Vol. 7, No. 2 2003
that ATP regulates mitochondrial Ca2+ uptake via a receptor-like mechanism. Methods. Rat livers were perfused with UW solution via the portal vein, harvested and homogenized. Mitochondria were separated from liver homogenate by differential centrifugation and mitochondrial Ca2+ uptake was determined by using 45Ca2+. After incubation at 37C in the presence 0.2 M 45Ca2+, 1mM pyruvate and 1 mM malate, the mitochondrial suspension was filtered and Ca2+ uptake was calculated from the radioactivity of the filters. A non-hydrolysable analog of ATP, AMPPNP (100 M), Ruthenium Red (inhibitor of mitochondrial Ca2+ uniporter, RR, 10 M) and P2Y receptor antagonist reactive blue-2 (RB-2, 300 M) were added to the incubation medium to determine their influence on Ca2+ uptake. The experiment was repeated on 3 animals and each measurement was performed in triplicates. Statistical analysis was performed using Student’s t-test, with p0.05 taken as significant. Results: 1. ATP analog AMP-PNP significantly activates mitochondrial Ca2+ uptake. 2. RR completely inhibits Ca2+ uptake by itself and in combination with AMP-PNP. 3. P2Y inhibitor RB-2 completely inhibits mitochondrial Ca2+ uptake in combination with AMP-PNP. Conclusions. 1. The effect of AMP-PNP suggests that intracellular ATP at concentration lower then normal activates mitochondrial Ca2+ uptake. 2. Inhibition of this effect by RR suggests that intracellular ATP activates Ca2+ uptake via the calcium uniporter. 3. The ability of RB-2 to cancel the effect of AMP-PNP and depress Ca2+ uptake below baseline suggests that ATP influences Ca2+ uptake via a P2Y receptor mechanism.
43 Biliary Complications in 96 Right Lobe Living Donor Liver Transplants Giovanni Varotti, Gabriel E Gondolesi, Luis Munoz, Sander Florman, Thomas M Fishbein, Sukru Emre, Myron E Schwartz, Charles Miller, Mount Sinai School of Medicine, New York, NY
Abstracts
271
Hemangioendotheliomas are exceedingly rare liver tumors that are often multi-focal and incompatible with resection. Liver transplantation has been anecdotally utilized in patients but significant series have not been reported. Methods: We retrospectively reviewed our transplant tumor database for all hemangioendothelioma patients who underwent liver transplantation. Results: Eighteen patients received liver transplants for the diagnosis of hemangioendotheliomas. The mean age of the group was 33.3 13.2 years (range 3-57 yrs) and was comprised of 12 females and 6 males. There were 16 Caucasians, 1 African American, and 1 Asian. The diagnosis was made by preoperative biopsy and the presence of lymph node invasion confirmed at the time of explantation. Antibody induction was utilized in 3 patients while IL-2 receptor antibody was utilized in 2 other patients. Maintenance immunosuppression consisted of prednisone (n18), cyclosporine (n10), tacrolimus (n8), azathioprine (n7), and Mycophenolate mofeltil (n4). Post-operative adjuvant chemotherapy was given to three patients (2 patients with node + disease). Mean follow-up was 27.2 35.8 months (range 6 to 110 months). Node positive disease was encountered in 3 patients. Recurrent disease was observed in three patients (16.7%), two of these had node + disease. The overall patient survival was 77% at 3-years. When compared the survival in the node + group was 33% with the 2 deaths occurring in the first six months post-op. While in contrast, survival in the node negative group was 75%, p0.001. The mean survival was 9.2 5.4 months for those with recurrent disease. Conclusions: Transplantation for hemangioendotheliomas can be performed safely with excellent 3-year survival. Unfortunately, node positive disease portends a high-risk for recurrence, which significantly diminishes patient survival.
45 Does Estrogen Protect Against Reperfusion Injury in the Liver? Carson Cunningham, M K Ghanta, Xinje Mu, Kevin N Boykin, Gazi B Zibari, LSUHSC Shreveport, Shreveport, LA
Introduction: Biliary reconstruction during right lobe living donor liver transplantation (RL LDLT) is the most technically challenging aspect of the procedure. This study documents the incidence, nature, and outcome of biliary complications following RL LDLT. Method: Between June 1999 and January 2002, 96 RL LDLT were performed in our center (91 adults; 5 children). We retrospectively reviewed the records of these recipients, noting the number of bile duct anastomosis; type of reconstruction; incidence, timing, treatment, and outcome of leaks and strictures; and patient survival. Results: Multiple ducts ( 2) were found in 58 grafts (60.4%). Roux-en-Y reconstruction was performed in 53 cases (55.2%), duct-to-duct in 39 (40.6%), and both in 4 cases (4.2%). Thirty-nine recipients (40.6 %) had biliary complications: 21 patients had leaks and 22 had strictures (4 patients had both). Six patients had multiple biliary leaks requiring multiple operations. Patients with 2 biliary anastomosis had a higher incidence of bile leaks (19% vs. 5.5%, pNS). The incidence of leaks was higher with Roux-en-Y compared to duct to duct (18.2% vs 7.3%; pNS); the opposite was for strictures (16.3% vs 31.7%; pNS). Leaks occur at a median of 12 days after transplant, while strictures presented at a median of 178.5 days. Freedom from biliary complications was 55% at 2 years. Two-year survival for patients with and without biliary leaks was 65% and 85%, respectively (p0.07). Overall 2-year patient and graft survival was 81% and 77%, respectively. Conclusion: The bile duct is still the Achilles’ Heel of the liver transplant, with a complication rate of 40% in RL LDLT. Leaks seem to be more common with multiple anastomosis and Roux-en-Y reconstructions; duct-to-duct reconstruction is more prone to stricture. Bile leaks require aggressive treatment to improve outcome.
Organ ischemia followed by reperfusion injury impacts many areas of surgical care. Ongoing research is directed at limiting or preventing reperfusion injury. Prior studies have shown female rats to have decreased lung injury after hemorrhagic shock followed by resuscitation. The purpose of our study was to investigate whether estrogen would protect against reperfusion injury in the murine liver. Twenty male C57BL/6 mice were divided into 2 groups: control and experimental. Each group underwent midline laparotomy and ligation of the vascular pedicle of the left lateral lobe of the liver for one hour. After one hour of ischemia, the left lateral lobe was allowed to reperfuse for 5 hours. After 5 hours of reperfusion, the carotid artery was cannulated and 0.5 cc of blood withdrawn. The abdomen was then re-opened and a biopsy of the left lateral lobe was taken to be stained with TUNEL reagent. The animal was then sacrificed. Mice in the experimental group were given a subcutaneous injection of estrogen twenty-four hours prior to laparotomy. Mean AST in the control group was 2368. Mean AST in the experimental group was 514. There was not a statistically significant difference between these two groups (p.1365). Mean ALT in the control group was 3767. Mean ALT in the experimental group was 861. Again, there was not a statistically significant difference between these groups (p.2025). Tissue specimens from neither the control group nor the experimental group had TUNEL positive cells indicating the start of apoptosis. Although mean transaminase levels between the control and experimental groups are not equal, the difference was not statistically significant.
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Liver Transplantation for Hemangioendothelioma Manish Gupta, Todd Merchen, Thomas M Beebe, Thomas G Gross, Rita R Alloway, Michael J Hanaway, Jennifer Trofe, Steve Rudich, M R First, E S Woodle, Joseph F Buell, The University of Cincinnati, Cincinnati, OH
Impact of Donor and Recipient Risk Factors on Survival and Quality of Life After Liver Transplantation Derek E Moore, Irene Feurer, C W Pinson, Vanderbilt University Medical Center, Nashville, TN
272
Journal of Gastrointestinal Surgery
Abstracts
Background: In an effort to expand the donor pool, marginal donors (with presumed marginal grafts) are increasingly used. The aim of this study was to compare graft and patient survival as well as health related quality of life (HRQOL) on the basis of optimal versus marginal donor organs and by other potential risk factors. Methods: 430 cadaveric liver transplants in 402 recipients between 1991 and 2002 at Vanderbilt University Medical Center were analyzed for graft and patient survival. Additionally, Karnofsky functional performance (FP) and HRQOL (SF-36 and Psychosocial Adjustment to Illness Scale) were measured in 75 recipients. Potential risk factors influencing these outcomes were assessed including donor age and weight, warm and cold ischemic time, recipient UNOS status and age, and gender matching. Data were analyzed via Kaplan-Meier techniques, Cox regression, and analysis of variance methods. Results: Graft survival (mean + SEM) was 44 + 8 versus 96 + 4 months when donors were 60 versus 60 years, respectively (p 0.01). Patient survival was 62 + 9 versus 106 + 3 months for these donor age groups (p0.01). Cold ischemic time (CIT) greater than versus less than 12 hours was associated with shorter graft survival (78 8 versus 97 3 months, p 0.01). A comparable pattern was seen for patient survival in relation to CIT (p0.03). Cox regression demonstrated that UNOS “status 1”, donor age, and CIT were independently associated with shorter graft survival (model p0.001, all predictors p0.05). Similarly, UNOS “status 1” and donor age were adversely related to patient survival (model p0.01, all predictors p0.05). FP and HRQOL improved over time following transplantation, but this improvement was not affected by donor or recipient characteristics, or CIT. Conclusions: This study demonstrates the effects of donor age, recipient urgency status, and CIT on survival following liver transplantation. However, these factors do not affect the trajectory of improvement in FP and HRQOL following liver transplantation.
47 Live Donor Liver Transplantation for Acute-on-Chronic Hepatitis B Liver Failure Chi-Leung Liu, Sheung-Tat Fan, Chung-Mau Lo, John Wong, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China Aim: The survival results of patients who suffered from acute-on-chronic liver failure (United Network for Organ Sharing priority status 2a) and received live donor liver transplant (LDLT) have been reported to be poor. The aim of the present study was to evaluate the survival outcomes of patients who underwent LDLT using right-lobe liver grafts for acuteon-chronic hepatitis B liver failure. Patients and Methods: The study comprised 32 patients who had acute-on-chronic hepatitis B liver failure and underwent LDLT using right-lobe liver grafts from June 1996 to March 2002. The mean ( SEM) MELD scores before liver transplantation was 36 1.8. LDLT using right-lobe liver graft including the middle hepatic vein was performed after informed consent was obtained from voluntary donors and preoperative evaluations were completed. Oral lamividine 100mg daily was started before transplant and maintained indefinitely afterwards for hepatitis B prophylaxis, and hepatitis B immune globulin was not used. Results: The mean preoperative intensive care unit stay was 2.4 days and the mean ( SEM) postoperative hospital stay was 38.1 5.8 days. At a median follow-up of 23 months, both patient and graft survival was 88%, respectively. Four recipients died after LDLT, and the causes of death included systemic candidiasis (n 1), necrotising pancreatitis (n 1), empyema thoracis (n 1), and biliary sepsis (n 1). The survival results were not different from those of 49 patients who underwent LDLT for elective conditions during the same study period (graft survival 82%, p 0.55; patient survival 84%, p 0.75). Two (6.3%) patients developed recurrent hepatitis B resulting from viral breakthrough 47 and 53 months, respectively, after transplantation, but remained well after treatment with adefovir. Post-operative complications occurred in 8 (25%) donors, but most of them were minor
complications. The mean ( SEM) hospital stay of the donors was 12.0 1.0 days. There was no donor mortality. Conclusion: When cadaveric organ donation is scarce, LDLT using right-lobe liver grafts represents a timely and effective therapeutic option for patients with acuteon-chronic hepatitis B liver failure. It results in satisfactory survival outcomes comparable to patients who receive LDLT for elective conditions.
48 Protective Effect of N2-Mercaptopropionylglcycine, on Liver During Ischemia/Reperfusion Process Emilio E Abdo, Marcel C Machado, Jose Eduardo Cunha, Telesphoro Bacchella, Fabio DeLuca, Jose J Gama-Rodrigues, University of Saint Paul-Brazil, Sao Paulo-Brazil, Brazil N2-mercaptopropionylglycine (N2-MPG), among other properties, is a powerful super oxide synthesis inhibitor and was tested as a preventive agent of metabolic and structural damage of hepatic parenchyma, in the ischemia/reperfusion process. Twenty-two rats and twenty-two dogs were divided into four groups: Group I: rats that received I.V. saline 0.9%; Group II: rats that received 100mg/kg of N2-MPG; Group III: dogs that received saline I.V. 0.9% and Group IV: dogs that received 100mg/kg N2-MPG. Ten minutes after the saline or drug administration, each group was submitted to left lobe normothermic liver ischemia for 25 minutes followed by reperfusion. Biochemical studies 24hrs. after reperfusion revealed a significantly low elevation of transaminase in animals of groups G-II (AST271182; ALT261161) and G-IV (AST10145; ALT 12389) when compared in the controls G-I (AST2144966; ALT18691040 00) and G-III (AST18002.1076.51; ALT277219), all in UI/dl. Histology study demonstrated a significantly minor aggression to animals of G-II and G-IV when compared to G-I and G-III. These results suggest an actual and significant release of free radicals of oxygen and that N2-MPG may have a significant protective effect on the liver parenchyma when submitted to normothermic ischemia/reperfusion process. Descriptors: Ischemia, Reperfusion, Liver, N2-Mercaptopropionylglicyne, antioxidants, Free Radicals.
49 Liver Transplantation for Neuroendocrine Tumors Sander Florman, Ben Toure, Leona Kim, Thomas M Fishbein, Sukru Emre, Charles Miller, Myron E Schwartz, Mount Sinai, New York, NY Introduction: Liver transplantation for the treatment of metastatic neuroendocrine tumors (NETs) is radical. While cure is not impossible, it is certainly improbable. The world’s experience with transplantation for this indication is limited to less than 150 cases with widely varying results and few 5-year disease-free survivors. We reviewed our experience with transplantation for patients with NETs. Methods: Since 1992, 43 patients with NET liver metastases have been evaluated at the Mount Sinai Hospital. Fifteen (34.9%) patients received only medical therapy. Sixteen (37.2%) patients underwent hepatic resection, either for localized tumor in hopes of cure, or for debulking of symptomatic metastases. Fourteen (32.6%) patients were evaluated and listed for transplantation. In general, the decision to proceed with transplantation was made in physically fit patients with unresectable tumors with uncontrollable symptoms due to tumor bulk and/or tumor hormone production. Two patients listed for transplantation underwent prior hepatic resection. Orthotopic liver transplantation was performed in the standard fashion with primary cyclosporine or tacrolimus immunosuppression, except in one living donor case performed without immunosuppression in identical twins. Results: Of the 14 patients evaluated and listed for transplant, 11 (78.6%) underwent liver transplantation, 3 with living donor grafts. Among the 3 patients listed but not transplanted, one was lost to follow-up, one died 14 months after listing, and one remains waiting over 4 years. There were