Phenotyping Hepatic Immune-Related Adverse Events in the Setting of Immune Checkpoint Inhibitor Therapy.

PURPOSE: We present and validate a rule-based algorithm for the detection of moderate to severe liver-related immune-related adverse events (irAEs) in a real-world patient cohort. The algorithm can be applied to studies of irAEs in large data sets. METHODS: We developed a set of criteria to define hepatic irAEs. The criteria include: the temporality of elevated laboratory measurements in the first 2-14 weeks of immune checkpoint inhibitor (ICI) treatment, steroid intervention within 2 weeks of the onset of elevated laboratory measurements, and intervention with a duration of at least 2 weeks. These criteria are based on the kinetics of patients who experienced moderate to severe hepatotoxicity (Common Terminology Criteria for Adverse Events grades 2-4). We applied these criteria to a retrospective cohort of 682 patients diagnosed with hepatocellular carcinoma and treated with ICI. All patients were required to have baseline laboratory measurements before and after the initiation of ICI. RESULTS: A set of 63 equally sampled patients were reviewed by two blinded, clinical adjudicators. Disagreements were reviewed and consensus was taken to be the ground truth. Of these, 25 patients with irAEs were identified, 16 were determined to be hepatic irAEs, 36 patients were nonadverse events, and two patients were of indeterminant status. Reviewers agreed in 44 of 63 patients, including 19 patients with irAEs (0.70 concordance, Fleiss' kappa: 0.43). By comparison, the algorithm achieved a sensitivity and specificity of identifying hepatic irAEs of 0.63 and 0.81, respectively, with a test efficiency (percent correctly classified) of 0.78 and outcome-weighted F1 score of 0.74. CONCLUSION: The algorithm achieves greater concordance with the ground truth than either individual clinical adjudicator for the detection of irAEs.

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

A Clinical Prediction Model to Assess Risk for Pancreatic Cancer Among Patients With Acute Pancreatitis.

OBJECTIVES: We aimed to develop and validate a prediction model as the first step in a sequential screening strategy to identify acute pancreatitis (AP) individuals at risk for pancreatic cancer (PC). MATERIALS AND METHODS: We performed a population-based retrospective cohort study among individuals 40 years or older with a hospitalization for AP in the US Veterans Health Administration. For variable selection, we used least absolute shrinkage and selection operator regression with 10-fold cross-validation to identify a parsimonious logistic regression model for predicting the outcome, PC diagnosed within 2 years after AP. We evaluated model discrimination and calibration. RESULTS: Among 51,613 eligible study patients with AP, 801 individuals were diagnosed with PC within 2 years. The final model (area under the receiver operating curve, 0.70; 95% confidence interval, 0.67-0.73) included histories of gallstones, pancreatic cyst, alcohol use, smoking, and levels of bilirubin, triglycerides, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin. If the predicted risk threshold was set at 2% over 2 years, 20.3% of the AP population would undergo definitive screening, identifying nearly 50% of PC associated with AP. CONCLUSIONS: We developed a prediction model using widely available clinical factors to identify high-risk patients with PC-associated AP, the first step in a sequential screening strategy.

Liver Stiffness Measurement and Risk Prediction of Hepatocellular Carcinoma After HCV Eradication in Veterans With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis secondary to chronic hepatitis C virus (HCV) are at risk for hepatocellular carcinoma (HCC) despite a sustained virological response (SVR). We examined whether post-SVR liver stiffness measurement (LSM) could be used to stratify HCC risk. METHODS: This was a retrospective cohort study of 1850 participants identified from the Veterans Health Administration, with HCV cirrhosis and SVR, followed up over 5099 person-years, from the time of post-SVR elastography until death, HCC, or the end of the study. RESULTS: The risk of HCC increased by 3% with every 1-kPa increase in LSM (adjusted hazard ratio [aHR], 1.03, 95% confidence interval [CI], 1.01-1.04; P < .001) and decreased with the number of years from SVR (aHR, 0.79; 95% CI, 0.70-0.90; P = .0003). The adjusted annual risk of HCC was 2.03% among participants with post-SVR LSM <10 kPa, 2.48% in LSM 10-14.9 kPa (aHR, 1.71; 95% CI, 1.01-2.88; P = .046), 3.22% for LSM 15-19.9 kPa (aHR, 1.59; 95% CI, 0.78-3.20; P = .20), 5.07% among LSM 20-24.9 kPa (aHR, 2.55; 95% CI, 1.30-5.01; P = .01), and 5.44% in LSM ≥25 kPa (aHR, 3.03; 95% CI, 1.74-5.26; P < .0001). The adjusted annual risk of HCC was < 0.4% in participants with LSM <5 kPa and without diabetes mellitus. CONCLUSIONS: LSM predicts rates of HCC in patients with HCV cirrhosis after SVR at multiple cutoff levels and offers a single test to predict portal hypertension-related complications and HCC. Patients with LSM <5 kPa in the absence of diabetes mellitus had a low risk of HCC in which surveillance could be discontinued.

The Association Between Homelessness and Key Liver-Related Outcomes in Veterans With Cirrhosis.

INTRODUCTION: Homelessness adversely affects patient outcomes in broad cohort studies; however, its impact on key liver-related outcomes in patients with cirrhosis is understudied. We aimed to address this knowledge gap using data from the Veterans Health Administration, a cohort disproportionately affected by homelessness. METHODS: This was a retrospective cohort study of the Veterans Health Administration patients with incident cirrhosis diagnosis between January 2008 and February 2022. Homeless status was classified at baseline and as time-updating variable during follow-up. Inverse probability treatment weighted Cox regression was performed to evaluate the association between homelessness and outcomes of all-cause mortality, cirrhosis decompensation, and hepatocellular carcinoma. RESULTS: A total of 117,698 patients were included in the cohort, of whom 14,243 (12.1%) were homeless at baseline. In inverse probability treatment weighted Cox regression, homelessness was associated with a 24% higher hazard of all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.22-1.26, P < 0.001). However, in competing risk regression models, homelessness was associated with a reduced subhazard of decompensation (subhazard ratio 0.86, 95% CI 0.84-0.88, P < 0.001) and hepatocellular carcinoma (subhazard ratio 0.86, 95% CI 0.83-0.89, P < 0.001). In cause-specific mortality analysis, homeless patients had significantly increased non-liver-related and liver-related mortality; however, the magnitude of effect size was greater for non-liver-related mortality (csHR 1.38, 95% CI 1.35-1.40, P < 0.001). DISCUSSION: Homelessness in veterans with cirrhosis is associated with increased all-cause mortality; however, this is likely mediated primarily through non-liver-related factors. Future studies are needed to explore drivers of mortality and improve mitigation strategies in these patients.

HCC is associated with diabetes and longitudinal blood glucose control in a national cohort with cirrhosis.

BACKGROUND: Diabetes is associated with HCC; however, the impact of longitudinal blood glucose (BG) control on HCC risk in cirrhosis is not well known. We investigated this knowledge gap in a cohort of United States Veterans with cirrhosis from 2015 to 2021. METHODS: We used repeated hemoglobin A1c measurements to categorize follow-up time according to BG control (defined as hemoglobin A1c < 7%) state over time: uncontrolled, nonsustained control (≤2 y), or sustained control (>2 y). We performed a sensitivity analysis using hemoglobin A1c < 8% to define BG control. We used Fine and Gray Cox proportional hazards regression with death and transplant as competing events to compare rates of incident HCC. RESULTS: Our study included 81,907 individuals, 56.2% of whom had diabetes at baseline. There were 8,002 incident HCCs. The rate of HCC was 18% higher in diabetes (95% CI: 13% - 24%), and the relative increase in the rate of HCC varied by etiology of cirrhosis from nonsignificant (HCV) to an increase of 120% (HBV). Uncontrolled and nonsustained BG control was associated with 1.80 (95% CI: 1.70-1.91) and 2.34 (95% CI: 2.21-2.48) times the rate of HCC compared to sustained BG control, respectively. Using Hgb A1c < 8% to define BG control, HCC rates in uncontrolled and nonsustained BG control were 2.43 (2.28-2.58) and 2.23 (2.11-2.36) times that observed in sustained BG control. CONCLUSIONS: Associations between diabetes and HCC in cirrhosis vary according to the longitudinal BG control state. Inadequate BG control is consistently associated with a higher risk of HCC, and long-term BG control should be considered in comprehensive cirrhosis care.

Risk of Hepatocellular Carcinoma After Spontaneous Clearance of Hepatitis C Virus and in Noncirrhosis Chronic Hepatitis C Patients With Sustained Virological Response: A Systematic Review.

In a hepatitis C virus (HCV)-controlled human infection model (CHIM), healthy volunteers are inoculated with HCV and then treated. Residual hepatocellular carcinoma (HCC) risk after viral clearance is an important consideration when evaluating the CHIM. We estimate HCC risk in spontaneously cleared HCV and in noncirrhosis after sustained virological response (SVR) to HCV treatment in a systematic review and using data from 3 cohorts: German anti-D, Taiwan, and US Veterans Affairs (VA). For noncirrhosis SVR, the overall HCC rate is 0.33 per 100 patient-years in meta-analysis. HCC rates for the German, Taiwan, and US Veterans Affairs cohorts are 0, 0.14, and 0.02 per 100 patient-years, respectively. Past hepatitis B virus exposure was not accounted for in the Taiwan cohort, while VA patients were likely tested based on liver disease/risk factors, which may confound HCC outcomes. The German cohort with no HCC after 44 years is most comparable to the CHIM participants. Although it is difficult to precisely estimate HCC risk from an HCV CHIM, the data suggest the risk to be very low or negligible.

Multidisciplinary teams, efficient communication, procedure services, and telehealth improve cirrhosis care: A qualitative study.

BACKGROUND: Cirrhosis care and outcomes are improved with access to subspecialty gastroenterology and hepatology care. In qualitative interviews, we investigated clinicians' perceptions of factors that optimize or impede cirrhosis care. METHODS: We conducted 24 telephone interviews with subspecialty clinicians at 7 Veterans Affairs medical centers with high- and low-complexity services. Purposive sampling stratified Veterans Affairs medical centers on timely post-hospitalization follow-up, a quality measure. We asked open-ended questions about facilitators and barriers of care coordination, access to appointments, procedures, transplantation, management of complications, keeping up to date with medical knowledge, and telehealth use. RESULTS: Key themes that facilitated care were structural: multidisciplinary teams, clinical dashboards, mechanisms for appointment tracking and reminders, and local or virtual access to transplant and liver cancer specialists through the "specialty care access network extension for community health care outcomes" program. Coordination and efficient communication between transplant and non-transplant specialists and between transplant and primary care facilitated timely care. Same-day access to laboratory, procedural, and clinical services is an indicator of high-quality care. Barriers included lack of on-site procedural services, clinician turnover, patient social needs related to transportation, costs, and patient forgetfulness due to HE. Telehealth enabled lower complexity sites to obtain recommendations for complex patient cases. Barriers to telehealth included lack of credit (eg, VA billing equivalent), inadequate staff, lack of audiovisual technology support, and patient and staff discomfort with technology. Telehealth was optimal for return visits, cases where physical examination was nonessential, and where distance and transportation precluded in-person care. Rapid telehealth uptake during the COVID-19 pandemic was a positive disruptor and facilitated use. CONCLUSIONS: We identify multi-level factors related to structure, staffing, technology, and care organization to optimize cirrhosis care delivery.

Antibiotic Exposure is Associated With a Risk of Esophageal Adenocarcinoma.

BACKGROUND & AIMS: Antibiotic exposure leads to changes in the gut microbiota. Our objective was to evaluate the association between antibiotic exposure and esophageal adenocarcinoma (EAC) risk. METHODS: We performed a nested case-control study using data from the Veterans Health Administration from 2004 through 2020. The case group consisted of patients who received an incident diagnosis of EAC. For each case, up to 20 matched controls were selected using incidence density sampling. Our primary exposure of interest was any oral or intravenous antibiotic use. Our secondary exposures included cumulative number of days of exposure and classification of antibiotics by various subgroups. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (aORs) for the risk of EAC associated with antibiotic exposure. RESULTS: The case-control analysis included 8226 EAC cases and 140,670 matched controls. Exposure to any antibiotic was associated with an aOR for EAC of 1.74 (95% confidence interval [CI], 1.65-1.83) vs no antibiotic exposure. Compared with no antibiotic exposure, the aOR for EAC was 1.63 (95% CI, 1.52-1.74; P < .001) for cumulative exposure to any antibiotic for 1 to 15 days; 1.77 (95% CI, 1.65-1.89; P < 0 .001) for 16 to 47 days; and 1.87 (95% CI, 1.75-2.01; P < .001) for ≥48 days, respectively (P for trend < .001). CONCLUSION: Exposure to any antibiotic is associated with an increased risk of EAC, and this risk increases as the cumulative days of exposure increase. This novel finding is hypothesis-generating for potential mechanisms that may play a role in the development or progression of EAC.

Induction Immunosuppression Does Not Worsen Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: Prior studies are inconsistent regarding the impact of antibody induction therapy on outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC). METHODS: Adults transplanted with HCC exception priority were identified from February 27, 2002, to March 31, 2019, using the United Network for Organ Sharing database. Time-to-event analyses evaluated the association of antibody induction therapy (none, nondepleting induction [NDI], depleting induction [DI]) with overall post-LT patient survival and HCC recurrence. Separate multivariable models adjusted for tumor characteristics on either last exception or on explant. The interaction of induction and maintenance regimen at LT discharge was investigated. RESULTS: Among 22 535 LTs for HCC, 17 688 (78.48%) received no antibody induction, 2984 (13.24%) NDI, and 1863 (8.27%) DI. Minimal differences in patient and tumor characteristics were noted between induction groups, and there was significant center variability in practices. NDI was associated with improved survival, particularly when combined with a calcineurin inhibitor (CNI) and antimetabolite (hazard ratio [HR] 0.73 versus no induction plus 3-drug therapy in the last exception model [ P < 0.001]; HR 0.64 in the explant model [ P = 0.011]). The combination of DI with CNI alone was also protective (HR 0.43; P = 0.003). Neither NDI nor DI was associated with tumor recurrence (all P > 0.1). However, increased HCC recurrence was observed with no induction plus CNI monotherapy (HR 1.47, P = 0.019; versus no induction plus 3-drug therapy). CONCLUSIONS: In conclusion, induction immunosuppression was not associated with worse post-LT outcomes in patients transplanted with HCC exception priority. An improvement in survival was possibly observed with NDI.

Using Telemedicine to Facilitate Patient Communication and Treatment Decision-Making Following Multidisciplinary Tumor Board Review for Patients with Hepatocellular Carcinoma.

BACKGROUND AND AIMS: A rapid increase in the use of telemedicine for delivering healthcare has occurred since the onset of the Covid-19 pandemic. There is evidence for using telemedicine to facilitate cancer care delivery for patients with hepatocellular carcinoma (HCC). Examining how telemedicine can be used to communicate multidisciplinary tumor board (MTB) recommendations for HCC has not been studied. This study has two specific aims: (1) to evaluate the patient perspective of the MTB review process and identify best strategies for communicating treatment recommendations for HCC and (2) to pilot test a telemedicine intervention following MTB review to assess patient feasibility and satisfaction with using telemedicine to facilitate treatment decision-making and treatment referral. METHODS: We conducted a mixed-methods study. First, semi-structured qualitative interviews were conducted among patients diagnosed with HCC who were discussed in MTB review at one of three VA Medical Centers (VAMC). We collected information about the MTB process from the patient perspective and identified strategies for improving communication and delivery of care. Rapid qualitative analysis was used to inform intervention development. Using our qualitative data, a MTB telemedicine pilot intervention was developed and implemented to assess the feasibility of using this approach for patients with HCC. RESULTS: Almost all patients (94%) in the pilot study would recommend telemedicine to other patients with HCC, and half of the patients (50%) preferred telemedicine over in-person visits. Many patients (81%) found communication through telemedicine an acceptable platform to deliver difficult cancer information. Overall, patients felt they understood their treatment recommendations and found them clear and useful. Further, patients reported that they enjoyed being included in the decision-making process and appreciated being able to have family members easily join them for the telemedicine visit. CONCLUSIONS: Using telemedicine to communicate treatment recommendations following MTB review was found to be feasible and an acceptable alternative to an in-person visit for patient with HCC. Future studies could include expanding this approach for communicating MTB recommendations to patients with other types of cancers.

Association Between Bariatric Surgery and Alcohol Use-Related Hospitalization and All-Cause Mortality in a Veterans Affairs Cohort.

Importance: Bariatric surgery procedures, in particular Roux-en-Y gastric bypass (RYGB), have been associated with subsequent alcohol-related complications. However, previous studies lack data to account for changes in body mass index (BMI) or alcohol use over time, which are key potential confounders. Objective: To evaluate the association between RYGB, sleeve gastrectomy, or gastric banding on subsequent alcohol use disorder (AUD)-related hospitalization and all-cause mortality as compared with referral to a weight management program alone. Design, Setting, and Participants: This cohort study included 127 Veterans Health Administration health centers in the US. Patients who underwent RYGB, sleeve gastrectomy, or gastric banding or who were referred to MOVE!, a weight management program, and had a BMI (calculated as weight in kilograms divided by height in meters squared) of 30 or greater between January 1, 2008, and December 31, 2021, were included in the study. Exposures: RYGB, sleeve gastrectomy, or gastric banding or referral to the MOVE! program. Main Outcomes and Measures: The primary outcome was time to AUD-related hospitalization from the time of bariatric surgery or MOVE! referral. The secondary outcome was time to all-cause mortality. Separate propensity scores were created for each pairwise comparison (RYGB vs MOVE! program, RYGB vs sleeve gastrectomy, sleeve gastrectomy vs MOVE!). Sequential Cox regression approaches were used for each pairwise comparison to estimate the relative hazard of the primary outcome in unadjusted, inverse probability treatment weighting (IPTW)-adjusted (generated from the pairwise logistic regression models), and IPTW-adjusted approaches with additional adjustment for time-updating BMI and categorical Alcohol Use Disorders Identification Test-Concise scores. Results: A total of 1854 patients received RYGB (median [IQR] age, 53 [45-60] years; 1294 men [69.8%]), 4211 received sleeve gastrectomy (median [IQR] age, 52 [44-59] years; 2817 men [66.9%]), 265 received gastric banding (median [IQR] age, 55 [46-61] years; 199 men [75.1%]), and 1364 were referred to MOVE! (median [IQR] age, 59 [49-66] years; 1175 men [86.1%]). In IPTW Cox regression analyses accounting for time-updating alcohol use and BMI, RYGB was associated with an increased hazard of AUD-related hospitalization vs MOVE! (hazard ratio [HR], 1.70; 95% CI, 1.20-2.41; P = .003) and vs sleeve gastrectomy (HR, 1.98; 95% CI, 1.55-2.53; P < .001). There was no significant difference between sleeve gastrectomy and MOVE! (HR, 0.76; 95% CI, 0.56-1.03; P = .08). While RYGB was associated with a reduced mortality risk vs MOVE! (HR, 0.63; 95% CI, 0.49-0.81; P < .001), this association was mitigated by increasing alcohol use over time. Conclusions and Relevance: This cohort study found that RYGB was associated with an increased risk of AUD-related hospitalizations vs both sleeve gastrectomy and the MOVE! program. The mortality benefit associated with RYGB was diminished by increased alcohol use, highlighting the importance of careful patient selection and alcohol-related counseling for patients undergoing this procedure.

Comparison of nivolumab and sorafenib for first systemic therapy in patients with hepatocellular carcinoma and Child-Pugh B cirrhosis.

BACKGROUND: Patients with decompensated cirrhosis are excluded or underrepresented in clinical trials of systemic therapies for hepatocellular carcinoma (HCC) and comparisons of available therapies are lacking. We aimed to compare overall survival for patients with HCC and Child-Pugh B cirrhosis treated with nivolumab or sorafenib as first systemic treatment. METHODS: We performed a retrospective cohort study in patients with HCC and Child-Pugh B cirrhosis treated at Veterans Affairs medical centers to compare overall survival, adverse events, and reason for discontinuation of therapy between patients treated with nivolumab or sorafenib as first systemic treatment. All statistical tests were 2-sided. RESULTS: Of those meeting inclusion criteria, 431 patients were treated with sorafenib and 79 with nivolumab. Median OS was 4.0 months (95% CI 3.5-4.8) in the sorafenib cohort and 5.0 months (95% CI 3.3-6.8) in the nivolumab cohort. In the multivariable Cox proportional hazards model, nivolumab was associated with a significantly reduced hazard of death compared to sorafenib (HR 0.69; 95% CI 0.52-0.91; p = 0.008). In a secondary analysis using propensity score methods, results did not reach statistical significance (HR 0.77; 95% CI 0.55-1.06; p = 0.11). Treatment was discontinued due to toxicity in 12% of patients receiving nivolumab compared to 36% receiving sorafenib (p = 0.001). CONCLUSION: In patients with HCC and Child-Pugh B cirrhosis, nivolumab treatment may be associated with improved overall survival and improved tolerability compared to sorafenib and should be considered for the first systemic treatment in this population.

Performance of risk prediction models for post-operative mortality in patients undergoing liver resection.

BACKGROUND: Liver resection is commonly performed for hepatic tumors, however preoperative risk stratification remains challenging. We evaluated the performance of contemporary prediction models for short-term mortality after liver resection in patients with and without cirrhosis. METHODS: This retrospective cohort study examined National Surgical Quality Improvement Program data. We included patients who underwent liver resections from 2014 to 2019. VOCAL-Penn, MELD, MELD-Na, ALBI, and Mayo risk scores were evaluated in terms of model discrimination and calibration for 30-day post-operative mortality. RESULTS: A total 15,198 patients underwent liver resection, of whom 249 (1.6%) experienced 30-day post-operative mortality. The VOCAL-Penn score had the highest discrimination (area under the ROC curve [AUC] 0.74) compared to all other models. The VOCAL-Penn score similarly outperformed other models in patients with (AUC 0.70) and without (AUC 0.74) cirrhosis. CONCLUSION: The VOCAL-Penn score demonstrated superior predictive performance for 30-day post-operative mortality after liver resection as compared to existing clinical standards.

Patterns of Care Utilization and Hepatocellular Carcinoma Surveillance: Tracking Care Across the Pandemic.

INTRODUCTION: We studied longitudinal trends in mortality, outpatient, and inpatient care for cirrhosis in a national cohort in the first 2 years of the coronavirus disease-2019 pandemic. We evaluated trends in hepatocellular carcinoma (HCC) surveillance and factors associated with completion. METHODS: Within the national cirrhosis cohort in the Veterans Administration from 2020 to 2021, we captured mortality, outpatient primary care provider, gastroenterology/hepatology (GI/HEP) visits, and hospitalizations. HCC surveillance was computed as percentage of time up to date with surveillance every 6 months (PTUDS). Multivariable models for PTUDS were adjusted for patient demographics, clinical factors, and facility-level variables. RESULTS: The total cohort was 68,073; 28,678 were eligible for HCC surveillance. Outpatient primary care provider and GI/HEP appointment rates initially dropped from 30% to 7% with a rebound 1 year into the pandemic and steady subsequent use. Telemedicine monthly visit rates rose from less than 10% to a peak of 20% with a steady gradual decline. Nearly 70% of Veterans were up to date with HCC surveillance before the pandemic with an early pandemic nadir of approximately 50% and 60% PTUDS 2 years into the pandemic. In adjusted models, use of a population-based cirrhosis dashboard (ß 8.5, 95% CI 6.9-10.2) and GI/HEP visits both in-person (ß 3.2, 95% CI 2.9-3.6) and telemedicine (ß 2.1, 95% CI 1.9-2.4) were associated with a higher PTUDS. DISCUSSION: Outpatient utilization and HCC surveillance rates have rebounded but remain below at baseline. Population-based approaches and specialty care for cirrhosis were associated with a higher completion of HCC surveillance.

Circulating messenger RNA variants as a potential biomarker for surveillance of hepatocellular carcinoma.

Background and rationale: Liver derived messenger ribonucleic acid (mRNA) transcripts were reported to be elevated in the circulation of hepatocellular carcinoma (HCC) patients. We now report the detection of high-risk mRNA variants exclusively in the circulation of HCC patients. Numerous genomic alleles such as single nucleotide polymorphisms (SNPs), nucleotide insertions and deletions (called Indels), splicing variants in many genes, have been associated with elevated risk of cancer. Our findings potentially offer a novel non-invasive platform for HCC surveillance and early detection. Approach: RNAseq analysis was carried out in the plasma of 14 individuals with a diagnosis of HCC, 8 with LC and no HCC, and 6 with no liver disease diagnosis. RNA from 6 matching tumors and 5 circulating extracellular vesicle (EV) samples from 14 of those with HCC was also analyzed. Specimens from two cholangiocarcinoma (CCA) patients were also included in our study. HCC specific SNPs and Indels referred as "variants" were identified using GATK HaplotypeCaller and annotated by SnpEff to filter out high risk variants. Results: The variant calling on all RNA samples enabled the detection of 5.2 million SNPs, 0.91 million insertions and 0.81 million deletions. RNAseq analyses in tumors, normal liver tissue, plasma, and plasma derived EVs led to the detection of 5480 high-risk tumor specific mRNA variants in the circulation of HCC patients. These variants are concurrently detected in tumors and plasma samples or tumors and EVs from HCC patients, but none of these were detected in normal liver, plasma of LC patients or normal healthy individuals. Our results demonstrate selective detection of concordant high-risk HCC-specific mRNA variants in free plasma, plasma derived EVs and tumors of HCC patients. The variants comprise of splicing, frameshift, fusion and single nucleotide alterations and correspond to cancer and tumor metabolism pathways. Detection of these high-risk variants in matching specimens from same subjects with an enrichment in circulating EVs is remarkable. Validation of these HCC selective ctmRNA variants in larger patient cohorts is likely to identify a predictive set of ctmRNA with high diagnostic performance and thus offer a novel non-invasive serology-based biomarker for HCC.

ACR Appropriateness Criteria® Management of Liver Cancer: 2022 Update.

The treatment and management of hepatic malignancies can be complex because it encompasses a variety of primary and metastatic malignancies and an assortment of local and systemic treatment options. When to use each of these treatments is critical to ensure the most appropriate care for patients. Interventional radiologists have a key role to play in the delivery of a variety of liver directed treatments including percutaneous ablation, transarterial embolization with bland embolic particles alone, transarterial chemoembolization (TACE) with injection of a chemotherapeutic emulsion, and transarterial radioembolization (TARE). Based on 9 clinical variants, the appropriateness of each treatment is described in this document. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study.

Background: The impact of nonalcoholic fatty liver disease (NAFLD) on overall survival (OS), treatment response and toxicity in patients with hepatocellular carcinoma (HCC) treated with sorafenib is unknown. We examined the impact of NAFLD on survival and toxicity in an international cohort of patients receiving sorafenib. Methods: Clinical and demographic data were collected from patients consecutively treated at specialist centres in Europe and North America. The impact of NAFLD on OS, sorafenib-specific survival and toxicity compared with other aetiologies of liver disease using multivariable Cox-proportional hazards and logistic regression modelling was assessed. Results: A total of 5201 patients received sorafenib; 183 (3.6%) had NAFLD-associated HCC. NAFLD-associated HCC patients were more likely to be older women (median age 65.8 versus 63.0 years, p < 0.01 and 10.4% versus 2.3%, < 0.01), with a median body mass index (BMI) of 29.4. After controlling for known prognostic factors, no difference in OS in patients with or without NAFLD was observed [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.84-1.18, p = 0.98]. NAFLD-associated patients had more advanced stage HCC when they commenced sorafenib [Barcelona Clinic Liver Class (BCLC) C/D 70.9% versus 58.9%, p < 0.01] and were more likely to be commenced on a lower starting dose of sorafenib (51.4 versus 36.4%, p < 0.01). There was no difference in sorafenib-specific survival between NAFLD and other aetiologies (HR: 0.96, 95% CI: 0.79-1.17, p = 0.96). Adverse events were similar between NAFLD and non-NAFLD HCC groups, including rates of greater than grade 2 hypertension (6.3% versus 5.8%, p = 1.00). Conclusion: Survival in HCC does not appear to be influenced by the presence of NAFLD. NAFLD-associated HCC derive similar clinical benefit from sorafenib compared with other aetiologies.

Modeling Optimal Clinical Thresholds for Elective Abdominal Hernia Repair in Patients With Cirrhosis.

Importance: Patients with cirrhosis have increased risk of postoperative mortality. Several models have been developed to estimate this risk; however, current risk estimation scores cannot compare surgical risk with the risk of not operating. Objective: To identify clinical optimal thresholds to favor operative or nonoperative management for a common cirrhosis surgical scenario, the symptomatic abdominal hernia. Design, Setting, and Participants: This was a Markov cohort decision analytical modeling study evaluating elective surgery vs nonoperative management for a symptomatic abdominal hernia in a patient with cirrhosis. Transition probabilities and utilities were derived from the literature and from data using an established cirrhosis cohort in the Veterans Health Administration. Participants included patients who were referred to a surgery clinic for a symptomatic abdominal hernia. Data were obtained from patients diagnosed with cirrhosis between January 1, 2008 and December 31, 2018. Data were analyzed from January 1 to May 1, 2022. Main Outcomes and Measures: Expected quality-adjusted life-years (QALYs) were estimated for each pathway and iterated over baseline model for end-stage liver disease-sodium (MELD-Na) scores ranging from 6 to 25. Markov models were cycled over a 5-year time horizon. Results: A total 2740 patients with cirrhosis (median [IQR] age, 62 [56-66] years; 2699 [98.5%] men) were referred to a surgery clinic for a symptomatic abdominal hernia; 1752 patients (63.9%) did not receive surgery. The median (IQR) follow-up was 42.1 (25.3-70.0) months. Using this cohort to estimate the mortality risk of operative and nonoperative pathways, an initial MELD-Na threshold of 21.3 points, below which surgery was associated with maximized QALYs was identified. Nonoperative management was associated with increased QALYs above this MELD-Na threshold. Although more patients experienced death with a surgical treatment decision across all initial MELD-Na values, this was counterbalanced by increased time spent in a resolved hernia state associated with increased utility. Model results were sensitive to the probability of hernia recurrence and hernia incarceration and utility decrement in the symptomatic hernia state. Conclusions and Relevance: This decision analytical model study found that elective surgical treatment for a symptomatic abdominal hernia was favored even in the setting of relatively high MELD-Na scores. Patient symptoms, hernia-specific characteristics, and surgeon and center expertise may potentially impact the optimal strategy, emphasizing the importance of shared decision-making.