Liver transplantation (LT) is the main indication for the treatment of end-stage liver disease but have to face organ shortages. Using marginal donors is an option to increase the donor pool. Previous studies showed that the graft procured using N-acetylcysteine (NAC) provides a longer survival compared to perfusion with standard solutions, especially in marginal liver donors. We now evaluate the effect of NAC perfusion compared to control (no NAC protocol) at a 5-year follow-up, with a special focus on the overall survival (OS) and graft survival.

Single-center, retrospective review of the OS and graft survival among NAC and control group, with a sub-stratification based on the LT indication.

140 donors were enrolled: 69 in the NAC protocol and 71 in the control group. The 5-year OS was 84% in the NAC protocol compared to 63% in the control (P = .0045). In LT for HCC, the OS at 5 years was 80% and 55% in the study group and control group, respectively (P = .04), with no statistical difference in the RFS (P = .46). Furthermore, in cost analysis, the resources needed for the NAC protocol is negligible compared to the control group. Beneficial tendency of NAC protocol application has been seen in the other organs (lungs, hearts, pancreas, kidney and intestine) CONCLUSION: The application of NAC infusion in liver donors improves the overall survival of the recipient, especially in the HCC and HCV LT indications.

This study aimed to investigate the relationship between the prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation and mammalian target of rapamycin (mTOR) pathway-related genes-TSC1/2.

We retrospectively analyzed the clinical data of 46 patients who underwent liver transplantation for HCC and performed next generation sequencing to analyze the relationship between the efficacy of sirolimus after liver transplantation for HCC and mutations in mTOR pathway-related genes, especially tuberous sclerosis complex (TSC) mutations.

The average age of 46 patients with liver transplantation for HCC was 51±21 years. After surgery, 35 patients received an anti-rejection/anti-tumor regimen that included sirolimus, and 11 patients did not receive sirolimus. There was no significant difference in survival rate between the two groups (P=0.761). The gene sequencing results showed mTOR-related pathway mutations in 10 patients, of whom five (10.9%) had TSC1/2 mutations. Of the 35 patients using sirolimus, those with mTOR-related mutations had significantly better survival rates than patients without mTOR-related mutations (P=0.016).

According to genetic sequencing results, a personalized treatment plan for specific genetic mutations should be selected in patients undergoing liver transplantation for HCC. Patients with mTOR-related gene mutations, especially TSC mutations, can gain significant benefits from the use of mTOR inhibitors such as sirolimus.

Background: Liver resection represents the first curative treatment to treat primary and secondary hepatic tumors. Thoracoscopic liver ablation is a viable and minimally invasive alternative treatment, especially for patients with previous multiple abdominal surgeries. The aim of the study was to evaluate the safety and efficacy of thoracoscopic ablation for liver tumors. Methods: Retrospective analysis of a prospective database of patients with liver tumors, treated with thoracoscopic trans-diagrammatic ablation (MWA or RFA) at our institution from 2012 to 2018. The primary endpoint was post-operative mortality at 30 days, while secondary endpoints were morbidity and efficacy of ablation (i.e., response rate evaluated according to mRECIST criteria, and overall patient survival). Patient demographics, operational characteristics, and complications were recorded. Results: A total of 13 nodules were treated in 10 patients with a median age of 65.5 years. Post-operative mortality was 0%, and overall morbidity was 40% (Clavien-Dindo I complications 30%, II 0%, III 10%, IV 0%). Complete radiological response was obtained in 83.3% of nodules at 3 months. After a median follow-up of 20.95 months, the local tumor progression rate was 30%, with an intra-segmental-recurrence of 30%, and an intra-hepatic-recurrence of 30%. The overall 1-, 2-, and 3-years survival rates were 80%, 58%, and 58%. Conclusion: Thoracoscopic trans-diaphragmatic ablation proved to be a safe and effective way to treat liver tumors when abdominal approach is not feasible. Considering the low morbidity, it is a viable option to treat patients with recurrent disease and/or previous multiple abdominal surgeries.

Hepatocellular carcinoma represents an important cause of morbidity and mortality worldwide. It is the sixth most common cancer and the fourth leading cause of cancer death. Liver transplantation is a key tool for the treatment of this disease in human therefore hepatocellular carcinoma is increasing as primary indication for grafting. Although liver transplantation represents an outstanding therapy for hepatocellular carcinoma, due to organ shortage, the careful selection and management of patients who may have a major survival benefit after grafting remains a fundamental question. In fact, only some stages of the disease seem amenable of this therapeutic option, stimulating the debate on the appropriate criteria to select candidates. In this review we focused on current criteria to select patients with hepatocellular carcinoma for liver transplantation as well as on the strategies (bridging) to avoid disease progression and exclusion from grafting during the stay on wait list. The treatments used to bring patients within acceptable criteria (down-staging), when their tumor burden exceeds the standard criteria for transplant, are also reported. Finally, we examined tumor reappearance following liver transplantation. This occurrence is estimated to be approximately 8%-20% in different studies. The possible approaches to prevent this outcome after transplant are reported with the corresponding results.

Concerns about an increased hepatocellular carcinoma (HCC) recurrence rate following direct-acting antiviral (DAA) therapy in patients with cirrhosis with a prior complete oncological response have been raised. Data regarding the impact of HCV treatment with DAAs on wait-list dropout rates in patients with active HCC and HCV-related cirrhosis awaiting liver transplantation (LT) are lacking. HCV-HCC patients listed for LT between January 2015 and May 2016 at Padua Liver Transplant Center were considered eligible for the study. After enrollment, patients were divided into 2 groups, depending on whether they underwent DAA treatment while awaiting LT or not. For each patient clinical, serological, and virological data were collected. HCC characteristics were radiologically evaluated at baseline and during follow-up (FU). For transplanted patients, pathological assessment of the explants was performed and recurrence rates were calculated. A total of 23 patients treated with DAAs and 23 controls were enrolled. HCC characteristics at time of LT listing were comparable between the 2 groups. Median FU was 10 and 7 months, respectively, during which 2/23 (8.7%) and 1/23 (4.3%) dropout events due to HCC progression were registered (P = 0.90). No significant differences in terms of radiological progression were highlighted (P = 0.16). A total of 9 out of 23 (39%) patients and 14 out of 23 (61%) controls underwent LT, and histopathological analysis showed no differences in terms of median number and total tumor volume of HCC nodules, tumor differentiation, or microvascular invasion. During post-LT FU, 1/8 (12.5%) DAA-treated patient and 1/12 (8.3%) control patient experienced HCC recurrence (P = 0.60). In conclusion, viral eradication does not seem to be associated with an increased risk of dropout due to neoplastic progression in HCV-HCC patients awaiting LT. Liver Transplantation 23 1103-1112 2017 AASLD.

Liver transplantation for hepatocellular carcinoma (HCC) is the best treatment option for patients with early-stage tumours and accounts for ∼20-40% of all liver transplantations performed at most centres worldwide. The Milan criteria are the most common criteria to select patients with HCC for transplantation but they can be seen as too restrictive. Several proposals have been made for a moderate expansion of the criteria, which result in good outcomes but with an increase in the risk of tumour recurrence. In this Review, we provide a comprehensive overview of the outcomes after liver transplantation for HCC, focusing on tumour recurrence in terms of surveillance, prevention and treatment. Additionally, novel surgical techniques have been developed to increase the available pool of organs for liver transplantation (such as living donor liver transplantation, donation after circulatory death and split livers), but the effect of these techniques on patients with HCC is still under debate. Thus, we will describe these techniques and expose the benefits and disadvantages of each surgical approach. Finally, we will comment on the limitations of the current priority policies for liver transplantation and the need to further refine them to better serve the population.

In western countries, hepatocellular carcinoma (HCC) is a major reason for orthotopic liver transplantation (OLT) with estimated recurrence rates between 15% and 20%. This selective literature review addresses follow-up care after OLT in HCC and current treatment options. Recurrence prediction is based on pathological tumor stage, vascular invasion, serum alfafetoprotein levels, and histological differentiation, but further advances are expected by molecular profiling techniques. Lower levels of immunosuppressive agents are associated with a lower risk for HCC recurrence. Retrospective studies indicate that mammalian target of rapamycin (mTOR) inhibitors as immunosuppression reduce the risk of HCC recurrence. However, prospective studies supporting this potential advantage of mTOR inhibitors are still lacking, and higher rejection rates were reported for sirolimus after OLT in HCC. Prognosis is poor in recurrent HCC, a longer interval between OLT and recurrence and feasibility of surgical resection are associated with improved survival. Systemic treatment with sorafenib is the current standard of care in patients with advanced-stage HCC not suitable for locoregional therapy. After OLT, combination of an mTOR inhibitor with sorafenib is feasible and frequently used in clinical practice. As safety and efficacy data are still limited, close clinical monitoring is mandatory.

Liver transplantation (LT) is a curative treatment for localized hepatocellular carcinoma (HCC), but the recurrence rate after LT is about 10-20%, with a dismal prognosis. Little data exist as to the natural history, treatment outcome and optimal treatment of recurrent HCC after LT. We reviewed various treatment modalities given to patients with recurrent HCC after LT.

Among 132 patients who underwent LT for localized HCC, we retrospectively reviewed medical records of 39 of the 132 patients who developed recurrent HCC after LT. We analyzed the clinical outcome of various treatment modalities and treatment-related adverse events.

A total of 39 (29%) of the original 132 patients had recurrent HCC, most recurrences (82%) having occurred within 1 year after LT and involved extrahepatic lesions. Only seven patients had recurrent disease limited to the liver. The median overall survival from the initial treatment of all relapsed patients was 6.9 months. There were various initial treatment modalities, namely palliative systemic chemotherapy, trans-catheter arterial chemo-embolization/infusion (TACE/I), radiation therapy (RT), surgical resection and no treatment. The median overall survival was 9.5 months for first-line chemotherapy, including those who had prior local therapy, 6.3 months TACE/I and 6.9 months for RT.

Various clinical approaches have been used to treat patients with recurrent HCC after LT in a clinical setting. More effective strategies and clinical guidelines for recurrent HCC following LT must be established.

This study was designed to analyze the clinical outcomes of the recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) and to evaluate the efficacy of a surgical resection in treating such a recurrence.

A total of 101 adult LDLT recipients with HCC between 1996 and 2007, including 17 who had recurrent HCC, were reviewed. The endpoints analyzed were survival from time of transplant and survival from time of recurrence. Recipient demographics, laboratory valuables, and tumor characteristics were analyzed. Any medical or surgical treatments that had been administered for any recurrence also were considered.

The mean duration until the initial recurrence after LDLT and the mean duration until death after the initial recurrence were 12.9 months and 12.0 months, respectively. A univariate analysis showed that gender, interferon therapy, early posttransplant tumor recurrence, and eligibility for a surgical resection all had a beneficial impact on survival from tumor recurrence. A surgical resection of tumor relapse was the most important variable in our study, and therefore the patients were divided into two groups: surgical therapy group (n = 9), and nonsurgical therapy group (n = 7). Interestingly, the overall survival rates of the surgical group were significantly better than those of the nonsurgical group and were similar to that of the patients without HCC recurrence.

Surgical therapy might be useful for patients who experience a recurrence of HCC after LDLT to improve their outcome, when such treatment is available.

This prospective study analyzed the dropout probability and intention-to-treat survival rates of patients with hepatocellular carcinoma (HCC) selected and treated according to our policy before liver transplantation (LT), with particular attention to those exceeding the Milan criteria. Exclusion criteria for LT were macroscopic vascular invasion, metastases, and poorly differentiated disease at percutaneous biopsy. A specific multi-modal adjuvant algorithm was used to treat HCC before LT. A total of 100 HCC patients were listed for LT: 40 exceeded the Milan criteria in terms of nodule size and number (MILAN OUT) either at listing or in list, while 60 patients continued to meet the criteria (MILAN IN). The Milan criteria did not prove to be a significant predictor of dropout probability or survival rates using Cox's analysis. Cumulative dropout probability at 6 and 12 months was 0% and 4% for MILAN OUT, and 6% and 11% for MILAN IN. The intention-to-treat survival rates at 1 and 3 years were 95% and 85% in MILAN OUT, and 84% and 69% in MILAN IN. None of the 68 transplanted patients had recurrent HCC after a median 16-month follow-up (0-69 months). In conclusion, LT may be effective for selected, aggressively-treated HCC patients exceeding the Milan criteria.

Partial hepatectomy (PH) and liver transplantation (LT) compete as first-line treatment for hepatocellular carcinoma (HCC). A prospectively collected database was retrospectively reviewed to establish when PH can compete with LT.

Between 1991 and 2002, PH was performed in 131 cases of HCC (Child-Pugh A-B, technically resectable tumor without metastases). To ascertain patient survival after PH, we compared this series with a group of 40 HCC patients (G1-G2 HCC with no gross vascular invasion or metastasis) enlisted for liver transplantation during the same period.

The 1-, 3-, and 5-year intention-to-treat survival rates were 75%, 52%, and 31% for resection and 89%, 71%, and 63% for transplantation. Two tumor-related variables (gross vascular invasion and histological grade) and three liver function parameters (Child-Pugh score, bilirubin, Okuda stage) proved to be independent predictors of survival after resection, whereas nodule size and number, and Milan criteria did not. The 5-year survival of the best candidates for resection (favorable tumor biology with very well preserved liver function, n = 52) was 58%. On a descriptive basis alone, this result did not differ significantly from the outcome in LT patients. PH patients with a poorly differentiated tumor and/or gross vascular invasion (n = 28) had the worst outcome, irrespective of their liver function parameters.

For technically resectable tumors without aggressive features (G3 or macroscopic vascular invasion), PH can only compete with LT, in terms of long-term survival, when patients with a well-preserved liver function are selected.

"Incidentally" identified hepatocellular carcinoma (iHCC) in liver explants after liver transplantation (LTx) is a frequently reported finding, which is characterized with a good prognosis. The purpose of this study was to evaluate the outcome of patients with these tumors in our series and in literature reports, and to compare their prognosis to that of HCC diagnosed preoperatively.

From April 1998 to December 2003, 432 patients underwent deceased-donor LTx at our center for nonmalignant indications. An additional 31 patients with a preoperative known HCC (pkHCC) received deceased-donor grafts. A literature search was performed intending to estimate the incidence of iHCC in liver explants and the outcome after LTx.

iHCC was found in 5 of the 432 patients. All five patients are currently alive without evidence of tumor recurrence after a median follow-up of 43 months. On the other hand, in the group of the 31 patients with pkHCC, 22 of them are at the moment alive in a median follow-up of 28 months. When comparing the two groups, no difference in survival could be found (P=0.1419 in log-rank test). Literature reports of 705 instances with iHCC over the past 20 years showed a statistical "better survival" in only 24 cases.

Literature reports showed a remarkable "deviation" of the expected tumor characteristics for the iHCC. Obviously, this is because of a widely characterization of iHCC, including also tumors which are rather undetected HCC during the waiting time to LTx. A more precise definition for the iHCC is needed.