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ABSTRACT Background and Aim Significant health disparities persist in alcohol‐associated liver disease (ALD), largely driven by social determinants of health (SDOH). However, the influence of neighbourhood‐level SDOH on ALD outcomes remains underexplored. In this study, we aimed to evaluate how neighbourhood‐level SDOH are associated with disease burden, comorbid conditions, and mortality in individuals with ALD. Methods We conducted a retrospective cohort study of patients with ALD in the Banner Health System, representing hospitals across Arizona, California, Nevada, Wyoming and Colorado, from January 2012 to October 2024 using ICD codes. Neighbourhood‐level SDOH were quantified using the Social Deprivation Index (SDI). Patients were stratified into quartiles based on SDI score, with Quartile 4 representing the most socioeconomically disadvantaged neighbourhoods. Primary outcomes included incidence of mortality, cirrhosis, major adverse liver outcome (MALO), Type 2 diabetes mellitus, any cancer, and major adverse cardiovascular events (MACE). A multivariable competing risk analysis was performed adjusting for age, sex, race/ethnicity, insurance type, primary language, smoking status, Type 2 diabetes mellitus, hypertension, hyperlipidemia, aspirin use, statin use, alcohol use disorder and a composite mental‐health/substance‐use disorder variable encompassing depression, anxiety disorders, post‐traumatic stress disorder, bipolar disorder, schizophrenia, and non‐alcohol substance use disorders. Results Among 11,394 patients with ALD and available SDI data, 6747 had ≥ 365 days of follow‐up. The average age was 51 years and 65.6% were female; 68.8% were non‐Hispanic White, 19.7% Hispanic, 5.9% Native American/Alaskan Native (NA), 3.2% Black, and 0.4% Asian/Pacific Islanders. Patients residing in the most disadvantaged neighbourhoods (Quartile 4) were significantly younger, more likely to be female, had a higher median BMI, and more frequently reported a non‐English primary language compared with those in the least disadvantaged areas (Quartile 1). Patients in the most deprived neighbourhoods were more likely to be Hispanic, Black, or Native American/Alaska Native and to be uninsured or on Medicaid, whereas those in the least disadvantaged neighbourhoods predominantly had private insurance. Individuals in Quartile 4 had increased mortality (adjusted hazard ratio [aHR]: 1.48, 95% Confidence Interval [CI]: 1.09–2.01) compared with individuals in Quartile 1. Conclusions In this large and demographically diverse ALD cohort, residing in socioeconomically disadvantaged neighbourhoods was associated with increased risk of mortality. These findings support the need for contextually tailored clinical interventions and broader treatment strategies that target upstream sociocultural and environmental factors that are associated with health outcomes. Addressing neighbourhood‐level SDOH through community engagement, policy reform, and cross‐sector partnerships to improve collaborative care efforts is needed to reduce health disparities in ALD.

Abstract Rationale Non-selective beta-blockers (BB) are the standard of care for variceal prophylaxis in patients with cirrhosis. It is unclear whether BB negatively affect exercise capacity in patients with portopulmonary hypertension (POPH) or hepatopulmonary syndrome (HPS). We hypothesize that BB use is associated with shorter six-minute walk distance (6MWD) in HPS and POPH than in patients without pulmonary vascular complications of liver disease. Methods The Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) Study enrolled patients evaluated for liver transplantation or pulmonary hypertension at eight U.S. centers (2013-2017). We conducted a retrospective analysis of 333 patients with HPS, POPH, and portal hypertension without lung complications to evaluate whether disease state modified the association of BB on 6MWD. Multivariable linear regression adjusted for a priori covariates including age, sex, body mass index (BMI), MELD-Na, and WHO functional class. An interaction term between disease category and BB use was included. Results We included 85 patients with HPS, 48 with POPH, and 200 patients with liver disease. Compared to liver disease controls, those with HPS were younger, had higher MELD-Na scores, and more often had worse WHO functional class. POPH patients were similar to controls in age and liver disease severity but had higher WHO functional class. Sex, BMI, and left ventricular ejection fraction did not differ significantly between groups. Higher age, BMI, MELD-Na, and WHO functional class were all significantly associated with lower 6MWD while male sex was associated with higher 6MWD. Adjusting for age, sex, BMI, MELD-Na score, and WHO functional class, there was a significant interaction between BB use and disease category (p = 0.024). Patients with HPS had a 53.4 m longer 6MWD with BB use (95% CI 4.21- 102.5, p = 0.03 for interaction) compared to liver disease controls, whereas patients with POPH had a 72.4 m longer 6MWD (95% CI 7.60- 137.2, p = 0.03 for interaction) compared to liver disease controls. Conclusion The association of BB with 6MWD in advanced liver disease appears to be modified by whether a person has a pulmonary vascular complication including HPS or POPH. The mechanisms for these differences and their clinical implications require further study. This abstract is funded by: NIH T32 Grant

ABSTRACT In normal health, the liver and lungs enjoy a close anatomic, physiologic, and functional relationship. In the context of pulmonary vascular disease, however, there is accumulating evidence that the interplay between the gut microbiome, hepatic system, and pulmonary vasculature (so‐called “gut‐liver‐lung” axis) plays an important role in driving disease pathogenesis and determining clinical outcomes. Despite recognizing the importance of the gut‐liver‐lung axis in pulmonary vascular disease however, little is known about the clinical characteristics, circulating factors, and physiologic pathways that mediate this important axis of communication. In this clinical and translationally focused review, we provide an overview of liver‐lung communication in normal physiology, and contrast this with gut‐liver‐lung derangements in pulmonary arterial hypertension, portopulmonary hypertension, and hepatopulmonary syndrome. We conclude with identifying key gaps in knowledge that will need to be addressed in order to manipulate the gut‐liver‐lung axis to prevent worsening pulmonary vascular disease, develop novel therapeutics, and improve patient outcomes.

Importance Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown. Objective To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance. Design, Setting, and Participants Phase 3, open-label, randomized clinical trial conducted at 4 United States–based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025). Intervention Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance. Main Outcomes and Measures Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory–Brain Tumor instrument (scale, 0-10; score change range, −10 to 10; −10 = best). A clinically meaningful Δ was defined as 0.98. Results Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory–Brain Tumor score from 2.69 to 2.37 (mean change, −0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, −1.06 [95% CI, −1.54 to −0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively). Conclusions and Relevance In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life. Trial Registration ClinicalTrials.gov Identifier: NCT03075072

Background and Aims: Liver transplant is a specialized treatment for a spectrum of indications that use a scarce resource. Transplant is guided by principles of justice, equity, and benefit, with a constant conflict between competing interests. Organs are a national resource with a goal of equitable distribution across sites. An AASLD guideline for the evaluation and selection of appropriate candidates for transplant has been available since 2005. Methods: A multidisciplinary writing group of liver transplant experts and a librarian convened over 24 months. The writing group reviewed the literature, generated guideline recommendations, and rated the level of evidence for each recommendation based on the Oxford Center for Evidence-Based Medicine. The group categorized the strength of recommendations based on the level of evidence, risk-benefit ratio, and patient preferences. Conclusions: Liver transplant is a lifesaving procedure that should be offered to selected patients with clear indications and a reasonable prospect of benefit. The evaluation is designed to identify those in need, to outline hurdles to a successful outcome, and to develop an effective transplant plan. The goal of this document is to provide a template for this process.

Abstract Background Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation and plays multiple roles in RNA splicing, DNA damage-response, cell cycle, and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action. Methods CDK12 copy number alterations and gene expression levels were analyzed in matched primary and brain metastatic patient tumors. Clinical significance was assessed by immunohistochemistry in a large cohort of primary breast cancer patient tumors. RNA sequencing, ChIP sequencing, and molecular studies were conducted to explore CDK12’s mechanism of action, and pharmacological studies were performed both in vitro and in vivo using models of advanced (endocrine-resistant and metastatic) estrogen receptor positive (ER+) disease. Results CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression was significantly associated with poor overall survival, particularly within the ER+/HER2-negative group. In ER+ endocrine resistant models, CDK12 regulated estrogen signaling pathways, with ER/MED1 identified as the master transcriptional complex directing CDK12-specific pro-tumorigenic gene programs. Pharmacological inhibition of CDK12 significantly reduced viability in endocrine resistant and metastatic cell and organoid models in vitro, and decreased metastatic spread in vivo. Conclusion This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.

PURPOSE Stereotactic radiation (SRS/SRT) as opposed to whole-brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases given the relatively favorable toxicity profile associated with stereotactic treatment. However, in patients with small cell lung cancer (SCLC), WBRT remains standard because of a lack of prospective data supporting SRS/SRT and concerns related to intracranial progression and neurologic death when WBRT is omitted. We conducted a single-arm, multicenter, phase II trial of SRS/SRT in patients with SCLC and 1-10 brain metastases to assess neurologic death rates relative to historical controls managed with WBRT (ClinicalTrials.gov identifier: NCT03391362 ). METHODS Patients were eligible if they had SCLC or an extrathoracic small cell primary and 1-10 brain metastases. Previous brain-directed radiation including prophylactic cranial irradiation was not permitted. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or systemic symptoms of a life-threatening nature. Close imaging-based surveillance of the brain post-SRS/SRT was used. RESULTS Between February 2018 and April 2023, 100 patients were enrolled. The median number of brain metastases was 2 (IQR, 1-4; range, 1-10). The median overall survival was 10.2 months; only 22% of patients required salvage WBRT. In total, 20 neurologic deaths were observed, relative to 64 non-neurologic deaths. The neurologic death rate at 1 year was 11.0% (95% CI, 5.8 to 18.1); the historical rate in patients managed with WBRT was 17.5%. CONCLUSION Our prospective, multi-institutional study demonstrated low rates of neurologic death when SRS/SRT as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases who are surveilled closely post-treatment, supporting the utility of stereotactic approaches in this population.

2011 Background: Radiation therapy forms the mainstay of management for patients with brain metastases. Published randomized trials have found improved quality of life with stereotactic radiation (SRS/SRT) over whole brain radiation (WBRT) in patients with ≤ 4 brain metastases; comparative trials in patients with >4 brain metastases are lacking. In addition, prior randomized trials have demonstrated the superiority of hippocampal avoidance WBRT (HA-WBRT) over traditional WBRT, but no study has compared SRS/SRT to HA-WBRT. Accordingly, we conducted a multicenter, phase 3 randomized trial comparing SRS/SRT to HA-WBRT in patients with 5-20 brain metastases. Methods: Eligible patients were age 18-80 with 5-20 brain metastases secondary to a solid primary other than small cell lung cancer, were naïve to prior brain-directed radiation, and lacked leptomeningeal disease. The primary endpoint was the average of patient-reported symptom severity and interference over the first six months post-baseline relative to baseline, using the MD Anderson Symptom Inventory–Brain Tumor (MDASI-BT) module, a validated instrument assessing 22 symptoms and 6 interference measures integral to quality of life, each scored 0-10 with higher scores indicating greater symptomatology/interference in function. The target effect size was a symptom severity of 0.70, corresponding to 50% of the observed difference between patients with a good (90-100) versus poor (≤80) Karnofsky performance status; with 80% power and a two-sided alpha of 0.05, 196 patients were required. Results: Between 4/2017-5/2024, 196 patients enrolled, 98 in each arm. The median number of brain metastases was 14 (IQR 11-18); 25% of patients underwent prior neurosurgical resection. Baseline mean MDASI-BT symptom severity scores were 2.2 (SRS/SRT arm) and 1.9 (HA-WBRT arm), p=0.20; respective interference scores were 3.5 and 3.2 (p=0.40). The average of weighted post-baseline severity and interference scores relative to baseline indicated lower symptomatology/inference in the SRS/SRT arm, meeting the primary endpoint of the study (difference between SRS/SRT and HA-WBRT: -1.06, p<0.001). Averaged post-baseline symptom severity scores minus baseline were -0.03 and 0.59 in the SRS/SRT and HA-WBRT arms, respectively (difference -0.62, with lower symptom severity in the SRS/SRT arm, p<0.001); respective interference estimates were -0.62 and 0.89 (difference -1.50, with lower interference in the SRS/SRT arm, p<0.001). Median survival was 8.3 and 8.5 months in the SRS/SRT and HA-WBRT arms, respectively (p=0.30). Conclusions: This phase 3 randomized trial indicates that patients with 5-20 brain metastases experience fewer symptoms and less interference in function after SRS/SRT as opposed to HA-WBRT, without compromise of survival, supporting SRS/SRT as the standard of care in this population. Clinical trial information: NCT03075072 .

Portopulmonary hypertension (POPH), pulmonary arterial hypertension that develops in the setting of portal hypertension, has long been of significant interest to the pulmonary, cardiology, and hepatology communities. Optimal management of POPH has been challenging to define due to a lack of evidence from clinical trials regarding pulmonary arterial hypertension therapies and uncertainty regarding the role of liver transplantation (LT). Initially, the high risk of intraoperative and early post-transplant death in predominantly untreated patients with POPH tempered consideration of LT. More recently, the observation that POPH can improve, and sometimes even resolve, following LT, has led to reconsideration of the role of LT in selected patients. The first International Liver Transplantation Society (ILTS) POPH and hepatopulmonary syndrome practice guideline was a multidisciplinary consensus of expert opinions based on available evidence. Since that publication, hemodynamic definitions, management approaches, and POPH MELD exception criteria have evolved, and there have been new randomized controlled trials in POPH as well as studies regarding long-term outcomes. In order to ensure the guidelines remained current and reflected recent evidence, the original writing committee of the 2016 guidelines, leaders of the ILTS Cardiovascular Special Interest Group, and colleagues active in POPH research were invited to participate in the writing committee. In this document, approved for publication by the ILTS executive council, we provide an update to the prior guidelines with expert recommendations to guide and advance POPH management. Recommendations in these guidelines are based on expert opinion and available evidence and were agreed upon by consensus.