Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: A multicenter study of 412 patients

AIM: To assess pre-orthotopic liver transplantation (OLT) factors that could be evaluated pre-operatively or con- trolled post-operatively associated with hepatocellular carcinoma (HCC) recurrence and disease-free survival after liver transplantation (LT).METHODS: Four hundred and twelve patients trans- planted for HCC between 1988 and 1998 in 14 French centers, who survived the postoperative period were studied. Kaplan Meier estimates were calculated for 24 variables potentially associated with recurrence of HCC. Uni- and multivariate analyses were conducted to iden- tify independent predictors of recurrence. RESULTS: Overall 5-year disease-free survival was 57.1%. By univariate analysis, variables associated with disease-free survival were: presence of cirrhosis (P = 0.001), etiology of liver disease (P = 0.03), α fetoprotein level (< 200, 200 to 2000, or > 2000; P < 0.0001), γ-GT activity (N, N to 2N or > 2N; P = 0.02), the number of nodules (1, 2-3 or ≥ 4; P = 0.02), maximal diameter of the largest nodule (< 3 cm, 3 to 5 cm or > 5 cm; P < 0.0001), the sum of the diameter of the nodules (< 3 cm, 3 to 5 cm, 5 to 10 cm or >10 cm; P < 0.0001), bi- lobar location (P = 0.01), preoperative portal thrombosis (P < 0.0001), peri-operative treatment of the tumor (P = 0.002) and chemoembolization (P = 0.03), tumor differentiation (P = 0.01), initial type of calcineurin inhibitor (P = 0.003), the use of antilymphocyte antibodies (P = 0.02), rejection episodes (P = 0.003) and period of LT (P < 0.0001). By multivariate analysis, 6 variables were independently associated with HCC recurrence: maximal diameter of the largest nodule (P < 0.0001), time of LT (P < 0.0001), tumor differentiation (P < 0.0001), use of anti-lymphocyte antibody (ATG) or anti-CD3 antibody (OKT3) (P = 0.005), preoperative portal thrombosis (P = 0.06) and the number of nodules (P = 0.06). CONCLUSION: This study identif ies immunosuppression, through the use of ATG or OKT3, as a predictive factor of tumor recurrence, and confi rms the prognostic value of tumor differentiation.

Prediction of early recurrence of hepatocellular carcinoma after liver transplantation based on computed tomography radiomics nomogram

Background:Early recurrence results in poor prognosis of patients with hepatocellular carcinoma(HCC)after liver transplantation(LT).This study aimed to explore the value of computed tomography(CT)-based radiomics nomogram in predicting early recurrence of patients with HCC after LT.Methods:A cohort of 151 patients with HCC who underwent LT between December 2013 and July 2019 were retrospectively enrolled.A total of 1218 features were extracted from enhanced CT images.The least absolute shrinkage and selection operator algorithm(LASSO)logistic regression was used for dimension reduction and radiomics signature building.The clinical model was constructed after the analysis of clin-ical factors,and the nomogram was constructed by introducing the radiomics signature into the clinical model.The predictive performance and clinical usefulness of the three models were evaluated using re-ceiver operating characteristic(ROC)curve analysis and decision curve analysis(DCA),respectively.Cali-bration curves were plotted to assess the calibration of the nomogram.Results:There were significant differences in radiomics signature among early recurrence patients and non-early recurrence patients in the training cohort(P<0.001)and validation cohort(P<0.001).The nomogram showed the best predictive performance,with the largest area under the ROC curve in the training(0.882)and validation(0.917)cohorts.Hosmer-Lemeshow testing confirmed that the nomogram showed good calibration in the training(P=0.138)and validation(P=0.396)cohorts.DCA showed if the threshold probability is within 0.06-1,the nomogram had better clinical usefulness than the clinical model.Conclusions:Our CT-based radiomics nomogram can preoperatively predict the risk of early recurrence in patients with HCC after LT.

Current strategies for preventing the recurrence of hepatocellular carcinoma after liver transplantation

BACKGROUND：Liver transplantation is the optimal treatment for a selected group of patients with moderate to severe cirrhosis and hepatocellular carcinoma（HCC）.Despite the strict selection of candidates,post-transplant recurrence often occurs and markedly reduces the long-term survival of patients with HCC.The present review focuses on the current strategies on preventing the recurrence of HCC after liver transplantation.DATA SOURCES： Relevant articles were identified by exten- sive searching of PubMed using the keywords ＂hepatocellular carcinoma＂, ＂recurrence＂ and ＂liver transplantation＂ between January 1996 and January 2014. Additional papers were searched manually from the references in key articles. RESULTS： The current theories of HCC recurrence after liver transplantation are： （i） the growth of pre-transplant occult metastases; （ii） the engraftment of circulating tumor cells released at the time of transplantation. Pre-transplant treatment aims to control local tumor by radiofrequency ablation, transarterial embolization and transarterial chemoembolization. The main objective during the operation is to prevent tumor cell dissemination. Post-transplant treatment includes systemic anticancer therapy, antiviral therapy, and most recently, immunotherapy. These strategies concentrate on the control of the tumor when the patients are waiting for transplant, to reduce the release of HCC cells during surgical procedures and to dear the occult HCC cells after transplantation.CONCLUSIONS： Much can be done to prevent HCC recurrence after liver transplantation. In future, effort is likely to be di- rected towards combining multidisciplinary approaches and various treatment modalities.

Liver transplantation for hepatocellular carcinoma： is zero recurrence theoretically possible？

BACKGROUND： Hepatocellular carcinoma（HCC） recurrence remains a key issue after liver transplantation. This study aimed to determine a subgroup of HCC patients within the Milan criteria who could achieve a theoretical goal of zero recurrence rates after liver transplantation.METHODS： Between 1999 and 2009, 179 patients who received liver transplantation for HCC within the Milan criteria were retrospectively included. Analysis of the factors associated with HCC recurrence was performed to determine the subgroup of patients at the lowest risk of recurrence.RESULTS： Seventy-two percent of the patients received a bridging therapy, including 54 liver resections. Eleven（6.1%） patients recurred within a delay of 19±22 months and ultimately died. Factors associated with recurrence were serum alpha-fetoprotein level 〉400 ng/m L, satellite nodules, poor differentiation, microvascular invasion and cholangiocarcinoma component. Recurrence rates decreased from 6.1% to 3.1% in patients without any of these factors.CONCLUSIONS： Among HCC patients within the Milan criteria, selecting patients with factors based on histology would allow tending towards zero recurrence, and prior histological assessment by liver biopsy or resection may be essential to rule out poorly differentiated tumors, microvascular invasion,and cholangiocarcinoma component.

Risk factors for fatal recurrence of hepatocellular carcinoma and their role in selecting candidates for liver transplantation

BACKGROUND: With the maturation and popularization of skills in liver transplantation (LT), patients with hepatocellular carcinoma (HCC) have an alternative choice. LT as a curative treatment for HCC provides good liver function and systemic condition to recipients. Preoperative tumor characteristics are critical in selecting optimal candidates for LT to optimize the use of donor livers and to achieve a long-term survival. The present study aimed to elucidate the risk factors of HCC involved in fatal recurrence in the first year after LT and to investigate their utility in selecting suitable candidates for LT. METHODS: From April 2002 to October 2005, 303 patients who had received orthotopic LT for HCC were reviewed. Of these patients, those with diffuse intrahepatic or multiple systemic recurrent lesions who died within I year after surgery were investigated as fatal recurrence group (48 patients) and the remaining patients including those who were disease-free without recurrence, those who were alive with recurrence in the first year, or those who died in the first year of other causes, served as control group (255). The two groups were compared by demographics, tumor, and histopathological characteristics for their prognostic significance by logistic regression analysis. RESULTS: Multivariate analysis between the fatal recurrence group and the control group showed that the presence of vascular invasion, a tumor size greater than 6.5 cm, and a preoperative serum alpha-fetoprotein (AFP) level greater than 1000 mu g/L were risk factors for fatal recurrence. Increased risk factors reduced the suitability of candidates for LT and diminished survival in the first year. 85.71% of the patients with all three risk factors, 37.84% of those with two factors, 13.64% of those with one factor, and 6.71% of those without risk factors died from tumor recurrence within I year after transplantation. CONCLUSIONS: Vascular invasion, tumor size >= 16.5 cm, and preoperative serum AFP level >= 1000 mu g/L, were significant predictors of fatal recurrence after LT for HCC. Patients with two or more risk factors should not be candidates for LT.

Initial experience with stereotactic body radiotherapy for intrahepatic hepatocellular carcinoma recurrence after liver transplantation

BACKGROUND Graft hepatocellular carcinoma(HCC)recurrence after liver transplant is more frequently encountered.Graft hepatectomy is technically challenging and is associated with high morbidity.Stereotactic body radiation therapy(SBRT)has been shown to be safe and effective for the treatment of primary HCC.However,its role in HCC recurrence in a liver graft remains unclear.AIM To evaluate the safety and efficacy of SBRT for the treatment of graft HCC recurrence after liver transplantation.METHODS A retrospective study was conducted.From 2012 to 2018,6 patients with intrahepatic HCC recurrence after liver transplant were treated with SBRT at Queen Mary Hospital,the University of Hong Kong.The primary outcome was time to overall disease progression and secondary outcomes were time to local progression and best local response,as assessed with the Modified response Evaluation Criteria for Solid Tumours criteria.Patients were monitored for treatment related toxicities and graft dysfunction.RESULTS A total of 9 treatment courses were given for 13 tumours.The median tumour size was 2.3 cm(range 0.7-3.6 cm).Two(22%)patients had inferior vena cava tumour thrombus.The best local treatment response was:5(55%)complete response,1(11%)partial response and 3(33%)stable disease.After a median follow up duration of 15.5 mo,no local progression or mortality was yet observed.The median time to overall disease progression was 6.5 mo.There were 6 regional progression in the liver graft(67%)and 2 distant progression in the lung(22%).There was no grade 3 or above toxicity and there was no graft dysfunction after SBRT.CONCLUSION SBRT appears to be safe in this context.Regional progression is the mode of failure.

Liver transplantation for hepatocellular carcinoma:Role of inflammatory and immunological state on recurrence and prognosis

Criteria for liver transplantation(LT)for hepatocellular carcinoma(HCC)and post-LT indicators of prognosis are historically based on the measurement of the tumor mass.Recently,high throughput technologies have increased the prediction of recurrence,but these tools are not yet routinely available.The interaction between HCC and the immune system has revealed an imbalance of lymphocyte phenotypes in the peritumoral tissue,and the increase of regulatory T cells with respect to cytotoxic lymphocytes has been linked to a higher rate of post-LT HCC recurrence.Moreover,some inflammatory markers have shown good reliability in predicting cancer reappearance after surgery,as a result of either a systemic inflammatory response or a decreased capacity of the organism to control the tumor growth.Among these markers,the neutrophil-tolymphocyte ratio appears to be the most promising and easily available serum parameter able to predict HCC recurrence after LT and following other types of treatment,although the exact mechanisms determining its elevation have not been clarified.Post-LT immunosuppression may impact on cancer control,and the exposure to high levels of calcineurin inhibitors or other immunusuppressants has recently emerged as a negative prognostic factor for HCC recurrence and patient survival.Despite the absence of prospective randomized trials,inhibitors of the mammalian target of rapamycin have been shown to be associated with lower rates of tumor recurrence compared to other immunosuppressors,suggesting their use especially in patients with HCC exceeding the conventional indication criteria for LT.

Does autologous blood transfusion during liver transplantation for hepatocellular carcinoma increase risk of recurrence?

AIM: To analyze outcomes in patients who underwent liver transplantation(LT) for hepatocellular carcinoma(HCC) and received autologous intraoperative blood salvage(IBS). METHODS: Consecutive HCC patients who underwent LT were studied retrospectively and analyzed according to the use of IBS or not. Demographic and surgical data were collected from a departmental prospective maintained database. Statistical analyses were performed using the Fisher's exact test and the Wilcoxon rank sum test to examine covariate differences between patients who underwent IBS and those who did not. Univariate and multivariate Cox regression models were developed to evaluate recurrence and death,and survival probabilities were estimated using the Kaplan-Meier method and compared by the log-rank test.RESULTS: Between 2002 and 2012,158 consecutive patients who underwent LT in the same medical center and by the same surgical team were identified. Among these patients,122(77.2%) were in the IBS group and 36(22.8%) in the non-IBS group. The overall survival(OS) and recurrence free survival(RFS) at 5 years were 59.7% and 83.3%,respectively. No differences in OS(P=0.51) or RFS(P=0.953) were detected between the IBS and non-IBS groups. On multivariate analysis for OS,degree of tumor differentiation remained as the only independent predictor. Regarding patients who received IBS,no differences were detected in OS or RFS(P=0.055 and P=0.512,respectively) according to the volume infused,even when outcomes at 90 d or longer were analyzed separately(P=0.518 for both outcomes).CONCLUSION: No differences in RFS or OS were detected according to IBS use. Trials addressing this question are justified and should be designed to detect small differences in long-term outcomes.

Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients

Hepatocellular carcinoma(HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation(LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC(i.e., "non-oncological factors"), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of nononcological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.

Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation

Liver transplantation(LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma(HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to85%of 3-to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation.These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral Published online: January 27, 2019 recurrence after LT.Liver transplantation(LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma(HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to85%of 3-to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation.These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral recurrence after LT.

Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation

AIM: To evaluated patterns and outcomes of hepatocellular carcinoma(HCC) recurrence after living donor liver transplantation(LDLT).METHODS: From 2001 to 2014, 293 patients underwent LDLT for HCC at our transplant center. We retrospectively reviewed 54(18.4%) patients with HCC recurrence after LDLT. We evaluated patterns and outcomes of HCC recurrence after LDLT, with particular attention to the Milan criteria at transplantation, treatments for HCC-recurrent patients, and factors related to survival after HCC recurrence. Furthermore, we evaluated the efficacy of combination treatment of sorafenib and an mT OR inhibitor.RESULTS: The 1-, 2-, and 3-year overall survival rates after HCC recurrence were 41.1%, 20.5%, and 15.4%, respectively. The median time interval between LDLT and HCC recurrence was 6.5 mo. Although recurrence rates according to the Milan criteria at LDLT were significantly different, HCC recurrence patterns and survival rates after HCC recurrence were not significantly different between the two groups. Time to recurrence < 12 mo(P = 0.048), multiple recurrences at HCC recurrence(P = 0.038), and palliative treatment for recurrent tumors(P = 0.003) were significant independent prognostic factors for poor survival after HCC recurrence in a multivariate analysis. The combination treatment of sorafenib and sirolimus showedsurvival benefits in the palliative treatment group(P = 0.005).CONCLUSION: Curative treatment for recurrent HCC after LDLT is the most important factor in survival rates after HCC recurrence and combination treatments of sorafenib and an m TOR inhibitor could have survival benefits in patients with HCC recurrence after LT in the palliative treatment group.

Liver transplantation for hepatocellular carcinoma on cirrhosis:Strategies to avoid tumor recurrence

Hepatocellular carcinoma(HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with chronic liver disease.Liver transplantation(LT) is potentially the optimal treatment for those patients with HCC who have a poor functional hepatic reserve due to their underlying chronic liver disease.However,due to the limited availability of donors,only those patients whose oncologic profile is favorable can be considered for LT.Despite the careful selection of candidates based on strict rules,10 to 20%of liver transplant recipients who have HCC in the native cirrhotic liver develop tumor recurrence after transplantation.The selection criteria presently employed to minimize the risk of recurrence are based on gross tumor characteristics defined by imaging techniques;unfortunately,the accuracy of imaging is far from being optimal.Furthermore,microscopic tumor features that are strictly linked with prognosis can not be assessed prior to transplantation.Pre-transplantation tumor downstaging may allow transplantation in patients initially outside the selection criteria and seems to improve the prognosis;it also provides information on tumor biology.Themain peculiarity of the transplantation setting,when this is compared with other modalities of treatment,is the need for pharmacological immunosuppression:this is based on drugs that have been demonstrated to increase the risk of tumor development.As HCC is an aggressive malignancy,immunosuppression has to be handled carefully in patients who have HCC at the time of transplantation and new categories of immunosuppressive agents should be considered.Adjuvant chemotherapy following transplantation has failed to show any significant advantage.The aim of the present study is to review the possible strategies to avoid recurrence of HCC after liver transplantation based on the current clinical evidence and the more recent developments and to discuss possible future directions.

Role of pre-transplant 18F-FDG PET/CT in predicting hepatocellular carcinoma recurrence after liver transplantation

The last two decades have seen a paradigm shift in the selection of patients with hepatocellular carcinoma(HCC)for liver transplantation.Microvascular invasion and differentiation have been the most significant factors affecting post-transplant recurrence;however,because of inherent disadvantages of pre-transplant biopsy,histological criteria never gained popularity.Recently,the selection criteria evolved from morphological to biological criteria,such as biomarkers and response to loco-regional therapy.With the introduction of multimodality imaging,combination of computed tomography with nuclear medicine imaging,particularly,18F-fluorodeoxyglucose positron emission tomography fulfilled an unmet need and rapidly became a critical component of HCC management.This review article will focus on the use of 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography in the pre-transplant evaluation of HCC patients with special discussion on its ability to predict HCC recurrence after liver transplantation.

Repeated Resection for Pulmonary Metastatic Hepatocellular Carcinoma after Liver Transplantation— Case Reports and a Proposal of Negative Predictors for the Recurrence after the Operation

Background: Orthotropic liver transplantation (OLTx) is recognized as a radical therapy for unresectable hepatocellular carcinoma (HCC) without distant metastasis. Although the outcome depends on distant recurrence of HCC, the predictors for recurrence after repeat resection are unknown. Case 1: A 52-year-old man, who had suffered from hepatitis B and underwent repeat local ablation therapies since 50 years old, underwent living-donor OLTx because of multiple HCC recurrence with tumor marker (TM) elevation but without distant metastasis. Histopathological diagnosis was moderately differentiated HCC. After the operation, he got TM normalization and was managed with cyclosporine A, without rejection. Although he underwent adjuvant chemotherapy, a pulmonary metastasis was found 1 year after the OLTx. He underwent wedge resection of the lung using video-assisted thoracoscopic surgery (VATS). Half a year after the operation, a recurrence was found in the transplanted liver with TM elevation. While a local ablation therapy was performed, TM was not normalized and new recurrence was found at the hilum of the right lung. Right upper sleeve lobectomy was performed, but he developed multiple recurrences, and died 4 months after the last operation. Case 2: A 32-year-old man, who has suffered from multiple HCC with hepatitis B and underwent hepatic resection and local ablation therapies since 28 years old, underwent living-donor OLTx because of multiple HCC recurrence without distant metastasis. Histopathological diagnosis was moderately differentiated HCC. He was managed using tacrolimus without rejection. Three years after the OLTx, a pulmonary recurrence was found without TM elevation. He underwent wedge resection using VATS. Four year after the last operation, a small recurrence was identified in the right lung without TM elevation, again. Wedge resection using VATS was performed. At the final follow-up visit, 3 years after the last operation, the patient was disease free with normal TM level. Comments: The long survivor without re-recurrence matched only few factors with negative predictors for recurrence after OLTx for HCC, while the other case had almost all factors present. The predictors may be useful also for the patients of the repeat pulmonary metastasectomy after OLTx for HCC.

Liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma:A multicenter study

BACKGROUND Patients with combined hepatocellular carcinoma and cholangiocarcinoma(cHCC-CC)are not traditionally considered eligible for liver transplantation(LT)AIM To compare outcomes between living donor LT(LDLT)patients with hepatocellular carcinoma(HCC)and LT patients with cHCC-CC and to identify risk factors for tumor recurrence and death after LT in cHCC-CC patients.METHODS Data for pathologically diagnosed cHCC-CC patients(n=111)who underwent LT from 2000 to 2018 were collected for a nine-center retrospective review.Patients(n=141)who received LDLT for HCC at Samsung Medical Center from January 2013 to March 2017 were selected as the control group.Seventy patients in two groups,respectively,were selected by 1:1 matching.RESULTS Cumulative disease-free survival(DFS)and overall survival(OS)in the cHCC-CC group were significantly worse than in the HCC group both before and after matching.Extrahepatic recurrence incidence in the cHCC-CC group was higher than that in the HCC group(75.5%vs 33.3%,P<0.001).Multivariate analysis demonstrated that the cHCC-CC group had significantly higher rates of tumor recurrence and death compared to the HCC group.In cHCC-CC subgroup analysis,frequency of locoregional therapies>3,tumor size>3 cm,and lymph node metastasis were predisposing factors for tumor recurrence in multivariate analysis.Only a maximum tumor size>3 cm was a predisposing factor for death.CONCLUSION The poor prognosis of patients diagnosed with cHCC-CC after LT can be predicted based on the explanted liver.Frequent regular surveillance for cHCC-CC patients should be required for early detection of tumor recurrence.

Radiological response and inflammation scores predict tumour recurrence in patients treated with transarterial chemoembolization before liver transplantation

AIM To investigate the prognostic value of the radiological response after transarterial chemoembolization(TACE)and inflammatory markers in patients affected by hepatocellular carcinoma(HCC)awaiting liver transplantation(LT).METHODS We retrospectively evaluated the preoperative pre dictors of HCC recurrence in 70 patients treated with conventional(n=16)or doxorubicin-eluting bead TACE(n=54)before LT.The patient and tumour characteristics,including the static and dynamic alpha-fetoprotein,neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio( LR)measurements,were recorded.Treatment response was classified according to the modified Response Evaluation Criteria in Solid Tumours(m RECIST)and the European Association for the Study of the Liver(EASL)criteria as complete response(CR),partial response( R),stable disease o progressive disease.After examination of the explanted livers,histological necrosis was classified as complete(100%of the cumulative tumour area),partia(50%-99%)or minimal(<50%)and was correlated with the preoperative radiological findings.RESULTS According to the pre-TACE radiological evaluation,22/70(31.4%)and 12/70(17.1%)patients were beyond Milan and University of San Francisco(UCSF)criteria,respectively.After TACE procedures,the objective response(CR+ R)rates were 71.4%and 70.0%according to m RECIST and EASL criteria,respectively.The agreement between the two guidelines in defining the radiological response was rated as very good both for the overall and target lesion response(weighted k-value:0.98 and 0.93,respectively).Complete and partial histological necrosis were achieved in 14/70(20.0%)and 28/70(40.0%)patients,respectively.Using histopathology as the reference standard,m RECIST criteria correctly classified necrosis in 72.9%(51/70)of patients and EASL criteria in 68.6%(48/70)of cases.The m RECIST non-response to TACE[Exp(b)=9.2, =0.012],exceeding UCSF criteria before TACE[Exp(b)=4.7, =0.033]and a preoperative LR>150[Exp(b)=5.9, =0.046]were independent predictors of tumour recurrence.CONCLUSION The radiological response and inflammatory markers are predictive of tumour recurrence and allow the proper selection of TACE-treated candidates for LT.

Predictors of early and late hepatocellular carcinoma recurrence

Hepatocellular carcinoma(HCC)is the most frequent liver neoplasm,and its incidence rates are constantly increasing.Despite the availability of potentially curative treatments(liver transplantation,surgical resection,thermal ablation),long-term outcomes are affected by a high recurrence rate(up to 70%of cases 5 years after treatment).HCC recurrence within 2 years of treatment is defined as“early”and is generally caused by the occult intrahepatic spread of the primary neoplasm and related to the tumor burden.A recurrence that occurs after 2 years of treatment is defined as“late”and is related to de novo HCC,independent of the primary neoplasm.Early HCC recurrence has a significantly poorer prognosis and outcome than late recurrence.Different pathogenesis corresponds to different predictors of the risk of early or late recurrence.An adequate knowledge of predictive factors and recurrence risk stratification guides the therapeutic strategy and post-treatment surveillance.Patients at high risk of HCC recurrence should be referred to treatments with the lowest recurrence rate and when standardized to combined or adjuvant therapy regimens.This review aimed to expose the recurrence predictors and examine the differences between predictors of early and late recurrence.

Impact of treatment modalities on patients with recurrent hepatocellular carcinoma after liver transplantation:Preliminary experience

Background:Post-liver transplantation(LT)hepatocellular carcinoma(HCC)recurrence still occurs in approximately 20%of patients and drastically affects their survival.This study aimed to evaluate the efficacy of various treatments for recurrent HCC after LT in a Chinese population.Methods:A total of 64 HCC patients with tumor recurrence after LT were enrolled in this study.Univariate and multivariate analyses were performed to identify factors affecting post-recurrence survival.Results:Of the 64 patients with recurrent HCC after LT,those who received radical resection followed by nonsurgical therapy had a median overall survival(OS)of 20.9 months after HCC recurrence,significantly superior to patients who received only nonsurgical therapy(9.4 months)or best supportive care(2.4 months).The one-and two-year OS following recurrence was favorable for patients receiving radical resection followed by nonsurgical therapy(93.8%,52.6%),poor for patients receiving only nonsurgical therapy(30.8%,10.8%),and dismal for patients receiving best supportive care(0%,0%;overall P<0.001).Median OS in sorafenib-tolerant patients treated with lenvatinib was 19.5 months,far surpassing the patients that discontinued sorafenib or were treated with regorafenib after sorafenib failure(12 months,P<0.001).Compared with tacrolimus-based immunosuppressive therapy,OS was significantly increased with sirolimus-based therapy at one and two years after HCC recurrence(P=0.035).Multivariate analysis showed radical resection combined with nonsurgical therapy for recurrent HCC and sorafenib-lenvatinib sequential therapy were independent favorable factors for post-recurrence survival.Conclusions:Aggressive surgical intervention in well-selected patients significantly improves OS after recurrence.A multidisciplinary treatment approach is required to slow down disease progression for patients with unresectable recurrent HCC.

Hepatocellular carcinoma recurrence after liver transplantation: Risk factors, screening and clinical presentation

Liver transplantation is the best treatment option for cirrhotic patients with earlystage hepatocellular carcinoma, but it faces the problem of scarcity of donors and the risk of tumor recurrence, which affects between 15% and 20% of the cases,despite the use of restrictive criteria. The risk of recurrence depends on a number of factors, related to the tumor, the patient, and the treatment, which are discussed in this review. Some of these factors are already well established, such as the histopathological characteristics of the tumor, Alpha-fetoprotein(AFP)levels, and waiting time. Other factors related to the biological behavior of the tumor and treatment should be recognized because they can be used in the refinement of the selection criteria of transplant candidates and in an attempt to reduce recurrence. This review also discusses the clinical presentation of recurrence and its prognosis, contributing to the identification of a subgroup of patients who may have better survival, if they are timely identified and treated.Development of recurrence after the first year, with AFP levels ≤ 100 ng/mL, and single site capable of locoregional therapy are associated with better survival after recurrence.

Liver transplantation for hepatocellular carcinoma:an update

BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. DATA SOURCES: PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. RESULTS: Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. CONCLUSIONS: Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate biomarkers of tumor biology.