Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

In-Depth Proteome Profiling of Small Extracellular Vesicles Isolated from Cancer Cell Lines and Patient Serum.

Extracellular vesicle (EV) secretion has been observed in many types of both normal and tumor cells. EVs contain a variety of distinctive cargoes, allowing tumor-derived serum proteins in EVs to act as a minimally invasive method for clinical monitoring. We have undertaken a comprehensive study of the protein content of the EVs from several cancer cell lines using direct data-independent analysis. Several thousand proteins were detected, including many classic EV markers such as CD9, CD81, CD63, TSG101, and Syndecan-1, among others. We detected many distinctive cancer-specific proteins, including several known markers used in cancer detection and monitoring. We further studied the protein content of EVs from patient serum for both normal controls and pancreatic cancer and hepatocellular carcinoma. The EVs for these studies have been isolated by various methods for comparison, including ultracentrifugation and CD9 immunoaffinity column. Typically, 500-1000 proteins were identified, where most of them overlapped with the EV proteins identified from the cell lines studied. We were able to identify many of the cell-line EV protein markers in the serum EVs, in addition to the large numbers of proteins specific to pancreatic and HCC cancers.

Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study.

BACKGROUND & AIMS: Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S. METHODS: The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC. RESULTS: Between April 10, 2013 and December 31, 2021, 1723 patients were enrolled and confirmed eligible. During median follow-up of 2.2 years (range, 0-8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years: 88 (81%) patients with very early/early Barcelona Clinic Liver Cancer stage (0, A), 20 (18%) intermediate stage (B), and 1 (1%) unknown stage. Risk factor analyses were restricted to 1325 patients, including 95 incident HCC, with at least 6 months of follow-up. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m2), and white (86.3%); 42.0% had history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease. Fourteen risk factors for HCC were significant (P < .05) in univariate analyses, and a multivariate subset was selected using stepwise logistic regression. The multivariate subset contained gender (P < .001; male; odds ratio [OR], 2.47; 95% confidence interval [CI], 1.54-4.07), years with cirrhosis (P = .004; OR, 1.06; 95% CI, 1.02-1.1), family history of liver cancer (P = .02; yes; OR, 2.69; 95% CI, 1.11-5.86), age (per 5 years; P = .02; OR, 1.17; 95% CI, 1.03-1.33), obesity (P = .02; yes; OR, 1.7; 95% CI, 1.08-2.73), aspartate aminotransferase (log(1+AST); P = .06; OR, 1.54; 95% CI, 0.97-2.42), alpha-fetoprotein (log(1+AFP); P = .07; OR, 1.32; 95% CI, 0.97-1.77), and albumin (P = .10; OR, 0.7; 95% CI, 0.46-1.07). CONCLUSIONS: Thus far, this is the largest prospective and geographically diverse study of a U.S. cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4% per 100 person-years.

Hepatocellular Carcinoma Surveillance Patterns and Outcomes in Patients With Cirrhosis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance is associated with improved early detection and reduced mortality, although practice patterns and effectiveness vary in clinical practice. We aimed to characterize HCC surveillance patterns in a large, diverse cohort of patients with HCC. METHODS: We conducted a retrospective cohort study of patients diagnosed with HCC between January 2008 and December 2022 at 2 large US health systems. We recorded imaging receipt in the year before HCC diagnosis: ultrasound plus α-fetoprotein (AFP), ultrasound alone, multiphasic contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI), and no liver imaging. We used multivariable logistic and Cox regression analysis to compare early tumor detection, curative treatment receipt, and overall survival between surveillance strategies. RESULTS: Among 2028 patients with HCC (46.7% Barcelona Clinic Liver Cancer stage A), 703 (34.7%) had ultrasound plus AFP, 293 (14.5%) had ultrasound alone, 326 (16.1%) had multiphasic CT/MRI, and 706 (34.8%) had no imaging in the year before HCC diagnosis. Over the study period, proportions without imaging were stable, whereas use of CT/MRI increased. Compared with no imaging, CT/MRI and ultrasound plus AFP, but not ultrasound alone, were associated with early stage HCC detection and curative treatment. Compared with ultrasound alone, CT/MRI and ultrasound plus AFP were associated with increased early stage detection. CONCLUSIONS: HCC surveillance patterns vary in clinical practice and are associated with differing clinical outcomes. While awaiting data to determine if CT or MRI surveillance can be performed in a cost-effective manner in selected patients, AFP has a complementary role to ultrasound-based surveillance, supporting its adoption in practice guidelines.

Regional Differences in Clinical Presentation and Prognosis of Patients With Post-Sustained Virologic Response Hepatocellular Carcinoma.

BACKGROUND & AIMS: Widespread use of direct-acting antivirals for hepatitis C virus infection has been paralleled with increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response (post-SVR HCC) worldwide. Few data compare regional differences in the presentation and prognosis of patients with post-SVR HCC. METHODS: We identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March 2015 and October 2021 from 30 sites in Europe, North America, South America, the Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis. RESULTS: Among 8796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of patients detected by surveillance (range: 59.5%-100%), median maximum tumor diameter (range, 1.8-5.0 cm), and the proportion with multinodular HCC (range, 15.4%-60.8%). The prognosis of patients highly varied by region (hazard ratio range, 1.82-9.92), with the highest survival rates in East Asia, North America, and South America, and the lowest survival rates in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early stage detection (Barcelona Clinic Liver Cancer stage 0/A, 71.0% vs 21.3%; P < .0001) and lower mortality rates (adjusted hazard ratio, 0.29; 95% CI, 0.18-0.46). CONCLUSIONS: Clinical characteristics, including early stage detection, and prognosis of post-SVR HCC differed significantly across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally.

An Emulated Clinical Trial of Deprescribing Proton Pump Inhibitors in Patients With Cirrhosis.

INTRODUCTION: Proton pump inhibitors (PPI) are overused and carry harms in cirrhosis. Deprescribing is advocated but has not been trialed. METHODS AND FINDINGS: We emulated a clinical trial using Medicare data. All patients were receiving chronic PPI therapy before a compensated cirrhosis diagnosis. We compared the risk death/decompensation over 3 years between continuous users and deprescribers. We find that PPI deprescription is associated with less ascites and that cumulative PPI use is associated with more ascites and encephalopathy. Ultimately, 71% of deprescribers restart PPIs. DISCUSSION: PPI deprescribing has benefits but requires ongoing support and alternative therapies for gastrointestinal symptoms.

Proportion of Time Covered by Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis.

INTRODUCTION: Hepatocellular carcinoma (HCC) surveillance is associated with improved early tumor detection, but effectiveness is limited by underuse. We characterized adherence to HCC surveillance using proportion of time covered (PTC) and estimated its association with clinical outcomes among patients with cirrhosis. METHODS: We conducted a retrospective cohort study of patients diagnosed with HCC between January 2008 and December 2022 at 2 large US health systems. We characterized PTC by imaging in the 12 and 24 months before HCC diagnosis. We used multivariable logistic and Cox regression analyses to assess the association between PTC and early HCC detection, receipt of curative treatment, and overall survival. RESULTS: Among 2,027 patients with HCC, 331 (51.4% Barcelona Clinic Liver Cancer 0/A) had been followed up for at least 12 months before diagnosis. The median PTC was 24.9% (interquartile range 1.1%-50.7%), with only 16.0% having semiannual imaging and 42.0% having annual surveillance. Semiannual and annual surveillance decreased to 6.3% and 29.6% when assessed over 24 months, although the median PTC remained unchanged at 24.9%. Receipt of gastroenterology/hepatology care had the strongest association with PTC, with median PTC of 36.7% and 3.8% for those with and without gastroenterology/hepatology care, respectively. PTC was independently associated with improved early HCC detection, curative treatment receipt, and overall survival. The median survival was 15.7, 26.8, and 32.7 months among those with PTC of <25% (n = 168 patients), PTC 25%-50% (n = 69 patients), and PTC >50% (n = 94 patients), respectively. DISCUSSION: The proportion of time covered by HCC surveillance in patients with cirrhosis remains low, highlighting a need for multilevel interventions.

Natural History of Indeterminate Liver Nodules in Patients With Advanced Liver Disease: A Multicenter Retrospective Cohort Study.

INTRODUCTION: Indeterminate liver nodules (ILNs) are frequently encountered on diagnostic imaging after positive hepatocellular carcinoma (HCC) surveillance results, but their natural history remains unclear. METHODS: We conducted a multicenter retrospective cohort study among patients with ≥1 newly detected LI-RADS 3 (LR-3) lesion ≥1 cm or LI-RADS 4 (LR-4) lesion of any size (per LI-RADS v2018) between January 2018 and December 2019. Patients were followed with repeat imaging at each site per institutional standard of care. Multivariable Fine-Gray models were used to evaluate associations between potential risk factors and patient-level time-to-HCC diagnosis, with death and liver transplantation as competing risks. RESULTS: Of 307 patients with ILNs, 208 had LR-3 lesions, 83 had LR-4 lesions, and 16 had both LR-3 and LR-4 lesions. HCC incidence rates for patients with LR-3 and LR-4 lesions were 110 (95% CI 70-150) and 420 (95% CI 310-560) per 1,000 person-year, respectively. In multivariable analysis, incident HCC among patients with LR-3 lesions was associated with older age, thrombocytopenia (platelet count ≤150 ×10 9 /L), and elevated serum alpha-fetoprotein levels. Among those with LR-4 lesions, incident HCC was associated with a maximum lesion diameter >1 cm. Although most patients had follow-up computed tomography or magnetic resonance imaging, 13.7% had no follow-up imaging and another 14.3% had follow-up ultrasound only. DISCUSSION: ILNs have a high but variable risk of HCC, with 4-fold higher risk in patients with LR-4 lesions than those with LR-3 lesions, highlighting a need for accurate risk stratification tools and close follow-up in this population.

The Future Role of Abdominal US in Hepatocellular Carcinoma Surveillance.

Abdominal US is currently the best-validated surveillance strategy for hepatocellular carcinoma (HCC) in at-risk patients. It is the only modality shown to have completed all five phases of validation and can achieve high sensitivity and specificity for HCC detection, especially when conducted by expert sonographers in high-volume centers. However, US also has limitations, including operator dependency and varying sensitivity in clinical practice. Further, the sensitivity of US for early-stage HCC detection is lower in patients with obesity or nonviral liver disease, increasingly common populations undergoing surveillance. Imaging-based and blood-based surveillance strategies, including abbreviated MRI and biomarker panels, may overcome some limitations of US-based surveillance. Both strategies have promising test performance in phase II and phase III biomarker studies and are undergoing prospective validation. Considering the variation in HCC risk and test performance between patients, there will likely be a shift away from a one-size-fits-all approach and toward precision screening, in which the "best" test is selected based on individual patient characteristics. In this upcoming era of precision HCC screening among patients with cirrhosis, US will likely continue to have an important, albeit reduced, surveillance role.

Association between bridging therapy and posttransplant outcomes in patients with HCC within Milan criteria: A systematic review and meta-analysis.

Liver transplantation is the curative therapy of choice for patients with early-stage HCC. Locoregional therapies are often employed as a bridge to reduce the risk of waitlist dropout; however, their association with posttransplant outcomes is unclear. We conducted a systematic review using Ovid MEDLINE and EMBASE to identify studies published between database inception and August 2, 2023, which reported posttransplant recurrence-free survival and overall survival among patients transplanted for HCC within Milan criteria, stratified by receipt of bridging therapy. Pooled HRs were calculated for each outcome using the DerSimonian and Laird method for a random-effects model. We identified 38 studies, including 19,671 patients who received and 20,148 patients who did not receive bridging therapy. Bridging therapy was not associated with significant differences in recurrence-free survival (pooled HR: 0.91, 95% CI: 0.77-1.08; I2 =39%) or overall survival (pooled HR: 1.09, 95% CI: 0.95-1.24; I2 =47%). Results were relatively consistent across subgroups, including geographic location and study period. Studies were discordant regarding the differential strength of association by pretreatment tumor burden and pathologic response, but potential benefits of locoregional therapy were mitigated in those who received 3 or more treatments. Adverse events were reported in a minority of studies, but when reported occurred in 6%-15% of the patients. Few studies reported loss to follow-up and most had a risk of residual confounding. Bridging therapy is not associated with improvements in posttransplant recurrence-free or overall survival among patients with HCC within Milan criteria. The risk-benefit ratio of bridging therapy likely differs based on the risk of waitlist dropout.

Contemporary management of pain in cirrhosis: Toward precision therapy for pain.

Chronic pain is highly prevalent in patients with cirrhosis and is associated with poor health-related quality of life and poor functional status. However, there is limited guidance on appropriate pain management in this population, and pharmacologic treatment can be harmful, leading to adverse outcomes, such as gastrointestinal bleeding, renal injury, falls, and hepatic encephalopathy. Chronic pain can be categorized mechanistically into three pain types: nociceptive, neuropathic, and nociplastic, each responsive to different therapies. By discussing the identification, etiology, and treatment of these three mechanistic pain descriptors with a focus on specific challenges in patients with cirrhosis, we provide a framework for better tailoring treatments, including nonpharmacologic therapies, to patients' needs.

Peak insulin drip rate associated with decreased infections post-solid organ transplant.

Infection and rejection outcomes were retrospectively analyzed in patients following liver transplant and separately following heart transplant with patients being stratified by their severity of immediate postoperative insulin resistance as measured by the peak insulin drip rate that was required to reduce glucose levels. For each group, these peak insulin drip rates were divided into quartiles (Q). In liver transplant patients (n = 207), those in Q4 (highest infusion rate) had significantly fewer infections up to 6 months post-transplant (42.3% vs. 60.0%, p = .036) and borderline fewer rejection episodes (25.0% vs. 40.0%, p = .066) compared to Q1-Q3 patients. To confirm these unexpected results, a subsequent similar analysis in heart transplant (n = 188) patients again showed that Q4 patients had significantly fewer infections up to 6 months (19.1% vs. 53.9%, p < .0001) compared to Q1-Q3 patients. Logistic regression in a subset of 103 cardiac transplant patients showed that the maximum glucose during surgery, prior MI, and hypertension were associated with severe insulin resistance (SIR) status, while the presence of pre-existing diabetes and BMI were not. We hypothesize that patients are who are able to mount a more robust counter-regulatory response that causes the insulin resistance may be healthier and thus able to mount a better response to infections.

Association between Patient Experience Scores and Low Utilization of Hepatocellular Carcinoma Treatment in the United States: A Surveillance, Epidemiology, and End Results-Consumer Assessment of Healthcare Providers and Systems Analysis (SEER-CAHPS).

PURPOSE: To study the experiences of patients with hepatocellular carcinoma (HCC) contributing to treatment discrepancy in the United States. MATERIALS AND METHODS: Using Surveillance, Epidemiology, and End Results data from National Cancer Institute (NCI), Medicare (2002-2015) beneficiaries with HCC who completed a Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey were included. Six CAHPS items (3 global scores: global care rating [GCR], primary doctor rating [PDR], and specialist rating [SR]; 3 composite scores: getting needed care [GNC], getting care quickly [GCQ], and doctor communication [DC]) assessed patient experience. Covariates assessed between treated and nontreated groups included patient, disease, hospital, and CAHPS items. RESULTS: Among 548 patients with HCC, 211 (39%) received treatment and 337 (61%) did not receive treatment. Forty-two percent (GCR), 29% (PDR), 30% (SR), 36% (GNC), 78% (GCQ), and 35% (DC) of patients reported less-than-excellent experiences on the respective CAHPS items. Chronic liver disease (CLD) was present in 52% and liver decompensation (LD) in 60%. A minority of the hospitals were NCI-designated cancer centers (47%), transplant centers (27%), and referral centers (9%). On univariable analysis, patients with at least a high school degree (odds ratio [OR], 1.9), admittance to a ≥400-bed hospital (OR, 2.7), CLD (OR, 3.0), or LD (OR, 1.7) were more likely to receive treatment, whereas older patients (≥75 years) (OR, 0.5) were less likely to receive treatment. On multivariable, patients with CLD (OR, 6.8) and an excellent experience in GNC with a specialist (OR, 10.6) were more likely to receive treatment. CONCLUSIONS: HCC treatment discrepancy may be associated with patient-related factors, such as lack of specialist care (GNC), and disease-related factors, such as absence of underlying CLD.

Downstaging hepatocellular carcinoma before liver transplantation: A multicenter analysis of the "all-comers" protocol in the Multicenter Evaluation of Reduction in Tumor Size before Liver Transplantation (MERITS-LT) consortium.

Patients with hepatocellular carcinoma meeting united network for organ sharing (UNOS)-downstaging (DS) criteria have excellent liver transplantation (LT) outcomes after DS. However, outcomes for "all-comers" (AC) patients with tumors initially exceeding UNOS-DS are poorly understood. Patients meeting AC (n = 82) or UNOS-DS (n = 229) at 7 LT centers in 4 UNOS regions were prospectively followed from 2015-2020. AC patients had a lower probability of successful DS (67% vs 83% within 12 months; P < .001). The 3-year survival was 69% for UNOS-DS vs 58% for AC (P = .05) and reduced to 30% in patients with Child-Pugh B/C cirrhosis or alpha-fetoprotein (AFP) ≥ 500. Five-year LT probability was 42% for AC vs 74% in UNOS-DS (P = .10). Thirty-eight percent were understaged on explant, with the increasing sum of the largest tumor diameter plus the number of lesions before LT (odds ratio 1.3; P = .01) and AFP ≥ 20 (odds ratio 5.9; P = .005) associated with understaging. Post-LT 3-year survival was 91% for AC vs 81% for UNOS-DS (P = .67). In this first prospective multiregional study of AC patients from the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium, we observed a 65% probability of successful DS. Three-year survival in AC was nearly 60%, though AC with Child-Pugh B/C or AFP ≥ 500 had poor survival. Explant pathology and 3-year post-LT outcomes were similar between cohorts, suggesting that LT is a reasonable goal in selected AC patients.

Successful living donor liver transplantation in a patient with hemophilia A and factor VIII inhibitor: A case report with perioperative recommendations.

Liver transplantation in patients with end-stage liver disease and coexisting hemophilia A has been described. Controversy exists over perioperative management of patients with factor VIII inhibitor predisposing patients to hemorrhage. We describe the case of a 58-year-old man with a history of hemophilia A and factor VIII inhibitor, eradicated with rituximab prior to living donor liver transplantation without recurrence of inhibitor. We also provide perioperative management recommendations from our successful multidisciplinary approach.

Blood-based biomarkers for hepatocellular carcinoma screening: Approaching the end of the ultrasound era?

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, in part because of inadequate early detection strategies. Current recommendations for screening consist of semi-annual abdominal ultrasound with or without serum alpha-fetoprotein in patients with cirrhosis and in demographic subgroups with chronic hepatitis B infection. However, this screening strategy has several deficiencies, including suboptimal early-stage sensitivity, false positives with subsequent harms, inter-operator variability in ultrasound performance, and poor adherence. A blood-based biomarker with sufficient performance characteristics for early-stage disease could overcome several of these barriers to improving early-stage detection. However, prior to use of a biomarker for screening in clinical practice, a multistep validation is required in order to understand test performance characteristics. These steps include case-control validation, followed by validation in prospective cohorts of at-risk patients. Until recently, we lacked adequate longitudinal validation cohorts for early HCC detection; however, several validation cohorts are maturing, including the Hepatocellular Carcinoma Early Detection Study and the Texas Hepatocellular Carcinoma Consortium, which will allow for rigorous validation of candidate biomarkers. While there are several promising biomarkers awaiting validation, in order to supplant abdominal ultrasound, a candidate biomarker must show adequate test performance and overcome practical hurdles to ensure adoption in clinical practice. The promise of blood-based biomarkers is significant, especially given the limitations of ultrasound-based screening; however, they require adequate validation and several logistical obstacles must be overcome prior to clinical implementation.

International Liver Cancer Association (ILCA) white paper on hepatocellular carcinoma risk stratification and surveillance.

Major research efforts in liver cancer have been devoted to increasing the efficacy and effectiveness of surveillance for hepatocellular carcinoma (HCC). As with other cancers, surveillance programmes aim to detect tumours at an early stage, facilitate curative-intent treatment, and reduce cancer-related mortality. HCC surveillance is supported by a large randomised-controlled trial in patients with chronic HBV infection and several cohort studies in cirrhosis; however, effectiveness in clinical practice is limited by several barriers, including inadequate risk stratification, underuse of surveillance, and suboptimal accuracy of screening tests. There are several proposed strategies to address these limitations, including risk stratification algorithms and biomarkers to better identity at-risk individuals, interventions to increase surveillance, and emerging imaging- and blood-based surveillance tests with improved sensitivity and specificity for early HCC detection. Beyond clinical validation, data are needed to establish clinical utility, i.e. increased early tumour detection and reduced HCC-related mortality. If successful, these data could facilitate a precision screening paradigm in which surveillance strategies are tailored to individual HCC risk to maximise overall surveillance value. However, practical and logistical considerations must be considered when designing and implementing these validation efforts. To address these issues, ILCA (the International Liver Cancer Association) adjourned a single topic workshop on HCC risk stratification and surveillance in June 2022. Herein, we present a white paper on these topics, including the status of the field, ongoing research efforts, and barriers to the translation of emerging strategies.

Risk of Hepatocellular Carcinoma in Patients With Indeterminate (LI-RADS 3) Liver Observations.

Early hepatocellular cancer (HCC) detection is associated with curative treatment and improved survival.1 The American Association for the Study of Liver Diseases recommends semiannual ultrasound and α-fetoprotein (AFP) in patients with cirrhosis, and those with abnormal results should undergo diagnostic multiphase computed tomography (CT) or magnetic resonance imaging (MRI).2 The Liver Imaging Reporting and Data System (LI-RADS) was devised to standardize reporting of liver observations in at-risk individuals, ranging from LR-1 ("definitely benign") to LR-5 ("definitely HCC''), with indeterminate observations classified as LR-3 ("intermediate probability of malignancy").3 A study among 999 cirrhosis patients found that indeterminate liver observations are common, being reported on diagnostic CT or MRI in 98 (38.3%) of 256 patients with abnormal ultrasound results.4 Prior studies have reported a wide range in HCC risk, from 4% to 31%, for LR-3 observations, so there is insufficient evidence to recommend a standardized strategy for monitoring LR-3 observations.5,6.

Clinical Outcomes of Patients With Suspicious (LI-RADS 4) Liver Observations.

Hepatocellular cancer (HCC) surveillance is associated with increased curative treatment and improved survival, underscoring its importance in patients with cirrhosis.1 Surveillance is 1 step in a larger HCC screening continuum, and those with abnormal screening results must undergo diagnostic evaluation with multiphase computed tomography (CT) or magnetic resonance imaging (MRI).2 The Liver Imaging Reporting and Data System (LI-RADS) classifies liver observations in at-risk patients based on risk of malignancy and HCC, with LR-5 observations having a positive predictive value exceeding 95% for HCC. However, indeterminate liver nodules (ie, LR-3 or LR-4) are commonly observed in clinical practice, associated with heterogenous HCC risk, and have large variations in practice management.3,4 We previously reported the natural history of LR-3 observations in a multicenter cohort of patients with cirrhosis, demonstrating a high annual incidence for HCC development of 8.4 cases per 100 person-years;5 however, the natural history of LR-4 observations remains uncertain. Herein, we aimed to characterize clinical outcomes in patients with LR-4 observations in a multicenter cohort.