LIVER TRANSPLANTATION WORLDWIDE COMMENTS

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1 LIVER TRANSPLANTATION 13: , 2007 LIVER TRANSPLANTATION WORLDWIDE Recurrent Hepatocellular Carcinoma is a Problem We Need To Tackle A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation. Xu J, Shen ZY, Chen XG, Zhang Q, Bian HJ, Zhu P, et al. Hepatology 2007;45: Orthotopic liver transplantation (OLT) is the only curative therapy of HCC with underlying cirrhosis, but due to HCC metastasis and recurrence, its benefit is limited to a small population who meet the strict selection criteria. We previously reported that Licartin ([ 131 I]mAb HAb18G/CD147) was safe and effective in treating HCC patients, and its antigen, HAb18G/ CD147, was closely related to HCC invasion and metastasis. Here, we reported a randomized controlled trial to assess the post-olt antirecurrence efficacy of Licartin in advanced HCC patients. We randomized 60 post-olt patients with HCC, who were at tumor stage 3/4 and outside the Milan criteria before OLT, into 2 groups. Three weeks after OLT, the treatment group received 15.4 MBq/kg of Licartin, while the control group received placebo intravenously for 3 times with an interval of 28 days. At 1-year follow-up, the recurrence rate significantly decreased by 30.4% (P ) and the survival rate increased by 20.6% (P ) in the treatment group, compared with those in the control group. For the control group versus the treatment group, the hazard ratio for recurrence was 3.60 (95% confidence interval [CI], ) and that for death was 3.87 (95% CI, ). Licartin treatment also resulted in an earlier decreased AFP level and a longer time of normal AFP level than placebo (P ). No Licartin-related toxic effects were observed. Conclusion: Licartin is a promising drug for preventing post-olt tumor recurrence in advanced HCC patients excluded by the currently strict criteria for OLT. HAb18G/CD147 can be a good drug target. The pre liver transplantation selection process for patients with hepatocellular carcinoma (HCC) is being continuously refined; yet, the problem of recurrent HCC remains. 1 In 1 study, recurrence was seen in approximately 15% of the patients transplanted for HCC, and most died. 2 Despite the use of either Milan or University of California at San Francisco criteria for selecting patients and allocating organs to recipients with HCC, preoperative imaging still understages 40%-55% of HCC tumors. 2,3 Thus, patients with HCC need to be re-evaluated after transplantation to check on the pathological stage of their tumors. Parfitt et al. 4 developed a pathological score for explanted livers to better predict recurrence. On the basis of this score, the investigators grouped their patients into 3 posttransplant risk categories for HCC recurrence: low ( 5%), intermediate (40%-65%), and high ( 95%). Other scoring systems will surely follow. Why rescore patients after transplantation for HCC recurrence? What can be done for patients who are found to be at high risk for HCC recurrence when they have already received a liver transplant? Should the surveillance schedule be modified in the different risk groups? Should the immunosuppressive medication be changed? Zhou et al. 5 reported on 36 patients with HCC being switched from tacrolimus to rapamycin. This small study, lacking statistical power, suggests that rapamycin-based immunosuppression may inhibit HCC recurrence. What should be done about treating patients at high risk for HCC recurrence? In this review, Xu et al. report on a randomized control trial using Licartin ([ 131 I]metuximab injection) to treat patients who underwent transplantation for HCC to prevent a recurrence. These authors previously reported on phase 1 and 2 trials with Licartin. 6 They enrolled in their study patients with stage 3 and 4 HCC (TNM classification) who were definitely outside the Milan criteria. They excluded patients with heart or kidney disease and bilirubin greater than 2.5 times the normal range. Sixty eligible patients who received donor livers from cadaver donors (voluntarily donated) were randomized between receiving treatment or receiving a placebo. All were single-blinded to the treatment. Thirty treated patients received Licartin 3 times at intervals of 28 days starting in the fourth week after the transplant. All patients received tacrolimus or cyclosporine A, mycophenolate mofetil, and prednisone. All patients were followed with liver ultrasonography, alpha-fetoprotein levels every 2 weeks, and computed tomography scans monthly. With a median follow-up of 12.3 months, 17 patients (57.1%) receiving the placebo and 8 receiving Licartin (26.7%) had tumor recurrence. This was a significant difference in the recurrence (P ). There was also a significant difference in survival between the 2 groups. There were no reported adverse events related to the Licartin treatment. Xu et al. concluded that Licartin is a promising drug to prevent HCC recurrence following liver transplantation. To the authors knowledge, this was the first prospective study evaluating antibody radioimmunotherapy for the prevention of HCC recurrence. Other studies with Abbreviation: HCC, hepatocellular carcinoma. DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 1058 LIVER TRANSPLANTATION WORLDWIDE similar or different treatment options are desperately needed to give hope to patients with high risk for HCC recurrence. 1. Onaca N, Davis GL, Goldstein RM, Jennings LW, Klintmalm GB. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver Transplantation. Liver Transpl 2007;13: Shah SA, Tan JC, McGilvray ID, Cattral MS, Cleary SP, Levy GA, et al. Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma. Transplantation 2006;81: Reddy MS, Manas DM. Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma. Transplantation 2007;83: Parfitt JR, Marotta P, Alghamdi M, Wall W, Khakhar A, Suskin NG, et al. Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence. Liver Transpl 2007; 13: Zhou J, Fan J, Wang Z, Wu ZQ, Qiu SJ, Huang XW, et al. Conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma: report of an initial experience. World J Gastroenterol 2006;12: Chen ZN, Mi L, Xu J, Song F, Zhang Q, Zhang Z, et al. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials. Int J Radiat Oncol Biol Phys 2006;65: Reexamining Old Techniques from a New Perspective Spatulated end-to-end bile duct reconstruction in orthotopic liver transplantation. Buczkowski AK, Schaeffer DF, Kim PT, Ho SG, Yoshida EM, Steinbrecher UP, et al. Clin Transplant 2007;21:7-12. Biliary complications continue to be a major source of morbidity following orthotopic liver transplantation. The aim of this study was to analyze the incidence and management of biliary complications related to the technique of bile duct reconstruction. The patients were stratified into two groups: group I (n 39) had bile duct reconstruction performed by an end-to-end single interrupted suture choledochocholedochostomy (EE-CDCD) and group II (n 38) had a spatulated end-to-end CDCD (spee-cdcd) reconstruction; both groups had an intraductal stent. The groups were similar in age, gender, liver transplant indications and Pugh score. Ten biliary complications (26%), including five bile leaks (13%) and five biliary strictures (13%), were observed in the EE-CDCD group, while one biliary stricture (2.6%) occurred in the spee-cdcd group (p 0.05). Subsequent imaging studies and endoscopic retrograde cholangiopancreatography were performed less often in patients undergoing spee- CDCD reconstruction (p 0.05). The technique of a spatulated end-to-end bile duct reconstruction provides a significant improvement in lowering biliary complication rates in liver transplant patients. Despite the modest number of cases in this study this technique shows promise and has become the technique of choice in our institution. The ever-increasing focus on quality in healthcare requires that we, as transplant surgeons, relook at how we have always practiced our art. Striving to improve outcomes for our transplant patients has always been integral to the transplantation field, but now new concepts such as root cause analysis, pay for performance, objective skill assessment, lean methods, and cumulative sum are slowly infiltrating our discipline. 1,2 This will require learning a new language and revisiting some very common practices. One of the basic techniques in liver transplantation is management of the bile duct. Englesbe et al. 3 reviewed how the prevention of biliary complications following liver transplantation is vital to transplant surgical quality improvement. These authors showed how surgical improvement initiatives are a sound financial investment. A significant cause of negative financial margins in the investigators hospital was biliary leak following liver transplantation. 3 Payors benefited even more when patients did not have a biliary leak. With financial incentives to both hospitals and payors to prevent transplant complications, transplant programs will be mandated to evaluate how they conduct their routine transplant techniques. In this review, Buczkowski et al. revisit their technique of bile duct reconstruction in orthotopic liver transplantation. They report on the surgical method of spatulated end-to-end choledochocholedochostomy versus an end-to-end method without spatulation. Over a 2-year period, 39 patients (group I) were treated with the end-to-end method without spatulation, and 38 patients (group II) received spatulation. Both groups had intraductal stents. Retrospective data were collected for group I, and prospective data were collected for group II. There were no differences in the donor characteristics between groups. Ten biliary complications (26%), including 5 bile leaks and 5 strictures, occurred in group I, with only 1 biliary stricture (2.6%) occurring in group II. The difference was significant (P 0.05). Certainly this method is not new, with 1 of the first reports on it having appeared in However, there can be no argument for the relevance of this report in today s quality climate. The current focus on quality will require that some very routine management practices be revisited. We will need objective reasons why we do something instead of the phrase because we have always done it that way. Striving to improve patient outcomes will continue to be integral to transplantation, but a new language to include such terms as financial margins and variance in practice skills will need to be adopted.

3 LIVER TRANSPLANTATION WORLDWIDE Perkins JD, Levy AE, Duncan JB, Carithers RL Jr. Using root cause analysis to improve survival in a liver transplant program. J Surg Res 2005;129: Axelrod DA, Guidinger MK, Metzger RA, Wiesner RH, Webb RL, Merion RM. Transplant center quality assessment using a continuously updatable, risk-adjusted technique (CUSUM). Am J Transplant 2006;6: Englesbe MJ, Dimick J, Mathur A, Ads Y, Welling TH, Pelletier SJ, et al. Who pays for biliary complications following liver transplant? A business case for quality improvement. Am J Transplant 2006;6: Neuhaus P, Blumhardt G, Bechstein WO, Steffen R, Keck H. Side-to-side anastomosis of the common bile duct is the method of choice for biliary tract reconstruction after liver transplantation. Transplant Proc 1990;22:1571. Computed Tomography Scanning Detecting Esophageal Varices Esophageal varices in patients with cirrhosis: multidetector CT esophagography comparison with endoscopy. Kim SH, Kim YJ, Lee JM, Choi KD, Chung YJ, Han JK, et al. Radiology 2007;242: Purpose: To evaluate the use of multidetector computed tomographic (CT) esophagography to grade esophageal varices and differentiate between varices at low risk and those at high risk for bleeding, with endoscopy as the reference standard. Materials and Methods: This study was approved by the institutional review board; all subjects gave informed consent. Ninety patients with cirrhosis (65 men, 25 women; mean age, 54.8 years; range, years) were prospectively enrolled and underwent endoscopy and CT esophagography. Esophageal varices were graded independently at endoscopy by two endoscopists. CT esophagograms were interpreted retrospectively with a four-point scale by two radiologists blinded to other findings. Interobserver agreement between each radiologist and endoscopist was determined; endoscopic and CT esophagographic grades of esophageal varices were correlated. Radiologist performance for differentiation between low- and high-risk varices for bleeding on the basis of morphology at endoscopy was evaluated with receiver operating characteristic analysis. Patients were interviewed to determine acceptance at both examinations. Results: Thirty-seven of 90 patients had grade 0, 23 had grade 1, 18 had grade 2, and 12 had grade 3 esophageal varices. Thus, 60 patients were determined to be in a low-risk group and 30 in a high-risk group for variceal bleeding at endoscopy. There was almost perfect agreement in grading esophageal varices between endoscopists. There was close correlation (P 0.001) and substantial agreement between endoscopic and CT esophagographic grades. Radiologist performance for differentiating between low- and high-risk varices was (area under receiver operating characteristic curve). Patient interview results revealed that CT esophagography had better acceptance than did endoscopy (P 0.001). Conclusion: Use of CT esophagography allows grading of esophageal varices and differentiation between lowand high-risk varices and shows better patient acceptance than does endoscopy. Evaluating prospective liver transplant patients includes screening for hepatocellular carcinoma (HCC) with computed tomography (CT) scanning and looking for esophageal varices with endoscopy. The presence of HCC can determine the extent of a patient s treatment, which can range from no transplantation to extra allocation points and transplantation sooner. A patient with varices that are at high risk for bleeding can be treated with beta blockers or undergo endoscopic variceal ligation. A single procedure that could adequately screen for both conditions has the potential for being cost-effective and more patient friendly and shortening the time for the pretransplant evaluation. CT scanning has been routinely used for HCC evaluation. In this article, S. H. Kim et al. report on the use of multidetector CT esophagography to grade esophageal varices and differentiate between varices with low and high risk for bleeding. Endoscopy was used as the reference standard, with digital images graded by 2 endoscopists. All patients were assigned to either a low-risk group or a high-risk group for bleeding. Multidetector CT esophagography with a 16-detector CT scanner (Sensation 16, Siemens Medical Systems, Forchheim, Germany) was performed within 4 hours after endoscopy. Air insufflation was performed through a 16- French catheter inserted into the upper esophagus through the mouth. Air injection was performed at a rate of 700 ml/30 seconds from 12 seconds before scanning to the time at which the scanner passed the gastroesophageal junction. Three CT phases precontrast, arterial, and portal were performed. Three-dimensional images of the esophagus were rendered. Ninety patients with cirrhosis were studied who were undergoing an evaluation for HCC without concurrent gastrointestinal bleeding or prior endoscopic variceal ligation. The performance of the radiologists for differentiating varices at low and high risk for bleeding had a sensitivity of 90.5%-93.3% and a specificity of 81.7%- 96.7%. S. H. Kim et al. concluded that multidetector CT scanning could be an adequate screen for high-risk varices. Y. J. Kim et al. 1 reported on their experience using routine helical liver CT scanning for the detection of esophageal varices. Their detection rate with this method was 92% for large varices and 53%-60% for small varices. CT scanning can also reveal other abnormalities, including ascites, gastric varices, splenomegaly, and portal-systemic shunts. 2 The value of CT scanning seems certain with respect to screening for HCC; it might now be adequate in screening for esophageal varices as well. Further study is needed in the liver transplant population to determine the cost effectiveness of multidetector CT esophagography. If nothing else, 1 screening

4 1060 LIVER TRANSPLANTATION WORLDWIDE instead of 2 would certainly offer a time advantage in shortening the pretransplantation evaluation process. 1. Kim YJ, Raman SS, Yu NC, To o KJ, Jutabha R, Lu DS. Esophageal varices in cirrhotic patients: evaluation with liver CT. AJR Am J Roentgenol 2007;188: Riggio O, Efrati C, Catalano C, Pediconi F, Mecarelli O, Accornero N, et al. High prevalence of spontaneous portalsystemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology 2005;42: Cirrhotic Cardiomyopathy: Multiple Reviews Cirrhotic cardiomyopathy. Milani A, Zaccaria R, Bombardieri G, Gasbarrini A, Pola P. Dig Liver Dis 2007;39: Decompensated liver cirrhosis is characterized by a peripheral vasodilation with a low-resistance hyperdynamic circulation. The sustained increase of cardiac work load associated with such a condition may result in an inconstant and often subclinical series of heart abnormalities, constituting a new clinical entity known as cirrhotic cardiomyopathy. Cirrhotic cardiomyopathy is variably associated with baseline increase in cardiac output, defective myocardial contractility and lowered systo-diastolic response to inotropic and chronotropic stimuli, down-regulated -adrenergic function, slight histo-morphological changes, and impaired electric recovery ability of ventricular myocardium. Cirrhotic cardiomyopathy is usually clinically latent or mild, likely because the peripheral vasodilation significantly reduces the left ventricle after-load, thus actually auto-treating the patient and masking any severe manifestation of heart failure. In cirrhotic patients, the presence of cirrhotic cardiomyopathy may become unmasked and clinically evident by certain treatment interventions that increase the effective blood volume and cardiac preload, including surgical or transjugular intrahepatic porto-systemic shunts, peritoneo-venous shunts (LeVeen) and orthotopic liver transplantation. Under these circumstances, an often transient overt congestive heart failure may develop, with increased cardiac output as well as right atrial, pulmonary artery and capillary wedge pressures. Several recent reviews on cirrhotic cardiomyopathy have been published, including this review by Milani et al. 1-3 Cirrhotic cardiomyopathy is defined as a chronic cardiac dysfunction in patients with cirrhosis characterized by blunted contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities, in the absence of known cardiac disease, as stated by a consensus of international experts during the World Congress of Gastroenterology held in Montreal in ,4 Cirrhotic cardiomyopathy was also reviewed in Liver Transplantation in Is there anything new in the interaction between liver transplantation and cirrhotic cardiomyopathy? As Milani et al. point out, cirrhotic cardiomyopathy is usually clinically latent or mild, likely because the peripheral vasodilation significantly reduces the left ventricle after-load, thus actually auto-treating the patient and masking any severe manifestation of heart failure. This situation can continue until major stresses on the cardiovascular system, such as liver transplantation, infections, and insertion of transjugular intrahepatic portosystemic shunts, unmask the presence of cirrhotic cardiomyopathy. 2 The course of a patient rapidly developing severe congestive heart failure soon after successful liver transplantation without a perioperative myocardial infarction is not uncommon. Such a patient requires several days in the intensive care unit, sometimes expiring. Can patients such as these be identified before transplantation? Even though patients with cirrhotic cardiomyopathy are reported to have a baseline increased cardiac output but blunted ventricular response to stimuli, systolic and/or diastolic dysfunction, absence of overt left ventricular failure at rest, electrophysiological abnormalities including a prolonged QT interval on electrocardiography, and chronotropic incompetence, a gold standard to identify patients at risk prior to transplantation is lacking. 2,5 It has been suggested that echocardiography or dynamic magnetic resonance cardiac imaging to evaluate diastolic function may be the best available screening test. 2 Most investigators have concluded that there are no firm diagnostic criteria that can be identified before transplantation. A recent review found no discernibly different cardiac workup factors following transplantation between patients who developed cirrhotic cardiomyopathy and those who did not (E. Y. Chan, personal communication; March 15, 2007). In addition, the prevalence of cirrhotic cardiomyopathy is unknown because of the difficult diagnostic parameters. Milani et al. conclude that the management of cirrhotic cardiomyopathy is largely empirical because of the paucity of literature. Cirrhotic cardiomyopathy does appear reversible after liver transplantation. 2,6 Liu and Lee 7 reported that liver transplantation reverses the alterations of increased ventricular wall thickness, diastolic dysfunction, and abnormal systolic response to stress present in patients with cirrhotic cardiomyopathy. 7 Following a prolonged posttransplant recovery period, it appears that most patients survive. The bottom line is that patients who develop heart failure following liver transplantation secondary to cirrhotic cardiomyopathy still cannot be identified before transplantation, and there is no particular treatment for these patients. As is so often the case, the final conclusion from all the recent reviews is that more studies are needed.

5 LIVER TRANSPLANTATION WORLDWIDE Alexander J, Mishra P, Desai N, Ambadekar S, Gala B, Sawant P. Cirrhotic cardiomyopathy: Indian scenario. J Gastroenterol Hepatol 2007;22: Baik SK, Fouad TR, Lee SS. Cirrhotic cardiomyopathy. Orphanet J Rare Dis 2007;2: Pozzi M, Ratti L, Guidi C, Milanese M, Mancia G. Potential therapeutic targets in cirrhotic cardiomyopathy. Cardiovasc Hematol Disord Drug Targets 2007;7: Lee SS. Cardiac abnormalities in liver cirrhosis. West J Med 1989;151: Myers RP, Lee SS. Cirrhotic cardiomyopathy and liver transplantation. Liver Transpl 2000;6(suppl 1, pt 4):S44 S Sampathkumar P, Lerman A, Kim BY, Narr BJ, Poterucha JJ, Torsher LC, et al. Post-liver transplantation myocardial dysfunction. Liver Transpl Surg 1998;4: Liu H, Lee SS. What happens to cirrhotic cardiomyopathy after liver transplantation? Hepatology 2005;42: James D. Perkins, M.D., Special Editor Liver Transplantation Worldwide University of Washington Medical Center Seattle, WA