Liver Transplantation For HCC Research Articles

Harnessing the Power of Immunotherapy in Liver Transplantation for HCC

Harnessing the Power of Immunotherapy in Liver Transplantation for HCC

Benefit and harm of waiting time in liver transplantation for HCC.

Liver transplantation is the most successful treatment for limited-stage HCC. The waiting time for liver transplantation (LT) can be a critical factor affecting the oncological prognosis and outcome of patients with HCC. Efficient strategies to optimize waiting time are essential to maximize the benefits of LT and to reduce the harm of delay in transplantation. The ever-increasing demand for donor livers emphasizes the need to improve the organization of the waiting list for transplantation and to optimize organ availability for patients with and without HCC. Current progress in innovations to expand the donor pool includes the implementation of living donor LT and the use of grafts from extended donors. By expanding selection criteria, an increased number of patients are eligible for transplantation, which necessitates criteria to prevent futile transplantations. Thus, the selection criteria for LT have evolved to include not only tumor characteristics but biomarkers as well. Enhancing our understanding of HCC tumor biology through the analysis of subtypes and molecular genetics holds significant promise in advancing the personalized approach for patients. In this review, the effect of waiting time duration on outcome in patients with HCC enlisted for LT is discussed.

Tracing anti-cancer immunity in patients undergoing liver transplantation for HCC after downstaging with immunotherapy

Tracing anti-cancer immunity in patients undergoing liver transplantation for HCC after downstaging with immunotherapy

Additional value of interleukin-6 level to predict histopathological features of hepatocellular carcinoma before liver transplantation

Background & AimsInflammatory biomarkers are increasingly used as outcome predictors in the field of oncology and liver transplantation for HCC, but no study has shown the prognostic value of IL6 after LT.The goal of this study was to evaluate the predictive value of IL-6 on histopathological features of HCC on explant, its predictive value on recurrence risk and its additional value to other scores and inflammatory markers at the time of transplantation. MethodsFrom 2009 to 2019, all adults transplanted with a first liver graft and diagnosed with HCC on the explant analysis were retrospectively included (n = 229). Only patients who had a pre-LT IL6 level determination were analysed in this study (n = 204). ResultsHigh IL-6 level at transplantation was associated with a significantly higher risk of vascular invasion (15% vs 6%; p = 0.023), microsatellitosis (11% vs 3%; p = 0.013), lower rate of histological response both in terms of complete response (2% vs 14%, p = 0.004) and of necrosis (p = 0.010).Patients with pre-LT IL-6 level > 15 ng/ml had a lower overall and cancer-specific survival (p = 0.013).Recurrence-free survival was lower in patients with IL-6 > 15 ng/ml with a 3-year recurrence-free survival of 88% versus 78% (p = 0.034). IL6 levels were significantly higher in patients with early recurrence compared to patients without (p = 0.002) or with late recurrence (p = 0.044). ConclusionsIL6 level at transplantation is an independent predictor of pejorative histological features of HCC and is associated to the risk of recurrence.

Tailored screening and management after liver transplantation for HCC

Tailored screening and management after liver transplantation for HCC

Improved recurrence-free survival in patients with HCC with post-transplant plasma exchange.

Total plasma exchange (TPE) can play a role in cancer treatment by eliminating immune checkpoint inhibitors. This study investigated whether TPE improved oncological outcomes in patients with HCC who underwent ABO-incompatible living donor liver transplantation (LT). The study included 152 patients who underwent ABO-incompatible living donor LT for HCC between 2010 and 2021 at Samsung Medical Center. Overall survival was analyzed using the Kaplan-Meier curve, whereas HCC-specific recurrence-free survival (RFS) was analyzed using the cumulative incidence curve after propensity score matching. Cox regression and competing risks subdistribution hazard models were used to identify the risk factors associated with overall survival and HCC-specific RFS, respectively. The propensity score matching resulted in 54 matched pairs, grouped according to whether they underwent postoperative TPE [post-transplant TPE(+)] or not [post-transplant TPE(-)]. The 5-year HCC-specific RFS cumulative incidence was superior in the post-transplant TPE (+) group [12.5% (95% CI: 3.1%-21.9%)] compared with the post-transplant TPE(-) group [38.1% (95% CI: 24.4%-51.8%), p = 0.005]. In subgroup analysis for patients with microvascular invasion and those beyond the Milan criteria, the post-transplant TPE(+) group showed significantly superior HCC-specific survival. The multivariable analysis also showed that postoperative TPE had a protective effect on HCC-specific RFS (HR = 0.26, 95% CI: 0.10-0.64, p = 0.004) and that the more post-transplant TPE was performed, the better RFS was observed (HR = 0.71, 95% CI: 0.55-0.93, p = 0.012). Post-transplant TPE was found to improve RFS after ABO-incompatible living donor LT for HCC, particularly in advanced cases with microvascular invasion and beyond Milan criteria. These findings suggest that TPE may have a potential role in improving oncological outcomes in patients with HCC undergoing LT.

PRO: Is liver organ allocation with MMaT-3 appropriate prioritization for patients with liver cancer?

PRO: Is liver organ allocation with MMaT-3 appropriate prioritization for patients with liver cancer?

Neoadjuvant programmed cell death 1 inhibitor before liver transplantation for HCC is not associated with increased graft loss.

Immune checkpoint inhibitors (ICIs) may lead to rejection and even graft loss of solid organ transplant recipients, making them not widely used in transplant patients. There is insufficient clinical experience in using ICIs as a bridging or downstaging therapy before transplantation. We performed a retrospective review of patients receiving programmed cell death 1 inhibitor (PD1) before liver transplantation for HCC in our center and analyzed the data of these patients with the purpose of investigating the safety and feasibility of preoperative PD1 inhibitor among liver transplant recipients and exploring the preoperative correlation ICIs and the postoperative risk of rejection and immune-related graft loss. A total of 16 patients enrolled in this study. Acute rejection occurred in 9 patients, with an incidence of 56.3%. The median time of rejection was 7 days after surgery. The median FK506 concentration at the time of rejection was 7.1μg/L. All rejection reactions were reversed after adjusting the immunosuppression regimen. The interval between the last PD1 inhibitor and transplantation in the rejection group was shorter than that in the nonrejection group, and there was a statistical difference [21.0 (15.5-27.5) days vs. 60.0 (34.0-167.0) days, p =0.01]. In conclusion, PD1 inhibitor is a safe and feasible method for bridging or downstaging treatment before liver transplantation. Although preoperative PD1 inhibitor may increase the incidence of postoperative rejection, it is not associated with increased immune-related graft loss and patient death.

Prognostic role of platelet lymphocyte ratio (PLR) among patients with hepatocellular carcinoma undergoing liver transplantation

Abstract Background Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, but it is so aggressive that is the third most common cause of cancer related death. We aim to study the role of PLR in prognosis of HCC and to see if it can be a predictor of overall survival and disease free survival among HCC patients that received liver transplantation in our centre. Patients and Methods This is a single centre retrospective analysis of prospectively collected data. The study was carried out in liver transplant institute of Inonu University, Malatya, Turkey. Consecutive patients that received liver transplantation for HCC and survive for at least 90 days post transplantation were included in the study. Data was collected regarding age, gender, presence or absence of cirrhosis, cause of cirrhosis, number of nodules, maximum size of the tumour, preoperative PLR, pre-transplant GGT, type of transplant, presence or absence of microvascular invasion, overall survival and disease free survival. The study was censored on June 2022. Data was analyzed using SPSS version 25. Results Platelet lymphocyte ratio was found to be significantly associated with some poor prognostic factors of HCC in our patients. We found that PLR is significantly associated with maximum tumour diameter (MTD) and total tumor diameter (TTD) with p= <0.0001 and 0.0016 respectively. Univariate analysis revealed that PLR is a predictor of worse DFS or OS but when subjected to multivariate analysis, we found that PLR is not an independent predictor of OS and DFS. Conclusion Platelet lymphocyte ratio is associated with poor prognostics feature of hepatocellular carcinoma.

Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant.

BACKGROUNDCholangiocarcinoma (CC) is a rare tumor that arises from the epithelium of the bile ducts. It is classified according to anatomic location as intrahepatic, perihilar, and distal. Intrahepatic CC (ICC) is rare in patients with cirrhosis due to causes other than primary sclerosing cholangitis. Mixed hepatocellular carcinoma-CC (HCC-CC) is a rare neoplasm that shows histologic findings of both HCC and ICC within the same tumor mass. Due to the difficulties in arriving at the correct diagnosis, patients eventually undergo liver transplantation (LT) with a presumptive diagnosis of HCC on imaging when, in fact, they have ICC or HCC-CC.AIMTo evaluate the outcomes of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma on pathological examination after liver transplant.METHODSPropensity score matching was used to analyze tumor recurrence (TR), overall mortality (OM), and recurrence-free survival (RFS) in LT recipients with pathologically confirmed ICC or HCC-CC matched 1:8 to those with HCC. Progression-free survival and overall mortality rates were computed with the Kaplan-Meier method using Cox regression for comparison.RESULTSOf 475 HCC LT recipients, 1.7% had the diagnosis of ICC and 1.5% of HCC-CC on pathological examination of the explant. LT recipients with ICC had higher TR (46% vs 11%; P = 0.006), higher OM (63% vs 23%; P = 0.002), and lower RFS (38% vs 89%; P = 0.002) than those with HCC when matched for pretransplant tumor characteristics, as well as higher TR (46% vs 23%; P = 0.083), higher OM (63% vs 35%; P = 0.026), and lower RFS (38% vs 59%; P = 0.037) when matched for posttransplant tumor characteristics. Two pairings were performed to compare the outcomes of LT recipients with HCC-CC vs HCC. There was no significant difference between the outcomes in either pairing.CONCLUSIONPatients with ICC had worse outcomes than patients undergoing LT for HCC. The outcomes of patients with HCC-CC did not differ significantly from those of patients with HCC.

Liver transplantation for HCC: validation of prognostic power of the RETREAT score for recurrence in a UK cohort.

The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC. LT for HCC between 2008 and 2018at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria. 346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR=1.19, p<0.001), micro-/macro-vascular invasion (HR=3.74, p=0.002) and AFP>20ng/ml (HR=3.03, p=0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p=0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p=0.004) and 0.38 (p=0.03) respectively). LT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance.

Outcomes of liver transplantation for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is the second-leading cause of liver transplantation (LT) performed for HCC. Despite this, little is known about the clinical characteristics and outcomes of NASH-HCC. Patients undergoing LT for HCC from 2001 to 2017at a single center were reviewed. Outcomes of NASH-HCC (n=51) were compared to other etiologies of HCC including hepatitis C (HCV) hepatitis B (HBV), and alcoholic liver disease (ALD). Outcomes of NASH-HCC were also compared to HCV in the direct-acting antiviral (DAA) era (2014-2017). The frequency of NASH-HCC as the primary indication for LT in patients with HCC increased significantly during the study period from 4.4% (2001-2008) to 15.6% in 2017. NASH-HCC patients were significantly older (median age 65 vs. 60; P<0.001) with significantly lower alpha-fetoprotein levels (7.5 vs. 26.5, P<0.001) compared to other etiologies. The 1-, 3-, and 5-year overall survival of NASH-HCC was 92%, 86%, and 80%. Overall survival of NASH-HCC was not significantly different compared to HCV, HBV, or ALD. Compared to HCV-HCC in the DAA era (n=99), NASH-HCC had comparable post-LT survival (3-year survival 87% vs. 86%, P=0.870). In this large single-center experience of NASH-HCC, we demonstrate favorable outcomes of NASH-HCC following LT comparable to other common etiologies of HCC.

Commentary: A preoperative model for predicting microvascular invasion and assisting in prognostic stratification in liver transplantation for HCC regarding empirical criteria

Commentary: A preoperative model for predicting microvascular invasion and assisting in prognostic stratification in liver transplantation for HCC regarding empirical criteria

Investigating the value of pre-treatment 18F-FDG PET/CT in predicting the pathological characteristic of hepatocellular carcinoma and recurrence after liver transplantation.

The aim of this study is to investigate the value of pre-treatment 18F-FDG PET/CT in predicting the pathological characteristic of HCC and recurrence after liver transplantation (LT). A total of 34 patients who underwent 18F-FDG PET/CT before LT for HCC and did not receive any other treatment were retrospectively enrolled in the study. The maximal standard uptake value of the tumor (T-SUVmax), normal liver tissues (L-SUVmax), and mediastinal blood pool (B-SUVmax) were derived, followed by the calculations of the T-SUVmax/L-SUVmax (T/L) and the T-SUVmax/B-SUVmax (T/B) ratios. Combined with the post-transplantation pathological results and ROC curve, the performance in predicting the pathological characteristic and the recurrence after LT were evaluated. The AUCs for T-SUVmax, T/L, and T/B in predicting the pathological grade of tumors were 0.820, 0.784, and 0.806, respectively. Alternatively, the AUCs for T-SUVmax, T/L, and T/B in predicting the recurrence after LT were 0.865, 0.899, and 0.931, respectively. The individual cutoff values were 5.0, 1.7, and 2.2, corresponding to a predication accuracy of 88.2%, 85.3%, and 88.2%, respectively. In addition, the AUCs for T/B in predicting microvascular invasion (mVI) and liver capsular invasion (LCI) were 0.825 and 0.788, respectively. The pre-treatment 18F-FDG PET/CT is effective for predicting recurrence of HCC after LT. In addition, it demonstrates values for predicting the pathological characteristic of HCC such as pathological grade, mVI, and LCI.

The Importance of AFP in Liver Transplantation for HCC.

The most common biomarker for HCC is serum alpha-fetoprotein (AFP). AFP is used for screening and diagnosing HCC, and also, it is used for predicting prognosis and monitoring the response to treatment. AFP secretion is associated with poor tumor histologic grade and aggressive tumor biological behavior. The risk of dropout on the waiting list for liver transplantation and the risk of tumor recurrence after liver transplantation are associated with high AFP serum levels. Therefore, using AFP levels for selecting patients to include on the liver transplantation waiting lists is critical. It is also known that a low AFP serum level before liver transplantation has limited informative value, but high AFP levels prior to liver transplantation indicate a higher risk for HCC recurrence. AFP's performance as a screening, diagnostic, and prognostic marker for HCC is not ideal, but it is the most frequently used biomarker in the management of HCC.

Living Donor Versus Deceased Donor Liver Transplantation for HCC.

Liver transplantation is the definitive treatment modality of the patients having an end-stage liver disease with hepatocellular carcinoma. The number of living donor liver transplantations has been increased because of the deceased donor organ shortage, especially in Asian countries. Reports of different clinics about the postoperative course and tumor recurrence rates comparing living donor versus deceased donor liver transplantations, besides patient selection criteria, are reviewed along with our clinic's experiences.

AS010 - Reassessment of the risk of recurrence (R3) after liver transplantation for HCC: validation of the R3 v.2 score and comparison with existing models: results of a multinational analysis in 2,444 patients

AS010 - Reassessment of the risk of recurrence (R3) after liver transplantation for HCC: validation of the R3 v.2 score and comparison with existing models: results of a multinational analysis in 2,444 patients

Liver Transplantation in Mixed Hepatocellular Carcinoma and Cholangiocarcinoma

Mixed hepatocellular carcinoma and cholangiocarcinoma (HCC-CC) are rare tumors, and the risk factors associated with them are not well understood yet. Moreover, the diagnosis of mixed HCC-CC can be complicated due to the difficulty in distinguishing mixed HCC-CC from HCC and intrahepatic CCC on radiological images. Serum tumor markers are useful when the radiological images are inconclusive. It remains unclear whether the prognosis of mixed HCC-CC differs from that of HCC. However, several studies have reported that the tumor recurrence and patient survival rates of mixed HCC-CC were similar to those of HCC after liver transplantation (LT) and liver resection. In this paper, we report that LT in patients with mixed HCC-CC achieves outcomes which are similar to those seen in LT for HCC. Therefore, the diagnosis of mixed HCC-CC should not be considered as a contraindication for LT. (J Liver Cancer 2019;19:85-90)

Adult liver transplant for hepatocellular carcinoma at Wits Donald Gordon Medical Centre in Johannesburg, South Africa

For those with unresectable hepatocellular carcinoma, liver transplantation is considered the treatment of choice. Since 2006, the transplant programme at Wits Donald Gordon Medical Centre (WDGMC) has offered liver transplantation for selected patients with hepatocellular carcinoma. While the number of patients transplanted was small, we are unaware of any published data from Southern Africa describing outcomes in this group of liver transplant recipients. The aim of this study was to describe our experience as a case series. The records of all patients with HCC who underwent deceased donor liver transplantation between April 2006 and March 2018 were reviewed retrospectively. Data were extracted from transplant clinic patient files, histopathology and pathology laboratory reports and an existing database of all liver transplant recipients at WDGMC. Patient survival was calculated from the time of transplant and survival estimates were determined by the Kaplan-Meier method. Thirty-one liver transplants were reviewed. The most common causes of underlying liver disease were infectious, mostly hepatitis B virus, and diseases of lifestyle including alcoholic/non-alcoholic steatohepatitis. Median age at transplant, 57 years (IQR 44-65 years), was younger than observed internationally, but consistent with reports from Africa. Male recipients predominated, in keeping with published trends. Overall, outcomes were worse than expected but for recipients who were within the University of California at San Francisco (UCSF) criteria for transplantation; survival was comparable to previously published data. Despite limitations, this is the first documented series of patients undergoing liver transplantation for HCC in South Africa and demonstrates that good results can be achieved in appropriately selected patients.

Liver Resection for Solitary Transplantable Hepatocellular Carcinoma: The Role of AFP-Score.

In 2012, the Liver Transplant French Study Group built the alpha-fetoprotein-score (AFP-score), which improved significantly the prediction of tumor recurrence in case of liver transplantation for HCC when compared to Milan criteria. The aim of the study was to test the AFP score in case of liver resection (LR) for HCC. From 1990 to 2012, 347 patients underwent a liver resection for HCC developed on chronic liver disease (CLD). All patients with solitary HCC <60mm were included. The primary end point was to investigate if the AFP-score at the first LR was predictive of recurrence and if recurrence occurred within the AFP-score. The secondary end points were overall survival (OS) and disease-free survival. One hundred and eight patients fulfilled the inclusions criteria. After a median follow-up of 65.4IQR [13-114] months, recurrence occurred in 64.8% (70/108) patients. Among the study population, 96 were "in AFP-score" (i.e., ≤2) of whom 60.4% (58/96) developed a recurrence that was cured in curative intent. In contrast, all patients "out AFP-score" experienced recurrence, and 25% were eligible for curative treatment. At the end of the follow-up, 26 patients were listed for liver transplantation (LT). Among them, 21 were finally transplanted. The 5-year OS after salvage LT was 68.5%95%CI [50.2-93.0]. AFP-score is a useful tool for patients selection after LR for solitary HCC developed on CLD. For patients "in AFP-score," up-front LR provides good survival and allows to avoid up-front LT in case of recurrence.