R. Mark Ghobrial

Optimal Utilization of Donor Grafts With Extended Criteria: A Single-Center Experience in Over 1000 Liver Transplants

Objective:Severely limited organ resources mandate maximum utilization of donor allografts for orthotopic liver transplantation (OLT). This work aimed to identify factors that impact survival outcomes for extended criteria donors (ECD) and developed an ECD scoring system to facilitate graft-recipient matching and optimize utilization of ECDs. Methods:Retrospective analysis of over 1000 primary adult OLTs at UCLA. Extended criteria (EC) considered included donor age (>55 years), donor hospital stay (>5 days), cold ischemia time (>10 hours), and warm ischemia time (>40 minutes). One point was assigned for each extended criterion. Cox proportional hazard regression model was used for multivariate analysis. Results:Of 1153 allografts considered in the study, 568 organs exhibited no extended criteria (0 score), while 429, 135 and 21 donor allografts exhibited an EC score of 1, 2 and 3, respectively. Overall 1-year patient survival rates were 88%, 82%, 77% and 48% for recipients with EC scores of 0, 1, 2 and 3 respectively (P < 0.001). Adjusting for recipient age and urgency at the time of transplantation, multivariate analysis identified an ascending mortality risk ratio of 1.4 and 1.8 compared to a score of 0 for an EC score of 1, and 2 (P < 0.01) respectively. In contrast, an EC score of 3 was associated with a mortality risk ratio of 4.5 (P < 0.001). Further, advanced recipient age linearly increased the death hazard ratio, while an urgent recipient status increased the risk ratio of death by 50%. Conclusions:Extended criteria donors can be scored using readily available parameters. Optimizing perioperative variables and matching ECD allografts to appropriately selected recipients are crucial to maintain acceptable outcomes and represent a preferable alternative to both high waiting list mortality and to a potentially futile transplant that utilizes an ECD for a critically ill recipient.

Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease

Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose‐finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double‐blind trial, patients with end‐stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 μg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty‐three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required. (Liver Transpl 2005;11:895–900.)

Recurrence of Hepatocellular Carcinoma Following Liver Transplantation A Review of Preoperative and Postoperative Prognostic Indicators

OBJECTIVE To review the preoperative and postoperative variables that predict hepatocellular carcinoma (HCC) recurrence following orthotopic liver transplantation (OLT). DATA SOURCES A collective review of the literature was conducted by searching the MEDLINE database using several key words: hepatocellular carcinoma, recurrence, liver transplantation, and salvage transplantation. STUDY SELECTION Reviews and original articles containing basic scientific observations and long-term clinical outcomes were included. DATA EXTRACTION Critical observations from peer-reviewed sources were incorporated in this review. DATA SYNTHESIS Overall, 11 studies were reviewed to determine the incidence of HCC recurrence following OLT and to identify prognostic variables of recurrence. Four studies were evaluated to determine the efficacy of salvage transplantation following liver resection. CONCLUSIONS Liver transplantation is a viable treatment option for select patients with HCC and end-stage liver disease. However, in approximately 20% of patients, recurrent HCC is the rate-limiting factor for long-term survival. Despite identification of clinical parameters that may stratify patients at high risk and exhaustive preoperative staging, cancer recurrence is likely the result of microscopic extrahepatic disease. With a desperate donor organ shortage, locoregional ablation techniques and resection are being employed in patients on the waiting list to serve as a bridge to OLT. Furthermore, some have advocated aggressive surgical resection of isolated metastasis in both the liver and extrahepatic viscera. Whether these creative strategies confer a survival advantage is unknown; it will require long-term follow-up to determine their efficacy.

Liver Transplantation for Fulminant Hepatic Failure: Experience With More Than 200 Patients Over a 17-Year Period

ObjectiveTo analyze outcomes after liver transplantation (LT) in patients with fulminant hepatic failure (FHF) with emphasis on pretransplant variables that can potentially help predict posttransplant outcome. Summary Background DataFHF is a formidable clinical problem associated with a high mortality rate. While LT is the treatment of choice for irreversible FHF, few investigations have examined pretransplant variables that can potentially predict outcome after LT. MethodsA retrospective review was undertaken of all patients undergoing LT for FHF at a single transplant center. The median follow-up was 41 months. Thirty-five variables were analyzed by univariate and multivariate analysis to determine their impact on patient and graft survival. ResultsTwo hundred four patients (60% female, median age 20.2 years) required urgent LT for FHF. Before LT, the majority of patients were comatose (76%), on hemodialysis (16%), and ICU-bound. The 1- and 5-year survival rates were 73% and 67% (patient) and 63% and 57% (graft). The primary cause of patient death was sepsis, and the primary cause of graft failure was primary graft nonfunction. Univariate analysis of pre-LT variables revealed that 19 variables predicted survival. From these results, multivariate analysis determined that the serum creatinine was the single most important prognosticator of patient survival. ConclusionsThis study, representing one of the largest published series on LT for FHF, demonstrates a long-term survival of nearly 70% and develops a clinically applicable and readily measurable set of pretransplant factors that determine posttransplant outcome.

Outcomes of acute rejection after interferon therapy in liver transplant recipients

Interferon alfa has been increasingly used against recurrent hepatitis C (HCV) disease in post‐liver transplant (LT) recipients. A serious potential adverse effect is acute rejection. We reviewed our experience using interferon‐based therapy (interferon or pegylated interferon with or without ribavirin) for treating recurrent HCV in LT recipients. Forty‐four LT recipients were treated with interferon for recurrent HCV. Five of the 44 patients developed acute rejection during interferon‐based therapy. These 5 patients started treatment of 42.4 ± 33.89 months (mean ± SD) after LT. Mean (± SD) histological activity index and fibrosis scores before initiating antiviral therapy were 8.8 (± 1.92) and 2.6 (± 0.55), respectively. Patients were treated for 3.3 ± 2.28 months (mean ± SD) prior to rejection. At the time of rejection, HCV load was not detectable in 4 of the 5 recipients. All 5 patients had tolerated interferon therapy, and none had stopped therapy because of adverse effects. The rejection was successfully treated in 3 patients. In 2 of those 3 patients, cirrhosis eventually developed. In the 2 patients who did not respond to rejection treatment, immediate graft failure occurred, leading to re‐LT in 1 patient and death from sepsis in the other. In conclusion, the results indicate that further studies are needed to assess the safety of interferon in LT recipients. Interferon‐based therapy may lead to acute rejection and subsequent graft loss and should therefore be used with caution. Treated recipients may also develop progressive cirrhosis despite achieving a sustained virological response. (Liver Transpl 2004;10:859–867.)

Predicting poor outcome following hepatectomy: analysis of 2313 hepatectomies in the NSQIP database

BACKGROUND For the past two decades multiple series have documented that liver resection has become safer. The purpose of this study was to determine the current status of hepatic resection in the USA by analysing the multi-institutional experience within the National Surgical Quality Improvement Program (NSQIP) dataset. METHODS Of the 363,897 cases in the 2005-2007 NSQIP Participant Use File, 2313 elective open hepatectomy cases were identified (1344 partial, 230 left, 510 right and 229 extended hepatectomies). A total of 57 perioperative risk factors and 28 postoperative complications were compared. To determine the applicability of NSQIP general risk models to hepatic surgery, the prognostic value of standard multivariate analysis was compared with the NSQIP general surgery aggregate risk indices (expected probability of morbidity [morbprob], expected probability of mortality [mortprob]). RESULTS The median age of patients listed in the database was 60 years; sex distributions were equivalent; 78% were White; 65% of patients had an ASA score of 3 or 4, and the most prevalent co-morbidity was hypertension (46%). A total of 41% of patients had disseminated cancer, 19% of whom had received chemotherapy within 30 days of surgery. The overall 30-day mortality rate was 2.5% (57/2313) and the 30-day major morbidity rate was 19.6% (453/2313). Multivariate analysis identified nine risk factors associated with major morbidity and two risk factors associated with mortality. In contrast, the morbprob and mortprob statistics did not predict outcomes accurately. For those patients who developed major morbidity, the median length of stay was longer (10 vs. 6 days; P = 0.001) and the mortality rate was higher (11.3% vs. 0.3%; P = 0.001). CONCLUSIONS Analysis of the NSQIP experience with hepatectomy indicates that the current mortality and major morbidity rate benchmarks are 2.5% and 19.6%, respectively. Poor outcomes were associated with nutritional status, liver function and the extent of hepatectomy. The NSQIP general surgery morbprob and mortprob values were relatively poor predictors of post-hepatectomy observed morbidity, indicating the need for specialty-specific NSQIP modelling.

MELD fails to measure quality of life in liver transplant candidates

Previous studies have demonstrated an association between Child Turcotte‐Pugh (CTP) class and impaired quality of life. However, the relationship between the model for end‐stage liver disease (MELD) score and quality of life (QOL) has not been well studied. In this study, quality of life questionnaires (Medical Outcomes Short Form 36 [SF‐36] and the Chronic Liver Disease Questionnaire [CLDQ]) were administered to 150 adult patients awaiting liver transplantation. We also collected demographic data and laboratory results and recorded manifestations of hepatic decompensation. The study found that all domains of the SF‐36 and CLDQ were significantly lower in our patient cohort than in normal controls (P < .001). There was a moderate negative correlation between CPT class and physical components of the SF‐36 (r = −.30), while there was a weak negative correlation (r = −.10) between CPT class and the mental component. There was a negative moderate correlation between CPT class and overall CLDQ (r = −.39, P < .001) and a weak correlation (r = −.20) between MELD score and overall CLDQ score. Both encephalopathy (correlation coefficient = −.713, P = .004) and ascites (correlation coefficient = −.68, P = .006) were predictive of the QOL using CLDQ (adjusted R2 = .1494 and f = 0.000). In conclusion, in liver transplant candidates, the severity of liver disease assessed by the MELD score was not predictive of QOL. The presence of ascites and/or encephalopathy was significantly associated with poor quality of life. CTP correlates better to QOL, probably because it contains ascites and encephalopathy. (Liver Transpl 2005;11:218–223.)

Longterm Outcomes for Whole and Segmental Liver Grafts in Adult and Pediatric Liver Transplant Recipients: A 10-Year Comparative Analysis of 2,988 Cases

BACKGROUND Data on longterm outcomes after liver transplantation with partial grafts are limited. We compared 10-year outcomes for liver transplant patients who received whole grafts (WLT), split grafts from deceased donors (SLT), and partial grafts from living donors (LDLT). STUDY DESIGN We conducted a single-center analysis of 2,988 liver transplantations performed between August 1993 and May 2006 with median followup of 5 years. Graft types included 2,717 whole-liver, 181 split-liver, and 90 living-donor partial livers. Split-liver grafts included 109 left lateral and 72 extended right partial livers. Living-donor grafts included 49 left lateral and 41 right partial livers. RESULTS The 10-year patient survivals for WLT, SLT, and LDLT were 72%, 69%, and 83%, respectively (p=0.11), and those for graft survival were 62%, 55%, and 65%, respectively (p=0.088). There were differences in outcomes between adults and children when compared separately by graft types. In adults, 10-year patient survival was significantly lower for split extended right liver graft compared with adult whole liver and living-donor right liver graft (57% versus 72% versus 75%, respectively, p=0.03). Graft survival for adults was similar for all graft types. Retransplantation, recipient age older than 60 years, donor age older than 45 years, split extended right liver graft, and cold ischemia time>10 hours were predictors of diminished patient survival outcomes. In children, the 10-year patient and graft survivals were similar for all graft types. CONCLUSIONS Longterm graft survival rates in both adults and children for segmental grafts from deceased and living donors are comparable with those in whole organ liver transplantation. In adults, patient survival was lower for split compared with whole grafts when used in retransplantations and in critically ill recipients. Split graft-to-recipient matching is crucial for optimal organ allocation and best use of a scarce and precious resource.

Hepatocellular carcinoma: a review

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated significant benefits in overall survival. While OLT remains the only curative surgical procedure, the shortage of available organs precludes this therapy for many patients with HCC.

Employment and quality of life in liver transplant recipients

The purposes of liver transplantation (LT) include the extension of survival, improvement in quality of life, and the return of the recipient as a contributing member of society. Employment is one measure of the ability to return to society. The aim of this study is to determine the factors affecting employment/subemployment after LT. A total of 308 adult liver transplant recipients who were seen at the University of California, Los Angeles were administered the Medical Outcomes Short Form 36 (SF‐36) and a questionnaire regarding work history and insurance coverage. Multivariate analysis were used to identify independent variables associated with posttransplantation employment. Interaction terms were used to examine effect modification. Of 308 transplant recipients, 218 (70.8%) worked prior to transplantation, and 78 (27%) worked posttransplantation. Pretransplant variables that were independently associated with posttransplantation employment included the following: lack of disability income (odds ratio [OR] = 1.86; 95% confidence interval [CI], 1.32‐7.18; P = 0.36); health maintenance organization (HMO)/preferred provider organization (PPO) insurance (OR = 3.08; 95% CI, 1.32‐7.18; P < 0.01); the number of hours worked (OR = 1.17; 95% CI, 1.08‐1.28; P < 0.01); and the lack of diabetes mellitus (OR = 0.23; 95% CI, 0.70‐0.73; P < 0.01). An interaction term between disability income and hours worked prior to transplantation (OR = 0.16; 95 % CI, 0.03‐0.83; P = 0.03) was independently associated with posttransplantation employment. In a separate regression model of SF‐36 responses, posttransplantation physical functioning (OR = 1.17; 95% CI, 1.10‐1.26; P < 0.01) and role‐physical (OR = 1.1; 95% CI, 1.02‐1.16; P < 0.01) were independently associated with employment after transplantation. In conclusion, HMO or PPO insurance, lack of disability income coverage prior to transplant, the absence of diabetes mellitus, the number of hours worked prior to transplantation, and high physical functioning were associated with posttransplantation employment. Liver Transpl 13:1330–1338, 2007.