Post-transplant Tumor Recurrence Research Articles

The impact of Karnofsky performance status on prognosis of patients with hepatocellular carcinoma in liver transplantation

BackgroundFunctional performance as measured by the Karnofsky Performance Status (KPS) scale has been linked to the outcomes of liver transplant patients; however, the effect of KPS on the outcomes of the hepatocellular carcinoma (HCC) liver transplant population has not been fully elucidated. We aimed to investigate the association between pre-transplant KPS score and long-term outcomes in HCC patients listed for liver transplantation.MethodsAdult HCC candidates listed on the Scientific Registry of Transplant Recipients (SRTR) database from January 1, 2011 to December 31, 2017 were grouped into group I (KPS 80–100%, n = 8,379), group II (KPS 50–70%, n = 8,091), and group III (KPS 10–40%, n = 1,256) based on percentage KPS score at listing. Survival was compared and multivariable analysis was performed to identify independent predictors.ResultsPatients with low KPS score had a higher risk of removal from the waiting list. The 5-year intent-to-treat survival was 57.7% in group I, 53.2% in group II and 46.7% in group III (P < 0.001). The corresponding overall survival was 77.6%, 73.7% and 66.3% in three groups, respectively (P < 0.001). Multivariable analysis demonstrated that KPS was an independent predictor of intent-to-treat survival (P < 0.001, reference group I; HR 1.19 [95%CI 1.07–1.31] for group II, P = 0.001; HR 1.63 [95%CI 1.34–1.99] for group III, P < 0.001) and overall survival(P < 0.001, reference group I; HR 1.16 [95%CI 1.05–1.28] for group II, P = 0.004; HR 1.53 [95%CI 1.26–1.87] for group III, P < 0.001). The cumulative 5-year recurrence rates was higher in group III patients (7.4%), compared with 5.2% in group I and 5.5% in group II (P = 0.037). However, this was not significant in the competing regression analysis.ConclusionsLow pre-transplant KPS score is associated with inferior long-term survival in liver transplant HCC patients, but is not significantly associated with post-transplant tumor recurrence.

The Effect of Pre-transplant Lipid Profile on Post-transplant Hepatocellular Carcinoma Recurrence: Retrospective Single-Center Analysis.

Plasma lipids have been shown to relate to tumor biology. We aimed to analyze the effect of pre-transplant plasma lipid profiles on post-transplant tumor recurrence in patients with hepatocellular carcinoma and to identify any possible relationship between the pre-transplant lipid profile with maximum tumor diameter, number of tumor nodules, tumor differentiation, portal vein invasion, or serum biomarker levels. Patients with hepatocellular carcinoma who underwent liver transplants between 2006 and 2021 had data collected pro- spectively and were analyzed retrospectively. Patients who did not have lipid profile data before transplant and whose post-transplant follow-up period was <90 days were excluded. Patients who had pre-transplant plasma lipid data and whose post-transplant follow-up period was >90 days were included in this study (n = 254). Lower high-density lipoprotein cholesterol levels were found to be significantly associated with post-Tx recurrence (38 vs 29.5, P < .001) and were also significantly associated with macroscopic portal vein thrombosis (39 vs 30.4, P < .021). There was no significant association between plasma lipids and tumor differentiation. Higher high-density lipoprotein cholesterol levels were significantly asso- ciated with good overall and disease-free survivals (P = .024 and P = .001). Pre-transplant low plasma high-density lipoprotein cholesterol levels were significantly associated with portal vein throm- bosis and poor post-transplant overall and disease-free survivals.

Protective benefit of minimally invasive liver surgery for hepatocellular carcinoma prior to transplant

Aim: The purpose of this study is to assess the benefit of laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) given recurrence and future need for liver transplantation (LT). Methods: Data on liver resections were gathered from the Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione (IRCCS-ISMETT) from 2003-2021. A retrospective analysis of 1408 consecutive adult patients who had a liver resection was performed with categorization based on the underlying disease process. A sub-analysis studied the 291 patients who had an LLR with an intention to transplant approach after LLR. Results: From 2012 to 2020, ISMETT’s mean annual LLR rate was 45%. Data suggests that a laparoscopic approach to iterative surgical treatment for HCC has demonstrated protective benefits. Compared to open surgery or LT, LLR is protective against the risk of de-listing, post-transplant patient death, tumor recurrence, adhesions, and bleeding in a cirrhotic patient. Kaplan Meier’s analysis showed no difference between post-LT survival curves for those with prior open abdominal surgery or LLR (P = 0.658). Conclusion: Laparoscopic surgery has important protective advantages over laparotomy surgery for the surgical treatment of HCC, particularly since treatment is not always curative. LLR can be considered a bridge therapy for transplantation, ensuring less crowding of waiting lists, a desirable condition in areas of donor storage.

Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma: Is Neo-Adjuvant Chemo-Radiation Therapy Really Necessary? An International, Multicenter Comparison

Introduction: The Mayo Clinic protocol for patients with unresectable perihilar cholangiocarcinoma (pCCA) is based on strict selection and neo-adjuvant chemo-radiation therapy (NAT) followed by liver transplantation (LT). With this protocol, 5-year survival up to 68% has been reported. It remains unclear whether these favorable results are attributable to NAT or strict selection only. Our aim was to compare outcomes after LT for unresectable pCCA after strict selection between patients with or without NAT. Method: International, multicenter, comparison of two cohorts of patients transplanted between 2011-2021, for unresectable pCCA using the Mayo Clinic selection criteria and receiving NAT (NAT+) or not (NAT-). Primary endpoint was overall survival. Secondary outcomes included post-transplant morbidity (including vascular complications) and tumor recurrence evaluated by inverse-probability-weighting and competing risk analysis. Results: A total of 49 patients underwent LT for unresectable pCCA (NAT+ n=27, NAT- n=22). Median age was 55 years. Median follow-up was 25 months. In the NAT+ group, the 1-, 3- and 5-year survival rates were 65%, 51% and 41%, respectively, compared to 91%, 68% and 53% for NAT- patients (p=0.20; Figure). Tumor 5-year recurrence rate was similar between groups: 32% in the NAT+ group versus 53% in the NAT- group (p=0.55). Major vascular complications (Clavien-Dindo grade ≥3A) post-LT were significantly higher in the NAT+ cohort with 11 patients (41%) versus 3 patients (14%) (p=0.04). Conclusions: Survival after LT for pCCA in strictly selected patients did not differ between patients with or without NAT. Post-transplant vascular complications were significantly higher in patients after NAT.

O-4 IMPACT OF BRIDGE THERAPY FOR HEPATOCELLULAR CARCINOMA IN PATIENTS SUBMITTED TO LIVER TRANSPLANTATION - BRAZILIAN MULTICENTER STUDY

Hepatocellular carcinoma (HCC) is one of the main indications for liver transplantation (LT). Bridge therapy (BT) is recommended when waiting time on transplant list is longer than six months to avoid tumor progression and dropout. Response to locoregional treatment has been considered as a good prognostic parameter in post-LT, however, its role still needs to be defined. To evaluate the role of BT for HCC on survival and post-LT tumor recurrence. Brazilian multicenter retrospective cohort study in HCC patients submitted to LT with clinical and radiological data analysis. Data related to HCC pre-LT treatment, type of treatment and the final response according to mRECIST criteria in the last pre-LT image exam were analyzed. Survival curves were presented using the Kaplan-Meier and compared using the log-rank test. 1,119 patients were included. 81% were males and mean age at LT was 58 ± 8.2 years. At HCC diagnosis, 85% were within Milan criteria (MC) by imaging studies and 67%, underwent BT prior to LT. TACE/TAE were performed in 80%, PEI 9%, RFA 3%, surgery 1% and combined therapy 7%. According to mRECIST, 37% showed complete response (CR), 38% partial response (PR), 12% stable disease (SD) and 13% progressive disease (PD) after BT. The overall survival (OS) was 63% in 5 years, with a mean follow-up of 28 months. The post-LT tumor recurrence was 8%. There was no difference in the risk of post-LT tumor recurrence or survival among patients who underwent BT or not or between the various types of treatment performed. However, patients who have CR to BT had a higher recurrence-free survival compared to patients with PR, SD or PD (p = 0.019). This study demonstrated the role of BT in LT, since patients with complete response, had a lower risk of post-transplant tumor recurrence.

Association of phenotypic transformation of circulating tumor cells and early recurrence in patients with hepatocellular carcinoma following liver transplantation

BackgroundCTCs play a critical role in the diagnosis and prognosis of liver cancer. However, there are few studies on whether different types of CTCs can predict the prognosis in patients with HCC following LT. MethodsRetrospective data including CTCs detected by the CanPatrolTM platform combined with RNA-ISH were collected and analyzed on 56 patients from December 2016 to December 2019 at the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. ResultsDuring the study period, fifty-six patients (51 males, 5 females) were included with an mean age of 52 ± 9 years. The 1-, 2- and 3-year recurrence rates of postoperative interstitial CTC-positive and CTC-negative groups were 21.7% vs 10.8%, 37.5% vs 10.8% and 55.5% vs 10.8%, confirming a statistically significant difference between the 2 groups (p = 0.044). The 1-, 2- and 3-year recurrence rates of the increasing interstitial CTCs group were 25.2%, 36.9% and 66.9%, while 12.6%, 24.4% and 24.4% in the decreasing and unchanged group, indicating a significant difference (p = 0.038). ConclusionCanPatrolTM platform presents a superior analytical sensitivity, and may be used as a dynamic monitoring tool for CTCs. And interstitial CTCs which are more aggressive and metastatic caused by EMT can be regarded as a predictor of post-transplant tumor recurrence after LT for HCC.

Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling

Tumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.

Impact of donor age on liver transplant outcomes in patients with hepatocellular carcinoma: analysis of the SRTR database

BackgroundDonor age is an important predictor for liver transplant recipients. Studies have not fully explored its impact on transplant outcomes in hepatocellular carcinoma (HCC) patients as well as its involvement in tumor recurrence.MethodsHCC patients who received liver transplants during 2010–2017 from the Scientific Registry of Transplant Recipients database were included. The recipients were divided into four groups based on donor age: I (≤ 34 years), II (35–49 years), III (50–64 years), and IV (≥ 65 years). Transplant outcomes, including the overall survival (OS), tumor recurrence, and risks, were evaluated.ResultsA total of 13,276 HCC recipients were included in this study. Statistical significant differences were observed in OS among the four groups. The best 5-year survival was 76.0% in group I, followed by 73.5% in group II, 72.8% in group III, and 69.2% in group IV (P < 0.001). However, the liver-specific survival did not differ among these groups (P = 0.260). Donor age was found to be the independent predictor of OS after adjusting for other variables (P < 0.001, ref. group I; 1.087 (0.979–1.208) for group II, P = 0.119; 1.124 (1.015–1.246) for group III, P = 0.025; 1.395 (1.215–1.602) for group IV, P < 0.001). In subgroup analysis, OS was significantly different in recipients with hepatitis C virus (HCV), but there was no significant difference for recipients with hepatitis B virus (HBV), alcoholic liver diseases and nonalcoholic steatohepatitis (NASH). The post-transplant cumulative tumor recurrence rates were similar among the four groups (P = 0.382).ConclusionsOlder donor age was associated with decreased OS but not liver-specific survival as well as post-transplant tumor recurrence in HCC recipients. Donor age also had different effects in patients with different underlying liver diseases.

Correlationship between Ki67, VEGF, and p53 and Hepatocellular Carcinoma Recurrence in Liver Transplant Patients

Background and Aims Patients with hepatocellular carcinoma (HCC) who undergo orthotopic liver transplantation (OLT) are at risk for posttransplant tumor recurrence. The aim of this study was to evaluate the correlation between the expression of Ki67, VEGF, and p53 in HCC and clinicopathological characteristics of HCC patients, as well as their predictive value for HCC recurrence after OLT. Methods 60 patients who underwent OLT and were found to have HCC in the liver explant. The expression of Ki67, VEGF, and p53 in HCC was detected by immunohistochemistry. Results Ki67 was associated with the tumor number and the grade of differentiation at baseline. VEGF was associated with the diameter and number of tumors, tumor differentiation, and lymph node metastasis. p53 was associated with the tumor diameter and tumor encapsulation. The expression of Ki67, VEGF, and p53 in HCC was correlated with the tumor recurrence after OLT, respectively. Among them, VEGF was an independent predictor for tumor recurrence after OLT. Conclusion Ki67, VEGF, and p53 are associated with the recurrence of HCC after OLT. VEGF independently predicts the recurrence of HCC.

Blood Salvage and Autotransfusion With Single Leukoreduction Does Not Increase the Risk of Tumor Recurrence After Liver Transplantation for Advanced Hepatocellular Carcinoma.

The aim of this study was to determine whether autotransfusion of salvaged blood with single leukoreduction is associated with post-transplant tumor recurrence in patients with advanced hepatocellular carcinoma (HCC). Previous studies have consistently demonstrated the safety of autotransfusion of salvaged and leukoreduced blood during liver transplantation for HCC. However, the effects of this technique remained unknown for advanced HCC. Of 349 patients who underwent living donor liver transplantation for advanced HCC: 74 of 129 without autotransfusion were matched with 74 of 220 with autotransfusion using propensity score based on tumor biology, allogeneic transfusion, and others. Survival analysis was performed with death as a competing risk event. The primary outcome was HCC recurrence. Recipients in autotransfusion group received 811 (497-1247) mL of salvaged blood with single leukoreduction. In the matched cohort, cumulative overall recurrence probability at 1/2/5 years after transplantation was 24.6%/ 38.3%/39.7% for nonautotransfusion group and 16.2%/23.1%/32.5% for autotransfusion group. There were no significant differences between the 2 groups in overall recurrence [hazard ratio (HR) = 0.72 (0.43-1.21)], intrahepatic recurrence [HR = 0.70 (0.35-1.40)], and extrahepatic recurrence [HR = 0.82 (0.46-1.47)]. Also, there were no significant differences in overall death [HR = 0.57 (0.29-1.12)], HCC-related death [HR = 0.59 (0.29-1.20)], and HCC-unrelated death [HR = 0.48 (0.09-2.65)]. When allogeneic transfusion was matched, autotransfusion was not significantly related to HCC recurrence, with more favorable probabilities for autotransfusion, in patients with advanced HCC. Thus, blood salvage and autotransfusion could be safely used with single leukoreduction, without double-filtered leukoreduction, during liver transplantation for HCC with potential benefits from avoiding allogeneic red blood cell transfusion.

Is the Rationale of Anatomical Liver Resection for Hepatocellular Carcinoma Universally Adoptable? A Hypothesis-Driven Review.

Surgical resection is the first-line curative treatment modality for resectable hepatocellular carcinoma (HCC). Anatomical resection (AR), described as systematic removal of a liver segment confined by tumor-bearing portal tributaries, may improve survival by reducing the risk of tumor recurrence compared with non-AR. In this article, we propose the rationale for AR and its universal adoption by providing supporting evidence from the advanced understanding of a tumor microenvironment and accumulating clinical experiences of locoregional tumor ablation therapeutics. AR may be advantageous because it completely removes the en-bloc by interrupting tumor vascular supply and thus extirpates the spreading of tumor microthrombi, if they ever exist, within the supplying portal vein. However, HCC is a hypervascular tumor that can promote neoangiogenesis in the local tumor microenvironment, which in itself can break through the anatomical boundary within the liver and even retrieve nourishment from extrahepatic vessels, such as inferior phrenic or omental arteries. Additionally, increasing clinical evidence for locoregional tumor ablation therapies, such as radiofrequency ablation, predominantly performed as a non-anatomical approach, suggests comparable outcomes for surgical resection, particularly in small HCC and colorectal, hepatic metastases. Moreover, liver transplantation for HCC, which can be considered as AR of the whole liver followed by implantation of a new graft, is not universally free from post-transplant tumor recurrence. Overall, AR should not be considered the gold standard among all surgical resection methods. Surgical resection is fundamentally reliant on choosing the optimal margin width to achieve en-bloc tumor niche removal while balancing between oncological radicality and the preservation of postoperative liver function. The importance of this is to liberate surgical resilience in hepatocellular carcinoma. The overall success of HCC treatment is determined by the clearance of the theoretical niche. Developing biomolecular-guided navigation device/technologies may provide surgical guidance toward the total removal of microscopic tumor niche to achieve superior oncological outcomes.

The Role of Salvage Transplantation in Patients Initially Treated With Open Versus Minimally Invasive Liver Surgery: An Intention-to-Treat Analysis.

Despite gaining wide consensus in the management of hepatocellular carcinoma (HCC), minimally invasive liver surgery (MILS) has been poorly investigated for its role in the setting of salvage liver transplantation (SLT). A multicenter retrospective analysis was carried out in 6 Italian centers on 211 patients with HCC who were initially resected with open (n=167) versus MILS (n=44) and eventually wait-listed for SLT. The secondary endpoint was identification of risk factors for posttransplant death and tumor recurrence. The enrolled patients included 211 HCC patients resected with open surgery (n=167) versus MILS (n=44) and wait-listed for SLT between January 2007 and December 2017. We analyzed the intention-to-treat survival of these patients. MILS was the most important protective factor for the composite risk of delisting, posttransplant patient death, and HCC recurrence (OR, 0.26; 95% confidence interval [CI], 0.11-0.63; P=0.003). MILS was also the only independent protective factor for the risk of post-SLT patient death (OR, 0.29; 95% CI, 0.09-0.93; P=0.04). After propensity score matching, MILS was the only independent protective factor against the risk of delisting, posttransplant death, and HCC recurrence (OR, 0.22; 95% CI, 0.07-0.75; P=0.02). On the basis of the current analysis, MILS seems protective over open surgery for the risk of delisting, posttransplant patient death, and tumor recurrence. Larger prospective studies balancing liver function and tumor stage are strongly favored to better clarify the beneficial effect of MILS for HCC patients eventually referred to SLT.

The Matching Status Between Donor and Recipient Hepatitis B Seroepidemiology Makes a Difference in Liver Transplantation for Hepatocellular Carcinoma.

INTRODUCTION:Antibody to hepatitis B core antigen (HBcAb) is known to be related with the prognosis for patients with hepatocellular carcinoma (HCC). This study aims to evaluate the prognostic capacity of HbcAb and other donor/recipient hepatitis B seroepidemiological indexes in transplantation for HCC.METHODS:Based on the national liver transplant registry, we analyzed the prognostic capacity of HBcAb in liver transplantation for patients with HCC of different etiological backgrounds. The hepatitis B virus (HBV)-related HCC cohort was further studied regarding donor/recipient hepatitis B seroepidemiology, and then divided into a training cohort (n = 1,222) and a validation cohort (n = 611) to develop a pretransplant recurrence-risk predicting nomogram.RESULTS:Positive HbcAb in recipients was related to an increased risk of post-transplant tumor recurrence in HBV-related (n = 1,833, P = 0.007), HCV-related (n = 79, P = 0.037), and non-B non-C HCC (n = 313, P = 0.017). In HBV-related HCC (n = 1,833), donor hepatitis B surface antigen (HbsAg) was also associated with post-transplant tumor recurrence (P = 0.020). Multivariate analysis showed that the matching status of recipient HbcAb and donor HbsAg (MSHB) was an independent prognostic factor (P = 0.017). HbcAb-positive recipients matched with HbsAg-positive donors displayed the worst post-transplant outcomes (P < 0.001). In the training cohort (n = 1,222), a risk-predicting nomogram was established based on α-fetoprotein, Milan criteria, and MSHB. The model showed excellent prognostic capacity and safely expanded Milan criteria in both training and validation cohorts (P < 0.001).DISCUSSION:Positive HbcAb in recipients increases the risk of post-transplant tumor recurrence in HCC with different etiological backgrounds. The nomogram based on MSHB is effective in predicting tumor recurrence after transplantation for HBV-related HCC.

Locoregional Therapy Protocols With and Without Radioembolization for Hepatocellular Carcinoma as Bridge to Liver Transplantation

The objective of this study was to compare posttransplant outcomes in patients undergoing bridging locoregional therapy (LRT) with Y-90 transarterial radioembolization (TARE) based protocol compared with transarterial chemoembolization based protocol for hepatocellular carcinoma (HCC) prior liver transplantation (LT). Patients listed for LT with HCC within the Milan criteria at our center who had bridging LRT were treated according to transarterial chemoembolization (TACE) based protocol from May 2012 to April 2014 and a TARE based protocol from October 2014 to December 2017. Early posttransplant survival and tumor recurrence were compared between the groups. Tumor response to LRT, microvascular invasion (mVI), and the rate of delisting was also evaluated. One hundred three patients who were listed for LT with HCC within the Milan criteria received LRT. LT was performed in 65 patients, 28 treated with TARE protocol and 37 on TACE protocol. There were no statistical differences in baseline pretransplant characteristics and tumor recurrence. There was a trend toward improved 3-year survival in the TARE group (92.9% vs. 75.7%; P=0.052). The mVI was seen in 1/28 (3.6%) explants in the TARE group compared with 10/37 (27%) in the TACE group (P=0.013). The TARE group also required fewer LRT treatments (1.46 vs. 2.43; P=0.001) despite no difference in time on the transplant list. Despite requiring fewer LRT treatments, there was significantly less mVI in the explants of patients treated with TARE protocol LRT as a bridge to LT as well as a trend toward improved 3-year survival. Therefore, TARE may be associated with improved tumor control and reduced post-LT recurrence.

Recurrence of hepatocellular carcinoma following deceased donor liver transplantation: case series.

Aim:We aimed to study the clinical and pathological characteristics of liver transplant recipients with hepatocellular carcinoma recurrence.Methods:We reviewed the data for 26 patients who had tumor recurrence after deceased donor liver transplant for hepatocellular carcinoma at the Johns Hopkins Hospital from January 2005 to December 2015.Results:In total, 88% of recipients were males. The mean age was 59 years. On explant, poor differentiation was detected in 43%, while 73% had microvascular invasion. Overall, 62% were diagnosed to be outside of Milan criteria. Out of these, 15% met the criteria for downstaging. Twenty (77%) patients had pre-transplant alpha fetoprotein levels ≥ 20 ng/mL. In 54% of patients, the location of hepatocellular carcinoma (HCC) recurrence was extrahepatic, followed by intrahepatic in 31% and both intra- and extrahepatic in 15%. The post-transplant tumor recurrence was diagnosed at a mean of 427 days (range 34–1502). Fifty percent of HCC recurrences were diagnosed within one year following liver transplant. Twenty (77%) patients received treatment for their recurrent HCC: external radiation (n = 10), surgical resections (n = 8; brain 4, spine 2, bone 1, and Whipple surgery 1), sorafenib (n = 7), locoregional therapy (n = 5). Overall, 24 out of 26 (92%) recipients died within four years after the transplant.Conclusion:HCC recurrence after liver transplant is infrequent. More than fifty percent of HCC recurrences following liver transplant are extrahepatic. Despite better recipient selection for liver transplant, the curative options are limited in recurrent cases and associated with extremely poor outcomes.

Homocysteine: A novel prognostic biomarker in liver transplantation for alpha-fetoprotein- negative hepatocellular carcinoma.

Precise recipient selection optimizes the prognosis of liver transplantation (LT) for hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is the most commonly used biomarker for diagnosis and prognosis of HCC in the clinical context. As a crucial molecule in methionine cycle, homocysteine (Hcy) level has been proved to be related to HCC progression and metastasis. We aimed to explore the prognostic capacity of pre-transplant serum Hcy level in LT for HCC. This study retrospectively enrolled 161 HCC patients who had underwent LT from donation after cardiac death (DCD) in the First Affiliated Hospital of Zhejiang University from 2015.01.01 to 2018.09.01. Pre-transplant serum Hcy level was incorporated into statistical analysis together with other clinical parameters and pathological features. From an overall perspective, significant difference was observed in Hcy level between recurrence (n= 61) and non-recurrence group (n= 100) though subsequent analysis showed unsatisfactory predicting performance. In the whole cohort, multivariate analysis showed that lnAFP (p= 0.010) and Milan criteria (MC, p< 0.001) were independent risk factors of HCC recurrence after LT. MA score based on MC and lnAFP performed well in predicting post-LT tumor recurrence with the AUROC at 0.836 (p< 0.001) and 3-year recurrence-free survival rate at 96.8% (p< 0.001) in the low risk group (n= 69). According to the clinical practice, serum concentration lower than 20 μg/L is considered as normal range of AFP. Elevated pre-transplant serum AFP (> 20 μg/L) predicts high HCC recurrence after LT. We further divided the 161 recipients into AFP- group (n= 77, AFP ⩽ 20 μg/L) and AFP+ group (n= 84, AFP > 20 μg/L). MA score was still well presented in the AFP+ group and the AUROC for tumor recurrence was 0.823 (p< 0.001), whereas the predicting accuracy was reduced in AFP- group (AUROC: 0.754, P< 0.001). After subsequent analysis, we found that elevated pre-transplant Hcy level (> 12.75 μmol/L) predicted increased tumor recurrence risk in AFP- group. The 3-year recurrence-free survival rates were 92.0% and 53.7% (p< 0.001) in low Hcy subgroup (n= 40) and high Hcy subgroup (n= 37) respectively. Multivariate analysis showed that Hcy (p= 0.040) and Milan criteria (p= 0.003) were independent risk factors for post-transplant tumor recurrence in AFP- group. Further combination of Hcy level and Milan criteria identified a subgroup of AFP- recipients with acceptable outcomes even though beyond Milan criteria (3-year recurrence-free survival rate: 77.7%, p< 0.001). As a classic predictor in HCC prognosis, AFP performed well in our study cohort when combined with Milan criteria. Homocysteine was an effective prognostic biomarker in LT for AFP- hepatocellular carcinoma. In recipients exceeding Milan criteria, acceptable post-transplant outcome could be seen in those with low Hcy and AFP level.

Post-transplant infection improves outcome of hepatocellular carcinoma patients after orthotopic liver transplantation

BACKGROUNDTumor recurrence after orthotopic liver transplantation (OLT) remains a serious threat for long-term survival of the recipients with hepatocellular carcinoma (HCC), since very few factors or measures have shown impact on overcoming HCC recurrence after OLT. Postoperative infection suppresses tumor recurrence and improves patient survival in lung cancer and malignant glioma probably via stimulating the immune system. Post-transplant infection (PTI), a common complication, is deemed to be harmful for the liver transplant recipients from a short-term perspective. Nevertheless, whether PTI inhibits HCC recurrence after OLT and prolongs the long-term survival of HCC patients needs to be clarified.AIMTo investigate the potential influence of PTI on the survival and tumor recurrence of patients with HCC after OLT.METHODSA total of 238 patients with HCC who underwent OLT between August 2002 and July 2016 at our center were retrospectively included and accordingly subdivided into a PTI group (53 patients) and a non-PTI group (185 patients). Univariate analyses, including the differences of overall survival (OS), recurrence-free survival (RFS), and post-recurrence survival (PRS), between the PTI and non-PTI subgroups as well as survival curve analysis were performed by the Kaplan-Meier method, and the differences were compared using the log rank test. The variables with a P-value < 0.1 in univariate analyses were included in the multivariate survival analysis by using a Cox proportional-hazards model.RESULTSThe 1-, 3-, and 5-year OS and RFS rates of the whole cohort were 86.6%, 69.0%, and 63.6%, and 75.7%, 60.0%, and 57.3%, respectively. The 1-, 3-, and 5-year OS rates for the PTI patient group (96.0%, 89.3%, and 74.0%) were significantly higher than those for the non-PTI group (84.0%, 63.4%, and 60.2%) (P = 0.033). The absence of PTI was an independent risk factor for dismal OS (relative risk [RR] = 2.584, 95%CI: 1.226-5.449) and unfavorable RFS (RR = 2.683, 95%CI: 1.335-5.390). Subgroup analyses revealed that PTI remarkably improved OS (P = 0.003) and RFS (P = 0.003) rates of HCC patients with vascular invasion (IV), but did not impact on OS (P = 0.404) and RFS (P = 0.304) of patients without VI. Among the patients who suffered post-transplant tumor recurrence, patients with PTI showed significantly better OS (P = 0.026) and PRS (P = 0.042) rates than those without PTI.CONCLUSIONPTI improves OS and RFS of the transplant HCC patients at a high risk for post-transplant death and tumor recurrence, which is attributed to suppressive effect of PTI on HCC recurrence.

A prognostic fingerprint in liver transplantation for hepatocellular carcinoma based on plasma metabolomics profiling

IntroductionTumor recurrence is a major cause of post-transplant mortality in liver transplantation for hepatocellular carcinoma (HCC). This study aimed to explore an effective noninvasive approach to accurately predict post-transplant tumor recurrence. Materials and methodsMetabolomics profiling was performed on pre-operative plasma from 122 HCC patients undergoing liver transplantation, 52 healthy controls (HC) and 25 liver cirrhosis (LC) patients. ResultsFive prognostic metabolites were identified by univariate analysis (P < 0.01), including phosphatidylcholine (PC) (16:0/P-18:1), PC(18:2/OH-16:0), PC(o-16:0/20:4), nutriacholic acid and 2-oxo-4-methylthiobutanoic acid. In the HCC group, PC(o-16:0/20:4), nutriacholic acid and 2-oxo-4-methylthiobutanoic acid were decreased, while PC(18:2/OH-16:0) was elevated compared with the LC group (e < 0.05). PC(16:0/P-18:1) was associated with tumor size, vascular invasion, and neutrophil-lymphocyte ratio (NLR; P < 0.05). Moreover, PC(18:2/OH-16:0) was also related to tumor number and NLR (P < 0.05). Multivariate cox regression showed that PC(16:0/P-18:1), PC(18:2/OH-16:0), nutriacholic acid and alpha-fetoprotein (AFP) were independent risk factors for tumor recurrence (P < 0.01). A prognostic fingerprint was established as a nomogram, which divided the patients into low risk (n = 45), moderate risk (n = 48) and highrisk groups (n = 29) with discriminated prognosis (P < 0.001). In patients fulfilling the Hangzhou criteria, the fingerprint/nomogram could also successfully stratify the patients into two groups with different recurrence risk (P < 0.05). ConclusionsThe established pre-operative plasma fingerprint/nomogram is efficient in the prediction of recurrence risk, which could facilitate candidate selection in liver transplantation for HCC.

Utility of Liquid Biopsy (CTCs) after Liver Transplantation in Cirrhotic Patients with Hepatocarcinoma

Introduction New markers associated with angiogenesis and tumor metastasis, such as circulating tumor cells (CTCs), are opening up new avenues in cancer management from the laboratory. The Aim of this work is to determine the number of CTCs in patients included in waiting list for liver transplantation of hepatocellular carcinoma and to study its possible association with the alpha fetoprotein tumor marker (AFP) and with clinical variables such as number of tumors, presence of tumor vascular invasion, waiting list time, time from diagnosis and post-transplant tumor recurrence. In addition, we intend to compare the pre-transplant levels of CTCs with those obtained one month, six months, one year and two years after the transplant. Materials and Methods Peripheral blood of 36 patients suffering hepatocellular carcinoma once included in waiting list for liver transplant was obtained. 29 of them were transplanted, 27 of whom had blood extracted one month after the transplant, 19 of them after 6 months and one year after the transplant and 11 of them two years after the transplant. In order to study the correlation between the concentration of CTCs and the concentration of AFP, number of tumors, time on waiting list and from diagnosis in the patients, the Rho Spearman test was used. The study of the association of the CTCs levels with vascular invasion and presence of post-transplant recurrence was conducted with Mann-Whitney U test. For the variation in the levels of CTCs before and after the transplant, the Wilcoxon (SPSS 15.0) test was used. Results The average concentration of CTCs in the 36 patients before transplant was 11.50 CTCs/10mL (RI=2.25-42). A statistically significant positive correlation was found between the pre-transplant levels of CTCs and the days on waiting list (Rho= 0,376 p=0,024). The CTCs were not correlated in a significant way with the AFP concentration, number of tumors and time since diagnosis. (p>0,05). Out of the 29 transplanted patients, 2 showed vascular invasion in liver. Differences in the levels of CTCs were found between the patients with and without vascular invasion (U=0,00 p=0,020), these being significantly higher in the patients with vascular invasion. However, no significant differences were found in the levels of CTCs of the patients with recurrence after transplantation (4 patients) as opposed to those who didn’t (U=42 p=0.611). Conclusions Our conclusion is that the levels of tumor cells in peripheral blood could be an unfavourable prognostic factor associated to longer waiting times and to the presence of vascular invasion by tumor with an increased risk of relapse and post-transplant metastasis. In addition, we can see how their levels decrease significantly after transplantation. However, it would be necessary to increase the number of patients in the study, as well as the follow-up time, in order to achieve greater clinical evidence for its utility.

Sarcopenia as a predictor of post-transplant tumor recurrence after living donor liver transplantation for hepatocellular carcinoma beyond the Milan criteria

To evaluate the association between sarcopenia and tumor recurrence after living donor liver transplantation (LDLT) in patients with advanced hepatocellular carcinoma (HCC), we analyzed 92 males who underwent LDLT for treating HCC beyond the Milan criteria. Sarcopenia was defined when the height-normalized psoas muscle thickness was <15.5 mm/m at the L3 vertebra level on computed tomography based on an optimum stratification method using the Gray’s test statistic. Survival analysis was performed with death as a competing risk event. The primary outcome was post-transplant HCC recurrence. The median follow-up time was 36 months. There was a 9% increase in recurrence risk per unit decrease in height-normalized psoas muscle thickness. Twenty-six (36.1%) of 72 sarcopenic recipients developed HCC recurrence, whereas only one (5.0%) of 20 non-sarcopenic recipients developed HCC recurrence. Recurrence risk was greater in sarcopenic patients in univariable analysis (hazard ratio [HR] = 8.06 [1.06–16.70], p = 0.044) and in multivariable analysis (HR = 9.49 [1.18–76.32], p = 0.034). Greater alpha-fetoprotein and microvascular invasion were also identified as independent risk factors. Incorporation of sarcopenia improved the model fitness and prediction power of the estimation model. In conclusion, sarcopenia appears to be one of the important host factors modulating tumor recurrence risk after LDLT for advanced HCC.