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INTRODUCTION: Liver disease is a significant public health problem in the United States, with notable racial disparities in mortality. This study examines liver disease mortality trends among Black and White populations during 1999–2020. METHODS: We used CDC WONDER database to ascertain liver disease age-standardized mortality rates in Black and White Americans. Annual percent change was calculated. Age-standardized absolute rate difference and rate ratios were computed by subtracting and dividing the White population's rate from that of the Black population. RESULTS: Liver diseases accounted for 171,627 Black and 1,314,903 White deaths during 1999–2020. Age-standardized mortality rates for Blacks decreased from 22.5 to 20.1 per 100,000 person-years (annual percentage change −0.4%, −0.6% to −0.2%), whereas an increase was observed for Whites, from 17.9 to 25.3 per 100,000 person-years (annual percentage change 1.4%, 1.4% to 1.7%). The rate ratio decreased from 1.26 (1.22–1.29) in 1999 to 0.79 (0.78–0.81) in 2020. This pattern was evident in all census regions, more pronounced among the younger (age 25–64 years) than older (age 65+ years) population and observed across different urbanization levels. The pattern may be attributable to increasing alcohol-related liver disease and metabolic dysfunction–associated steatotic liver disease–related deaths in Whites and tapering in viral hepatitis and primary liver cancer–related deaths in Blacks. Despite notable improvement, racial disparities persist in primary liver cancer and viral hepatitis among the Black population. DISCUSSION: The rise in alcohol-related liver disease and metabolic dysfunction–associated steatotic liver disease–related deaths among Whites, and enduring liver cancer and viral hepatitis disparities in the Black population, underscores the urgent need for tailored public health interventions.

Background: Graft-versus-host disease (GVHD) is a common complication of hematopoietic cell transplantation, and its incidence is low in liver transplantation (LT). Estimating the incidence of GVHD after LT is challenging due to the paucity of available data from the United Network for Organ Sharing. This is the first national analysis of the incidence and risk factors of GVHD after LT. Methods: This retrospective cohort study used the National Readmission Database to calculate the incidence rate of GVHD within 1 year of LT using survival analysis. The predictors of GVHD were identified using univariate and multivariate Cox regression analyses. Results: From 2010 to 2020, of 88,433 LTs, 383 cases of GVHD occurred within 1 year after LT, resulting in an incidence rate of 1.0% (95% CI: 0.8%–1.3%). We observed no statistically significant change in the incidence of GVHD after LT from 2010 to 2020 (beta-coefficient, −0.07%; 95% CI: −0.17% to 0.04%, p = 0.188). Interestingly, alcohol-associated liver disease was associated with a lower risk of GVHD (adjusted HR, 0.57; 95% CI: 0.36–0.91, p = 0.018), whereas a higher risk was found to be related to a secondary diagnosis of COVID-19 on index admission. Conclusion: Our study found that the incidence rate of GVHD within 1 year of LT in the United States was 1.0% and remained stable from 2010 to 2020. The predictors associated with GVHD include alcohol-associated liver disease and COVID-19. Our study provides valuable insights into the incidence, risk factors, and outcomes of GVHD after LT.

5094 Background: In prior studies, basal vs. luminal differentiation portends differential response to a) androgen suppression (AS) duration for high-risk prostate cancer (PCa) (NRG-GU-TS006) and b) docetaxel chemotherapy (CT) and AS for metastatic hormone-sensitive disease (CHAARTED). In NRG-GU-TS006, basal tumors appeared to benefit the most from longer duration of AS while those with luminal subtype did not whereas, in CHAARTED, luminal subtype had greater benefit from addition of CT. Herein, we examined basal-luminal subtyping to predict differential response to the addition of CT in the setting of high-risk PCa treated with AS and definitive radiotherapy (AS + RT) in NRG/RTOG 0521. Methods: Per pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available NRG biobank biopsy specimens from patients enrolled on the NRG/RTOG 0521 phase III trial, which randomized patients to AS + RT +/- CT. The highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA). Basal-luminal subtypes were generated using a 215-gene PCa subtyping classifier (PSC), a second generation PAM50 basal-luminal model. Treatment effects in Luminal Proliferating (LP) and non-LP subtypes were examined with Cox (for overall survival, OS, and metastasis-free survival, MFS) and Fine & Gray (for distant metastasis, DM) multivariable (MVA) models adjusted for age and trial risk stratification, as well as with restricted mean survival times (RMST). Results: Of 183 samples available for analysis (91 from control and 92 from the CT arm), 52 (28%) were classified as LP subtype. Median follow-up for OS was 9.9 years. No significant differences in clinical or pathological variables were observed between LP and non-LP subtypes. In MVA, we did not detect any significant LP subtype-by-CT treatment interaction but observed evidence of non-proportional hazards (Grambsch-Therneau test, p<0.05). In unselected patients, 5- and 10-year RMST difference between the arms was 0.9 (95% CI [-1.5, 3.4], p=0.46) and 5.7 (95% CI [-2.5, 13.9], p=0.17) months of OS. Stratifying by tumor subtype, at 5 years the RMST difference in months was 3.8 (95% CI [0.3, 7.2], p=0.03) for LP and -0.2 ([-3.4, 2.9], p=0.89) for non-LP. The RMST difference in months at 10-years was 13.7 (95% CI [-0.2, 27.5], p=0.053) for LP and 2.5 ([-7.6, 12.5], p=0.63) for non-LP. Conclusions: In pre-treatment biopsy samples from a Phase 3 trial cohort of localized high-risk men, luminal-basal subtyping of tumors demonstrated differential response to docetaxel CT. Similar to results from the CHAARTED trial of metastatic disease, LP tumors may derive greater benefit from addition of CT. Validation of these findings may enable effective earlier use of CT in men with PCa.

ABSTRACT Achalasia in a patient with liver cirrhosis decompensated by esophageal varices is an extremely rare presentation with complex management implications. We describe a case of achalasia and malnutrition in a male patient with esophageal varices treated by endoscopic ultrasound–guided botulinum toxin injection. After treatment, the patient's dysphagia dramatically improved, and his weight loss stabilized, which allowed an important window to remove the barrier of nutritional status for transplant candidacy. Endoscopic ultrasound–guided botulinum toxin injection to avoid varices is potentially a safer method for delivering botulinum toxin injection to the lower esophageal sphincter in a patient with esophageal varices.

AbstractBackgroundProstate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression‐based subtyping model based on prostate‐specific biological processes was sought.MethodsUnsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts.ResultsClustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01–0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09–0.51).ConclusionsWith the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features.Plain language summary Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors—the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.

241 Background: We previously reported on the use of gene expression profiling to characterize four primary subtypes in an analysis of over 100,000 prostate cancer primary tumors. Here we examine these subtypes and response to radiation (RT) after prostatectomy or chemotherapy in addition to androgen deprivation therapy (ADT) in hormone-sensitive metastatic prostate cancer (mHSPC). Methods: We examined a 215-gene prostate subtyping classifier (PSC) which groups luminal and basal gene expression profiles into one of four subtypes; luminal differentiated (LD), luminal proliferating (LP), basal immune (BI) and basal neuroendocrine-like (BN). The log-rank method was used to compare (i) metastasis-free survival between patients who did and did not receive salvage RT in the META855 cohort of localized disease patients treated with radical prostatectomy (n=855) and the (ii) overall survival of patients on the Phase III mHSPC EA3805 CHAARTED trial of ADT or ADT + docetaxel chemotherapy (n=160). Results: After radical prostatectomy, patients with BI tumors derived benefit from RT in terms of metastasis-free survival ( P=9.23e-4) while those with other subtype tumors did not (Each Log-rank P≥0.5). Patients with metastatic disease and LP tumors derived benefit from docetaxel (Log-rank P=0.002) while those with other subtypes tumors did not (Log-rank P=0.2). Conclusions: Basal-luminal subtyping segments tumors by relevant biological processes with potential implications for identifying patients who benefit from salvage radiation post prostatectomy and addition of docetaxel to ADT in mHSPC.

Objectives: The development and evaluation of percutaneous thrombectomy devices for pulmonary embolism (PE) pose a need for standardized large in vivo models with representative anatomical and physiological conditions and clots analogs. In this study, we present a swine model of PE model employing human-derived clot analogs. Material and Methods: Baseline angiographic and physiological pressure measurements were obtained in six adult Yorkshire pigs (45–65 kg) and results were benchmarked for interspecies comparison with published human data using fluoroscopic examinations, intra-arterial pressure measurements, and histologic studies. Then, clot analogs were created ex vivo employing banked human blood and a subset incubated in iodinated contrast for fluoroscopic visualization. Clot analogs were then embolized via a femoral venous access and angiographic/physiological consequences were evaluated. Results: The main, right, and left pulmonary artery diameters were 24 ± 1.1 mm, 16.5 ± 0.8 mm, and 12.6 ± 1.2 mm, respectively. The angle between the main pulmonary artery at the bifurcation point was approximately 90–95°. The clot analogs were heterogeneous and had increased fibrin content along the clot length. The overall composition was 96.63% red blood cell (RBC)/3.37% fibrin in the initial section, 48.85% RBC/51.15% fibrin in the intermediate section, and 3.44% RBC/96.56% fibrin in the final section. Embolization of the clot analogs resulted in distal occlusion of the right and left pulmonary arteries. Conclusions: This swine model coupled with clot analog is able to accurately mimic human anatomical and physiological conditions in PE making it feasible for the evaluation of pulmonary thrombectomy devices.

Emergence of SARS-CoV-2 variants of concern (VOCs), including the highly transmissible Omicron and Delta strains, has posed constant challenges to the current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified messenger RNA (mRNA) vaccine that expresses the more conserved viral nucleoprotein (mRNA-N) and show that mRNA-N vaccination alone can induce modest control of SARS-CoV-2. Critically, combining mRNA-N with the clinically proven S-expressing mRNA vaccine (mRNA-S+N) induced robust protection against both Delta and Omicron variants. In the hamster models of SARS-CoV-2 VOC challenge, we demonstrated that, compared to mRNA-S alone, combination mRNA-S+N vaccination not only induced more robust control of the Delta and Omicron variants in the lungs but also provided enhanced protection in the upper respiratory tract. In vivo CD8 + T cell depletion suggested a potential role for CD8 + T cells in protection conferred by mRNA-S+N vaccination. Antigen-specific immune analyses indicated that N-specific immunity, as well as augmented S-specific immunity, was associated with enhanced protection elicited by the combination mRNA vaccination. Our findings suggest that combined mRNA-S+N vaccination is an effective approach for promoting broad protection against SARS-CoV-2 variants.

Objective: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons. Background: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC. Methods: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014–2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers. Results: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P<0.001). Conclusion: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC.

Objectives To integrate morphological, haemodynamic and mechanical analysis of carotid atheroma driving plaque disruption. Materials and methods First, we analysed the phenotypes of carotid endarterectomy specimens in a photographic dataset A, and matched them with the likelihood of preoperative stroke. Second, laser angioscopy was used to further define the phenotypes in intact specimens (dataset B) and benchmark with histology. Third, representative vascular geometries for each structural phenotype were analysed with Computational Fluid Dynamics (CFD), and the mechanical strength of the complicated atheroma to resist penetrating forces was quantified (n=14). Results In dataset A (n=345), ulceration (fibrous cap disruption) was observed in 82% of all plaques, intraplaque haemorrhage in 68% (93% subjacent to an ulcer) and false luminal formation in 48%. At least one of these ‘rupture’ phenotypes was found in 97% of symptomatic patients (n=69) compared with 61% in asymptomatic patients. In dataset B (n=30), laser angioscopy redemonstrated the structural phenotypes with near-perfect agreement with histology. In CFD, haemodynamic stress showed a large pulse magnitude, highest upstream to the point of maximal stenosis and on ulceration the inflow stream excavates the necrotic core cranially and then recirculates into the true lumen. Based on mechanical testing (n=14), the necrotic core is mechanically weak and penetrated by the blood on fibrous cap disruption. Conclusions Fibrous cap ulceration, plaque haemorrhage and excavation are sequential phenotypes of plaque disruption resulting from the chiselling effect of haemodynamic forces over unmatched mechanical tissue strength. This chain of events may result in thromboembolic events independently of the degree of stenosis.