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BACKGROUND AND AIMS: The Liver Reporting and Data System (LI-RADS) is the standard classification of imaging findings of hepatic abnormalities for hepatocellular carcinoma (HCC) surveillance. We aimed to study the course of LI-RADS 3 and 4 (LR-3 and LR-4) abnormalities through correlations with explant pathology. METHODS: A single center retrospective study of liver transplant recipients between January 2016 and September 2019 with HCC on explant pathology was conducted. Eligible patients were divided into three subgroups based on their LI-RADS classification: LR-3/4, LR-5 only, and combination of LR-3/4/5. RESULTS: There were 116 eligible patients with 99 LR-3/4 observations (60 LR-3 and 39 LR-4); the rest had LR-5 lesions. LR-4 more often than LR-3 observations progressed to LR-5 (36% vs 12%) and with shorter duration during follow-up (median 175 days and 196 days). Mean size growth of LR-3 and LR-4 abnormalities were 2.6 and 3.8 mm; median growth rates were 0.2 and 0.4 mm/month, respectively. Numbers of HCC lesions per explant, largest HCC lesion size, and cumulative size were higher in LR-3/4/5 subgroup than LR-5 subgroup (P = 0.007, 0.007 and 0.006, respectively); 68% of LR-3 and 82% of LR-4 abnormalities were confirmed HCC on explant (P = 0.09). CONCLUSION: Compared to LR-3, more LR-4 abnormalities progressed to LR-5 (12% and 36%, respectively) in a shorter time and with faster growth rate. A high proportion of LR-3 and LR-4 lesions (68% and 82%, respectively) were confirmed HCC on explant, raising the question of whether excluding HCC based on radiologic criteria alone is adequate in those with LR-3/4 abnormalities.

The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013).Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/5 cm and 39.1% in NoDS/5 cm, P 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P 0.001).In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Liver transplantation (LT) is curative for most patients with hepatocellular carcinoma (HCC). However, 10%-15% of patients experience HCC recurrence. Patients who are reported as within Milan criteria by imaging are frequently found to be outside the criteria on explant. This under-staging of HCC worsens post-LT outcomes. However, risk factors for under-staging have not been elucidated. Furthermore, it is not known if there is regional or center-level variation in under-staging. We conducted a retrospective analysis of adult patients transplanted for HCC in the United Network for Organ Sharing (UNOS) database between 2012 and 2016. Under-staging was determined on the basis of comparing pre-LT imaging to explant findings. Kaplan-Meier methods and Cox regression were used to evaluate the impact of under-staging on HCC recurrence and post-LT survival. Mixed effects logistic regression was used to identify risk factors for under-staging and to study regional and center-level variation in adjusted analyses. A total of 5424 patients were included in the cohort, of whom 24.9% (n = 1353) were under-staged. Post-LT HCC recurrence and death were significantly associated with under-staging (each P < 0.001). In adjusted analyses, independent predictors of under-staging included age (odds ratio [OR], 1.13 per 10 years; 95% confidence interval [CI], 1.03-1.25), male sex (OR, 1.61; 95% CI, 1.36-1.89), down-staging (OR, 4.03; 95% CI, 2.65-6.11), and pre-LT alpha-fetoprotein (P < 0.001). There was also significant variation in under-staging between UNOS regions and among transplant centers, ranging from 14.8% to 38.1%. We report novel risk factors for HCC under-staging, which worsens post-LT outcomes. Significant center-level and regional variation in under-staging highlights the need for standards that achieve greater uniformity in staging.

BACKGROUND: Liver transplantation (LT) is an accepted therapeutic option for hepatocellular carcinoma (HCC) in patients with cirrhosis. Despite careful candidate selection, HCC recurrence occurs. We aimed to describe the predictors of recurrence, clinical presentation, and predictors of survival after HCC recurrence post-LT. METHODS: Patients with recurrent HCC after LT between January 1996 and December 2017 were retrospectively reviewed. RESULTS: Of 711 patients, 96 (13.5%) patients had post-LT HCC recurrence. The median time to recurrence was 17.1 months, and the median survival was 10.1 months. Initial recurrence was more often in the graft (34.4%), and most (60.4%) had multiple recurrent lesions, and 26% were in multiple sites. In multivariate analysis, factors associated with shorter survival were poorly differentiated histology in explant (Hazard ratio [HR] = 1.96; p = 0.027), bilirubin ≥1.2 mg/dL (HR = 2.47; p = 0.025), and albumin

OBJECTIVE The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). BACKGROUND LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. METHODS Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. RESULTS Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil-lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). CONCLUSIONS For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

Background & aimsUnited Network of Organ Sharing (UNOS) has adopted uniform criteria for downstaging (UNOS-DS) of hepatocellular carcinoma (HCC) before liver transplantation (LT), but the downstaging success rate and intention-to-treat outcomes across broad geographic regions are unknown.MethodsIn this first multiregional study (7 centers, 4 UNOS regions), 209 consecutive patients with HCC undergoing downstaging based on UNOS-DS criteria were prospectively evaluated from 2016 to2019.ResultsProbability of successful downstaging to Milan criteria and dropout at 2 years from the initial downstaging procedure was 87.7% and 37.3%, respectively. Pretreatment with lectin-reactive α-fetoprotein ≥10% (hazard ratio, 3.7; P= .02) was associated with increased dropout risk. When chemoembolization (n= 132) and yttrium-90 radioembolization (n= 62) were compared as the initial downstaging treatment, there were no differences in Modified Response Evaluation Criteria In Solid Tumors response, probability of or time to successful downstaging, waiting list dropout, or LT. Probability of LT at 3 years was 46.6% after a median of 17.2 months. In the explant, 17.5% had vascular invasion, and 42.8% exceeded Milan criteria (understaging). The only factor associated with understaging was the sum of the number of lesions plus largest tumor diameter on the last pre-LT imaging, and the odds of understaging increased by 35% per 1-unit increase in this sum. Post-LT survival at 2 years was 95%, and HCC recurrence occurred in 7.9%.ConclusionIn this first prospective multiregional study based on UNOS-DS criteria, we observed a successful downstaging rate of >80% and similar efficacy of chemoembolization and yttrium-90 radioembolization as the initial downstaging treatment. A high rate of tumor understaging was observed despite excellent 2-year post-LT survival of 95%. Additional LRT to reduce viable tumor burden may reduce tumor understaging.

Purpose To identify and characterize the delayed effects of transarterial radioembolization (TARE) on the liver. Materials and Methods A single-institution retrospective analysis was undertaken of all patients who received TARE between 2005 and 2014 and survived at least 1 year from the initial TARE (n = 106). Patients were evaluated for the presence or absence of radioembolization-induced chronic hepatotoxicity (RECHT) occurring at least 6 months after TARE. The mean age of patients was 63 years of age, and the malignancy most commonly treated was neuroendocrine tumor (54%). Adjudication of hepatic decompensation to RECHT versus alternative causes was performed by a multidisciplinary panel of specialists from hepatology, radiation oncology, and interventional radiology. Results Eight patients were excluded from analysis because of liver transplantation (2) or incomplete data (6). RECHT occurred in 13 of 98 patients (13%), and 5 deaths (5%) occurred from hepatic decompensation. There were a total of 69 toxicity events in patients developing RECHT. The most common events were elevation of alkaline phosphatase (10), decrease in serum albumin (10), and development of ascites (9). RECHT patients had a higher intrahepatic tumor volume (P = .021) and a higher number of hepatic comorbidities leading to cirrhosis (P = .015). Conclusions Delayed radiation-induced hepatic toxicity occurred in 13% of patients following radioembolization, with 5 fatalities adjudicated to be a result of the treatment. Tumor involvement of greater than 50% of the liver and cirrhosis were predisposing factors for RECHT.

CHLT is successful and increasing, with excellent survival for both cardiac and liver grafts. Outcomes are equivalent to single‐organ transplants, and there are potential immunological benefits compared with heart transplant alone. Evaluation and decision to proceed for dual‐organ transplant requires careful assessment by both organ teams at experienced centers to choose the appropriate recipients.

Transplant eligibility for hepatocellular carcinoma (HCC) is determined by the imaging identification of tumor burden within the Milan criteria. Transjugular intrahepatic portosystemic shunt(s) (TIPS) reduce portal hypertension but may impact HCC visualization. It was hypothesized that the presence of pretransplant TIPS would correlate with occult HCC and reduced survival. A single-center, retrospective, case control study was performed among liver transplant recipients with HCC (2000-2017). The primary endpoint was occult disease on explant pathology. Backward stepwise logistic regression was performed. The secondary endpoints disease-free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and Cox regression analysis. Of 640 patients, 40 had TIPS and more frequently exhibited occult disease (80.0% versus 43.1%; P

PURPOSE Hepatocellular carcinoma (HCC) has well-defined environmental risk factors. In addition, epidemiologic studies have suggested hereditary risk factors. The goals of this study were to determine the rate of pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes in patients with HCC, possible enrichment of P/LP variants in particular genes, and potential impact on clinical management. MATERIALS AND METHODS A prospective study at a tertiary medical center enrolled 217 patients with a personal history of HCC. Multigene panel testing was performed for 134 cancer predisposition genes in all patients. The rate of P/LP variants was compared with population rates. A separate retrospective cohort included 219 patients with HCC who underwent testing at a commercial laboratory. RESULTS In the prospective cohort, P/LP germline variants were identified in 25 of 217 patients with HCC (11.5%). Four patients (1.8%) had P/LP variants in the highly penetrant cancer genes BRCA2 (n = 2), MSH6 (n = 1), and PMS2 (n = 1). In addition, multiple patients had P/LP variants in FANCA (n = 5) and BRIP1 (n = 4), which were significantly enriched in HCC compared with the general population. Detection of P/LP variants led to changes in clinical management in regard to therapy selection, screening recommendations, and cascade testing of relatives. In a separate retrospective analysis of 219 patients with HCC, 30 (13.7%) were positive for P/LP variants including 13 (5.9%) with highly penetrant genes APC (n = 2), BRCA1 (n = 1), BRCA2 (n = 6), MSH2 (n = 2), or TP53 (n = 2). CONCLUSION P/LP germline variants in cancer predisposition genes were detected in 11%-14% of patients with HCC. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.

Introduction: Currently there is no biomarker or test to accurately measure liver function in Fontan-associated liver disease. The dual cholate test (HepQuant SHUNT) is a noninvasive, flow-dependent assay measuring hepatic clearance of a bile acid, cholate, and may serve as a useful measure of liver function in the Fontan. We aim to measure cholate clearance in a cohort of Fontan patients and compare to normal controls. Methods: Single center, prospective pilot study of Fontan patients ≥ 18 years. Hepatic clearance of orally administered d4-cholate and intravenously administered 13C-cholate were measured in peripheral venous samples after 5, 20, 45, 60, and 90 minutes. Portal hepatic filtration rate (HFR), systemic HFR, shunt fraction (systemic HFR/portal HFR), and disease severity index (DSI) were calculated. Decline in HFRs and increase in shunt fraction or DSI is indicative of impaired liver function. Two-sided t-tests were used to compare values between Fontans and controls. Results: Twelve Fontan patients were enrolled (33% female, median age 29.9 [range 23.6 - 41.0] years). Median total bilirubin was 0.8 (range 0.3-2.1) mg/dL, AST 30.5 (range 16-55) U/L, ALT 32 (range 11-53) U/L, alkaline phosphatase 87 (range 42-191) U/L and platelets 177 (range 130-428) 10 3 /μL. Mean cardiac index was 3.0 ± 0.5 L/min/m 2 . Cholate clearance was lower in Fontans compared to controls (Figure). Mean portal HFR (mL/min/kg) in Fontans was lower than controls (15.1 ± 10.9 vs 29.1 ± 9.0; p Conclusions: Fontan patients demonstrate reduced hepatic function compared to normal controls but there is considerable variability. Future studies using the dual cholate test will examine the relationship between liver and cardiac function, as well as risk of adverse clinical outcome, in the Fontan.

The incidence of hepatocellular carcinoma (HCC) is growing in the United States, especially among the elderly. Older patients are increasingly receiving transplants as a result of HCC, but the impact of advancing age on long-term posttransplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium of 4980 patients. We divided the patients into 4 groups by age at transplantation: 18 to 64 years (n=4001), 65 to 69 years (n=683), 70 to 74 years (n=252), and ≥75years (n=44). There were no differences in HCC tumor stage, type of bridging locoregional therapy, or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic, and cancer-related factors on multivariable analysis. A dose-response effect of age on survival was observed, with every 5-year increase in age older than 50years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non-HCC-related mortality (P=0.004), and not HCC-related death (P=0.24). To delineate the precise cause of death, we further analyzed a single-center cohort of patients who received a transplant as a result of HCC (n=302). Patients older than 65years had a higher incidence of de novo cancer (18.1% versus 7.6%; P=0.006) after transplantation and higher overall cancer-related mortality (14.3% versus 6.6%; P=0.03). Even carefully selected elderly patients with HCC have significantly worse posttransplant survival rates, which are mostly driven by non-HCC-related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve the outcomes in elderly patients who received a transplant as a result of HCC.

Purpose of review Understanding the mechanisms involved in immune protection provided by a hepatic allograft is imperative as further therapies for highly sensitized patients could be developed and thus expanding the donor pool and improving outcomes. Recent findings The clinical data from immune protection comes mainly from combined liver and kidney transplants with excellent results in overall survival and also that of the allograft. This phenomenon has also been observed in dual liver transplants with heart, lung, skin and intestines, albeit with less data. In heart transplant recipients, the liver allograft has proven to be protective even in cases of highly sensitized patients with at least equal survival and rejection outcomes to recipients of heart alone. Although not fully understood, the mechanisms for immune benefit proposed are extensive at different levels of the hepatic immune system. Some of these mechanisms include chimerism, T-cell deletion, the presence of peripheral regulatory T cells and donor-specific antibody neutralization. Summary Combined heart and liver transplantation is an infrequent but growing procedure due to increasing need in the adult congenital heart disease and cardiac amyloid populations. Given the ever expanding need for heart transplantation, understanding immunological phenomena that could expand the donor pool could, subsequently, increase the number of transplants.

Summary The coronavirus disease 2019 (COVID-19) pandemic has shattered the meticulously developed processes by which we delivered quality care for patients with cirrhosis. Care has been transformed by the crisis, but enduring lessons have been learned. In this article, we review how COVID-19 will impact cirrhosis care. We describe how this impact unfolds over 3 waves; i) an intense period with prioritized high-acuity care with delayed elective procedures and routine care during physical distancing, ii) a challenging ‘return to normal’ following the end of physical distancing, with increased emergent decompensations, morbidity, and systems of care overwhelmed by the backlog of deferred care, and iii) a protracted period of suboptimal outcomes characterized by missed diagnoses, progressive disease and loss to follow-up. We outline the concrete steps required to preserve the quality of care provided to patients with cirrhosis. This includes an intensification of the preventative care provided to patients with compensated cirrhosis, proactive chronic disease management, robust telehealth programs, and a reorganization of care delivery to provide a full service of care with flexible clinical staffing. Managing the pandemic of a serious chronic disease in the midst of a global infectious pandemic is challenging. It is incumbent upon the entire healthcare establishment to be strong enough to weather the storm. Change is needed.

Background & Aims Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. Methods We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). Results Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3–12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3–12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. Conclusions Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

Interferon treatment of hepatitis C virus (HCV) infection after liver transplantation (LT) can result in immune-mediated graft dysfunction (IGD). The occurrence of, risk factors for, and outcomes of IGD with direct-acting antiviral (DAA) therapy have not been reported. We conducted a multicenter study of HCV+LT recipients who did or did not develop DAA-IGD (1 case: 2 controls-33 vs 66). Among all treated between 2014 and 2016, DAA-IGD occurred in 3.4% (33/978). IGD occurred only after treatment completion (76.0 [IQR, 47.0;176]). Among those treated, 48% had plasma cell hepatitis, 36% acute cellular rejection, 6% chronic rejection, and 9% combined findings. Median time to liver enzyme resolution was 77.5 days (IQR, 31.5;126). After diagnosis, hospitalizations, steroid-induced hyperglycemia, and infection occurred in a higher percentage of cases vs controls (33% vs 7.5%, 21% vs 1.5%, 9% vs 0%; all P < .05). Only one IGD patient died and none required retransplant. A multivariate regression analysis found that liver enzyme elevations during and soon after DAA therapy completion correlated with subsequent IGD. In conclusion, while DAA-IGD is uncommon, liver enzyme elevations during or after DAA therapy may be a sign of impending IGD. These indicators should guide clinicians to diagnose and treat IGD early before the more deleterious later clinical presentation.

To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC).Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited.Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013).Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P0.001; 4+ LRTs: HR 2.5, P0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044).Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.

Background & Aims There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. Methods We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). Results Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70–1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70–1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. Conclusion In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

The natural history and clinical consequences of Fontan-associated liver disease (FALD) are not well-characterized. We aim to describe the frequency of adverse outcomes and identify clinical risk factors for such outcomes in FALD. This is a single-center, retrospective cohort study of adult Fontan

Objectives Stereotactic body radiotherapy (SBRT) is potentially curative treatment for small hepatocellular carcinomas (HCC), but data are limited on its efficacy and toxicity. We hypothesized that SBRT can achieve excellent local control (LC) with acceptable toxicity treating HCC lesions, even in advanced cirrhosis. Materials and methods Thirty-seven nonmetastatic HCC patients received SBRT to 43 lesions between October 2012 and April 2016. Median dose was 50 Gy/5 fractions. All Child-Pugh (CP) ≥B patients underwent a planned 1-month break after the first 3 fractions to assess hepatic toxicity. Patients were treated without separately placed fiducial markers using Linac-based SBRT with breath-hold (67%) or 4D-computed tomography with compression belt (33%) to reduce motion. Patients underwent magnetic resonance imaging q3 months post-SBRT. Results Median age was 65 (range, 44 to 88). Pre-SBRT mean CP was 6.4 (range, A5 to C11). Nine (24%) had CP≥B8. Thirty-one of 33 patients (93%) had prior liver-directed therapy (median 2). Seventeen (40%) had solitary lesions. Median lesion diameter was 2.7 cm (range, 1.1 to 5.6). Median follow-up was 14 months (range, 2 to 45). There was 1 local failure (multifocal HCC with 3 prior transarterial chemoembolization). LC, freedom from liver progression, and overall survival at 12 months was 95%, 66%, 87% in the full cohort, and 100%, 76%, 93% for patients with solitary lesions. Four had grade 3 toxicity (ascites [n=2]/gastrointestinal bleed [n=1]/capsular pain [n=1]). Eight of 9 CP≥B8 patients had no grade ≥3 hepatic toxicity. Conclusions SBRT for HCC is well-tolerated even in patients with advanced cirrhosis and prior liver-directed treatment and provides excellent LC even for larger lesions that cannot be controlled with radiofrequency ablation. LC with SBRT compares favorably to other liver-directed therapies. Prospective studies comparing SBRT with other liver-directed therapies are warranted.

Patients with hepatocellular carcinoma (HCC) exceeding Milan criteria on explant pathology are at increased risk of recurrence and death. Discordance between contemporary magnetic resonance imaging (MRI) and explant pathology, and preoperative characteristics predictive of discordance are not well understood.Patients who underwent orthotopic liver transplantation for HCC after preoperative MRI were identified in a prospectively collected institutional database (January 2003 to December 2013). Patients were dichotomized to "within" or "outside" Milan criteria by both imaging and explant pathologic evaluation. Binary logistic regression and Kaplan-Meier methodology were used to identify independent predictors of imaging/pathologic discordance and its impact on posttransplant survival.Of 318 patients with HCC meeting Milan criteria by MRI at the time of orthotopic liver transplantation, 248 (78.0%) remained within a pathological correlate of Milan criteria on explant examination. Understaging was associated with worse median recurrence-free survival (64.0 months vs 140.0 months, P = 0.002) and overall survival (96.0 months vs 143.0 months, P = 0.005), and did not vary between patients exceeding criteria due to tumor explant greater than 5 cm, more than 3 tumor foci, or a tumor greater than 3 cm in the setting of multifocality. Discordance was independently associated with an increasing serum alpha fetal protein level (odds ratio, 2.82; 95% confidence interval, 1.37-5.79; P = 0.005).Underestimating HCC burden before liver transplant remains frequent despite contemporary imaging technologies. Patients with an increasing alpha fetal protein before transplantation may benefit from more frequent testing or novel neoadjuvant therapies.

Erythropoietic protoporphyria (EPP) is a rare inherited disorder of the heme biosynthesis pathway resulting in the accumulation of protoporphyrins in the blood, erythrocytes, and other tissues. Because of a gene mutation in the FECH gene, ferrochelatase, the enzyme involved in the final step of heme synthesis, is deficient in these patients. Although the major symptom of this disorder is photosensitivity, rarely, it can cause progressive liver disease requiring liver transplantation (LT). However, LT is not curative and only bone marrow transplantation (BMT) can correct the underlying enzymatic defect. Because liver disease results from accumulation of protoporphyrin in the liver, LT without hematopoietic stem cell transplantation leaves the new liver at risk for similar EPP-related damage. A handful of pediatric patients undergoing sequential LT and stem cell transplantation have been described in the literature; however, to date none has been described in detail in adults. We report a case of an adult male with EPP and liver failure who successfully underwent a sequential liver and hematopoietic stem cell transplantation (HSCT).

OBJECTIVE: This study aimed to compare the incidence of radiologically unrecognized (occult) hepatocellular carcinoma (HCC) lesions in explant hepatectomy specimens from orthotopic liver transplants (OLTs) performed for HCC with rates of HCC intrahepatic recurrence after resection. SUMMARY OF BACKGROUND DATA: Resection of HCC is associated with high rates of intrahepatic HCC recurrence. However, it is unclear whether these recurrences represent incomplete resection of unrecognized metastatic lesions from the primary tumor or subsequent de novo tumor formation due to inherent biological proclivity for HCC formation. METHODS: We collected patient, tumor, and pathology data on HCC patients treated surgically from 3696 OLTs in the Organ Procurement and Transplantation (OPTN) national database, 299 OLTs at a single transplant center, and 232 partial hepatectomies from a hepatobiliary cancer center. RESULTS: In the OPTN and high-volume transplant center cohorts, 37% and 42% of patients had occult HCC lesions on explant pathology, respectively. Among cancer center patients, the 2-year recurrence rate was 46%, and 74% of patients who recurred presented with liver only recurrence. CONCLUSION: Although the transplant and resection populations differ, occult multifocality is common in transplant explants and similar to the 46% early recurrence rate following partial hepatectomy. These data suggest that non-curative resection often results from occult intrahepatic multifocality present at the time of resection rather than a malignant predisposition of the remnant liver with de novo tumorigenesis.

Risk factors for hepatocellular carcinoma (HCC) recurrence after liver transplantation have been well described. It has been surmised that longer time on the waitlist may select for tumors with a lower-risk of recurrence posttransplant, as patients with unfavorable tumor characteristics would be delisted due to tumor progression. Utilizing national explant pathology records from transplant recipients waitlisted with T2 HCC exception points, this study explored the correlation between waiting time and the development of pathologic HCC features associated with increased risk of tumor recurrence. Of 1976 explant pathology reports submitted nationally between April 8, 2012 and June 30, 2013, 1453 (73.5%) were from recipients with automatic T2 HCC exception points. There was no association between pretransplant waiting time and the proportion of HCC explants with either: (i) a poorly differentiated tumor; (ii) macrovascular invasion; (iii) HCC beyond Milan or University of California San Francisco criteria; (iv) HCC beyond the "up-to-seven" criteria; or (v) extra-hepatic or lymph node involvement. Though there was a statistically significant increase in microvascular invasion in recipients with pretransplant waiting 6-12 months, this association was not seen when adjusted for United Network for Organ Sharing region. These findings suggest that waiting time alone may not select for tumors with more favorable characteristics.

Background & Aims There is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy. Methods We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 health care systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting. Results Of 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16–0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33–0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18–0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55–2.33). Conclusions In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

270 Background: TGF-β, the strongest known immunosuppressive cytokine, modulates the hepatic immune response to various antigens and to ionizing radiation. When activated, TGF-β blocks the effector T-cell response to cellular destruction and the release of tumor-specific antigens. Preclinical data demonstrate that neutralizing TGF-β during radiation effectively generates a CD8+ T-cell response to multiple endogenous tumor antigens, thereby generating an in-situ vaccine against a tumor. We hypothesized that the combination of TGF-β receptor inhibition plus SBRT would produce a potent and clinically effective antitumor immune response against HCC. Methods: Patients received galunisertib (LY2157299 monohydrate) on days 1-14 of each 28 day cycle. SBRT was delivered in a single fraction of 18 Gy between days 15-28 of C1. Pre-treatment and on-treatment biopsies were obtained, as well as serial blood collections for CTCs, ctDNA and PBMCs. Results: 15 patients with advanced HCC and Child’s Pugh A cirrhosis were treated. 9/15 (60%) had a prior history of infectious hepatitis, three of whom had active viremia at time of enrollment. 6/15 (40%) had received prior systemic therapy for HCC and 12/15 (80%) had received prior liver directed therapy. The most common treatment-related toxicities were: fatigue (53%), nausea (47%), increased alkaline phosphatase (33%), abdominal pain (33%), vomiting (20%), decreased white blood cell count (20%). All drug-related toxicities were grade 1 or 2, with the exception of one patient who had grade 3 achalasia, thought possibly to be related to study drug. Median PFS was 3.68mo. There were two confirmed partial responses (PRs) and six additional patients had stable disease (SD) for at least four months, resulting in a disease control rate (DCR) of 53%. Both PRs included shrinkage of lesions that had not been radiated. Translational studies are currently underway. Conclusions: The combination of galunisertib with SBRT in patients with advanced HCC is a well-tolerated regimen. In this small pilot study, we observe a DCR of 53% including two PRs. These results warrant further study of this therapeutic combination in advanced HCC. Clinical trial information: NCT02906397.

TPS528 Background: Hepatocellular carcinoma (HCC) is a common and lethal malignancy with few effective treatment options. Inherently aggressive disease biology combined with the immunosuppressive hepatic microenvironment creates a unique therapeutic challenge. TGF-β, the strongest known immunosuppressive cytokine [1, 2], modulates the hepatic immune response to various antigens and to ionizing radiation [3, 4]. TGF-β is constitutively released by liver cells and plays a key role in the early and late pathogenesis of HCC [5-7] by dampening the local T-cell response to the oncogenic hepatitis B and –C viruses [4, 8-11]. TGF-β is activated by ionizing radiation, where it blocks the effector T-cell response to cellular destruction and the release of tumor-specific antigens [4]. Preclinical data demonstrate that neutralizing TGF-β during radiation therapy effectively generates a CD8+ T-cell response to multiple endogenous tumor antigens [4], thereby generating an in-situ vaccine against a tumor [12-17]. We hypothesize that the combination of TGF-β receptor inhibition plus radiation therapy will produce a potent and clinically effective antitumor immune response against HCC. Methods: We have enrolled 9 of 15 planned patients on study NCT02906397. Eligibility criteria include inoperable HCC, Childs Pugh score of ≤7, and either failure of or refusal to take sorafenib. Patients must be 4 weeks from prior therapy and may not be taking immunosuppressants. Patients with major cardiac disease or abnormalities or a predisposition toward aneurysm development are excluded. Patients receive galunisertib on days 1-14 of 28 day cycles. SBRT will be delivered in a single fraction of 18 Gy between days 15-28 of C1. Pre-treatment and on-treatment biopsies are obtained, as well as serial blood collections for circulating tumor material. Immunologic evaluation will include TCR deep sequencing to track T-cell receptor clones, analysis of serum inflammatory cytokines, analysis of myeloid and B cell activation, multiplex flow cytometry of PBMCs to measure percentages and absolute counts of T-cell subsets and tissue assessment of immune markers. Peripheral and tissue levels of TGF-β will be assessed. Clinical trial information: NCT02906397.

468 Background: LRT is used in treating HCC, but is associated with a risk of hepatotoxicity, which is not accurately predicted by traditional measures of liver function. In this pilot study, we evaluated the change in liver function after LRT as measured by a test using dual, oral and IV, cholate clearances (HepQuantSHUNT). Our hypothesis is that LRT would impose a significant reduction in the disease severity index (DSI) measured in the HepQuant SHUNT test, as an indicator of reduced liver function. Methods: We conducted a prospective cohort study of 11 subjects undergoing LRT for HCC. HepQuantSHUNT was performed at baseline (T0) and 4-10 weeks after LRT (T1). Clinical assessment was performed at T0 and T1, and at 12-18 weeks after LRT (T2). Decompensation was defined as either a new complication of cirrhosis or an increase in Child-Pugh (CP) score by ≥2 points. Results: Median age was 61 years, 73% were men, 55% had hepatitis C. Median CP score was 7[5-8], including 36%CP A and 64%CP B. Subjects had a BCLC stage A(64%) or BCLC stage B(36%) HCC. LRT modalities were TACE (45%) or SBRT (55%). From T0 to T1, there was a reduction in oral cholate clearance(422[235-768] vs 339[208-362], p = 0.03) and in IV cholate clearance(210[150-300] vs 191[144-203],p = 0.04) as well as a trend towards a worsening disease severity index (DSI) (32.0[19.5-37.8] vs 33.0[29.7-38.0],p = 0.10); however, there was no significant change in MELD(12[9-13]vs 11[10-12],p = 0.72) or CP score(7[5-8] vs 7[6-8],p = 0.15). 89% of the subjects had a reduction in oral and IV cholate clearance, and 78% had a worsening DSI; while 44% subjects had increase in CP score, and 56% had an increase in MELD. Decompensation was observed in 43% of CP B patients and none of CP A patients; and in 60% patients with a DSI > 35, and none of the patients with DSI < 35. Conclusions: The dual cholate clearance assay HepQuant-SHUNT detects a deterioration in liver function after LRT for HCC more frequently than clinical measures of liver function. DSI 35 might be a cutoff for risk of clinical decompensation after LRT for HCC. Additional research is needed to evaluate the role of the HepQuant SHUNT test in improving the selection of Child B patients for LRT.

Nonalcoholic steatohepatitis (NASH) is one of the most common liver disorders in North America. The mechanism of liver injury in NASH involves insulin resistance and oxidative stress as well as cytokine release. Therapeutic interventions aimed at enhancing insulin sensitivity or reducing oxidative stress have been studied. The role of peptide hormones secreted by adipose tissue--adipocytokines--in the potential pathogenesis of NASH is an area of intense research. As the function of adipokines in modulating hepatic inflammation and fibrosis is elucidated, the potential for novel treatment strategies in patients with NASH is likely to be realized.

Due to the risk of waitlist dropout from tumor progression, liver transplant candidates with hepatocellular carcinoma (HCC) within Milan criteria (MC) receive standardized exception points. An expansion of this process to candidates with HCC beyond MC has been proposed, though it remains controversial. This study sought to better define the utilization of exception points in candidates with HCC beyond MC and the associated outcomes. We reviewed all nonstandardized HCC applications that underwent formal regional review board evaluation between January 1, 2005 and March 2, 2011; 2184 initial HCC exception point applications were submitted. Of these, 41.9% fulfilled MC, 26.6% fulfilled University of California-San Francisco (UCSF) criteria and 17.6% exceeded UCSF criteria. The majority of applications were accepted: 89.8% within UCSF and 71.2% beyond UCSF. There was a significantly (p < 0.001) higher risk of death on the waitlist or within 90 days of waitlist removal for candidates within UCSF (12.4%) or beyond UCSF (13.0%) criteria, compared to candidates with HCC within MC (6.0%). However, posttransplant outcomes were similar. While these results suggest increasing access to candidates with HCC beyond MC, comprehensive documentation of tumor characteristics and of successful downstaging is needed to ensure priority is restricted to those with the highest likelihood of favorable posttransplant outcome.

Hepatocellular carcinoma (HCC) is a major health problem worldwide and accounts for 80–90% of the cases of primary liver cancer. Although the majority of HCC cases are reported in the developing world, the incidence of HCC has been increasing in several developed countries, including the United States [1]. Globally, between 70% and 90% of cases of HCC are associated with a background of established cirrhosis. HCC can also occur in those without cirrhosis, usually in those with chronic infection with hepatitis B [2–4]. Overall, the diagnosis of hepatocellular carcinoma is associated with a poor long-term survival [5]. However, small HCC tumors, often detected by surveillance, could qualify for curative treatments which are associated with a 5-year survival exceeding 50% [6–8].

To study the patients with main pancreatic duct dilation on computed tomography (CT) and thereby to provide the predictive criteria to identify patients at high risk of significant diseases, such as pancreatic cancer, and to avoid unnecessary work up for patients at low risk of such diseases.Patients with dilation of the main pancreatic duct on CT at Emory University Hospital in 2002 were identified by computer search. Clinical course and ultimate diagnosis were obtained in all the identified patients by abstraction of their computer database records.Seventy-seven patients were identified in this study. Chronic pancreatitis and pancreatic cancer were the most common causes of the main pancreatic duct dilation on CT. Although the majority of patients with isolated dilation of the main pancreatic duct (single duct dilation) had chronic pancreatitis, one-third of patients with single duct dilation but without chronic pancreatitis had pancreatic malignancies, whereas most of patients with concomitant biliary duct dilation (double duct dilation) had pancreatic cancer.Patients with pancreatic double duct dilation need extensive work up and careful follow-up since a majority of these patients are ultimately diagnosed with pancreatic cancer. Patients with single duct dilation, especially such patients without any evidence of chronic pancreatitis, also need careful follow-up since the possibility of pancreatic malignancy, including adenocarcinoma and intraductal papillary mucinous tumors, is still high.

Recurrent abdominal pain and recurrent pancreatitis are common problems associated with some patients with cystic fibrosis (CF). There is no known effective method to prevent recurrent abdominal pain and recurrent pancreatitis in such patients. The objective of this study was to determine whether nocturnal hydration (NH) prevents recurrent abdominal pain and recurrent acute pancreatitis in patients with adult-onset CF. Adult CF patients who were referred to our Pancreatic Diseases Clinic for recurrent abdominal pain and pancreatitis were enrolled in the study. Each patient was encouraged to drink plenty of water during the night and established a 6-month diary (3 months before and 3 months after NH was initiated), recording the frequency and severity of their abdominal pain, the amount of pain medication taken, and the volume of their water intake. We also reviewed the number of doctor's clinic visits, emergency room visits, and hospitalizations for about 1 year before and 1 year after the initiation of the NH. The frequency and the severity of abdominal pain in this group of patients were significantly reduced. The amount of pain medication and the number of emergency room visits and hospitalizations for abdominal pain and acute pancreatitis were reduced. NH is a simple and cost-effective method to prevent recurrent abdominal pain and pancreatitis in patients with adult-onset CF.

Interstitial pneumonitis, often related to infectious etiologies, occurs commonly in HIV-infected patients. However, hypersensitivity pneumonitis from noninfectious etiologies, including environmental stimuli or drug exposure, is an unusual etiology of interstitial pneumonitis in HIV-infected patients. We report a patient with AIDS who developed a dapsone-induced hypersensitivity pneumonitis mimicking Pneumocystis carinii (PCP) pneumonia. We believe drug-induced hypersensitivity pneumonitis should be considered in the differential diagnosis of interstitial pneumonia in HIV-infected patients in whom infectious etiologies have been ruled out.

Background & Aims Patients with recurrent hepatitis C virus infection treated with pegylated interferon (PEG) after liver transplantation can develop severe immune-mediated graft dysfunction (IGD) characterized by plasma cell hepatitis or rejection. Methods We conducted a multicenter case-control study of 52 liver transplant recipients with hepatitis C to assess the incidence of, risk factors for, and outcomes of PEG-IGD. Data from each patient were compared with those from 2 matched patients who did not develop PEG-IGD (n = 104). We performed a multivariate analysis of risk factors and analyzed treatment and outcomes of graft dysfunction subtypes. Results Overall incidence of PEG-IGD during a 10-year study period was 7.2%. Risk factors included no prior PEG therapy (odds ratio=5.3; P P = .03), and immune features (mainly plasma cell hepatitis) on pre-PEG therapy liver biopsies (odds ratio=3.9; P = .005). The PEG-IGD group had lower long-term patient (61.5% vs 91.3% of controls) and graft (38.5% vs 85.6% of controls) survival and higher rates of retransplantation (34.6% vs 6.7% of controls) (all, P P = .002), a high level of alkaline phosphatase at PEG initiation (HR = 1.003; P = .005), and lack of a sustained virologic response (HR = 3.3; P = .04). Variables associated with graft failure included a high level of alkaline phosphatase at PEG initiation (HR = 1.002; P = .04) and lack of a sustained virologic response (HR = 2.1; P = .04). Conclusions PEG-IGD has high morbidity and mortality and is not associated with increased rates of virologic response. It is important to avoid PEG therapy in liver transplant recipients with specific clinical, biochemical, and histologic risk factors for PEG-IGD.

AIM: To determine factors affecting the outcome of patients with cirrhosis undergoing surgery and to compare the capacities of the Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) score to predict that outcome. METHODS: We reviewed the charts of 195 patients with cirrhosis who underwent surgery at two teaching hospitals over a five-year period. The combined endpoint of death or hepatic decompensation was considered to be the primary endpoint. RESULTS: Patients who reached the endpoint had a higher MELD score, a higher CTP score and were more likely to have undergone an urgent procedure. Among patients undergoing elective surgical procedures, no statistically significant difference was noted in the mean MELD (12.8 ± 3.9 vs 12.6 ± 4.7, P = 0.9) or in the mean CTP (7.6 ± 1.2 vs 7.7 ± 1.7, P = 0.8) between patients who reached the endpoint and those who did not. Both mean scores were higher in the patients reaching the endpoint in the case of urgent procedures (MELD: 22.4 ± 8.7 vs 15.2 ± 6.4, P = 0.0007; CTP: 9.9 ± 1.8 vs 8.5 ± 1.8, P = 0.008). The performances of the MELD and CTP scores in predicting the outcome of urgent surgery were only fair, without a significant difference between them (AUC = 0.755 ± 0.066 for MELD vs AUC = 0.696 ± 0.070 for CTP, P = 0.3). CONCLUSION: The CTP and MELD scores performed equally, but only fairly in predicting the outcome of urgent surgical procedures. Larger studies are needed to better define the factors capable of predicting the outcome of elective surgical procedures in patients with cirrhosis.