Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.     

Salvage locoregional therapies for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the second most common cause of cancerrelated death worldwide. Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies, recurrence rates remain high. In contrast to first-line treatment for HCC, which relies on several factors, including clinical staging, tumor burden, and liver function, there is no consensus or general treatment recommendations for recurrent HCC(R-HCC). Locoregional therapies include a s...     

Live-donor liver transplantation for hepatocellular carcinoma

Live-donor liver transplantation (LDLT) is a valuable option for patients with hepatocellular carcinoma (HCC) because compared with deceased-donor liver transplantation (DDLT), the tumor could be eradicated early. However, a higher incidence of recurrence is observed when the result is compared with DDLT. The difference is explained by the timing of transplant because only patients with slow HCC growth (and probably less aggressive tumors) can wait for DDLT. Nevertheless, arecent survey of results of LDLT for HCC in Asia indicated that the 3-year survival rate is approximately 60–80%, which is better than that of any treatment modalities for inoperable HCC associated with poor liver function. LDLT for HCC is still worthwhile to pursue and deserves further evaluation.     

Impact of antiviral therapy on post-hepatectomy outcome for hepatitis B-related hepatocellular carcinoma

The outcome after curative resection for hepatocellular carcinoma (HCC) remains unsatisfactory due to the high recurrence rate after surgery. In patients with hepatitis B virus (HBV)-related HCC, which is the majority of patients with HCC in Asia, a high viral load is a strong risk factor for HCC recurrence. It is logical to believe that antiviral therapy may improve the post-operative outcome by promoting viral clearance and hepatocyte regeneration, as well as improving residual liver volume in HCC patients with hepatitis B. However, the effect of antiviral therapy on clinical outcomes after liver resection in patients with HBV-related HCC remains to be established. There are two main groups of antiviral treatment for HBV-oral nucleos(t)ide analogues and interferon. Interferon treatment reduces the overall incidence of HBV-related HCC in sustained responders. However, side effects may limit its long-term clinical application. Nucleos(t)ide analogues carry fewer side effects and are potent in terms of viral suppression when compared to interferon and are typically implemented for patients with more advanced liver diseases. They may also improve the outcome after curative resection for HBV-related HCC. There are increasing evidence to suggest that antiviral therapy could suppress HBV, decrease the perioperative reactivation of viral replication, reduce liver injury, preserve the liver function before and after operation, and may lower the risk of HCC recurrence. After all, antiviral therapy may improve the survival after liver resection by reducing recurrence and delaying the liver damage by the virus, resulting in a higher chance of receiving aggressive salvage therapy during HCC recurrence.     

Solitary pulmonary metastasis arising thirteen years after liver transplantation for HBV-related hepatocellular carcinoma

We described a 59-year-old male patient who underwent liver transplantation in 1989 for hepatocellular carcinoma (HCC) complicating hepatitis B virus (HBV) cirrhosis. In 2001 (12 years after liver transplantation), he developed a lung metastasis of HCC without intrahepatic recurrence and the resection was done. In July 2003, he was symptom free without any recurrence. HCC metastasis can develop even after a very long time of liver transplantation. Many HCCs grow slowly, and the growth rate of recurrent tumors in patients receiving immunosuppressive therapy is significantly greater than that of those who do not receive immunosuppressive therapy.     

Ablative strategies for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the most common primary liver cancer and is the fifth leading cause of cancer death worldwide and the third leading cause of all diseases worldwide. Liver transplantation, surgical resection and ablation are the three main curative treatments for HCC. Liver transplantation is the optimal treatment option for HCC, but its usage is limited by the shortage of liver sources.Surgical resection is considered the first choice for early-stage HCC, but it does not apply t...     

18F-FDG PET/CT纳入肝细胞癌肝移植标准的趋势与价值

肝移植是治疗肝细胞癌(HCC)的有效方法,为降低HCC肝移植术后可能出现较高肿瘤复发率,有学者率先提出著名的Milan标准。但该标准过于严格,部分患者因其肿瘤病变较大或多个结节,虽其生物行为相对“温良”,也被排除在等待肝移植名单之外,随之世界各地出现了众多的“扩大Milan版标准”。HCC组织病理学的微血管侵犯(MVI)、肿瘤组织低分化与HCC肝移植术后较高复发率有显著相关性。复习总结了近年来国内外18氟-脱氧葡萄糖(18F-FDG)PET/CT在HCC肝移植方面的应用文献,发现18F-FDG在HCC病变部位不同的摄取程度,反映了肿瘤组织生物学行为特征即侵袭性的差异;18F-FDG高摄取与HCC病变的MVI、低分化呈正相关;18F-FDG还能敏感、准确地发现HCC肝外转移灶。认为术前18F-FDG PET/CT结果对HCC肝移植预后评估有巨大价值,将其结果纳入HCC肝移植标准是趋势所归,也有望统一“扩大Milan版标准”。建议新的肝移植标准可定义为,原则上遵循Milan标准;对超出Milan标准者,满足HCC病变18F-FDG PET/CT阴性,且排除大血管侵犯和肝外转移。     

Chinese expert consensus on neoadjuvant and conversion therapies for hepatocellular carcinoma

The low resection and high recurrence rates in hepatocellular carcinoma (HCC) are the major challenges to improving prognosis. Neoadjuvant and conversion therapies are underlying strategies to overcome these challenges. To date, no guideline or consensus has been published on the neoadjuvant and conversion therapies in HCC. Recent studies showed that neoadjuvant therapy for resectable HCC and conversion therapy for unresectable HCC are safe, feasible, and effective. Neoadjuvant and conversion therapies have the following advantages in treating HCC: R0 resection with sufficient volume of future liver remnant, relatively simple operation, and wide applicability. Therefore, it was necessary to conduct a widely accepted consensus among the experts in China who have extensive expertise and experience in treating HCC using neoadjuvant and conversion therapies, which is important to standardize the application of neoadjuvant and conversion therapies for the management of HCC. The strategies of neoadjuvant therapy include the selection of the eligible patients, therapy regimen, cycles, effect evaluations, and multidisciplinary treatment. The management of patients with insufficient volume of future liver remnant and patients who cannot achieve R0 resection is the key to the strategies of conversion therapy. Here, we present the resultant evidence- and experience-based consensus to guide the application of neoadjuvant and conversion therapies in clinical practice.     

Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.     

Recurrence of hepatocellular carcinoma: multicentric occurrence or intrahepatic metastasis? A viewpoint in terms of pathology

Recurrence after successful surgical or nonsurgical treatment of hepatocellular carcinoma (HCC) is caused either by intrahepatic metastasis or by metachronously multicentric occurrence. Intrahepatic metastasis is a major cause of recurrence of advanced HCCs with varying degrees of vascular invasion, and multicentric occurrence is a frequent cause of recurrence in small HCCs with no obvious vascular invasion. It is estimated that at least 20% of small HCCs have a high probability of recurrence due to multicentric occurrence, based on the finding that adenomatous hyperplasia (AH) and/or atypical adenomatous hyperplasia (AAH), which are considered premalignant lesions, are found in the vicinity of resected small HCCs with liver cirrhosis. However, because neither AH nor AAH occur in HCC cases without liver cirrhosis, most recurrence of HCC in noncirrhotic liver is considered to be due to intrahepatic metastasis or to de novo hepatocarcinogenesis. In a survey of autopsy cases of liver cirrhosis with small HCC, smaller HCC nodules were found in other liver slices in 50% of cases, and it is estimated that approximately 50% of HCC is already multicentric in the early stage.     

Successful hepatic resection for recurrent hepatocellular carcinoma after lenvatinib treatment: A case report

BACKGROUNDLenvatinib has been shown to be noninferior to sorafenib regarding prognosis and recurrence rate in patients with unresectable hepatocellular carcinoma (HCC) who have not received prior systemic chemotherapy. In patients treated with lenvatinib, 40% of cases achieved sufficient tumor reduction to make potential surgery possible. However, the outcomes of such surgery are unknown. We report a successful case of hepatic resection for recurrent HCC after lenvatinib treatment.CASE SUMMARYA 69-year-old man underwent right anterior sectionectomy for HCC in segment 8 of the liver. Ten months later, he was found to have an intrahepatic HCC recurrence that grew rapidly to 10 cm in diameter with sternal bone metastases. After confirming partial response to lenvatinib administration for 2 mo, a second hepatectomy was performed. Pathological examination showed that 80% of the tumor was necrotic. The patient did not develop any adverse effects under lenvatinib treatment. He was discharged at 25 d after surgery. Radiation therapy for bone metastases continued to be given under lenvatinib, and the patient has remained alive for 1 year after the second hepatectomy.CONCLUSIONThe prognosis of patients with recurrent HCC may be improved by liver resection combined with prior lenvatinib therapy.     

肝移植术后肝癌复发防治进展

肝移植是根治性治疗肝癌的方法之一,但肝移植术后肝癌复发严重影响移植患者的长期生存。通过积极的预防措施,免疫抑制剂调整,早期发现以及全面制订肝癌复发后的干预措施,有助于提高肝癌肝移植患者临床疗效并改善长期生存。为了进一步改善肝移植患者预后,从预防复发及复发后的治疗两大方面对肝移植术后肝癌复发的最新防治进展进行归纳和总结。     

Solitary pulmonary metastasis arising thirteen years after liver transplantation for HBV-related hepatocellular carcinoma

We described a 59-year-old male patient who underwent liver transplantation in 1989 for hepatocellular carcinoma (HCC) complicating hepatitis B virus (HBV) cirrhosis. In 2001 (12 years after liver transplantation), he developed a lung metastasis of HCC without intrahepatic recurrence and the resection was done. In July 2003, he was symptom free without any recurrence. HCCmetastasis can develop even after a very long time of liver transplantation. Many HCCs grow slowly, and the growth rate of recurrent tumors in patients receiving immunosuppressive therapy is significantly greater thanthat of those who do not receive immunosuppressive therapy.     

A long-term survivor of ruptured hepatocellular carcinoma after hepatic resection

Abstract We treated a patient who had previously undergone a hepatic resection for ruptured hepatocellular carcinoma (HCC) but developed a solitary peritoneal recurrence at the site of the incision 8 years and 9 months later. Since no other recurrence was evident, we resected the tumour. The primary tumour was 2.5 cm in size and histological examination revealed HCC without any histological risk factors for intrahepatic recurrence. The peritoneal tumour consisted of less differentiated cancer cells than those found in the primary tumour. The positive rates of Ki-67 were 10% in the primary tumour and 23.3% in the peritoneal recurrence. The DNA indexes in both tumours were considered to be identical.
The comparison between the primary and peritoneal tumours suggested that the histological differentiation and proliferation activity can change after recurrence, in spite of consistent DNA ploidy contents. Clinically, a patient who undergoes a hepatic resection for ruptured HCC can survive for a long time, such as 10 years, if they have good liver function and small HCC without any histological risk factors for intrahepatic recurrence. However, since late recurrence is possible, a follow up for as long as 10 years is recommended.     

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.     

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.     

Management of chronic hepatitis B in severe liver disease

In the past few decades,chronic hepatitis B(CHB)has evolved from a disease that was untreatable and progressive,to one that can be easily controlled with antiviral therapy.However,patients with severe liver disease still remain difficult to treat despite the availability of highly potent nucleos(t)ide analogs.These include those with underlying cirrhosis,severe flares of CHB,hepatocellular carcinoma(HCC),and for those undergoing liver transplantation.For those with established cirrhosis,antiviral therapy should be considered for all,as unpredictable flares can still occur,which can be fatal for those with advanced chronic liver disease.However,even with effective viral suppression,the development of HCC can still occur.For patients with severe flares of CHB,although the use of antiviral can improve long term outcomes,a significant proportion may still die without liver transplantation.The short term prognosis of these patients is dependent on both the severity of flare and underlying pre-existing liver disease.In patients with decompensated cirrhosis,liver failure secondary to severe flares,or those with HCC,liver transplantation may be curative.After liver transplantation,long term antiviral therapy is required to prevent graft loss from recurrent hepatitis B infection.The use of hepatitis B immune globulin(HBIG)in combination with an oral antiviral agent has been the mainstay of post-transplant antiviral regimen for over adecade.With newer and more potent antiviral agents such as tenofovir and entecavir,use of these agents along with HBIG have demonstrated to be effective in preventing significant recurrence in the long term.     

Selection of patients with hepatocellular carcinoma for liver transplantation: Past and future

The aim of liver transplantation(LT) for hepatocellular carcinoma(HCC) is to ensure a rate of disease-free survival similar to that of patients transplanted due to benign disease. Therefore, we are forced to adopt strict criteria when selecting candidates for LT and prioritizing patients on the waiting list(WL), to have clarified indications for bridging therapy for groups at risk for progression or recurrence, and to establish certain limits for downstaging therapies. Although the Milan criteria(MC) remain the standard and most employed criteria for indication of HCC patients for LT by far, in the coming years, criteria will be consolidated that take into account not only data regarding the size/volume and number of tumors but also their biology. This criteria will mainly include the alpha fetoprotein(AFP) values and, in view of their wide variability, any of the published logarithmic models for the selection of candidates for LT. Bridging therapy is necessary for HCC patients on the WL who meet the MC and have the possibility of experiencing a delay for LT greater than 6 mo or any of the known risk factors for recurrence. It is difficult to define single AFP values that would indicate bridging therapy(200, 300 or 400 ng/m L); therefore, it is preferable to rely on the criteria of a French AFP model score 2. Other single indications for bridging therapy include a tumor diameter greater than 3 cm, more than one tumor, and having an AFP slope greater than 15 ng/m L per month or 50 ng/m L for three months during strict monitoring while on the WL. When considering the inclusion of patients on the WL who do not meet the MC, it is mandatory to determine their eligibility for downstaging therapy prior to inclusion. The upper limit for this therapy could be one lesion up to 8 cm, 2-3 lesions with a total tumor diameter up to 8 cm, or a total tumor volume of 115 cm~3. Lastly, liver allocation and the prioritization of patients with HCC onthe WL should take into account the recently described HCC model for end-stage liver disease, which considers hepatic function, HCC size and the number and the log of AFP values. This formula has been calibrated with the survival data of non-HCC patients and produces a dynamic and more accurate assessment model.     

Prophylactic liver transplantation for high-risk recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the second most common cause of cancer-related death in the world. Radical treatment of HCC in early stages results in a long disease-free period and improved overall survival. The choice of optimal management strategy for HCC mainly depends on the severity of the underlying liver disease. For patients with decompensated liver cirrhosis and HCC within Milan criteria(MC), liver transplant(LT) is the choice of treatment. However, for patients with good residual liver reserve and HCC within MC, selection of other curative treatments such as liver resection(LR) or radiofrequency ablation may be a reasonable alternative. For patients without cirrhosis, LR can result in an overall survival similar to that provided by LT. Therefore, it is an accepted alternative to LT especially in areas with organ shortage. However, the cumulative 5-year recurrence rate of HCC post LR might be as high as 70%. For initial transplant-eligible(within MC) patients with recurrent HCC post LR, salvage liver transplant(SLT) was first proposed in 2000. However, most patients with recurrent HCC considered for SLT are untransplantable cases due to HCC recurrence beyond MC or comorbidity. Thus, the strategy of opting for SLT results in the loss of the opportunity of LT for these patients. Some authors proposed the concept of "de principe liver transplant"(i.e., prophylactic LT before HCC recurrence) to prevent losing the chance of LT for these potential candidates. Factors associated with the failure of SLT will be dissected and discussed in three parts: Patient, tumor, and underlying liver disease. Regarding patient-related factors, the rate of transplantability depends on patient compliance. Patients without regular follow-up tend to develop HCC recurrence beyond MC at the time of tumor detection. Advancing age is another factor related to severe comorbidities when LT is considered for HCC recurrence, and these elderly candidates become ineligible as time goes by. Regarding tumor-related factors, histopathological features of the resected specimen are used mostly for determining the prognosis of early HCC recurrences. Suchprognostic factors include the presence of microvascular invasion, poor tumor differentiation, the presence of microsatellites, the presence of multiple tumors, and the presence of the gene-expressing signature associated with aggressive HCC. These prognostic factors might be used as a selection tool for SLT or prophylactic LT, while remaining mindful of the fact that most of them are also prognostic factors for post-transplant HCC recurrence. Regarding underlying liver disease-related factors, progression of chronic viral hepatitis and high viral load may contribute to the development of late(de novo) HCC recurrence as a consequence of sustained inflammatory reaction. However, correlation between the severity of liver fibrosis and tumor recurrence is still controversial. Some prognostic scoring systems that integrate these three factors have been proposed to predict recurrence patterns after LR for HCC. Theoretically, after excluding patients with high risk of post-transplant HCC recurrence, either by observation of a cancer-free period or by measurement of biological factors(such as alpha fetoprotein), prophylactic LT following curative resection of HCC could be considered for selected patients with high risk of recurrence to provide longer survival.     

Novel biomarkers GEP/ABCB5 regulate response to adjuvant transarterial chemoembolization after curative hepatectomy for hepatocellular carcinoma

Background: Transarterial chemoembolization(TACE) is the most commonly used adjuvant therapy for hepatocellular carcinoma(HCC) after curative resection. Responses to TACE are variable due to tumor and patient heterogeneity. We had previously demonstrated that expression of Granulin-epithelin precursor(GEP) and ATP-dependent binding cassette(ABC)B5 in liver cancer stem cells was associated with chemoresistance. The present study aimed to evaluate the association between GEP/ABCB5 expression and response to adjuvant TACE after curative resection for HCC. Methods: Patients received adjuvant TACE after curative resection for HCC and patients received curative resection alone were identified from a prospectively collected database. Clinical samples were retrieved for biomarker analysis. Patients were categorized into 3 risk groups according to their GEP/ABCB5 status for survival analysis: low(GEP-/ABCB5-), intermediate(either GEP +/ABCB5-or GEP-/ABCB5 +) and high(GEP +/ABCB5 +). Early recurrence(recurrence within 2 years after resection) and disease-free survival were analyzed. Results: Clinical samples from 44 patients who had followed-up for more than 2 years were retrieved for further biomarker analysis. Among them, 18 received adjuvant TACE and 26 received surgery alone. Patients with adjuvant TACE in the intermediate risk group was associated with significantly better overall survival and 2-year disease-free survival than those who had surgery alone( P = 0.036 and P = 0.011, respectively). Adjuvant TACE did not offer any significant differences in the early recurrence rate, 2-year disease-free survival and overall survival for patients in low and high risk groups. Conclusions: Adjuvant TACE can only provide survival benefits for patients in the intermediate risk group(either GEP +/ABCB5-or GEP-/ABCB5 +). A larger clinical study is warranted to confirm its role in patient selection for adjuvant TACE.