Prediction of hepatocellular carcinoma biological behaviorin patient selection for liver transplantation

Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma(HCC)patients for liver transplantation(LT).These criteria,which are often inappropriate to express the tumor’s biological behavior and aggressiveness,offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT.Alpha-fetoprotein(AFP)and its progression as well as AFP-m RNA,AFP-L3%,des-γ-carboxyprothrombin,inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes.Several other markers for patient selection including functional imaging studies such as18F-FDG-PET imaging,histological evaluation of tumor grade,tissue-specific biomarkers,and molecular signatures have been outlined in the literature.HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients.While AFP,its progression,and HCC response to pretransplant therapy have already been used as a part of an integrated prognostic model for selecting patients,the utility of other markers in the transplant setting is still under investigation.This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients.

Systematic review of surgical resection vs radiofrequency ablation for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents one of the most common neoplasms worldwide. Surgical resection and local ablative therapies represent the most frequent first lines therapies adopted when liver transplantation can not be offered or is not immediately accessible. Hepatic resection (HR) is currently considered the most curative strategy, but in the last decade local ablative therapies have started to obtain satisfactory results in term of efficacy and, of them, radiofrequency ablation (RFA) is considered the reference standard. An extensive literature review, from the year 2000, was performed, focusing on results coming from studies that directly compared HR and RFA. Qualities of the studies, characteristics of patients included, and patient survival and recurrence rates were analyzed. Except for three randomized controlled trials (RCT), most studies are affected by uncertain methodological approaches since surgical and ablated patients represent different populations as regards clinical and tumor features that are known to affect prognosis. Unfortunately, even the available RCTs report conflicting results. Until further evidences become available, it seems reasonable to offer RFA to very small HCC (< 2 cm) with no technical contraindications, since in this instance complete necrosis is most likely to be achieved. In larger nodules, namely > 2 cm and especially if > 3 cm, and/or in tumor locations in which ablation is not expected to be effective or safe, surgical removal is to be preferred.

Hepatic flow optimization in full right split liver transplantation

Split liver transplantation for two adults offers a valuable opportunity to expand the donor pool for adult recipients.However,its application is mainly hampered by the physiological limits of these partial grafts.Small for size syndrome is a major concern during transplantation with partial graft and different techniques have been developed in living donor liver transplantation to prevent the graft dysfunction.Herein,we report the first application of synergic approaches to optimise the hepatic hemodynamic in a split liver graft for two adults. A Caucasian woman underwent liver transplantation for alcoholic cirrhosis(MELD 21)with a full right liver graft (S5-S8)without middle hepatic vein.Minor and accessory inferior hepatic veins were preserved by splitting the vena cava;V5 and V8 were anastomosed with a donor venous iliac patch.After implantation,a 16G catheter was advanced in the main portal trunk.Inflow modulation was achieved by splenic artery ligation.Intraportal infusion of PGE1 was started intraoperatively and discontinued after 5 d.Graft function was immediate withnormalization of liver test after 7 d.Nineteen months after transplantation,liver function is normal and graft volume is 110%of the recipient standard liver volume. Optimisation of the venous outflow,inflow modulation and intraportal infusion of PGE1 may represent a valuable synergic strategy to prevent the graft dysfunction and it may increase the safety of split liver graft for two adults.

Selection tool alpha-fetoprotein for patients waiting for liver transplantation: How to easily manage a fractal algorithm

Alpha-fetoprotein(AFP) behavior in patients with hepatocellular carcinoma(HCC) waiting for liver transplant(LT) represents a perfect biological example of a fractal model in which its progressive modification and possible future prediction of its values are very hard to capture. As a consequence, AFP represents a useful but poorly manageable tool to increase the ability to better select HCC patients waiting for LT. Trying to find a "filrouge" in the recent literature, no definitive answers can be done to several open questions:(1) the best AFP value to adopt;(2) the best cut-off measurement; and(3) the best way to comfortably capture the effective, time-related, fluctuations of this biological marker. More, structured and prospective, studies using serial determination of AFP values within and without the context of locoregional therapies are needed in order to find the "ideal"(static and dynamic) cut-off values allowing to respond to all the still open questions in this field of transplant oncology.

Liver transplantation in adults:Choosing the appropriate timing

Liver transplantation is indicated in patients with acute liver failure,decompensated cirrhosis,hepatocellular carcinoma and rare liver-based genetic defects that trigger damage of other organs.Early referral to a transplant center is crucial in acute liver failure due to the high mortality with medical therapy and its unpredictable evolution.Referral to a transplant center should be considered when at least one complication of cirrhosis occurs during its natural history.However,because of the shortage of organ donors and the short-term mortality after liver transplantation on one hand and the possibility of managing the complications of cirrhosis with other treatments on the other,patients are carefully selected by the transplant center to ensure that transplantation is indicated and that there are no medical,surgical and psychological contraindications.Patients approved for transplantation are placed on the transplant waiting list and prioritized according to disease severity.Thus,the appropriate timing of transplantation depends on recipient disease severity and,although this is still a matter of debate,also on donor quality.These two variables are known to determine the "transplant benefit"(i.e.,when the expected patient survival is better with,than without,transplantation) and should guide donor allocation.

Locoregional therapy response in patients with hepatocellular cancer waiting for liver transplantation:Only selection or biological effect?

Locoregional treatments(LRT) represent a broad strategy used for reducing the risk of drop-off and contextually improving the survivals in patients with hepatocellular cancer receiving a liver transplantation(LT). However, it is not sufficiently clear if LRT are only a surrogate of tumor aggressiveness or if they consent a real benefit in terms of tumor stabilization. A recent study by Pommergaard et al reported the results from the European Liver Transplant Registry. Patients receiving LRT before LT had better 5-year survival rates respect to no-LRT cases(69.7% vs 65.8%; P < 0.001). When the number of LRT was tested, one-to-two treatments were connected with improved survivals respect to no treatment [hazard ratio(HR) = 0.85 and 0.71, respectively]. The efficacy of LRT was also reported in the presence of larger tumors(HR = 0.78) and micro-macrovascular invasion(HR = 0.71). The results observed in the present study are partially in discordance with other analyses showing a detrimental effect of LRT. The main problem in the interpretation of these results is connected with the possible initial selection biases present in the studies. The most recent guidelines suggest to perform LRT before the transplant, but the level of evidence is typically low due to the absence of prospectively designed studies.

New insights in the management of the middle hepatic vein dilemma

When the first series of adult-to-adult living donor liver transplantation(A2A-LDLT)were performed in Hong Kong[1],it was immediately clear that great technical challenges existed,mainly concerning the middle hepatic vein(MHV)tributaries management.

Composite hepatocellular and hemangiosarcomatous tumor: The prognosis is determined by the sarcomatous component

Nowadays, mixed liver tumors are more frequently diagnosed due to better imaging, advanced immunohistochemistry (IHC) staining techniques and better knowledge of hepatic tumorigene- sis [1–3] . Such tumors represent a mosaic of components with dis- tinct histogenesis and carcinogenic pathways. As their occurrence in the liver is very rare, their behavior and natural history are difficult to determine, and their management remains empirical. An uncommon case of a composite tumor harboring hepatocellular carcinoma (HCC) and hepatic hemangiosarcoma (HHS) components in a liver transplant (LT) recipient is reported herein.

Current concepts in hepatic resection for hepatocellular carcinoma in cirrhotic patients

Hepatocellular carcinoma(HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with liver cirrhosis.Liver resection is considered the most potentially curative therapy for HCC patients when liver transplantation is not an option or is not immediately accessible.This review is aimed at investigating the current concepts that drive the surgical choice in the treatment of HCC in cirrhotic patients;Eastern and Western perspectives are highlighted.An extensive literature review of the last two decades was performed,on topics covering various aspects of hepatic resection.Early post-operative and long-term outcome measures adopted were firstly analyzed in an attempt to define an optimal standardization useful for research comparison.The need to avoid the development of post-hepatectomy liver failure represents the "conditio sine qua non" of surgical choice and the role of the current tools available for the assessment of liver function reserve were investigated.Results of hepatic resection in relationship with tumor burden were compared with those of available competing strategies,namely,radiofrequency ablation for early stages,and trans-arterial chemoembolization for intermediate and advanced stages.Finally,the choice for anatomical versus non-anatomical,as well as the role of laparoscopic approach,was overviewed.The literature review suggests that partial hepatectomy for HCC should be considered in the context of multi-disciplinary evaluation of cirrhotic patients.Scientific research on HCC has moved,in recent years,from surgical therapy toward non-surgical approaches and most of the literature regarding topics debated in the present review is represented by observational studies,whereas very few well-designed randomized controlled trials are currently available;thus,no robust recommendations can be derived.

Hypothermic oxygenated perfusion for a steatotic liver graft

To the Editor:Donor steatosis represents a well-known risk factor for primary non-function,early allograft dysfunction,and biliary complications after liver transplantation(LT)[1,2].Recently,machine perfusion(MP)technology has been implemented in the clinical practice,with the primary intent to assess the graft quality and to optimize the organ selection process[3].A limited number of articles has been published specifically investigated the role of MP in steatotic livers[4–10],with few of them looking at the role of hypothermic MP.

From portal to splanchnic venous thrombosis:What surgeons should bear in mind

The present study aims to review the evolution of surgical management of portal(PVT) and splanch-nic venous thrombosis(SVT) in the context of liver transplantation over the last 5 decades. PVT is more commonly managed by endovenous thrombectomy, while SVT requires more complex technical expedients. Several surgical techniques have been proposed, such as extensive eversion thrombectomy, anastomosis to collateral veins, reno-portal anastomosis, cavo-portal hemi-transposition, portal arterialization and combined liver-intestinal transplantation. In order to achieve satisfactory outcomes, careful planning of the surgical strategy is mandatory. The excellent results that are ob-tained nowadays confirm that, even extended, splanch-nic thrombosis is no longer an absolute contraindication for liver transplantation. Patients with advanced portal thrombosis may preferentially be referred to specialized centres, in which complex vascular approaches and even multivisceral transplantation are performed.

Prognostic criteria for postoperative mortality in 170 patients undergoing major right hepatectomy

BACKGROUND: Postoperative hepatic failure is a dreadful complication after major hepatectomy and carries high morbidity and mortality rates. In this study, we assessed the accuracy of the 50/50 criteria (bilirubin >2.9 mg/dL and international normalized ratio >1.7 on postoperative day 5) and the Mullen criteria (bilirubin peak >7 mg/dL on postoperative days 1-7) in predicting death from hepatic failure in patients undergoing right hepatectomy only. In addition, we identified prognostic factors linked to intra-hospital morbidity and mortality in these patients. METHODS: One hundred seventy consecutive patients underwent major right hepatectomy at a tertiary medical center from 2000 to 2008. Nineteen (11.2%) patients suffered from liver cirrhosis. Univariate and multivariate analyses were performed to identify predictors of intra-hospital mortality, morbidity and death from hepatic failure. RESULTS: The intra-hospital mortality was 6.5% (11/170). Of the six patients who died from hepatic failure, one was positive for the 50/50 criteria, but all six patients were positive for the Mullen criteria. Multivariate analysis showed that male gender, hepatitis C (HCV), hepatocellular carcinoma, postoperative bilirubin >7 mg/dL and ALT<188 U/L on postoperative day 1 were predictive of death from hepatic failure in the postoperative period. Age >65 years, HCV, reoperation, andrenal failure were significant predictors of overall intra-hospital mortality on multivariate analysis. CONCLUSIONS: The Mullen criteria were more accurate than the 50/50 criteria in predicting death from hepatic failure in patients undergoing right hepatectomy. A bilirubin peak >7 mg/dL in the postoperative period, HCV positivity, hepatocellular carcinoma, and an ALT level <188 U/L on postoperative day 1 were associated with death from hepatic failure in our patient population.

Uncommon indications for associating liver partition and portal vein ligation for staged hepatectomy:a systematic review

Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)represents an innovative surgical technique used for the treatment of large hepatic lesions at high risk for post-resection liver failure due to a small future liver remnant.The most significant amount of literature concerns the use of ALPPS for the treatment of hepatocellular carcinoma(HCC),cholangiocarcinoma(CCC),and colorectal liver metastases(CRLM).On the opposite,few is known about the role of ALPPS for the treatment of uncommon liver pathologies.The objective of the present study was to evaluate the current literature on this topic.A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines.Eligible articles published up to February 2020 were included using the MEDLINE,Scopus,and Cochrane databases.Among the 486 articles screened,45 papers met the inclusion criteria,with 136 described cases of ALPPS for rare indications.These 136 cases were reported in 18 different countries.Only in two countries,namely Germany and Brazil,more than ten cases were observed.As for the ALPPS indications,we reported 41(30.1%)cases of neuroendocrine tumor(NET)metastases,followed by 27(19.9%)cases of gallbladder cancer(GBC),nine(6.6%)pediatric cases,six(4.4%)gastrointestinal stromal tumors,six(4.4%)adult cases of benign primary liver disease,four(2.9%)adult cases of malignant primary liver disease,and 43(31.6%)adult cases of malignant secondary liver disease.According to the International ALPPS Registry data,less than 10%of the ALPPS procedures have been performed for the treatment of uncommon liver pathologies.NET and GBC are the unique pathologies with acceptable numerosity.ALPPS for NET appears to be a safe procedure,with satisfactory long-term results.On the opposite,the results observed for the treatment of GBC are poor.However,these data should be considered with caution.The rationale for treating benign pathologies with ALPPS appears to be weak.No definitive response should be given for all the other pathologies.Multicenter studies are needed with the intent to clarify the potentially beneficial effect of ALPPS for their treatment.