De novo Hepatocellular Carcinoma after Liver Transplantation

Liver transplantation is the definitive therapy for patients with advanced liver disease and its complications. Patients who are transplanted with a diagnosis of hepatocellular carcinoma (HCC) are at risk of recurrent cancer, and these patients are monitored on a regular basis for recurrence. In contrast, de novo HCC following liver transplantation is a very rare complication, and recipients without HCC at the time of transplantation are not screened. We describe the clinical features of de novo HCC over a decade after achieving a sustained viral response with treatment of hepatitis C and two decades after liver transplantation. Our case highlights the necessity of screening for HCC in the post-transplant patient with advanced liver disease even after viral clearance.     

Recommendations for Hepatitis B Immunoglobulin and Antiviral Prophylaxis Against Hepatitis B Recurrence After Liver Transplantation

The combination of hepatitis B immunoglobulin and potent nucleos(t)ide analogs after liver transplantation is considered as the standard of care for prophylaxis against hepatitis B virus recurrence. However, the recommended doses, route of administration, and duration of HBIG administration remain unclear. Moreover, hepatitis B immunoglobulin-free prophylaxis with potent nucleos(t)ide analogs has shown promising disease outcomes in preventing hepatitis B virus recurrence. The current recommendations, produced by the Turkish Association for the Study of the Liver, Acute Liver Failure and Liver Transplantation Special Interest Group, suggest a reduced need for hepatitis B immunoglobulin administration with effective long-term suppression of hepatitis B virus replication using potent nucleos(t)ide analogs after liver transplantation.     

Sorafenib in the Treatment of Advanced Hepatocellular Carcinoma

Management of advanced hepatocellular carcinoma (HCC) is still a challenge to physicians since these patients are not candidates for surgical or ablative therapy. The disease carries a very poor prognosis with an expected survival of 4–6 months. No chemotherapeutic agent has been proven to improve the clinical outcome in such patients. A multikinase inhibitor, sorafenib, previously tested and found effective in other solid tumors recently found to significantly improve survival in patients with advanced HCC. Sorafenib exerts its action through inhibition of several kinases involved in both tumour cell proliferation and angiogenesis. It was well tolerated at a dose of 400 mg twice daily and permanent discontinuation of the drug was rarely required.     

Juvenile Hepatocellular Carcinoma in a Healthy Liver

Primary hepatocellular carcinoma (HCC) in patients ＜30 years old is extremely rare. In younger patients, HCC develops against a background of persistent hepatitis B virus infection. We herein report a 23-year-old woman with HCC with all-negative hepatitis virus markers developing in an apparently healthy liver. Imaging studies showed a 50-mm hypervascular mass in segment 4 of the left liver lobe, compatible with HCC. The patient underwent surgical resection. A histological examination showed the presence of poorly differentiated HCC. The patient was diagnosed with HCC developing in a healthy liver. This is an extremely rare case of non-B non-C HCC.     

Application and Impact of Antiviral Therapy for Patients with HBV-Related Hepatocellular Carcinoma Receiving Sorafenib and Lenvatinib Treatment

Overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) has improved in the era of multi-line sequential therapy. The application of antiviral therapy and its impact on survival for patients with HBV-related HCC needs to be reassessed. The aim of this study was to evaluate the application and impact of antiviral therapy on survival for patients with HBV-related HCC receiving tyrosine kinase inhibitor (TKI) therapy. Patients with advanced HBV-related HCC treated with sorafenib or lenvatinib as first-line therapy with (n = 377) and without (n = 182) nucleos(t)ide analogue (NUC) therapy were retrospectively enrolled. Prognostic factors of OS were evaluated. Secular trends in the increased application of NUC therapy and improved survival were observed in the last decade. The HBV reactivation rate in patients without NUC therapy was 6.6%. By multivariate analysis, baseline low HBV viral load, achieving undetectable HBV DNA after TKI therapy, and ability to receive second-line therapy were found to be independent predictors of OS. In subgroup patients with NUC therapy, starting NUC before TKI was associated with a better OS. In conclusion, the application of antiviral therapy for patients with HBV-related HCC receiving TKI therapy has increased over time. Achieving complete virological suppression may contribute to a better OS in patients with advanced HBV-related HCC.     

UNOS Down-Staging Criteria for Liver Transplantation of Hepatocellular Carcinoma: Systematic Review and Meta-Analysis of 25 Studies

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Ethnic Differences in Hepatocellular Carcinoma: Implications for Liver Transplantation

Liver transplantation (LT) as a treatment for Hepatocellular Carcinoma (HCC) provides excellent outcomes if restricted to patients who meet the Milan criteria (MC). The aim of this study was to evaluate the influence of ethnicity on eligibility for LT based on the MC. This is a retrospective cohort study of patients diagnosed with HCC at our institution between January 2000 and September 2005. We identified 169 patients, of whom 135 were male (80%), 108 were Caucasian (64%), 29% were African American (AA) and 7% were of other ethnicity. Eighty two patients (49%) met the MC at diagnosis. Age, gender, severity of liver disease or insurance status was not predictive of meeting MC at diagnosis. Ethnicity was the only significant predictor for failure to meet MC. Significantly fewer Caucasians exceeded the MC compared to AA (44 vs. 71%; P = 0.0015). Conclusion AA are more likely to present with HCC that exceeds the MC.     

Hepatocellular Carcinoma in Non-cirrhotic Liver Arises with a More Advanced Tumoral Appearance: A Single-Center Cohort Study

BackgroundA small proportion of all hepatocellular carcinomas (HCCs) arise in a non-cirrhotic liver (NCL). However, our knowledge about the HCCs developing in a NCL is scarce. This study was undertaken to investigate the characteristics and survival course of this patient group.MethodsWe retrospectively analyzed the database of patients with HCC at a tertiary center during a 10-year period (2009-2019). All demographic, clinical, laboratory, and tumoral features with survival outcomes were compared between the HCC-CL and HCC-NCL groups.ResultsOut of 384 HCC cases, 11.2% (n = 43) had no cirrhosis. The dominant etiology in the HCC-NCL group was hepatitis B virus (n = 26, 60.5%), followed by non-alcoholic fatty liver disease (n = 10, 23.2%), and hepatitis C virus (n = 7, 16.3%). The maximum tumor diameter was approximately 2 times larger in the HCC-NCL group (HCC-NCL: 90 mm vs. HCC-CL: 46.5 mm, P < .001). The proportion of patients with vascular (HCC-NCL: 27.9% vs. HCC-CL: 8.6%, P < .001) and extrahepatic invasion (HCC-NCL: 14% vs. HCC-CL: 3%, P = .001) were prominently higher in the HCC-NCL group. Patients with HCC-NCL were less often detected in early-curable stages (BCLC 0-A) than those in the HCC-CL group (HCC-NCL: 16.3% vs. HCC-CL: 34.9%, P = .004). The overall survival was not different between the 2 groups (HCC-NCL: 19.4 ± 9.8 months vs. HCC-CL: 17.5 ± 2.3 months, P = .581).ConclusionHCC in NCL is diagnosed at more advanced tumoral stages with larger tumor size and more often with vascular and extrahepatic spread. Despite the preserved liver functions, the overall survival is not prolonged in HCCs without cirrhosis, due to the late recognition.     

Sorafenib for Treatment of Hepatocellular Carcinoma: A Systematic Review

Background  

Sorafenib, a drug that inhibits Raf serine/threonine kinases mediating cell proliferation and receptor tyrosine kinases involved in angiogenesis, is approved for treatment of advanced hepatocellular carcinoma.     

Efficacy and Safety of Ramucirumab in Patients with Unresectable Hepatocellular Carcinoma with Progression after Treatment with Lenvatinib

Objective A survival benefit was demonstrated for ramucirumab (RAM) in patients with unresectable hepatocellular carcinoma (uHCC) and α-fetoprotein (AFP) concentrations ≥400 ng/mL who had previously received sorafenib (SOR). However, it is unclear whether RAM has a similar efficacy in patients with uHCC that progresses after lenvatinib (LEN) treatment. This study aimed to evaluate the early anti-tumor response to RAM as a second-line treatment for advanced uHCC after LEN treatment. Methods We retrospectively assessed the efficacy and safety of RAM at 6 weeks after initiation. The therapeutic effects were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients We evaluated 7 patients with uHCC who received RAM as a second- or third-line treatment after LEN failure. Results The disease control rate (DCR) was 28.6% (2 of 7 patients). After the initiation of RAM, a rapid disease progression resulted in 1 patient death after 19 days. The median progression-free survival (PFS) was 41 days. There were no grade 3 or 4 treatment-related adverse events. At 6 weeks, there was no deterioration in the modified albumin-bilirubin (mALBI) grade. In patients with an imaging response of stable disease (SD), the rate of AFP production decreased from the baseline. Conclusion RAM may have a therapeutic potential for the suppression of uHCC progression in patients previously treated with LEN, as well as for maintaining the liver function during treatment. Evaluating the AFP trends may therefore be useful for predicting RAM effectiveness.     

Hepatocellular Carcinoma: Downstaging to Liver Transplantation as Curative Therapy

Hepatocellular carcinoma (HCC) ranks among the leading cancer-related causes of morbidity and mortality worldwide. Downstaging of HCC has prevailed as a key method to curative therapy for patients who present with unresectable HCC outside of the listing criteria for liver transplantation (LT). Even though LT paves the way to lifesaving curative therapy for HCC, perpetually severe organ shortage limits its broader application. Debate over the optimal protocol and assessment of response to downstaging treatment has fueled immense research activity and is pushing the boundaries of LT candidate selection criteria. The implicit obligation of refining downstaging protocol is to ensure the maximization of the transplant survival benefit by taking into account the waitlist life expectancy. In the following review, we critically discuss strategies to best optimize downstaging HCC to LT on the basis of existing literature.     

Hepatocellular Carcinoma and Liver Transplantation: State of the Art

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in chronic liver disease and cirrhosis. The incidence of HCC is growing worldwide.With respect to any other available treatment for liver cancer, liver transplantation (LT) has the highest potential to cure. LT allows for removal at once of both the tumor (“seed”) and the damaged-hepatic tissue (“soil”) where cancerogenesis and chronic liver disorders have progressed together. The Milan criteria (MC) have been applied worldwide to select patients with HCC for LT, yielding a 4-year survival rate of 75%. These criteria represent the benchmark for patient selection and are the basis for comparison with any other suggested criteria.However, MC are often considered to be too restrictive, and recent data show that between 25% and 50% of patients with HCC are currently transplanted beyond conventional indications. Consequently, any unrestricted expansion of selection criteria will increase the need for donor organs, lengthen waiting periods, increase drop-out rates, and impair outcomes on intention-to-treat analysis. Management of HCC recurrence after LT is challenging. There are a few reports available regarding the safety and efficacy of sorafenib for HCC recurrence after LT, but the data are heterogeneous. A multi-center prospective randomized controlled trial comparing placebo with sorafenib is advised. Alternatively, a meta-analysis of patient survival with sorafenib for HCC recurrence after LT could be helpful to characterize the therapeutic benefit and safety of sorafenib.Here, we review the use of LT for HCC, with particular emphasis on the selection criteria for transplantation in patients with HCC and management of HCC recurrence after LT.     

Liver transplantation for HCC: its role

Liver transplantation (LT) is the only treatment that offers a chance of cure for hepatocellular carcinoma (HCC) and the underlying liver cirrhosis simultaneously, but the availability of liver grafts and the aggressiveness of tumor recurrence are critical limiting factors of LT for patients with HCC. In most Asian countries, the serious shortage of deceased donors and the strong demand for LT has lead to the development of living-donor LT (LDLT) as a practical alternative replacing deceased-donor LT (DDLT). Grafts in Western countries are issued from DDLT and graft allocations are under the responsibilities of state agencies which apply strict rules based on the MELD (model for end-stage liver disease) score. Considering that HCC recurrence is the most common cause of post-transplant patient death, recipient candidates should be prudently selected through objectively established criteria. Points in addition to the MELD score can be allotted to patients with HCC providing that the HCC remains within the Milan criteria. The increasing number of LT candidates with HCC results in increasing waiting periods, which necessitate the consideration of pretransplant treatment of HCC, including partial liver resection. Both specific Western units and some Asian major LDLT centers have challenged the Milan criteria. The eligibility criteria of both DDLT and LDLT for HCC are likely to be expanded more than before, but this still requires further qualified risk–benefit analyses. The development of new effective treatment modalities before LT and for HCC recurrence might expand the selection criteria further without incurring an increased recurrence rate.     

Outcomes of Nonalcoholic Steatohepatitis After Liver Transplantation: An Updated Meta-Analysis and Systematic Review

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Efficacy of Prophylactic Endoscopic Variceal Sclerotherapy in Patients with Hepatocellular Carcinoma

Abstract: A setrospective study to determine the influence of prophylactic endoscopic sclerotherapy on the survival rate of patients with hepatocellular carcinoma complicated by esophageal varices was conducted. The subjects included 132 patients without esophageal varices at the time of diagnosis (NV group), 37 patients with hepatocellular carcinoma for whom prophylactic sclerotherapy had been performed for risky esophageal varices (PS group) and 26 patients with hepatocellular carcinoma and risky varices for whom prophylaxis was not performed (NPS group). Multiple regression analysis was used to identify factors affecting the survival rate of the 132 patients without esophageal varices. A tumor embolus in the primary branch or main trunk of the portal vein adversely affected long-term survival in these patients. The patients were further divided into 2 subgroups, namely those with (Vp3) and without (Vp0-Vp2) tumor emboli in the main trunk and primary branch of the portal vein. In the Vp0– Vp2 emboli subgroup, the patients who received prophylactic sclerotherapy and the patients without varices had similar survival rates. Patients without prophylactic sclerotherapy had a significantly shorter survival rate than the group without varices and the prophylactic sclesotherapy group (p<0.01 and p<0.05). A significant bleeding rate was observed in the group without prophylaxis and not in the group with prophylaxis. However, in the Vp3 subgroup, the survival rate in each group was identical. Thus prophylactic variceal sclerotherapy is indicated for patients with hepatocellular carcinoma who do not have tumor emboli in the main trunk or primary branch of portal vein.     

Therapeutic Results of Computed-Tomography-Guided Transcatheter Arterial Chemoembolization for Local Recurrence of Hepatocellular Carcinoma After Initial Transcatheter Arterial Chemoembolization: The Results of 85 Recurrent Tumors in 35 Patients

The aim of this study was to retrospectively evaluate the long-term results of transcatheter arterial chemoembolization (TACE) for the treatment of local recurrence of hepatocellular carcinoma (HCC) after the first TACE. Between September 1992 and October 2004, 85 recurrent HCC nodules of 35 patients were treated by TACE. During the median follow-up period of 15.5 months (range 1.9–58.6 months), 58 of the 85 treated tumors developed local recurrence again after the second TACE. The overall 6-, 12-, and 36-month recurrence-free rates of these tumors after the second TACE were 47.0%, 36.2%, and 25.8%, respectively. Local recurrence of HCC after the first TACE was treated by a second TACE with equivalent efficacy as that of the initial TACE, if segmental chemoembolization was achieved. We regard TACE as the treatment of choice for the management of local recurrence of HCC.     

Hemoperitoneum as a First Manifestation of Hepatocellular Carcinoma in Western Patients with Liver Cirrhosis

Hemoperitoneum is a well-known form of hepatocellular carcinoma presentation and represents a frequent complication in countries with a high incidence of hepatocellular carcinoma, but it is rarely seen in Western countries. Our aim was to report the results and describe the arteriographic and CT-scan characteristics in a series of seven consecutive patients. They were admitted to our hospital because of hemoperitoneum due to ruptured tumor as a first manifestation of hepatocellular carcinoma, and the rupture was effectively controlled by transcatheter arterial embolization. From April 1989 to April 1998, 440 consecutive patients were admitted to our liver unit with the diagnosis of hepatocellular carcinoma and liver cirrhosis. Fourteen patients (3%) presented with acute hemoperitoneum due to tumor rupture as a first manifestation of hepatocellular carcinoma. We here report our experience in the group of patients treated by transcatheter arterial embolization. Mean age was 67.1 ± 5 years (range, 61–73). All patients presented with sudden abdominal pain, abdominal distension, and four patients had symptoms of acute anemia. In all cases the ruptured tumor was subcapsular. The procedure was effective in the control of bleeding in all cases, without significant impairment in liver function or treatment-related deaths. In six of the seven patients, a self-limited postembolization syndrome was observed. Mean survival time was 273 ± 488.7 days (range: 15–1290). Three patients survived more than six months but at the time of evaluation, only one patient was alive. In conclusion, the present results confirm that transcatheter arterial embolization is an effective and well-tolerated treatment in the management of hemoperitoneum due to ruptured hepatocellular carcinoma in patients with liver cirrhosis.