivity of 44% and a specificity of 99%. Combining BiliSeq version 2/version 3 testing with pathologic assessment improved the sensitivity to 88% and maintained a high specificity of 97%. High-risk populations, such as Hispanic, germline carrier, and PSC patients, also showed improvement in sensitivity with BiliSeq version 2/version 3 (74% to 86%) compared with pathologic assessment (26% to 50%). Further, actionable molecular alterations were identified in 20% of BiliSeq version 3-positive neoplasms and modified patient management in 30% of these cases. CONCLUSIONS:Applying BiliSeq version 2/version V3 testing to ERCP-obtained specimens improved the diagnostic evaluation of bile duct strictures, achieving higher sensitivity, especially for PSC, and maintained high specificity compared with traditional methods. This study highlights the importance of next-generation sequencing for precise diagnosis and therapeutic intervention.

Tumor-derived exosomes contribute to the formation of a hepatic pre-metastatic niche (PMN) by activating Kupffer cells (KCs) and hepatic stellate cells (HSCs), thereby promoting metastatic seeding. Whether exercise modulates exosome-driven PMN formation and subsequent liver metastasis remains unclear. Eight-week-old male mice were randomized to sedentary (SED) and exercise training (ExT) groups. Mice were pre-educated with cancer-derived exosomes to induce a hepatic PMN and subsequently subjected to experimental liver metastasis model. Kupffer cells were isolated for transcriptomic and mechanistic analyses. Pharmacologic inhibition of TREM-1 signaling was performed to assess pathway-specific effects. Exercise training significantly attenuated hepatic PMN formation and reduced metastatic burden in exosome-educated mice. Exosome uptake by KCs was comparable between SED and ExT groups; however, ExT reduced KC inflammatory activation. Transcriptomic analysis identified downregulation of the TREM-1 signaling pathway in ExT KCs. Reduced TREM-1 activity was associated with diminished NF-κB activation in HSCs, decreased fibronectin deposition, and increased HSC apoptosis. Pharmacologic TREM-1 inhibition recapitulated key anti-metastatic effects observed with exercise. Exercise training attenuates tumor exosome–induced hepatic pre-metastatic niche formation through modulation of Kupffer cell inflammatory signaling, in part via suppression of TREM-1. Targeting TREM-1 signaling significantly reduces experimental liver metastasis and may represent a therapeutic approach that partially recapitulates the anti-metastatic effects of exercise. These findings support further investigation into exercise and innate immune modulation as strategies to influence early metastatic niche biology.

Hepatic ischemia-reperfusion (I/R) injury triggers release of small extracellular vesicles (sEVs) that can function as systemic conveyors of inflammatory signals. While sEV-mediated immune cell modulation has been studied extensively in vitro, knowledge is based largely on sEVs derived from cultured cells, rather than injured tissues. Consequently, the immunological impact of liver I/R-sEVs is poorly understood. Here, we combined in vitro and in vivo approaches with sEVs purified from mouse livers subjected to I/R to define their influence on dendritic cells (DCs). In vitro, in contrast to sham-sEVs, I/R-sEVs activated syngeneic bone marrow-derived DCs (BMDCs), inducing upregulation of costimulatory molecules and enhancing their capacity to stimulate naive allogeneic T-cells. In contrast, liver DCs (LDCs) were refractory to liver I/R-sEV-mediated activation. This differential responsiveness may in part reflect greater I/R-sEV internalization by BMDCs. To assess in vivo relevance, labeled sham or I/R-sEVs were administered intravenously. Following systemic delivery, syngeneic I/R-sEVs, but not sham-sEVs, accumulated in liver and spleen of otherwise naive mice exhibiting different patterns of uptake by immune cell populations. In the spleen, macrophages and B-cells were the principal I/R-sEV-acquiring populations, whereas in the liver, sEV uptake was dominated by macrophages and neutrophils. Additionally, while splenic DCs showed increased expression of activation markers and T-cell stimulatory activity following exposure to I/R-sEVs, LDCs were unresponsive. These findings identify liver-I/R-sEVs as promotors of extra-hepatic DC maturation/activation, whereas liver-resident DCs were refractory to I/R-sEV stimulation. The findings have implications for regulation of inflammatory responses following liver I/R injury.

e16238 Background: As liver transplantation (LT) indications expand, it is increasingly explored for select patients with hepatic malignancies far beyond conventional LT criteria. These far-advanced tumors are characterized by very large or innumerable lesions, extreme tumor marker elevation, and previously treated extrahepatic metastatic disease. We evaluated oncologic and survival outcomes following LT across five malignancy types. Methods: We retrospectively reviewed patients undergoing LT from 2015–2025 for far-advanced hepatocellular carcinoma (HCC), hilar cholangiocarcinoma (hCCA), intrahepatic cholangiocarcinoma (iCCA), nonresectable colorectal liver metastases (nCRLM), and metastatic neuroendocrine tumors (NET). Far-advanced disease was defined by excessive tumor size or burden, extreme tumor marker elevation, and/or treated extrahepatic metastases prior to LT. Tumor characteristics and survival outcomes/Kaplan–Meier estimation were analyzed. Results: Fifty-six patients underwent LT, 93% via living donors. All malignancy groups demonstrated extensive tumor burden with high rates of multifocal or innumerable hepatic disease and biomarker elevation. Treated extrahepatic metastases were present in 55% of HCC and 29% of nCRLM recipients. Median overall survival was 2.7 years for HCC, 1.9 years for hCCA, 2.6 years for iCCA, 2.4 years for nCRLM, and 6.8 years for NET. Recurrence ranged from 18–64%, and mortality from 9–50%, with NET demonstrating the most favorable outcomes. Conclusions: In carefully selected patients with hepatic malignancies far exceeding traditional LT criteria, LT, predominantly via living donor pathways, may achieve meaningful survival despite high-risk tumor features. These findings support the feasibility of LT within an expanding transplant oncology paradigm and emphasize selection strategies guided by tumor biology rather than conventional criteria alone. HCC N=11 hCCA N=14 iCCA N=11 nCRLM N=14 NET N=6 Age at Transplant, years (median) 31 46 59 53 58 Sex (n, %Male) 4 (36%) 10 (71%) 7 (64%) 11 (79%) 6 (100%) Living Donor Liver Transplant (n, %) 11 (100%) 13 (93%) 11 (100%) 14 (100%) 3 (50%) Number of hepatic lesions (n, %) 1-3 4-7 8-10 Innumerable 3 (27%)5 (45%)2 (18%)1 (9%) 14 (100%) 9 (82%)1 (9%)1 (9%) 5 (36%)3 (21%)2 (14%)4 (29%) 1 (16%)5 (83%) Max Tumor Diameter (mean, cm) 10 3.6 7.0 6.6 4.8 Extrahepatic Metastatic disease (n, %) 6 (55%) 0 0 4 (29%) 0 Pre-LT Oncologic Treatments (n, %) Liver Resection 7 (63%) 3 (23%) 0 5 (36%) 2 (33%) Local-Regional Therapy 11 (100%) 0 6 (55%) 0 0 Hepatic Artery Infusion Pump -- -- -- 7 (50%) -- Systemic Chemotherapy 9 (82%) 14 (100%) 8 (73%) 14 (100%) 5 (83%) Radiation Therapy 2 (18%) 11 (79%) 0 2 (14%) 0 Immunotherapy 7 (64%) 0 2 (18%) 0 0 Recurrence Post Transplant (n, %) 7 (64%) 5 (36%) 2 (18%) 7 (50%) 3 (50%) Deaths Post Transplant (n, %) 3 (27%) 4 (29%) 1 (9%) 4 (29%) 3 (50%) Overall Survival (median, years) 2.7 1.9 2.6 2.4 6.8

Osteosarcoma is the most common primary pediatric bone malignancy. One promising new target is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase that targets p27 for proteasomal degradation, driving cellular proliferation. Knockout (KO) of Skp2 in an immunocompetent transgenic mouse model of osteosarcoma improved survival, drove apoptosis, and induced antitumor immunity. In this study, we applied single-cell RNA-sequencing (scRNA-seq) to primary osteosarcoma tumors from Osx-Cre conditional Rb1/Trp53 KO mice. We further compared with models of Skp2 disruption: Skp2 KO or disruption of the Skp2-p27 interaction (resulting in p27 overexpression). We report that murine osteosarcoma models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. Skp2 disruption led to reduction of T-cell exhaustion and upregulation of interferon (IFN) signaling, as well as induction of cell type-specific replicative and endoplasmic reticulum stress, which we validated with proteomics analysis. Furthermore, we showed that IFN induction was correlated with improved survival in patients with osteosarcoma. Additionally, our scRNA-seq analysis uncovered decreased expression of metastasis-related gene signatures in Skp2-disrupted osteosarcoma, which we validated by a strong reduction in lung metastasis in the Skp2 KO mice. Finally, we report several mechanisms potentially used by osteosarcoma to escape from Skp2 targeting, including upregulation of Myc targets, induction of genomic instability, overexpression of alternative E3 ligases, and lineage plasticity. These mechanistic insights into osteosarcoma tumor biology and Skp2 function suggest novel targets for new, synergistic therapies, whereas the data and our comprehensive analysis may serve as a public resource for further big data-driven osteosarcoma research. SIGNIFICANCE:Our single-cell study of murine osteosarcoma models uncovers Skp2 function in metastasis, genomic instability, and immune activation and reveals additional target pathways to overcome resistance to Skp2 disruptions.

Background: Pivotal first-line immune checkpoint inhibitor (ICI) trials in advanced hepatocellular carcinoma (HCC) largely restricted enrollment to patients with Child-Pugh A liver function, leaving outcomes in patients with more advanced hepatic dysfunction poorly defined. We evaluated survival, tumor response, and early mortality across Child-Pugh A, B, and C classes in a real-world integrated health-system cohort. Methods: We identified 264 consecutive patients with HCC who received first-line ICI-based systemic therapy at the University of Pittsburgh Medical Center between September 2015 and November 2024, with follow-up through December 2025. Child-Pugh class was re-adjudicated at ICI initiation. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, objective response rate, disease control rate, and 90-day mortality. Results: The cohort included 113 patients with Child-Pugh A, 124 with Child-Pugh B, and 27 with Child-Pugh C liver function. Median overall survival was 25.0 months, 13.3 months, and 4.2 months, respectively. Ninety-day mortality was 5.4%, 16.3%, and 40.7%, while objective response rate was 25.5%, 17.0%, and 5.6%. In multivariable Cox regression, Child-Pugh B and C remained independently associated with mortality compared with Child-Pugh A. Among patients who survived at least 90 days, disease control in Child-Pugh C was 38.5%, approaching that observed in Child-Pugh A. Conclusions: In this real-world HCC cohort, worsening Child-Pugh class was associated with progressively shorter survival and higher early mortality after first-line ICI therapy. Although outcomes in Child-Pugh C were poor overall, a subset of patients experienced durable survival or disease control. These findings support careful individualized treatment consideration rather than automatic exclusion of selected Child-Pugh C patients from ICI-based therapy.

Abstract Introduction: Surgical intervention is crucial in managing cancer patients, yet it can increase tumor recurrence risk due to pro-tumorigenic innate immunity. We hypothesized that surgical stress can induce prolonged rewiring of bone marrow cells that can differentiate into a pro-tumorigenic phenotype upon stimulation. Methods: Wild type C57BL/6J mice were subject to surgical stress including laparotomy, liver ischemia reperfusion and hepatectomy. Sham surgery includes anesthesia without further manipulation. MC38 (murine colorectal cancer cells) were subcutaneously inoculated 1- or 3-weeks post-surgery. Neutrophil depletion is done by anti-Ly6G monoclonal antibodies administration. Results: Wild type mice subjected to different surgical stress showed significantly increased tumor volumes when tumor was inoculated subcutaneously 1- or 3-weeks post-surgery. However, neutrophil-depleted mice subjected to surgical stress showed no significant increase of cancer growth compared to wild type mice. These findings are correlated with transcriptomic analysis on tumor-associated neutrophils which exhibited enhanced production of pro-inflammatory factors that promote tumor growth. Circulating neutrophils after surgical stress also showed similar pro-inflammatory markers persistently upregulated after surgery in the absence of cancer. Furthermore, mice showed increased tumor volume when received bone marrow cells from surgery-preconditioned mice compared to sham mice. Analysis on bone marrow progenitor cells specifically showed enhanced proliferation of granulocyte-monocyte progenitors (GMPs) after surgery compared to sham mice. Additionally, proliferation of GMPs is enhanced in surgery-preconditioned mice compared to sham mice in response to cancer inoculation. Single-cell analysis of bone marrow progenitor cells revealed persistent transcriptomic changes post-surgery, while transcriptional factor enrichment revealed CCAAT/enhancer binding proteins (C/EBP) to be potential drivers of these persistent changes. Analysis of post-surgical plasma revealed acute increase of IL-1β and HMGB1 post-surgery. In vitro short-term (3 days) treatment of bone marrow progenitor cells with IL-1β or HMGB1 resulted in enhanced proliferation of GMPs and persistent upregulation of pro-tumorigenic gene markers in induced neutrophils. Conclusions: Surgery-induced IL-1β and HMGB1 can induce persistent changes in bone marrow progenitor cells that can produce pro-tumorigenic neutrophils in response to cancer cells. IL-1β and HMGB1 can serve as targets to improve cancer patient prognosis after surgical resection. Citation Format: Zhengyi He, Hamza O. Yazdani, Tony Haykal, Ruiqi Yang, Celine Tohme, Rihito Kanamaru, Krish Wasson, Anthony Gebran, Silvia Liu, David A. Geller, Jian-Hua Luo, Samer Tohme, . Surgery-induced long term innate immune changes facilitate tumor progression [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 1586.

We compared demographic and clinical characteristics of patients with gastroenteropancreatic (GEP) and lung neuroendocrine tumors (NETs) enrolled in the NET-PRO study to those in the U.S. Surveillance Epidemiology and End Results (SEER) program to evaluate the comparability of NET-PRO as a resource for real-world evidence generation and patient reported outcomes (PROs). NET-PRO enrolled adults with GEP or lung NETs from 14 health systems between 2018 and 2024. SEER data included patients diagnosed with NETs from 2018 to 2021 across 22 U.S. cancer registries. We compared age, sex, race/ethnicity, tumor site, stage, and surgery between cohorts using standardized mean differences (SMDs), with values ≥ 0.2 interpreted as meaningful. We analyzed 1,974 GEP-NET and 394 lung NET patients in NET-PRO versus 38,942 and 11,265, respectively, in SEER. Most demographic and clinical characteristics were broadly similar between cohorts, with trivial differences by sex (SMDs 0.16–0.22) and moderate differences in mean age (SMD = 0.47 for lung NETs). Race/ethnicity differences were larger, with Non-Hispanic White patients overrepresented in NET-PRO (SMDs 0.53–0.84). Tumor site and stage distributions differed modestly. Surgery rates were comparable for GEP-NETs but higher among NET-PRO lung NET patients (SMD = 0.47). NET-PRO demonstrates broadly comparable demographic characteristics to SEER across factors such as age and sex. While race/ethnicity differences highlight areas for improved inclusion, other areas of variation suggest important future research covariates. These findings support the contextual comparability of NET-PRO with the broader NET population and its value as a resource for real-world evidence generation. NCT05064150 (Start Date: 2022-05-10).

BACKGROUND:Liver transplantation stands as the primary treatment for end-stage liver disease, with demand surging in recent decades because of expanded indications. However, hepatic ischemia/reperfusion injury can lead to liver transplant failure in both deceased donor and living donor transplantation. This study explored whether preconditioning donor livers through exercise training (ExT) could mitigate cold ischemic injury posttransplantation. METHODS:Donor C57BL/6 mice underwent ExT via treadmill running or remained sedentary. After 4 wk, the donor liver underwent cold storage and subsequent orthotopic liver transplantation or ex vivo warm reperfusion. RESULTS:Donor liver from mice subjected to ExT showed significantly decreased hepatic injury on reperfusion. Tissue histology revealed decreased sinusoidal congestion, vacuolization, and hepatocellular necrosis in livers from ExT mice, and immunofluorescence staining further revealed a decreased number of apoptotic cells in ExT grafts. Livers from ExT donors expressed decreased intragraft inflammatory cytokines cascade, decreased neutrophil infiltration and neutrophil extracellular traps, and increased M2 phenotype of recipient macrophages compared with grafts from sedentary mice. After cold storage, liver grafts from ExT donors showed decreased accumulation of reactive oxygen species and decreased levels of cytochrome c and high mobility group box 1 released in the liver effluent. In addition, ExT grafts showed upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and higher levels of mitochondrial content. Similar effects of decreased hepatic injury were observed in wild-type mice when pretreated with a PGC-1α stimulator ZLN005 instead of ExT. CONCLUSIONS:These findings suggest that augmenting hepatocytic mitochondrial content through donor exercise or PGC-1α stimulation may offer therapeutic avenues to mitigate postreperfusion inflammation and improve transplant outcomes.

KD of iNOS regulated gene expressions of selected EMT markers

Expression of iNOS and EMT markers in different cancers

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Due to the advanced stage in which HCC presents, most patients are only eligible for transarterial chemoembolization (TACE) or radioembolization (Y90). The purpose of this study is to examine the differences in survival and health-related quality of life (HRQOL) in patients diagnosed with HCC and treated with TACE or Y90. Two hundred thirty-four patients with HCC were enrolled in studies examining HRQOL between 2003–2009. HRQOL was evaluated using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep). Between-group differences were examined using chi-square and ANOVA. Survival was assessed using Kaplan–Meier and Cox regression analyses. Significant baseline differences between patients treated with TACE versus Y90 were found. Patients who received Y90 tended to be older (p < 0.001), female (p < 0.001), had fewer lesions (p = 0.03), had smaller tumors (p = 0.03), and were less likely to have vascular invasion (p = 0.04). After adjusting for demographic and disease-specific factors, no significant differences in HRQOL were observed at 3 months (p = 0.79) or 6 months (p = 0.75). Clinically meaningful differences were found, with the TACE group reporting greater physical, social, and emotional well-being at 3 and 6 months and greater overall HRQOL at 6 months. No significant differences in survival were found. Treatment with TACE and Y90 was similar with regard to survival. However, TACE showed statistically and clinically meaningful benefits in physical, social/family, and emotional well-being. Further research is warranted to identify profiles of patients who may demonstrate a preferential response to either TACE or Y90. Hepatocellular carcinoma (HCC) is the fifth most common type of cancer worldwide. For most patients with HCC, two procedures known as transarterial chemoembolization (TACE) and radioembolization (Y90), represent their most promising treatment options. The purpose of this study is to examine the differences in survival and health-related quality of life (HRQOL) in patients diagnosed with HCC and treated with TACE or Y90. In this sample, patients treated with TACE reported better HRQOL in the domains of physical, social, and emotional well-being at 3- and 6 months post-treatment and greater overall HRQOL at 6 months. There were no significant differences in patient survival based on the type of treatment they received. More research is needed to identify what treatment factors and patient characteristics might be associated with better HRQOL after being treated with TACE or Y90.

e16234 Background: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are common medications used for managing hypertension and cardiovascular conditions. There is growing evidence that these medications may also modulate tumor microenvironment (TME), including in immune cell infiltration, angiogenesis, and fibrosis in certain lung, GI, and GU cancers. However, this has not been examined in hepatocellular carcinoma (HCC), where the renin-angiotensin system has been implicated in promoting tumor growth and immune evasion, offering a potential strategy to improve immunotherapy outcomes in advanced HCC. Methods: Patients with unresectable HCC who were treated with immune checkpoint inhibitors at UPMC Hillman Cancer Center between 2015-2024 were included in this retrospective analysis. Concurrent ACEi/ARB use was defined as any ongoing therapy while on immunotherapy regimen. Multivariate Cox proportional hazard model was used to evaluate progression free survival (PFS) and overall survival (OS). Results: A total of 293 patients were included in this analysis. Most common immunotherapy regimens used included atezolizumab/bevacizumab (n = 140, 48%), nivolumab (n = 75, 26%), and durvalumab/tremelimumab (n = 57, 19%). 64 (22%) were stage I/II at time of immunotherapy initiation, 121 (41%) were stage III, and 108 (37%) were stage IV. 141 patients (49%) had viral-associated HCC, 72 (25%) had alcohol-associated HCC, and 64 (26%) had no HCV/HBV exposure or significant alcohol use. 129 patients (44%) had concurrent ACEi/ARB use. Multivariate analysis adjusting for cancer stage and etiology showed concurrent ACEi/ARB use was associated with improved PFS (HR = 0.76, 95% CI 0.59-0.99, p = 0.039). No significant difference was seen in OS (HR = 0.81, 95% CI 0.59-1.1, p = 0.175). Subgroup analysis by etiology showed concurrent ACEi/ARB use was only associated with significantly improved PFS for patients with alcohol-associated HCC (HR 0.49, 95% CI 0.28-0.86, p = 0.014). Differences in PFS was not observed in viral-associated group (HR 0.79, 95% CI 0.54-1.1, p = 0.207) or non-viral/non-alcohol group (HR 1.0, 95% CI 0.57-1.6, p = 0.811). Conclusions: Our data suggests that patients with advanced HCC treated with immune checkpoint inhibitor therapy had improved PFS with concurrent use of ACEi/ARB medications within alcohol-associated HCC population specifically, potentially due to the differing tumor microenvironment of alcohol-associated HCC. Given the frequency of ACEi/ARB use, it will be important to validate this result in larger disease cohorts and/or prospective disease specific trials.