Development and Validation of a Noninvasive Model for the Detection of High-Risk Varices in Patients with Unresectable HCC.

BACKGROUND & AIMS: Noninvasive variceal risk stratification systems have not been validated in patients with hepatocellular carcinoma (HCC), which presents logistical barriers for patients in the setting of systemic HCC therapy. We aimed to develop and validate a noninvasive algorithm for the prediction of varices in patients with unresectable HCC. METHODS: We performed a retrospective cohort study in 21 centers in the United States including adult patients with unresectable HCC and Child-Pugh A5-B7 cirrhosis diagnosed between 2007 and 2019. We included patients who completed an esophagogastroduodonoscopy (EGD) within 12 months of index imaging but before HCC treatment. We divided the cohort into a 70:30 training set and validation set, with the goal of maximizing negative predictive value (NPV) to avoid EGD in low-risk patients. RESULTS: We included 707 patients (median age, 64.6 years; 80.6% male; 74.0% White). Median time from HCC diagnosis to EGD was 47 (interquartile range, 114) days, with 25.0% of patients having high-risk varices. A model using clinical variables alone achieved an NPV of 86.3% in the validation cohort, whereas a model integrating clinical and imaging variables had an NPV 97.4% in validation. The clinical and imaging model would avoid EGDs in more than half of low-risk patients while misclassifying 7.7% of high-risk patients. CONCLUSIONS: A model incorporating clinical and imaging data can accurately predict the absence of high-risk varices in patients with HCC and avoid EGD in many low-risk patients before the initiation of systemic therapy, thus expediting their care and avoiding treatment delays.

Resection of NAFLD/NASH-related Hepatocellular Carcinoma (HCC): Clinical Features and Outcomes Compared with HCC Due to Other Etiologies.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the leading causes of hepatocellular carcinoma (HCC) worldwide. Limited data exist on surgical outcomes for NAFLD/NASH-related HCC compared with other HCC etiologies. We evaluated differences in clinicopathological characteristics and outcomes of patients undergoing surgical resection for NAFLD/NASH-associated HCC compared with other HCC etiologies. METHODS: Demographic, clinicopathological features, and survival outcomes of patients with surgically resected HCC were collected. NAFLD activity score (NAS) and fibrosis score were assessed by focused pathologic review in a subset of patients. RESULTS: Among 492 patients screened, 260 met eligibility (NAFLD/NASH [n = 110], and other etiologies [n = 150]). Median age at diagnosis was higher in the NAFLD/NASH HCC cohort compared with the other etiologies cohort (66.7 vs. 63.4 years, respectively, P = .005), with an increased percentage of female patients (36% vs. 18%, P = .001). NAFLD/NASH-related tumors were more commonly >5 cm (66.0% vs. 45%, P = .001). There were no significant differences in rates of lymphovascular or perineural invasion, histologic grade, or serum AFP levels. The NAFLD/NASH cohort had lower rates of background liver fibrosis, lower AST and ALT levels, and higher platelet counts (P < .01 for all). Median overall survival (OS) was numerically shorter in NAFLD/NASH vs other etiology groups, however, not statistically significant. CONCLUSIONS: Patients with NAFLD/NASH-related HCC more commonly lacked liver fibrosis and presented with larger HCCs compared with patients with HCC from other etiologies. No differences were seen in rates of other high-risk features or survival. With the caveat of sample size and retrospective analysis, this supports a similar decision-making approach regarding surgical resection for NAFLD/NASH and other etiology-related HCCs.

Hepatology Consultants Often Disagree on Etiology of Abnormal Liver Biochemistries in COVID-19 but Agree on Management.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with elevated liver biochemistries in approximately half of hospitalized patients, with many possible etiologies. AIM: To assess agreement on the etiology of abnormal liver biochemistries and diagnostic recommendations in COVID-19. METHODS: Twenty hepatology consultations were reviewed by three senior hepatologists who provided a differential diagnosis and diagnostic recommendations. Kappa agreement on the primary etiology was calculated. RESULTS: Kappa agreement between hepatologists on the primary etiology of elevated liver biochemistries was 0.10 (p = 0.03). Agreement was greater around drug-induced liver injury 0.51 (p < 0.0001) and SARS-CoV-2-related liver injury 0.17 (p = 0.03). Serial liver biochemistries were recommended in all consultations over other evaluations. CONCLUSION: In COVID-19, elevated liver biochemistries present a diagnostic challenge and can often be monitored conservatively.

Immediate administration of antiviral therapy after transplantation of hepatitis C-infected livers into uninfected recipients: Implications for therapeutic planning.

The practice of transplanting hepatitis C (HCV)-infected livers into HCV-uninfected recipients has not previously been recommended in transplant guidelines, in part because of concerns over uncontrolled HCV infection of the allograft. Direct-acting antivirals (DAAs) provide an opportunity to treat donor-derived HCV-infection and should be administered early in the posttransplant period. However, evidence on the safety and efficacy of an immediate DAA treatment approach, including how to manage logistical barriers surrounding timely DAA procurement, are required prior to broader use of HCV-positive donor organs. We report the results of a trial in which 14 HCV-negative patients underwent successful liver transplantation from HCV-positive donors. Nine patients received viremic (nucleic acid testing [NAT]-positive) livers and started a 12-week course of oral glecaprevir-pibrentasvir within 5 days of transplant. Five patients received livers from HCV antibody-positive nonviremic donors and were followed using a reactive approach. Survival in NAT-positive recipients is 100% at a median follow-up of 46 weeks. An immediate treatment approach for HCV NAT-positive liver transplantation into uninfected recipients is safe and efficacious. Securing payer approval for DAAs early in the posttransplant course could enable need-based allocation of HCV-positive donor organs irrespective of candidate HCV status, while averting chronic HCV allograft infection.

Partial splenic embolization is superior to intravenous somatostatin for decreasing portal pressure in cirrhotic patients: a dynamic self-controlled cohort study.

AIMS: The efficacy of somatostatin in altering splanchnic hemodynamics in cirrhotic portal hypertension is still controversial. We aimed to establish the dynamic effect of somatostatin on portal pressure in cirrhotic patients and compared its effect with Partial Splenic Embolization (PSE). METHODS: Eighteen patients with cirrhotic portal hypertension were prospectively recruited. The wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP) were repeatedly measured at baseline, 1-, 5-, 10- and 20-min after initiating somatostatin infusion. After somatostatin infusion cessation and washout, WHVP and FHVP were measured before and after PSE. The change in all the variables between time points was analyzed. RESULTS: Decreased hepatic venous pressure gradient (HVPG) 5-min after initiation of infusion was identified compared with baseline level (19.6%; p-value: .042), which was achieved through elevated FHVP (37.5%; p-value: 9.26e - 04). There was no significant decrease in WHVP at any time point during somatostatin infusion. The HVPG (17.4%; p-value: 1.27e - 04) and WHVP (10.4%; p-value: 3.00e - 03) post-PSE significantly decreased compared to the washout level. No significant distribution differences in the number of patients with HVPG decrease by a percentage relative to the baseline level were identified between the 5-min time point and post-PSE. CONCLUSION: Our study indicates that somatostatin administration does not decrease WHVP within 20 min at clinically recommended doses. While somatostatin did decrease HVPG, this effect was achieved through increased FHVP, providing a possible explanation for its unclear efficacy. In contrast, PSE decreases both the WHVP and the HVPG.

An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma.

Circulating tumor cells (CTCs) are shed into the bloodstream by invasive cancers, but the difficulty inherent in identifying these rare cells by microscopy has precluded their routine use in monitoring or screening for cancer. We recently described a high-throughput microfluidic CTC-iChip, which efficiently depletes hematopoietic cells from blood specimens and enriches for CTCs with well-preserved RNA. Application of RNA-based digital PCR to detect CTC-derived signatures may thus enable highly accurate tissue lineage-based cancer detection in blood specimens. As proof of principle, we examined hepatocellular carcinoma (HCC), a cancer that is derived from liver cells bearing a unique gene expression profile. After identifying a digital signature of 10 liver-specific transcripts, we used a cross-validated logistic regression model to identify the presence of HCC-derived CTCs in nine of 16 (56%) untreated patients with HCC versus one of 31 (3%) patients with nonmalignant liver disease at risk for developing HCC (P < 0.0001). Positive CTC scores declined in treated patients: Nine of 32 (28%) patients receiving therapy and only one of 15 (7%) patients who had undergone curative-intent ablation, surgery, or liver transplantation were positive. RNA-based digital CTC scoring was not correlated with the standard HCC serum protein marker alpha fetoprotein (P = 0.57). Modeling the sequential use of these two orthogonal markers for liver cancer screening in patients with high-risk cirrhosis generates positive and negative predictive values of 80% and 86%, respectively. Thus, digital RNA quantitation constitutes a sensitive and specific CTC readout, enabling high-throughput clinical applications, such as noninvasive screening for HCC in populations where viral hepatitis and cirrhosis are prevalent.

Barriers to Use of Palliative Care and Advance Care Planning Discussions for Patients With End-Stage Liver Disease.

BACKGROUND & AIMS: Despite evidence for the benefits of palliative care (PC) referrals and early advance care planning (ACP) discussions for patients with chronic diseases, patients with end-stage liver disease (ESLD) often do not receive such care. We sought to examine physicians' perceptions of the barriers to PC and timely ACP discussions for patients with ESLD. METHODS: We conducted a cross-sectional survey of hepatologists and gastroenterologists who provide care to adult patients with ESLD, recruited from the American Association for the Study of Liver Diseases 2018 membership registry. Using a questionnaire adapted from prior studies, we assessed physicians' perceptions of barriers to PC use and timely ACP discussions; 396 of 1236 eligible physicians (32%) completed the questionnaire. RESULTS: The most commonly cited barriers to PC use were cultural factors that affect perception of PC (by 95% of respondents), unrealistic expectations from patients about their prognosis (by 93% of respondents), and competing demands for clinicians' time (by 91% of respondents). Most respondents (81%) thought that ACP discussions with patients who have ESLD typically occur too late in the course of illness. The most commonly cited barriers to timely ACP discussions were insufficient communication between clinicians and families about goals of care (by 84% of respondents) and insufficient cultural competency training about end-of-life care (81%). CONCLUSION: There are substantial barriers to use of PC and timely discussions about ACP-most hepatologists and gastroenterologists believe that ACP occurs too late for patients with ESLD. Strategies are needed to overcome barriers and increase delivery of high-quality palliative and end-of-life care to patients with ESLD.

Physicians' Perspectives on Palliative Care for Patients With End-Stage Liver Disease: A National Survey Study.

Specialty palliative care (PC) is underused for patients with end-stage liver disease (ESLD). We sought to examine attitudes of hepatologists and gastroenterologists about PC for patients with ESLD. We conducted a cross-sectional survey of these specialists who provide care to patients with ESLD. Participants were recruited from the American Association for the Study of Liver Diseases membership directory. Using a questionnaire adapted from prior studies, we examined physicians' attitudes about PC and whether these attitudes varied based on patients' candidacy for liver transplantation. We identified predictors of physicians' attitudes about PC using linear regression. Approximately one-third of eligible physicians (396/1236, 32%) completed the survey. Most (95%) believed that centers providing care to patients with ESLD should have PC services, and 86% trusted PC clinicians to care for their patients. Only a minority reported collaborating frequently with inpatient (32%) or outpatient (11%) PC services. Most believed that when patients hear the term PC, they feel scared (94%) and anxious (87%). Most (83%) believed that patients would think nothing more could be done for their underlying disease if a PC referral was suggested. Physicians who believed that ESLD is a terminal condition (B = 1.09; P = 0.006) reported more positive attitudes about PC. Conversely, physicians with negative perceptions of PC for transplant candidates (B = -0.22; standard error = 0.05; P < 0.001) reported more negative attitudes toward PC. In conclusion, although most hepatologists and gastroenterologists believe that patients with ESLD should have access to PC, they reported rarely collaborating with PC teams and had substantial concerns about patients' perceptions of PC. Interventions are needed to overcome misperceptions of PC and to promote collaboration with PC clinicians for patients with ESLD.

Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage.

DNA damage initiates a series of p53 pulses. Although much is known about the interactions surrounding p53, little is known about which interactions contribute to p53's dynamical behavior. The simplest explanation is that these pulses are oscillations intrinsic to the p53/Mdm2 negative feedback loop. Here we present evidence that this simple mechanism is insufficient to explain p53 pulses; we show that p53 pulses are externally driven by pulses in the upstream signaling kinases, ATM and Chk2, and that the negative feedback between p53 and ATM, via Wip1, is essential for maintaining the uniform shape of p53 pulses. We propose that p53 pulses result from repeated initiation by ATM, which is reactivated by persistent DNA damage. Our study emphasizes the importance of collecting quantitative dynamic information at high temporal resolution for understanding the regulation of signaling pathways and opens new ways to manipulate p53 pulses to ask questions about their function in response to DNA damage.

Sex and Size Disparities in Access to Liver Transplant for Patients With Hepatocellular Carcinoma.

Importance: Women on the liver transplant waiting list are less likely to undergo a transplant than men. Recent approaches to resolving this disparity have involved adjustments to Model for End-Stage Liver Disease (MELD) scoring, but this will not affect candidates who rely on exception scores rather than calculated MELD score, the majority of whom have hepatocellular carcinoma (HCC). Objective: To evaluate the association between female sex, candidate size, and access to liver transplant among wait-listed patients with HCC. Design, Setting, and Participants: This retrospective cohort study used US transplant registry data of all adult (aged ≥18 years) wait-listed liver transplant candidates receiving an HCC exception score between January 1, 2010, and March 2, 2023. Exposure: Wait-listed liver transplant candidate sex. Main Outcomes and Measures: The association of female sex with (1) deceased-donor liver transplant (DDLT) and (2) death or waiting list removal for health deterioration were estimated using multivariable competing-risks regression. Results with and without adjustment for candidate height and weight (mediators of the sex disparity) were compared. Results: The cohort included 31 725 candidates with HCC (mean [SD] age at receipt of exception, 61.2 [7.1] years; 76.3% men). Compared with men, women had a lower 1-year cumulative incidence of DDLT (50.8% vs 54.0%; P < .001) and a higher 1-year cumulative incidence of death or delisting for health deterioration (16.2% vs 15.0%; P = .002). After adjustment, without accounting for size, women had a lower incidence of DDLT (subdistribution hazard ratio [SHR], 0.92; 95% CI, 0.89-0.95) and higher incidence of death or delisting (SHR, 1.06; 95% CI, 1.00-1.13) compared with men. When adjusting for candidate height and weight, there was no association of female sex with incidence of DDLT or death or delisting. However, at a height cutoff of 166 cm, short women compared with short men were still less likely to undergo a transplant (SHR, 0.93; 95% CI, 0.88-0.99). Conclusions and Relevance: In this study, women with HCC were less likely to receive a DDLT and more likely to die while wait-listed than men with HCC; these differences were largely (but not entirely) explained by sex-based differences in candidate size. For candidates listed with exception scores, additional changes to allocation policy are needed to resolve the sex disparity, including solutions to improve access to size-matched donor livers for smaller candidates.

HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions.

BACKGROUND: HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions. METHODS: We utilized computational deconvolution and cell-cell interaction analyses to cell type-specific (tumor-enriched and vessel-enriched) spatial transcriptomic data collected from 41 resected HCC tissue specimens. RESULTS: We report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner. CONCLUSIONS: Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous signaling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer-endothelial cell interactions and related drug targets.

Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker.

Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10-17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. SIGNIFICANCE: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 µL plasma are novel, rapid, cost-effective tools in cancer detection and monitoring. See related commentary by Doucet and Cristofari, p. 2502. This article is featured in Selected Articles from This Issue, p. 2489.