Lee, David D

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.

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 ≥75 years (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 50 years 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 65 years 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.

Background and Aims 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). Approach and Results 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 time >12 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). Conclusions 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.

Background. Currently, no surveillance guidelines for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) exist. In this retrospective, multicenter study, we have investigated the role of surveillance imaging on postrecurrence outcomes. Methods. Patients with recurrent HCC after LT from 2002 to 2016 were reviewed from 3 transplant centers (University of California San Francisco, Mayo Clinic Florida, and University of Toronto). For this study, we proposed the term cumulative exposure to surveillance (CETS) as a way to define the cumulative sum of all the protected intervals that each surveillance test provides. In our analysis, CETS has been treated as a continuous variable in months. Results. Two hundred twenty-three patients from 3 centers had recurrent HCC post-LT. The median follow-up was 31.3 months, and median time to recurrence was 13.3 months. Increasing CETS was associated with improved postrecurrence survival (hazard ratio, 0.94; P < 0.01) as was treatment of recurrence with resection or ablation (hazard ratio, 0.31; P < 0.001). An receiver operating characteristic curve (area under the curve, 0.64) for CETS covariate showed that 252 days of coverage (or 3 surveillance scans) within the first 24 months provided the highest probability for aggressive postrecurrence treatment. Conclusions. In this review of 223 patients with post-LT HCC recurrence, we found that increasing CETS does lead to improved postrecurrence survival as well as a higher probability for aggressive recurrence treatment. We found that 252 days of monitoring (ie, 3 surveillance scans) in the first 24 months was associated with the ability to offer potentially curative treatment.

Background. Aorto-hepatic conduits can provide arterial inflow for liver transplants in cases where the native hepatic artery is unsuitable for use. Methods. Clinical outcomes of all patients undergoing liver transplantation (LT) with an aorto-hepatic conduit between 2000 and 2016 were included. Recipients were divided into 2 groups: those with a supraceliac (SC) aortic conduit (N = 22) and those with an infrarenal (IR) aortic conduit (N = 82). Results. There was no difference in calculated model for end-stage liver disease score between the 2 groups. The SC group received grafts with a higher mean donor risk index (1.69 versus 1.48; P = 0.02). Early allograft dysfunction was 18.2% in the SC group and 29.3% in the IR group (P = 0.30). In the SC group, 10.5% of patients required initiation of postoperative continuous renal replacement therapy compared to 12.1% of patients in the IR group (P = 0.69). No difference in the rate of postoperative acute kidney injury was seen between the 2 groups (P = 0.54). No significant difference in median creatinine at 1 year was seen between the SC (1.2 mg/dL; IQR 1–1.3) and IR (1.2 mg/dL; IQR 0.9–1.5) groups (P = 0.85). At a median follow-up of 5.3 years, thrombosis of the aortic conduit occurred in 0% of patients in the SC group and 6.1% of patients in the IR group (P = 0.24). Graft survival was not significantly different between the 2 groups (P = 0.47). Conclusions. No difference in renal dysfunction as demonstrated by need for post-LT continuous renal replacement therapy, acute kidney injury, or creatinine at 1 year post-LT was seen between SC and IR aortic conduits. A slight trend of higher conduit thrombosis rate was seen with IR compared to SC aortic conduits; however, this did not reach statistical significance. Both SC and IR aortic conduits represent reasonable options when the native hepatic artery is unsuitable for use.

It has been suggested that microsteatosis does not negatively impact graft survival following liver transplantation (LT). The present study represents the largest series on donor livers with significant microsteatosis and investigates the impact of microsteatosis on perioperative factors such as postreperfusion syndrome (PRS), early allograft dysfunction (EAD), and postoperative renal dysfunction. Clinical outcomes of all patients undergoing LT with donor livers with isolated microsteatosis (≥30%; n = 239) between 2000 and 2017 were compared with a propensity score–matched cohort of patients undergoing LT with donor livers with no steatosis (n = 239). Patients in the microsteatosis group had a higher rate of PRS (33.1% versus 24.2%; P = 0.03), EAD (38.2% versus 23.0%; P < 0.001), and continuous renal replacement therapy (CRRT) requirement following LT (10.9% versus 3.6%; P = 0.002) than the no steatosis group. No difference in patient (P = 0.33) or graft survival (P = 0.18) was observed between the 2 groups. On multivariate regression, livers with microsteatosis had an increased risk of graft loss with retransplant recipients (hazard ratio [HR], 1.59; P < 0.001), increasing Model for End‐Stage Liver Disease (MELD) score (HR, 1.13; P = 0.01), and organs from donation after circulatory death donors (HR, 1.46; P = 0.003). In conclusion, recipients of donor livers with significant microsteatosis are at an increased risk of PRS, EAD, and postoperative renal dysfunction requiring CRRT. Livers with significant microsteatosis should be avoided in retransplant recipients and in recipients with high biological MELD scores. Once appropriately selected recipients of these livers are able to overcome the initial perioperative implications of using these donor livers, longterm patient and graft survival is similar to recipients receiving grafts with no steatosis.

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.

The frequency at which steatotic deceased donor liver grafts are encountered will likely continue to increase. Utilization of liver grafts with moderate‐to‐severe steatosis for liver transplantation (LT) has been previously shown to be associated with increased rates of primary nonfunction and decreased recipient survival. In order to better inform clinical decision making and guide future research, critical evaluation of the literature on donor liver steatosis and posttransplantation outcome is needed. This literature review aims to provide the “skinny” on using deceased donor steatotic livers for LT.

Background. The present multicenter study investigated whether equivalent outcomes to primary liver transplant (LT) could be achieved with liver retransplant (reLT) and whether improvements in outcomes have taken place over time, particularly in the direct-acting antiviral era. Methods. All reLT performed at Mayo Clinic Florida, Mayo Clinic Rochester, and Mayo Clinic Arizona were divided into era 1 (2002–2007), era 2 (2008–2012), and era 3 (2013–2017) based on the date of reLT. Results. Improvement in graft survival (GS) after reLT was seen over the 3 eras (P < 0.001). In era 1, GS after reLT was inferior to primary LT (P < 0.001), whereas no difference was seen between reLT and primary LT in era 2 (P = 0.68) or era 3 (P = 0.36). A significantly higher proportion of patients achieved sustained viral response (SVR) within the first year after reLT in each subsequent era (era 1: 10.3%, era 2: 22.5%, and era 3: 100%) (P < 0.001). Graft survival was superior in patients undergoing reLT for recurrent hepatitis C virus who achieved SVR after reLT compared with those who did not (P = 0.03). Conclusions. Results similar to primary LT were achieved in era 3. These improvements coincide with the availability of direct-acting antivirals, which resulted in a 100% SVR rate in era 3 and a decrease in the number of patients undergoing reLT for recurrent hepatitis C virus. The historic dogma that reLT results in inferior outcomes should be revisited.