Advancing Surveillance Strategies for Hepatocellular Carcinoma: A New Era of Efficacy and Precision.

Hepatocellular carcinoma (HCC) is one of the few cancers with a 5-year survival that has remained below 20%; however, prognosis differs by tumor stage at diagnosis. Curative treatment options among patients with early-stage HCC afford a median survival of 5-10 years. Accordingly, international society guidelines recommend semi-annual HCC surveillance in at-risk patients, including those with cirrhosis or high-risk chronic hepatitis B infection. Surveillance is associated with increased early-stage HCC detection and curative treatments, leading to reduced HCC-related mortality. Abdominal ultrasound has been the cornerstone for HCC surveillance for the past two decades, but recent data have highlighted its suboptimal sensitivity for early-stage HCC detection, particularly in patients with obesity and those with non-viral etiologies of liver disease. The combination of ultrasound plus alpha fetoprotein (AFP) has higher sensitivity for early-stage HCC detection than ultrasound alone, although the combination still misses over one-third of HCC at an early stage. Emerging imaging and blood-based biomarker strategies have promising data in biomarker phase 2 (case-control) and phase 3 (cohort) studies. Beyond ultrasound, Magnetic resonance imaging (MRI) is the best-studied imaging strategy, with superior sensitivity and specificity compared to ultrasound in a cohort study. Abbreviated MRI protocols have been proposed to address concerns about MRI radiological capacity, costs, and patient acceptance. Of biomarker strategies, GALAD (a panel including gender, age, AFP, AFP-L3, and DCP) is the best validated, with promising sensitivity for early-stage HCC detection in a national multi-center cohort study. Liquid biopsy biomarkers, including methylated DNA markers, have also shown promising accuracy in case-control studies. Abbreviated MRI and GALAD are now entering prospective trials that examine clinical outcomes such as early-stage HCC detection and screening-related harms, which are essential data to understand for adoption in clinical practice. As additional surveillance strategies become available, it will allow an era of precision surveillance in which optimal surveillance modalities are tailored to individual patient risk and expected test performance.

Systemic Therapies for Hepatocellular Carcinoma in India.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in India. This review explores the epidemiological trends and the landscape of systemic therapy for HCC in the Indian context, acknowledging the recent shift in etiology from viral hepatitis to lifestyle-associated factors. A comprehensive review of the literature was conducted, including data from the Global Cancer Observatory and the Indian Council of Medical Research, along with a critical analysis of various clinical trials. The article investigates systemic therapies in-depth, discussing their mechanisms, efficacy, and adaptation to Indian healthcare framework. Progression-free survival with a hazard ratio of ≤0.6 compared to sorafenib, overall survival of ∼16-19 months, and objective response rate of 20-30% are the defining thresholds for systemic therapy clinical trials. Systemic therapy for advanced HCC in India primarily involves the use of tyrosine kinase inhibitors such as sorafenib, lenvatinib, regorafenib, and cabozantinib, with sorafenib being the most commonly used drug for a long time. Monoclonal antibodies such as ramucirumab and bevacizumab and immune-checkpoint inhibitors, such as atezolizumab, nivolumab, and pembrolizumab, are expanding treatment horizons. Lenvatinib has emerged as a cost-effective alternative, and the combination of atezolizumab and bevacizumab has demonstrated superior outcomes in terms of overall survival and progression-free survival. Despite these advances, late-stage diagnosis and limited healthcare accessibility pose significant challenges, often relegating patients to palliative care. Addressing HCC in India demands an integrative approach that not only encompasses advancements in systemic therapy but also targets early detection and comprehensive care models. Future strategies should focus on enhancing awareness, screening for high-risk populations, and overcoming infrastructural disparities. Ensuring the judicious use of systemic therapies within the constraints of the Indian healthcare economy is crucial. Ultimately, a nuanced understanding of systemic therapeutic options and their optimal utilization will be pivotal in elevating the standard of HCC care in India.

Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis.

BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

Immunotherapy vs Best Supportive Care for Patients With Hepatocellular Cancer With Child-Pugh B Dysfunction.

Importance: Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated. Objective: To evaluate the association of immune checkpoint inhibitor (ICI)-based therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction. Design, Setting, and Participants: This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status. Exposures: Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n = 141) or nivolumab (n = 46). Main Outcomes and Measures: OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups. Results: The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P < .001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death. Conclusions and Relevance: The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.

Neoadjuvant and adjuvant systemic therapy in HCC: Current status and the future.

Surgical therapies in patients with early-stage HCC can afford long-term survival but are often limited by the continued risk of recurrence, underscoring an interest in (neo)adjuvant strategies. Prior attempts at adjuvant therapy using tyrosine kinase inhibitors failed to yield significant improvements in recurrence-free survival or overall survival. Advances in the efficacy of systemic therapy options, including the introduction of immune checkpoint inhibitors, have fueled renewed interest in this area. Indeed, the IMBrave050 trial recently demonstrated significant improvements in recurrence-free survival with 1 year of adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing surgical resection or ablation, with several other ongoing trials in this space. There is a strong rationale for consideration of the administration of these therapies in the neoadjuvant setting, supported by early clinical data demonstrating high rates of objective responses, although larger trials examining downstream outcomes are necessary, particularly considering the possible risks of this strategy. In parallel, there has been increased interest in using systemic therapies as a bridging or downstaging strategy for liver transplantation. Current data suggest the short-term safety of this approach, with acceptable rates of rejection, so immunotherapy is not considered a contraindication to transplant; however, larger studies are needed to evaluate the incremental value of this approach over locoregional therapy. Conversely, the use of immunotherapy is currently discouraged after liver transplantation, given the high risk of graft rejection and death. The increasing complexity of HCC management and increased consideration of (neo)adjuvant strategies highlight the critical role of multidisciplinary care when making these decisions.

Financial burden in a US cohort of patients with HCC.

BACKGROUND: High financial burden for patients has been reported for multiple types of cancer, but there are limited data in those with HCC. We aimed to describe the financial burden for patients diagnosed with HCC and identify correlates of high financial burden. METHODS: We used the IQVIA PharMetrics Plus for Academics database to identify commercially insured patients diagnosed with HCC between 2006 and 2021. Patient financial liability was defined as the difference between allowed and paid amounts from adjudicated insurance claims. We reported total and HCC-related financial liabilities (i.e., cost for HCC-related claims), with high total financial liability defined as ≥$3000 annually and high HCC-related financial liability as ≥$1000 annually. We used multivariable logistic regression modeling to identify factors associated with high total and HCC-related financial liability. RESULTS: Among 11,609 patients with HCC, the median total financial liability during the year after HCC diagnosis was $2955 (Q1-Q3: $972-$6293). Nearly half (45%) of patients experienced high total financial liability, with the greatest liability incurred in the 3-month period immediately following HCC diagnosis. Older age, increased comorbidity, and cirrhosis-related complications were associated with higher total patient liability. Patient liability also varied by type of HCC treatment, with systemic therapy and liver transplantation having the highest financial liability in multivariable analysis. However, only 66.7% of the patients experienced HCC-related liability. CONCLUSIONS: Patients with HCC experience significant financial liability underscoring a need for price transparency as well as financial counseling in this population.

PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer.

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.

Psychiatric disorders in patients with hepatocellular carcinoma: A large US cohort of commercially insured individuals.

BACKGROUND/AIMS: Patients with hepatocellular cancer (HCC) are vulnerable to psychological distress given a new cancer diagnosis superimposed on pre-existing chronic liver disease. We aimed to characterise the psychiatric burden in HCC, risk factors for incident diagnosis and treatment patterns over time. METHODS: Using IQVIA PharMetrics® Plus for Academics-a nationally representative claims database of the commercially insured US population-we identified psychiatric diagnoses and treatment among patients with newly diagnosed HCC. Multivariable logistic regression modelling identified factors associated with psychiatric diagnosis and treatment. RESULTS: Of 11,609 patients with HCC, 2166 (18.6%) had a psychiatric diagnosis after cancer diagnosis with depression (58.3%) and anxiety (53.0%) being most common. Women (aOR 1.33, 95% CI [1.19-1.49]), pre-existing psychiatric diagnoses (aOR 9.12 [8.08-10.3]) and HCC treatment type (transplant: aOR 2.15 [1.66-2.77]; locoregional therapies: aOR 1.74 [1.52-1.99]; hospice: aOR 2.43 [1.79-3.29]) were significantly associated with psychiatric diagnosis. Female sex, ascites, higher comorbidity and treatment type were associated with incident psychiatric diagnosis. Pharmacotherapy was used in 1392 (64.3%) patients with a psychiatric diagnosis, with antidepressants (46.2%) and anxiolytics (32.8%) being most common. Psychiatric diagnoses increased from 14.8% in 2006-2009 to 21.1% in 2018-2021 (p < 0.001). In almost 20% of patients with pre-existing psychiatric conditions, therapy was discontinued after HCC diagnosis. CONCLUSIONS: Nearly 2 of 10 patients with HCC were diagnosed with a psychiatric condition after cancer diagnosis with unique sociodemographic and clinical risk factors identified. This highlights a risk for increased psychological burden in need of early evaluation and treatment among patients with newly diagnosed HCC.

HES V2.0 outperforms GALAD for detection of HCC: A phase 3 biomarker study in the United States.

BACKGROUND AND AIMS: The original hepatocellular carcinoma early detection screening (HES) score, which combines alpha-fetoprotein (AFP) with age, alanine aminotransferase, and platelets, has better performance than AFP alone for early HCC detection. We have developed HES V2.0 by adding AFP-L3 and des-gamma-carboxy prothrombin to the score and compared its performance to GALAD and ASAP scores among patients with cirrhosis. APPROACH AND RESULTS: We conducted a prospective-specimen collection, retrospective-blinded-evaluation phase 3 biomarker cohort study in patients with cirrhosis enrolled in imaging and AFP surveillance. True-positive rate (TPR)/sensitivity and false-positive rate for any or early HCC were calculated for GALAD, ASAP, and HES V2.0 scores within 6, 12, and 24 months of HCC diagnosis. We calculated the AUROC curve and estimated TPR based on an optimal threshold at a fixed false-positive rate of 10%. We analyzed 2331 patients, of whom 125 developed HCC (71% in the early stages). For any HCC, HES V2.0 had higher TPR than GALAD overall (+7.2%), at 6 months (+3.6%), at 12 months (+7.2%), and 24 months (+13.0%) before HCC diagnosis. HES V2.0 had higher TPR than ASAP for all time points (+5.9% to +12.0%). For early HCC, HES V2.0 had higher sensitivity/TPR than GALAD overall (+6.7%), at 12 months (+6.3%), and 24 months (+14.6%) but not at 6 months (+0.0%) and higher than ASAP for all time points (+13.4% to +18.0%). CONCLUSIONS: In a prospective cohort study, HES V2.0 had a significantly higher performance for identifying new HCC, including early stage, than GALAD or ASAP.

Impact of the Early COVID-19 Pandemic on Incidence and Outcomes of Hepatocellular Carcinoma in the United States.

INTRODUCTION: Access to hepatocellular carcinoma (HCC) surveillance and treatments were disrupted during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to characterize the impact of the pandemic on HCC incidence and mortality rates, treatment, and outcomes in the United States. METHODS: Two nationwide databases, the United States Cancer Statistics and the National Vital Statistics System, were used to investigate HCC incidence and mortality between 2001 and 2020. Trends in age-adjusted incidence rate (aIR) and adjusted mortality rate (aMR) were assessed using joinpoint analysis. The 2020 aIR and aMR were projected based on the prepandemic data and compared with actual values to assess the extent of underdiagnosis. We assessed differences in HCC characteristics, treatment, and overall survival between 2020 and 2018-2019. RESULTS: The aIR of HCC in 2020 was significantly reduced compared with 2019 (5.22 vs 6.03/100K person-years [PY]), representing a 12.2% decrease compared with the predicted aIR in 2020 (5.94/100K PY). The greatest extent of underdiagnosis was observed in Black (-14.87%) and Hispanic (-14.51%) individuals and those with localized HCC (-15.12%). Individuals staged as regional or distant HCC were also less likely to receive treatment in 2020. However, there was no significant difference in short-term overall survival in 2020 compared with 2018-2019, with HCC mortality rates remaining stable (aMR: 2.76 vs 2.73/100K PY in 2020 vs 2019). DISCUSSION: The COVID-19 pandemic resulted in underdiagnosis of HCC, particularly early stage disease and racial ethnic minorities, and underuse of HCC-directed treatment. Longer follow-up is needed to determine the impact of the COVID-19 pandemic on HCC-related mortality.

Effectiveness of mailed outreach and patient navigation to promote HCC screening process completion: a multicentre pragmatic randomised clinical trial.

BACKGROUND: Hepatocellular carcinoma (HCC) is plagued by failures across the cancer care continuum, leading to frequent late-stage diagnoses and high mortality. We evaluated the effectiveness of mailed outreach invitations plus patient navigation to promote HCC screening process completion in patients with cirrhosis. METHODS: Between April 2018 and September 2021, we conducted a multicentre pragmatic randomised clinical trial comparing mailed outreach plus patient navigation for HCC screening (n=1436) versus usual care with visit-based screening (n=1436) among patients with cirrhosis at three US health systems. Our primary outcome was screening process completion over a 36-month period, and our secondary outcome was the proportion of time covered (PTC) by screening. All patients were included in intention-to-screen analyses. RESULTS: All 2872 participants (median age 61.3 years; 32.3% women) were included in intention-to-screen analyses. Screening process completion was observed in 6.6% (95% CI: 5.3% to 7.9%) of patients randomised to outreach and 3.3% (95% CI: 2.4% to 4.3%) of those randomised to usual care (OR 2.05, 95% CI: 1.44 to 2.92). The intervention increased HCC screening process completion across most subgroups including age, sex, race and ethnicity, Child-Turcotte-Pugh class and health system. PTC was also significantly higher in the outreach arm than usual care (mean 37.5% vs 28.2%; RR 1.33, 95% CI: 1.31 to 1.35). Despite screening underuse, most HCC in both arms were detected at an early stage. CONCLUSION: Mailed outreach plus navigation significantly increased HCC screening process completion versus usual care in patients with cirrhosis, with a consistent effect across most examined subgroups. However, screening completion remained suboptimal in both arms, underscoring a need for more intensive interventions. TRIAL REGISTRATION NUMBER: NCT02582918.

Prognostic Value of Liver Biomarkers in Hepatocellular Carcinoma Patients Undergoing Yttrium 90 Transarterial Radioembolization (TARE): A Retrospective Pilot Study.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide. The prognosis for HCC depends on the tumor stage, and curative therapies are more accessible in the early stages. However, effective treatments are available even in advanced stages. Transarterial radioembolization (TARE) is an alternative to transarterial chemoembolization (TACE) with reduced risk and extended disease progression time. Identifying prognostic indicators and treatment response biomarkers remains crucial. The purpose of this study was to assess the association between biomarkers related to fibrosis, liver function, and immune inflammation with tumor response to yttrium 90 transarterial radiotherapy (Y90 or TARE) in patients with HCC. METHODS: This study enrolled patients who underwent Y90 radiotherapy for bridging, downstaging, or palliative treatment after discussion in a multidisciplinary tumor board. Using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), tumor response was classified into two groups: "responders" (complete and partial response) and "non-responders" (stable and progressive disease). Logistic regression analysis was used to evaluate the association between predictors, biomarkers such as aspartate aminotransferase (AST)-to-platelet ratio index (APRI), fibrosis-4 (FIB-4), albumin-bilirubin (ALBI) score, model for end-stage liver disease (MELD) score, MELD sodium, and the systemic immune-inflammatory indexes, at established cut-offs and tumor response. RESULTS: Of 35 patients, 22 (63%) were Whites and non-Hispanics, 32 (91%) were diagnosed with cirrhosis, and 14 (40%) of these had a viral etiology. According to mRECIST, 18 (51%) patients were classified as "responders." In multivariable logistic regression analysis, biomarkers associated with tumor response were ALBI score ≤-2.8 (odds ratio (OR) 6.1, 95%CI 2.7-14.4) and the neutrophil-to-lymphocyte ratio (NLR) ≤ 1.92 (OR 5.1, 95%CI 0.8-11.9). Biomarkers had moderate accuracy in predicting tumor response (C-statistic 0.75). CONCLUSION: The ALBI score is a reliable predictor of treatment response following TARE. The NLR index may offer further prognostic information, and both biomarkers can be used in combination; however, further research in larger sample sets is needed.

PNPLA3, Obesity, and Heavy Alcohol Use in Cirrhosis Patients May Exert a Synergistic Increase Hepatocellular Carcinoma Risk.

BACKGROUND & AIMS: In patients with cirrhosis, continued heavy alcohol consumption and obesity may increase risk of hepatocellular carcinoma (HCC). We examined whether germline susceptibility to hepatic steatosis not only independently predisposes to HCC but may also act synergistically with other risk factors. METHODS: We analyzed data from 1911 patients in 2 multicenter prospective cohort studies in the United States. We classified patients according to alcohol consumption (current heavy vs not current heavy), obesity (body mass index ≥30 vs <30 kg/m2), and PNPLA3 I148M variant status (carrier of at least one G risk allele vs noncarrier). We examined the independent and joint effects of these risk factors on risk of developing HCC using Cox regression with competing risks. RESULTS: Mean age was 59.6 years, 64.3% were male, 28.7% were Hispanic, 18.3% were non-Hispanic Black, 50.9% were obese, 6.2% had current heavy alcohol consumption, and 58.4% harbored at least 1 PNPLA3 G-allele. One hundred sixteen patients developed HCC. Compared with PNPLA3 noncarriers without heavy alcohol consumption, HCC risk was 2.65-fold higher (hazard ratio [HR], 2.65; 95% confidence interval [CI], 1.20-5.86) for carriers who had current heavy alcohol consumption. Compared with noncarrier patients without obesity, HCC risk was higher (HR, 2.40; 95% CI, 1.33-4.31) for carrier patients who were obese. PNPLA3 and alcohol consumption effect was stronger among patients with viral etiology of cirrhosis (HR, 3.42; 95% CI, 1.31-8.90). PNPLA3 improved 1-year risk prediction for HCC when added to a clinical risk model. CONCLUSIONS: The PNPLA3 variant may help refine risk stratification for HCC in patients with cirrhosis with heavy alcohol consumption or obesity who may need specific preventive measures.

Psychiatric diagnoses are common after liver transplantation and are associated with increased health care utilization and patient financial burden.

Psychiatric disorders after liver transplantation (LT) are associated with worse patient and graft outcomes, which may be amplified by inadequate treatment. We aimed to characterize the burden of psychiatric disorders, treatment patterns, and associated financial burden among liver transplantation recipients (LTRs). IQVIA PharMetrics (R) Plus for Academics-a large health plan claims database representative of the commercially insured US population-was used to identify psychiatric diagnoses among adult LTRs and assess treatment. Multivariable logistic regression analysis identified factors associated with post-LT psychiatric diagnoses and receipt of pharmacotherapy. Patient financial liability was estimated using adjudicated medical/pharmacy claims for LTRs with and without psychiatric diagnoses. Post-LT psychiatric diagnoses were identified in 395 (29.5%) of 1338 LTRs, of which 106 (26.8%) were incident cases. Treatment varied, with 67.3% receiving pharmacotherapy, 32.1% psychotherapy, 21.0% combination therapy, and 21.5% no treatment. Among 340 LTRs on psychotropic medications before transplant, 24% did not continue them post-LT. Post-LT psychiatric diagnoses were independently associated with female sex, alcohol-associated liver disease (ALD), prolonged LT hospitalization (>2 wk), and pre-LT psychiatric diagnosis. Incident psychiatric diagnoses were associated with female sex, ALD, and prolonged LT hospitalization. Patients with a post-LT psychiatric diagnosis had higher rates of hospitalization (89.6% vs. 81.5%, p <0.001) and financial liability (median $5.5K vs. $4.6K USD, p =0.006). Having a psychiatric diagnosis post-LT was independently associated with experiencing high financial liability >$5K. Over 1 in 4 LTRs had a psychiatric diagnosis in a large national cohort, yet nearly a quarter received no treatment. LTRs with psychiatric diagnoses experienced increased health care utilization and higher financial liability. Sociodemographic and clinical risk factors could inform high-risk subgroups who may benefit from screening and mitigation strategies.

Role of biomarkers in the diagnosis and management of HCC.

For many cancers, biomarkers have served as an important tool across the cancer care continuum from risk stratification and early detection to diagnosis and treatment. Alpha-fetoprotein (AFP) remains one of the few validated biomarkers for patients with HCC. Although AFP has shown potential for each of these steps, its performance, when used alone, has often been suboptimal. There continue to be discordant recommendations about AFP's value when combined with ultrasound for surveillance, as well as its role in diagnostic algorithms. Conversely, high AFP levels are associated with aggressive tumor biology and survival, so it remains a key factor for the selection of candidates for liver transplant. There have been immense efforts to identify and validate additional biomarkers for each of these steps in the HCC care continuum. Indeed, biomarker panels have shown promising data for HCC risk stratification and surveillance among patients with cirrhosis, as well as prognostication and detection of minimal residual disease in patients undergoing HCC treatment. Several large prospective studies are currently ongoing to evaluate the role of these emerging biomarkers in clinical practice.

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.

Downstaging with Atezolizumab-Bevacizumab: A Case Series.

Background/aims: Hepatocellular carcinoma (HCC) is generally diagnosed at an advanced stage, which limits curative treatment options for these patients. Locoregional therapy (LRT) is the standard approach to bridge and downstage unresectable HCC (uHCC) for liver transplantation (LT). Atezolizumab-bevacizumab (atezo-bev) can induce objective responses in nearly one-third of patients; however, the role and outcomes of downstaging using atezobev remains unknown. Methods: In this retrospective single-center study, we included consecutive patients between November 2020 and August 2023, who received atezo-bev with or without LRT and were subsequently considered for resection/LT after downstaging. Results: Of the 115 patients who received atezo-bev, 12 patients (10.4%) achieved complete or partial response and were willing to undergo LT; they (age: 58.5 years; women-17%; Barcelona Clinic Liver Cancer Stage System B/C:5/7) had received 3-12 cycles of atezo-bev, and 4 of them had received prior LRT. Three patients died before LT, while three were awaiting LT. Six patients underwent curative therapies: four underwent living donor LT after a median of 79.5 (54-114) days following the last atezo-bev dose, one underwent deceased donor LT 38 days after the last dose, and one underwent resection. All but one patient had complete pathologic response with no viable HCC. Three patients experienced wound healing complications, and one required re-exploration and succumbed to sepsis. After a median follow-up of 10 (4-30) months, none of the alive patients developed HCC recurrence or graft rejection. Conclusions: Surgical therapy, including LT, is possible after atezo-bev therapy in wellselected patients after downstaging.

Clinician-Level Knowledge and Barriers to Hepatocellular Carcinoma Surveillance.

Importance: Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is underused. Identifying potentially modifiable factors to address barriers in HCC surveillance is critical to improve patient outcomes. Objective: To evaluate clinician-level factors contributing to underuse of HCC surveillance in patients with cirrhosis. Design, Setting, and Participants: This survey study included primary care clinicians (PCCs) and gastroenterology and hepatology clinicians at 5 safety-net health systems in the US. Clinicians were surveyed from March 15 to September 15, 2023, to assess knowledge, attitudes, beliefs, perceived barriers, and COVID-19-related disruptions in HCC surveillance in patients with cirrhosis. Data were analyzed from October to November 2023. Main Outcome and Measures: HCC surveillance knowledge was assessed with 6 questions querying the respondent's ability to correctly identify appropriate use of HCC surveillance. Attitudes, perceived barriers, and beliefs regarding HCC surveillance and perceived impact of the COVID-19 pandemic-related disruptions with HCC surveillance were assessed with a series of statements using a 4-point Likert scale and compared PCCs and gastroenterology and hepatology clinicians. Results: Overall, 347 of 1362 clinicians responded to the survey (25.5% response rate), among whom 142 of 237 (59.9%) were PCCs, 48 of 237 (20.3%) gastroenterology and hepatology, 190 of 236 (80.5%) were doctors of medicine and doctors of osteopathic medicine, and 46 of 236 (19.5%) were advanced practice clinicians. On HCC knowledge assessment, 144 of 270 (53.3%) scored 5 or more of 6 questions correctly, 37 of 48 (77.1%) among gastroenterology and hepatology vs 65 of 142 (45.8%) among PCCs (P < .001). Those with higher HCC knowledge scores were less likely to report barriers to HCC surveillance. PCCs were more likely to report inadequate time to discuss HCC surveillance (37 of 139 [26.6%] vs 2 of 48 [4.2%]; P = .001), difficulty identifying patients with cirrhosis (82 of 141 [58.2%] vs 5 of 48 [10.4%]; P < .001), and were not up-to-date with HCC surveillance guidelines (87 of 139 [62.6%] vs 5 of 48 [10.4%]; P < .001) compared with gastroenterology and hepatology clinicians. While most acknowledged delays during the COVID-19 pandemic, 62 of 136 PCCs (45.6%) and 27 of 45 gastroenterology and hepatology clinicians (60.0%) reported that patients with cirrhosis could currently complete HCC surveillance without delays. Conclusions and Relevance: In this survey study, important gaps in knowledge and perceived barriers to HCC surveillance were identified. Effective delivery of HCC education to PCCs and health system-level interventions must be pursued in parallel to address the complex barriers affecting suboptimal HCC surveillance in patients with cirrhosis.

Brief alcohol interventions are underutilized in persons with nonalcohol-associated chronic liver diseases.

BACKGROUND: Brief alcohol interventions use patient-provider communication to promote alcohol cessation. We characterized the receipt of this intervention in chronic liver disease (CLD). METHODS: We surveyed patients with CLD for weekly drinking patterns and examined associations with patient-provider communication receipt. RESULTS: Among 840 participants, 82.1% and 56.5% reported ≥1 standard drink weekly and excessive alcohol consumption, respectively. Patient-provider communication was lower in noncirrhotic (adjusted odds ratio:0.34, 95% CI: 0.22-0.54) and nonalcohol-associated CLD (adjusted odds ratio: 0.22, 95% CI: 0.15-0.34) among individuals drinking ≥1 standard drink weekly, and similarly in noncirrhotic CLD (adjusted odds ratio: 0.45, 95% CI: 0.21-0.95) among those with excessive drinking. CONCLUSIONS: Brief alcohol interventions are underutilized in noncirrhotic and nonalcohol-associated CLD.