Living related liver transplantation for recurrent hepatocellular carcinoma in a normal liver

The role of liver transplantation for hepatocellular carcinoma (HCC) is evolving. In patients with advanced liver disease and early stage HCC, transplantation offers the best hope for cure. A living donor offers the optimal approach to a timely transplant, before disease progression obviates the potential benefit. But extending the indications beyond those designated by the United Network for Organ Sharing (UNOS) for liver transplantation for HCC is controversial [Hepatology 2001: 33: 1073; Liver Transplant 2000: 6: S1]. Cadaver split techniques and use of living donors are potentially compelling ways to test the limitations of liver transplantation for HCC, without notably reducing the cadaver organ pool. Herein, we report a rare case of a patient who developed a well-differentiated HCC in a normal liver. After resection of the index lesion and, later, of a remote recurrent lesion, a living donor liver transplant was offered. The natural history of this lesion and the management of transplantation in this setting are discussed.     

Pattern and management of recurrent hepatocellular carcinoma after liver transplantation

A series of 132 patients who underwent liver transplantation for primary liver cancer was collected from three different Italian hospitals and studied for recurrence of hepatocellular carcinoma after liver replacement. Twenty-one patients (15.9%) had a neoplastic recurrence after an average follow-up period of 7.8 months after transplantation (range, 1–25 months); 15 (71%) occurred within the first 18 months after transplant and only two recurred later than 2 years. The sites of recurrence were grafted liver (19%), lung (19%), bone (14%), and other (5%). Eight patients (38%) had multiple organ involvement at the onset. After 1, 2, 3, and 4 years the overall survival rates were 62%, 43%, 29%, and 23%, respectively. The tumor factors related to early cancer recurrence after transplantation were diameter of nodules more than 3 cm (P < 0.05), tumor stage not meeting the "Milan criteria" (P < 0.03), and presence of peri-tumoral capsule (P < 0.05); the number of nodules, TNM stage, presence of vascular invasion, alpha-fetoprotein level more than 150 UI/l, pre-transplant chemoembolization and resectability of cancer deposits did not seem to be related to early recurrence. The prognosis differed in the 7 patients with resectable recurrences (57% 4-year survival) and the 14 patients with unresectable disease (14% 4-year survival) (P < 0.02). Better patient selection and new combined medical strategies could reduce the incidence of and mortality from liver cancer recurrence after transplantation. The role of surgical resection of recurrence should be further investigated. Received for publication on May 26, 1997; accepted on July 3, 1997     

肝移植术后复发性肝细胞癌的多学科治疗

肝移植(liver transplantation,LT)是目前治疗原发性肝癌的最有效措施,尽管经过严格的选择标准,但术后常常发生复发,影响着患者的长期存活。据报道,肝移植术后复发(recurrence after liver transplantation)的发生率估计在6%～50%,并且在移植后的前两年中更常发生。本文就肝移植术后复发的多学科治疗策略进行综述。     

Cost‐effectiveness of screening for recurrent hepatocellular carcinoma after liver transplantation

Ladabaum U, Cheng SL, Yao FY, Roberts JP. Cost‐effectiveness of screening for recurrent hepatocellular carcinoma after liver transplantation.
Clin Transplant 2011: 25: 283–291. © 2010 John Wiley & Sons A/S. Abstract: The effectiveness of screening and treatment of recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) remains undefined. Our aim was to evaluate the potential cost‐effectiveness of screening for recurrent HCC after LT. We constructed a Markov model of the natural history after LT for HCC. We superimposed screening with computed tomography, alpha‐fetoprotein, and chest X‐ray every six months for 1–5 yr after LT, with resection for treatable recurrence. Screening only those whose explant pathology exceeded Milan Criteria (MC) for two yr cost $138 000/life‐yr gained, and the incremental cost of screening all patients was $340 000/life‐yr gained. Screening for longer than two yr incurred progressively higher incremental costs/life‐yr gained. The most critical variable in sensitivity analyses was the survival benefit of finding a resectable recurrence. With the most favorable assumptions for a two‐yr screening duration, screening those whose explant pathology exceeded MC cost $91 000/life‐yr gained. In conclusion, screening for HCC recurrence after LT would probably yield most of its benefit in the first two yr, but at a relatively high cost/life‐yr gained. Screening for two yr in only those whose explant pathology exceeds MC may be relatively cost‐effective depending on the survival benefit of resection.     

Liver transplantation in hepatocellular carcinoma

Liver transplantation is one option of surgical treatment for cirrhotic patients with hepatocellular carcinoma, it not only treats the malignancy but also the underlying disease. After an initial period of disappointing results, mainly due to lack of adequate selection, survival nowadays is similar to that obtained by cirrhotic patients without tumor. Currently the scarcity of donors is the main limitation in the treatment of this type of patients. Increased time on the waiting list does compromise the results if they are analyzed in an intention-to-treat basis. Adjuvant therapy on the waiting list (ethanol injection, chemoembolization, surgery, etc.) or the use of marginal grafts in order to increase the donor pool may be some alternatives to overcome this deficit. The development of adult living donor liver transplantation has proved to be a good alternative in this type of patients even if they do not fulfill the conventional criteria.     

Feasibility of salvage liver transplantation for patients with recurrent hepatocellular carcinoma

BACKGROUND: Recurrence is the most frequent cause of treatment failure after hepatocellular carcinoma (HCC) resection. Salvage liver transplantation is an alternative treatment for recurrent HCC. The transplantability for patients with recurrent HCC has not been well studied. STUDY DESIGN: This study sought to determine how many patients with recurrent HCC are still candidates for liver transplantation, and to ascertain the possible time from HCC recurrence to the loss of transplantability. In an university hospital setting, 154 of the 252 patients receiving primary HCC resection, from January 1992 through December 1996, had recurrence and were analyzed. The mean follow-up time was 6 years. Among the 154 patients, 74 patients (group 1) were not eligible for liver transplantation according to the Milan criteria, while 80 patients were eligible (group 2). Demographic characteristics of both groups were compared and the curve of transplantability was calculated. RESULTS: When compared with group 1 patients, group 2 patients displayed more cirrhosis (p = 0.007), lower pTNM stage (p = 0.004), were older (p = 0.004), presented with smaller tumors (p < 0.001), and displayed a longer disease-free interval (p < 0.001). In group 1, only 47% (35/74) patients were eligible for liver transplantation at the time of index hepatectomy, in contrast to 84% (67/80) in the group 2 patients, p < 0.001. The median time from HCC recurrence to the time they were no longer transplantable was 38 months. The total time from the index HCC resection to the time of loss of transplantability was 83 months. CONCLUSION: In a cohort of patients after resection for their primary HCC, 33% patients had no recurrence and were not in need for liver transplantation in a mean follow-up of 72 months. About 52% of the patients with recurrent HCC still meet the criteria for liver transplantation. For patients with some certain characteristics, resection of the primary HCC may postpone the time of liver transplantation and prolong the time in which a suitable donor searched, while primary liver transplantation may be considered for those patients with factors of low transplantability after recurrence.     

Clinical analysis of emergency liver transplantation: the role of living donor liver transplantation

The current liver allocation system requires reevaluation because of the advancements in peri‐transplantation care and surgical techniques. And, the role of living donor liver transplantation (LDLT) in an emergency has not been determined yet. Retrospective review of all patients undergoing emergency liver transplantation (LT) from January 2000 to June 2010 was conducted, and clinical data were analyzed. Of the total 505 LTs, 69 patients (13.7%) underwent an emergency LT. Of these, 54 patients (78.3%) underwent LDLT using a right liver, and 15 patients (21.7%) underwent deceased donor liver transplantation (DDLT). The overall hospital mortality was 21.7% (15/69). The leading cause of death after transplantation was sepsis (60.0%). Multivariate analysis demonstrated that a model for end‐stage liver disease (MELD) >33 [hazard ratio (HR), 16.6; 95% confidence interval (CI), 1.443–191.632; p = 0.024] and existence of pre‐transplantation intubation (HR, 18.2; 95% CI, 1.463–225.483; p = 0.024) were independent factors associated with poor survival after emergency LT. LDLT group and DDLT group showed no difference in hospital mortality (p = 0.854) and graft survival (p = 0.861). Thus, MELD score and respiratory insufficiency could be parameters predicting post‐transplant survival. And, LDLT using the right liver could be an appropriate alternative to DDLT in an emergency.     

Clinical significance of gastrointestinal bleeding after living donor liver transplantation

The clinical presentations of gastrointestinal bleeding (GIB) occurring after living donor liver transplantation (LDLT) have not been fully described. We performed a retrospective analysis of 297 LDLT cases. Nineteen patients (6.4%) experienced GIB after LDLT. The etiology of GIB included bleeding at the jejunojejunostomy following hepaticojejunostomy (n = 13), peptic ulcer disease (n = 2), portal hypertensive gastropathy (n = 2), and other causes (n = 2). Hemostasis was achieved in 13 patients (68.4%) by endoscopic (n = 3), surgical (n = 1), or supportive treatments (n = 15), but not in the other six patients. Graft dysfunction (P < 0.001), hepaticojejunostomy (P = 0.01), portal vein pressure at the end of surgery >20 mmHg (P = 0.002), and operative blood loss >10 L (P = 0.004) were risk factors. One‐year graft survival rate was significantly lower in patients with GIB than in patients without GIB (P < 0.001). The inhospital mortality rate was 52.6% for patients with GIB, 75.0% for patients with graft dysfunction, and 14.3% for patients without graft dysfunction (P = 0.028). Despite its infrequency after LDLT, GIB has strong correlation with graft dysfunction and inhospital mortality.     

Effect of living donor liver transplantation on outcome of children with inherited liver disease and hepatocellular carcinoma

We described six children with heritable liver disease and hepatocellular carcinoma treated with living-related liver transplantation. Underlying liver diseases were type-1 tyrosinemia (three patients), progressive familial intrahepatic cholestasis type II (two patients), and Wilson's disease (one patient). Two of the tumors were found incidentally during liver transplantation. Number of nodules was 12, 15, 3, 2, and 1 (in two patients). Three patients were treated with chemotherapy before the procedure. Chemotherapy was not given to any patient after liver transplantation. The mean follow-up was 17.7 +/- 6 months (range: 7-24). All patients are tumor recurrence free. Both graft and patient survival rates are 100% at a median of 18.5 months follow-up. Physicians in charge of treating children with heritable liver disease should screen them periodically for the development of hepatocellular carcinoma. Liver transplantation may offer these children better survival rates.     

Ten years survival with excellent outcome after living donor liver transplantation from 70 years old donor for primary hepatic neuroendocrine carcinoma: Case report

BACKGROUNDPrimary hepatic carcinoid tumors (PHCT) are rare entities; they are even rarer than extrahepatic neuroendocrine gastrointestinal tumors with only about 95 cases reported in the literature. An extrahepatic primary tumor must be excluded to confirm the diagnosis of PHCT.CASE PRESENTATIONWe report a case of a 42-year-old male patient with a primary hepatic neuroendocrine carcinoma, who successfully underwent living donor liver transplantation from his 70 years old mother with 10 years follow-up. Both donor and recipient are still alive and in the good health.CONCLUSIONLiving liver donation from elderly donors for the patients with irresectable neuroendocrine liver malignancies can be as safe as deceased donation or liver donation from young donors (age < 50). Living donation from elderly donors might significantly expand the donor pool for patients with liver neuroendocrine tumors (NET) and potentially reduce waiting list mortality. Especially young patients with irresectable NET can benefit from this option. However, case–control studies are needed to verify the advantage of living liver transplantation (LDLT) for the patients with irresectable liver NET and to define selection criteria for these patients.     

Impact of incidentally found hepatocellular carcinoma on the outcome of living donor liver transplantation

Hepatocellular carcinoma (HCC) nodules newly found in the explant liver have been observed, but the impact on patient prognosis is not known. Sixty HCC patients who underwent living donor liver transplantation were the subjects of the study. Radiologic findings prior to transplantation and pathologic findings of the explant liver were compared. Histologic characteristics of preoperatively overlooked tumors were examined. The influence of the discrepancy between these findings on tumor recurrence was evaluated. A total of 227 HCC nodules were found in the explant livers. Of these, 91 nodules (40%) were newly found by pathologic examination. They were smaller and more likely to be well differentiated than the others. The number and size of the tumors were underestimated in 50% (30/60) and 32% (19/60), respectively. There was no significant difference in the recurrence-free survival rate between patients who met the Milan criteria both in the pre- and post-transplant evaluation (n = 29) and those who met the Milan criteria preoperatively, but exceeded the criteria in the explant (n = 19). Nodules newly found in the explant liver had little impact on recurrence-free survival. A decision for liver transplantation according to the Milan criteria based on preoperative evaluation is valuable for securing an excellent outcome.     

Long‐term results for living donor liver transplant recipients with hepatocellular carcinoma using intraoperative blood salvage with leukocyte depletion filter

Massive intraoperative bleeding during liver transplantation often requires large amounts of blood products. The goal of this study was to investigate long‐term outcomes of living donor liver transplantation (LDLT) recipients with hepatocellular carcinoma (HCC) who underwent intraoperative use of intraoperative blood salvage (IBS) and leukocyte depletion filter (LDF). In this study, we included 230 LDLT recipients with HCC from two transplantation centers, between February 2002 and December 2007. Group 1 patients (n = 121) underwent intraoperative IBS with LDF and group 2 patients (n = 109) did not. The amount of autotransfused, filtered red blood cells (RBCs) in group 1 was 1590.2 ± 1486.8 ml, which corresponded to 5.9 units of allogenic leukocyte‐depleted RBCs saved. The incidences of renal dysfunction, postoperative bleeding, and urinary tract infection in group 2 were higher than in group 1 (P < 0.05). Recurrence‐free survival rates for 1, 3, and 5 years were 91.3%, 83.3%, and 83.3%, respectively, in group 1, and 84.6%, 79.0%, and 77.4%, respectively, in group 2 (P = 0.314). IBS using LDF does not increase the risk of cancer recurrence during LDLT for recipients with HCC. Therefore, the use of IBS with LDF appears to be safe for LDLT recipients with HCC.     

肝癌肝移植术后肝癌复发预测指标的研究进展

肝癌肝移植术后肝癌的复发和转移严重制约了肝移植治疗肝癌的效果。移植术后肝癌复发相关预测指标的检测,对早期预防肝癌复发及提高无瘤生存率具有重要临床参考价值。     

Indication of liver transplantation for hepatocellular carcinoma in Japan

Approximately 20,000 patients die of hepatocellular carcinoma (HCC) annually in Japan and most of them are hepatitis B virus (HBV) or hepatitis C virus (HCV) carriers. Recently, small HCC, less than 3 cm in diameter, have frequently been found by ultrasonography in the follow-up of patients with chronic liver diseases. Such cases are mainly treated by either surgical resection or percutaneous ethanol injection therapy (PEIT) with a satisfactory 5 year survival rate of 50%. In addition, the survival rate of advanced cases has gradually improved thanks to transcatheter arterial chemo-embolization combined with PEIT, radiation, hyperthermia, or immune therapy. On the other hand, our autopsy study has indicated a high frequency of extrahepatic metastasis in advanced cases. From these results, liver transplantation for HCC does not seem to be the treatment of first choice, at present, in Japan. In the future, the means to control the underlying infection of HBV or HCV as well as making an accurate imaging diagnosis for the detection of extrahepatic metastasis will become inevitably more important for successful liver transplantation in HCC.This report is the gist of a paper read at the 91st Annual Meeting of the Japanese Surgical Society, Kyoto, Japan, 1991     

A possible role of microRNAs as predictive markers for the recurrence of hepatocellular carcinoma after liver transplantation

With favourable 5‐year survival rates up to 75%, liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). Nonetheless, tumour recurrence after LT remains a challenge. The aim of this retrospective study was to develop a predictive score for tumour recurrence after LT by combining clinical parameters with HCC biomarkers (microRNA). A microRNA (miRNA) microarray analysis was used to compare miRNA expression patterns in tissue samples of 40 patients with and without HCC recurrence after LT. In a screening cohort (n = 18), the miRNA analysis identified significant differences in the expression of 13 miRNAs in patients with tumour recurrence. Using the most significant miRNAs in this screening cohort, we could develop a predictive score, which combined the expression levels of miR‐214, miR‐3187 and the Milan criteria, and we could define low‐ and high‐risk groups for tumour recurrence and death. The above score was evaluated in a second and independent cohort (n = 22). In contrast to the Milan criteria alone, this score was significantly associated with tumour recurrence. Our analysis indicated that the use of a specific miRNA expression pattern in combination with a limited tumour burden as defined by the Milan criteria may lead to a more accurate prediction of tumour recurrence.     

成人活体肝移植

活体肝移植（LDLT）最初作为一种降低等待做肝移植患者死亡率的方法。日本京都大学LDLT开始于1990年6月,移植例数逐年增加,临床应用范围从小儿扩展到成人。肝脏右叶移植物的应用在LDLT具有重要临床意义,已经成为成人间LDLT标准方法。由于肝脏右叶移植物在LDLT移植后成功应用,近年来成人LDLT例数显著增加,自1990年6月至2005年12月,京都大学附属病院已完成了1140例LDLT手术,其中包括477例成人LDLT手术（年龄大于18岁）。HBV和HCV相关性肝硬化和肝癌是LDLT最常见的适应证,截至2005年12月,随访统计结果表明成人LDLT术后总的5年生存率为69．1％。     

Antiviral therapy for recurrent hepatitis C reduces recurrence of hepatocellular carcinoma following liver transplantation

Recurrence of hepatocellular carcinoma (HCC) is one of the major concerns following liver transplantation (LT). With the potential antitumor properties of interferon (IFN), their role in prevention of HCC recurrence is to be defined. We retrospectively reviewed 46 patients who underwent LT for hepatitis C virus (HCV)‐related HCC between January 2004 and December 2008. Twenty‐four (52.2%) patients with biopsy‐proven HCV recurrence received antiviral therapy (IFN group); their outcomes were compared with 22 patients (control group). There was no significant difference for tumor size, number, and type of neo‐adjuvant therapy between the two groups. The 1‐ and 3‐year overall patient survival (100% vs. 90.9% and 87.3% vs. 71.8%; P = 0.150) and tumor‐free survival (100% vs. 72.7% and 83.1% vs. 67.5%; P = 0.214) between IFN and control group were comparable. HCC recurrence was the most common cause of death (n = 6 of 12, 50%), all in the control group. During follow‐up, seven (15.2%) patients developed HCC recurrence: one (4.1%) in the IFN group and six (27.3%) in the control group (P < 0.05). In conclusions, HCC recurrence rate and related deaths were significantly lower in patients that received post‐transplant antiviral therapy for recurrent HCV.     

成人-成人活体右半肝移植16例报告

目的　报道东京大学 16例成人终末期肝病患者进行活体右半肝移植的经验。方法　统计自 2 0 0 0年 10月到 2 0 0 1年 4月 ,对 16例成人终末期肝病患者进行了活体右半肝移植。供体和受体的平均体重分别为 5 5kg(42 - 78kg)和 5 7kg(41- 81kg)。结果　供体手术的平均失血量为 80 0ml(30 0 - 16 0 0ml) ,供体的平均住院时间为 12d(6 - 38d)。 14例供体未输血。 1例供体术后发生并发症。移植肝的平均重量为 719g(45 0 - 10 5 0g) ,所有移植肝均立即恢复功能 ,病人精神状态康复 ,凝血酶原时间恢复正常。 2例受体需要再次手术探查。 2例患者死亡 (1例在术后 16d死于全身性念珠菌感染 ,另 1例在术后 2 6d死于门静脉栓塞 )。结论　认为采用右半肝的活体肝移植可以提供足够体积和功能的肝脏达到较好的结果 ,为成年患者的肝移植提供了新的选择