Treatment of HCC in Patients Awaiting Liver Transplantation

Liver transplantation (LT) is the treatment of choice for many patients with unresectable hepatocellular carcinoma (HCC), but long waiting time due to the shortage of donor organs can result in tumor progression and drop-out from LT candidacy. Furthermore, even in candidates meeting the restrictive Milan criteria there is risk of HCC recurrence; this risk rises significantly when patients with more advanced HCC are included. In an effort to address these issues, treatment of HCC in patients awaiting LT has become widespread practice. In this review the various modalities employed in the pre-LT setting are presented, and the evidence for benefit with regard to (1) improvement of post-LT survival, (2) down-staging of advanced HCC to within Milan criteria and (3) preventing waiting list drop-out is considered. Chemoembolization, radiofrequency ablation and ethanol injection all have well-documented antitumor activity; however, there is no high level evidence that waiting list HCC treatment with these modalities is effective in achieving any of the three above-mentioned aims. Nevertheless, particularly in the United States, where continued waiting list priority depends on maintaining HCC within Milan criteria, use of nonsurgical HCC treatment will likely continue in an effort to forestall tumor progression and waiting list drop-out.     

Low Prevalence of Colonization with Vancomycin-Resistant Enterococcus in Patients Awaiting Liver Transplantation

The orthotopic liver transplant (OLT) population has been particularly affected by the increase in vancomycin-resistant enterococcus (VRE) infections in recent years. Pre-transplant colonization prevalence, the role of spontaneous bacterial peritonitis (SBP) antimicrobial prophylaxis as a risk factor, and the risk of post-OLT infection in colonized patients are all unknowns. We prospectively evaluated OLT candidates at our center with the aim of answering these questions. Vancomycin-resistant enterococcus colonization status was determined by rectal culture. Data collected included illness severity, antibiotic use (including SBP prophylaxis), waiting time, previous hospitalizations, and invasive procedures. Eighty-eight patients (31 female, 57 male, median age 52 years) were enrolled. The most common diagnoses were hepatitis C (49%), primary sclerosing cholangitis (13.6%), and alcoholic liver disease. Median MELD score was 11.5 (range 7-24), and median waiting time was 551 days (range 1-2224). Vancomycin-resistant enterococcus risk factors were common in our patients: recent hospitalization in 16%, recent antibiotic exposure in 39%, and renal insufficiency in 7%. Seventeen percent were receiving SBP prophylaxis. Despite the presence of established risk factors, VRE colonization prevalence was 3.4%. Preliminary limited data showed poor correlation between screening rectal cultures and operative/peri-operative cultures. Vancomycin-resistant enterococcus colonization prevalence in an OLT candidate population with mid-level MELD scores was low, and SBP prophylaxis was not a significant risk factor.     

Photodynamic Therapy Provides Local Control of Cholangiocarcinoma in Patients Awaiting Liver Transplantation

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)‐directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP‐directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol‐driven neoadjuvant chemoradiation and ERCP‐directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP‐directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention‐to‐treat disease‐free survival was 75% at mean follow‐up of 28.1 months. In summary, ERCP‐directed PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT.     

Ethical Issues in Split Versus Whole Liver Transplantation

Technologic advances in split liver transplantation have resulted in an ethical dilemma. Although splitting a liver maximizes the number of patients receiving an organ transplant, it may increase the morbidity and mortality for the individual patient receiving the split liver. This essay explores the ethical issues involved in the allocation of split livers, and proposes general policy guidelines for the allocation of split versus whole liver transplants.     

Cryopreserved Liver Cell Transplantation Controls Ornithine Transcarbamylase Deficient Patient While Awaiting Liver Transplantation

Liver cell transplantation was performed in a child with urea cycle disorder poorly equilibrated by conventional therapy as a bridge to transplantation. A 14-month-old boy with ornithine transcarbamylase (OTC) deficiency received 0.24 billion viable cryopreserved cells/kg over 16 weeks. Tacrolimus and steroids were given as immunosuppressive treatment while the patient was kept on the pre-cell transplant therapy. Mean blood ammonia level decreased significantly following the seven first infusions, while urea levels started to increase from undetectable values. After those seven infusions, an ammonium peak up to 263 microg/dL, clinically well tolerated, was observed. Interestingly, blood urea levels increased continuously to reach 25 mg/dL, after the last three infusions. Eventually, he benefited from elective orthotopic liver transplantation (OLT) and the post-surgical course was uneventful. We conclude that use of cryopreserved cells allowed short- to medium-term metabolic control and urea synthesis in this male OTC-deficient patient while waiting for OLT.     

Adult Liver Transplant Candidate Attitudes Toward Graft Sharing Are Not Obstacles to Split Liver Transplantation

Split liver transplantation (SLT) benefits society by increasing the total number of transplants that can be performed, but it is yet unknown if a decreased post-transplant survival (in comparison to whole liver transplantation) would make participation in SLT less appealing to adult liver transplant candidates. A 20-item questionnaire was administered to 50 adult candidates to assess attitudes toward SLT and organ sharing. The overall attitudes of 60% of participants were classified as utilitarian (maximizing benefit to greatest number of candidates), while 26% were classified as self-preserving (maximizing individual benefit) and 14% were undecided. Ninety percent of participants would be willing to share even if expected survival was less than that of whole liver transplantation, and 69% felt that pediatric candidates should have priority over adult candidates. In conclusion, attitudes toward graft sharing and the possibility of compromised survival benefit are not barriers to SLT for most adult liver transplant candidates.     

肝动脉变异与肝移植

目的总结肝移植中供体及受体肝动脉变异情况与重建方式。方法回顾我院2002年3月～2005年12月107例肝移植供体与107例受体肝动脉变异情况及重建方式。术后应用Doppler超声、胆道镜及介入方法监测肝动脉及胆道并发症的发生情况。结果107例肝移植之供、受体肝动脉(214例肝动脉),3例术中、术后死于多器官功能衰竭,有20例次肝动脉变异,经过术中良好的重建,其结果显示肝动脉及胆道并发症3例(3/19),较正常肝动脉吻合者(15/85)无显著性差异(P>0.05)。结论肝动脉变异发生率约9.35%左右,肝移植时供肝切取、修整及受体病肝切除应引起高度重视,术中良好的重建能取得好的效果。     

Hepatocellular Carcinoma Patients Are Advantaged in the Current Liver Transplant Allocation System

Patients with hepatocellular carcinoma (HCC) within Milan criteria receive priority on the liver transplant waiting list (WL) and compete with non‐HCC patients. Dropout from the WL is an indirect measure of transplant access. Competing risks (CR) evaluation of dropout for HCC and non‐HCC patients has not previously been reported. Patients listed between 16 March 2005 and 30 June 2008 were included. Probability of dropout was estimated using a CR technique as well as a Cox model for time to dropout. Overall, non‐HCC patients had a higher dropout rate from the WL than HCC patients (p < 0.0001). This was reproducible throughout all regions. In Cox regression, tumor size, model for end‐stage liver disease (MELD) score and alpha fetoprotein (AFP) were associated with increased dropout risk. Multivariable analysis with CR showed that MELD score and AFP, were most influential in predicting dropout for HCC patients. The index of concordance for predicting dropout with the CR was 0.70. HCC patients appear to be advantaged in the current allocation scheme based on lower dropout rates without regard to geography. A continuous score incorporating MELD, AFP and tumor size may help to prioritize HCC patients to better equate dropout rates with non‐HCC patients and equalize access.     

Renal Function in Patients with Orthotopic Liver Transplantation

Due to multiple reasons, acute renal failure (ARF) commonly develops in the early postoperative period of orthotopic liver transplantation (OLT) recipients. The records of OLT recipients between 1999 and 2004 were evaluated. Age, gender, primary disease, history of diabetes, immunosuppressive drugs, pre- and postoperative renal function tests, serum electrolytes, dialysis, liver functions tests, and renal function tests in follow-up period were noted. We followed 16 patients with OLT in our center. ARF developed in 8 patients. Dialysis was performed in only 2 patients, and other patients with ARF were managed with conservative measures. Hypertensive crisis and cerebrovascular stroke developed in 1 diabetic hypertensive patient.     

Reduced Priority MELD Score for Hepatocellular Carcinoma Does Not Adversely Impact Candidate Survival Awaiting Liver Transplantation

The liver organ allocation policy of the United Network for Organ Sharing (UNOS) is based on the model for end-stage liver disease (MELD). The policy provides additional priority for candidates with hepatocellular carcinoma (HCC) who are awaiting deceased donor liver transplantation (DDLT). However, this priority was reduced on February 27, 2003 to a MELD of 20 for stage T1 and of 24 for stage T2 HCC. The aim of this study was to determine the impact of reduced priority on HCC candidate survival while on the waiting list. The UNOS database was reviewed for all HCC candidates listed after February 27, 2002, The HCC candidates were grouped into two time periods: MELD 1 (listed between February 27, 2002, and February 26, 2003) and MELD 2 (listed between February 27, 2003 and February 26, 2004). For the two time periods, the national DDLT incidence rates for HCC patients were 1.44 versus 1.53 DDLT per person-year (p = NS) and the waiting times were similar for the two periods (138.0 +/- 196.8 vs. 129.0 +/- 133.8 days; p = NS). Furthermore, the 3-, 6- and 12-month candidate, patient survival and dropout rates were also similar nationally. Regional differences in rates of DDLT for HCC were observed during both MELD periods. Consequently, the reduced MELD score for stage T1 and T2 HCC candidates awaiting DDLT has not had an impact nationally either on their survival on the waiting list or on their ability to obtain a liver transplant within a reasonable time frame. However, regional variations point to the need for reform in how organs are allocated for HCC at the regional level.     

Hepatic Artery Chemoembolization for Hepatocellular Carcinoma in Patients Listed for Liver Transplantation

We retrospectively analyzed all listed patients having hepatic artery chemoembolization (HACE) for hepatocellular carcinoma (HCC) stage T2 or less. Outcomes were transplantation, waiting list removal, death, and HCC recurrence. Twenty patients (mean age 55.7 years; 15 males) were identified. Twelve (60%) were transplanted, seven (35%) were removed from the list and one (5%) remains listed. Fourteen (70%) are alive. All 12 transplanted patients are alive (mean 2.94 years); one of seven removed from the list is alive (mean 1.45 years). Survival was significantly higher for those transplanted or listed vs. removed from the list (100% vs. 14.3%, p = 0.0002). No HCC's recurred. Three patients (15%) were removed from the list after prolonged waiting times before MELD. Hepatic artery chemoembolization induced deterioration and removal from the list of one (5%) patient. Survival for those transplanted was excellent(100%), but overall survival was significantly lower (61.3%) at a mean 5.48 years. Hepatic artery chemoembolization for listed patients with 相似文献   

Bone Disorders in Patients With Chronic Liver Disease Awaiting Liver Transplantation

Background

An important complication of chronic liver disease is osteodystrophy, which includes osteoporosis and the much rarer osteomalacia. Both conditions are associated with significant morbidity through fractures resulting in pain, deformity, and immobility. Liver transplantation may further deteriorate bone metabolism. The aim of the present study was to investigate the frequency and severity of hepatic osteodystrophy among patients with liver cirrhosis who were referred for liver transplantation. We also evaluated modifications in bone metabolism after liver transplantation.

Materials and methods

We recruited 35 consecutive patients with chronic liver disease who were undergoing assessment for transplantation over a 1-year period. Bone mass in the total skeleton and proximal hip was evaluated using a dual-energy X-ray absorptiometry device (Lunar Prodigy Advance, GE Healthcare, USA). According to World Health Organization recommendations, osteoporosis was defined as a T score < −2.5 and osteopenia as T score between −1 and −2.5.

Results

We enrolled in the study 35 patients, including 8 females and 27 males of overall mean age of 57 ± 7, who showed a viral etiology (57%) or alcohol etiology (28%), Child-Pugh 8.7 ± 2.3. The overall prevalence of osteodystrophy was 40% (26% osteopenia and 14% osteoporosis). No difference was evident according to gender, severity of liver disease (Child-Pugh, Model for End-stage Liver Disease), or origin of liver disease. A subgroup of 10 transplanted patients reached 3-month follow-up, showing total body T score with a significant decrease after 3 months while femoral T scores tended to decrease insignificantly.

Conclusions

This study revealed a high prevalence of low bone mineral density among cirrhotic patients before liver transplantation. We suggest that both bone mineral density and biochemical examinations should be considered to be routine tests to identify the status of bone mass and bone metabolism among recipients prior to liver transplantation.     

改良背驮式原位肝移植手术各期的液体管理

目的 探讨改良背驮式原位肝移植围术期血容量的变化及液体管理.方法 对56例改良背驮式原位肝移植患者实施术中液体管理,术中持续监测心电图(ECG)、有创血压(ABP)、心率(HR)、中心静脉压(CVP)及肺动脉压(PAP),部分病例监测连续心排量(CCO).记录肝移植各期的出入量.结果 56例患者均顺利渡过手术期,术中总出血量平均为(3 895.8±2 443.9)ml(无肝前期及新肝期出血量相当,无肝期较少),总出液量(6 784.3±3 928.8)ml(以新肝期为主),总输血量(4 563.8±1 361.7)ml,总入液量(8 721.8±3 396.4)ml.无肝期HR增快、BP及CVP下降显著(均P＜O.05).结论 改良背驮式原位肝移植患者手术期间出入量变化极大,术中密切监测患者各项循环指标,加强液体管理,维持血容量和血流动力学的稳定,保护患者重要器官是手术成功的关键.     

Regional Variations in Peer Reviewed Liver Allocation Under the MELD System

The Model for End-Stage Liver Disease (MELD) is used to assign priority for liver transplantation candidates. The Organ Procurement and Transplantation Network (OPTN) approved recognized exceptional diagnoses (RED's) for which MELD fails to accurately measure priority. Centers can request increased MELD points in cases not recognized by this policy (non-RED's). Our aim was to compare regional practices to justify non-RED requests for MELD adjustments. The UNOS/OPTN database was queried to extract all adult cases for which a non-RED MELD adjustment was requested from 2/27/02 until 8/27/03. The data were stratified by region and justification. Data for 29,510 listings were available. 26,947 had complete diagnosis information. There were 827 non-RED requests of which 477 (57.7%) petitions were approved by the regional review boards (RRBs). The approval rate varied significantly among regions (range: 28-75%, p<0.0001). The most common non-RED's were complications of portal hypertension (48%). The percentage of patients listed with non-RED's varied significantly among regions (0.7-8.3 %, p<0.0001), as did the proportion of patients transplanted with non-RED's (2.1-31.9%, p<0.0001). Demographics did not differ among regions requesting non-REDs.Widespread regional variations exist in the handling of requests for non-REDs. These variations point to the need for reform to standard exception criteria.     

Improved Survival After Liver Transplantation in Patients with Hepatopulmonary Syndrome

Hepatopulmonary syndrome (HPS) is present in 10–32% of chronic liver disease patients, carries a poor prognosis and is treatable by liver transplantation (LT). Previous reports have shown high LT mortality in HPS and severe HPS (arterial oxygen (PaO₂) ≤50 mmHg). We reviewed outcomes in HPS patients who received LT between 2002 and 2008 at two transplant centers supported by a dedicated HPS clinic. We assessed mortality, complications and gas exchange in 21 HPS patients (mean age 51 years, MELD score 14), including 11/21 (52%) with severe HPS and 5/21 (24%) with living donor LT (median follow‐up 20.2 months after LT). Overall mortality was 1/21 (5%); mortality in severe HPS was 1/11 (9%). Peritransplant hypoxemic respiratory failure occurred in 5/21 (24%), biliary complications in 8/21 (38%) and bleeding or vascular complications in 6/21 (29%). Oxygenation improved in all 19 patients in whom PaO₂ or SaO₂ were recorded. PaO₂ increased from 52.2 ± 13.2 to 90.3 ± 11.5 mmHg (room air) (p < 0.0001) (12 patients); a higher baseline macroaggregated albumin shunt fraction predicted a lower rate of postoperative improvement (p = 0.045) (7 patients). Liver transplant survival in HPS and severe HPS was higher than previously demonstrated. Severity of HPS should not be the basis for transplant refusal.     

Liver Transplantation for Hepatocellular Carcinoma: Results of Down‐Staging in Patients Initially Outside the Milan Selection Criteria

Conventional criteria for liver transplantation for patients with hepatocellular carcinoma are single HCC ≤ 5 cm or less than or equal to three HCCs ≤ 3 cm. We prospectively evaluated the possibility of slightly extending these criteria in a down‐staging protocol, which included patients initially outside conventional criteria: single HCC 5–6 cm or two HCCs ≤ 5 cm or less than six HCCs ≤ 4 cm and sum diameter ≤ 12 cm, but within Milan criteria in the active tumors after the down‐staging procedures. The outcome of patients down‐staged was compared to that of Milan criteria after liver transplantation and since the first evaluation according to an intention‐to‐treat principle. From 2003 to 2006, 177 patients with HCC were considered for transplantation: the transplantation rate was comparable between the Milan and down‐staging groups: 88/129 cases (68%) versus 32/48 cases (67%), respectively. At a median follow‐up of 2.5 years after transplantation, the 1 and 3 years' disease‐free survival rates were comparable: 80% and 71% in the Milan group versus 78% and 71% in the down‐staging. The actuarial intention‐to‐treat survival was 27/48 patients (56.3%) in the down‐staging and 81/129 cases (62.8%) in the Milan group, p = n.s. The proposed down‐staging criteria provide a comparable outcome to the conventional criteria.     

A Decision Analysis Model Identifies the Interval of Efficacy for Transarterial Chemoembolization (TACE) in Cirrhotic Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation

Introduction For liver transplant candidates with hepatocellular carcinoma (HCC), the ability of neoadjuvant transarterial chemoembolization (TACE) to improve outcomes remains unproven. The objective of our study was to determine if there was a specific time interval where neoadjuvant TACE would decrease the number of HCC patients removed from the pretransplant waitlist. Materials and Methods A decision model was developed to simulate a randomized trial of neoadjuvant treatment with TACE vs. no TACE in 600 virtual patients with HCC and cirrhosis. Transition probabilities for TACE morbidity (1 ± 1%), TACE response rates (30 ± 20%), and disease progression (7 ± 7% per month) were assigned by systematic review of the literature (18 reports). Sensitivity analyses were performed to determine time thresholds where TACE would decrease the number of delisted patients. Results TACE treatment had statistical benefit at waitlist time breakpoints of 4 and 9 months (P < 0.05). When waitlist times were less than 4 months, waitlist attrition was similar (20% vs. 34%, P = 0.08). When waitlist times exceed 9 months, waitlist dropout rates re-equilibrated (33% vs. 46%, P = 0.06). Review of the current literature determined that only those studies reporting on patients with waitlist times between 4 and 9 months found a benefit to neoadjuvant TACE. Conclusions This analysis indicates that the benefit of neoadjuvant TACE may be limited to those patients transplanted from 4 to 9 months from first TACE. These data may help transplant programs to tailor TACE treatments based on predicted waitlist times to achieve optimal resource utilization and improved organ allocation efficiency. Presented at the 7th World Congress of the International Hepato Pancreato Biliary Association Meeting, September 6, 2006, Edinburgh, Scotland.     

Wilson''''s病患者亲体部分肝移植和全肝移植术后血清铜蓝蛋白及尿铜水平的变化

目的　总结Wilson’s病患者亲体肝移植和全肝移植术后血清铜蓝蛋白及尿铜水平的恢复情况。方法　自 2 0 0 0年 9月至 2 0 0 3年 11月我院为 2 6例Wilson’s病患者施行了肝移植术 ,均并发终末期肝硬变 ,其中 3例发生急性肝功能衰竭。术前血清铜蓝蛋白和尿铜水平分别为 (12 4 .8± 2 2 .8)mg/L和 (15 2 4 .8± 32 8.6 ) μg/ 2 4h ,其中行活体部分肝移植 2 2例 ,全肝移植 4例 ,亲体肝移植供体术前血清铜蓝蛋白水平为 (2 30 .4± 2 9.6 )mg/L ,尿铜水平均 <5 0μg/ 2 4h。结果　所有患者手术顺利 ,全肝移植患者术后 1、3、6及 12个月血清铜蓝蛋白和尿铜水平分别为 (32 0 .2±36 .8)mg/L、(380 .4± 4 5 .6 )mg/L、(36 0 .5± 37.6 )mg/L、(35 6 .2± 2 7.6 )mg/L和 (2 4 0 .4± 2 2 .8) μg/ 2 4h、(86 .5± 10 .6 ) μg/ 2 4h、(5 4 .2± 6 .8) μg/ 2 4h及 (46 .8± 3.4 ) μg/ 2 4h ;亲体肝移植患者术后 1、3、6及 12个月血清铜蓝蛋白和尿铜水平分别为 (2 16 .8± 2 0 .4 )mg/L、(2 4 8.5± 32 .6 )mg/L、(2 85 .4± 4 4 .3)mg/L、(2 6 0 .2± 36 .6 )mg/L和(380 .8± 37.6 ) μg/ 2 4h、(15 0 .6± 2 4 .5 ) μg/ 2 4h、(75 .5± 9.6 ) μg/ 2 4h及 (6 0 .3± 5 .8) μg/ 2 4h。结论　全肝移植和亲体肝     

Hepatitis C Infection in Liver Transplantation

Hepatitis C-associated liver failure is the most common indication for liver transplantation and recurs nearly universally following transplantation. Histological evidence of recurrence is apparent in approximately 50% of HCV-infected recipients in the first postoperative year. Approximately 10% of HCV-infected recipients will die or lose their allograft secondary to hepatitis C-associated allograft failure in the medium term. While the choice of calcineurin inhibitor and/or the use of azathioprine have not been clearly shown to affect histological recurrence of hepatitis C or the frequency of rejection in hepatitis C-infected recipients, cumulative exposure to corticosteroids is associated with increased mortality, higher levels of HCV viremia and more severe histological recurrence. In contrast to nonhepatitis C-infected recipients, treatment for acute cellular rejection is associated with attenuated patient survival among recipients with hepatitis C. The development of steroid-resistant rejection is associated with a greater than five-fold increased risk of mortality in HCV-infected liver transplant recipients. In lieu of large studies in a post-transplant population therapy with pegylated interferon (+/- ribavirin) should be considered in recipients with histologically apparent recurrence of hepatitis C before total bilirubin exceeds 3 mg/dL. The role of hepatitis C immunoglobulin and new immunosuppression agents in the management of post-transplant hepatitis C infection is still evolving. Overall, HCV-infected recipients who undergo retransplantation experience 5-year patient and graft survival rates that are similar to recipients undergoing retransplantation who are not HCV-infected.