An early regional experience with expansion of Milan Criteria for liver transplant recipients.

The Milan Criteria (MC) showed that orthotopic liver transplantation (OLT) was an effective treatment for patients with nonresectable, nonmetastatic HCC. There is growing evidence that expanding the MC does not adversely affect patient or allograft survival following OLT. The adult OLT programs in UNOS Region 4 reached an agreement allowing lesions outside MC (one lesion <6 cm, ≤3 lesions, none >5 cm and total diameter <9 cm-[R4 T3]) to receive the same exception points as MC lesions. Kaplan-Meier curves and log-rank tests were used to compare survival data. Chi-squared and Mann-Whitney U tests were used to compare patient data. A p-value of <0.05 was considered significant. All statistical analyses were performed on SPSS 15 (SPSS, Chicago, IL). Four hundred and forty-five patients were transplanted for HCC (363-MC and 82-R4 T3). Patient demographics were found to be similar between the two groups. Three year patient, allograft and recurrence free survival between MC and R4 T3 were found to be 72.9% and 77.1%, 71% and 70.2% and 90.5% and 86.9%, respectively (all p > 0.05). We report the first regionalized multicenter, prospective study showing benefit of OLT in patients exceeding MC based on preoperative imaging.

Successful conversion to rapamycin for calcineurin inhibitor-related neurotoxicity following liver transplantation.

INTRODUCTION: Neurotoxicity is a well-recognized side effect of calcineurin inhibitors. Rapamycin is considered to be significantly less neurotoxic than calcineurin inhibitors (CNIs). The aim of this study was to retrospectively analyze a group of post-liver transplant patients who had been converted to rapamycin because of CNI-related neurotoxicity. PATIENTS AND METHODS: Orthotopic liver transplantation (OLT) was performed in 56 consecutive patients between April 1, 2003, and August 15, 2004. Immunosuppression was administered with tacrolimus, mycophenolic acid, and corticosteroids. RESULTS: Seven patients were converted to rapamycin due to new-onset neurotoxicity or exacerbation of previous neurological symptoms secondary to CNI. None of the patients had toxic levels tacrolimus (>15 ng/mL) at the time of symptoms, which persisted despite reduction of CNI dose. The indications for conversion were: (1) peripheral neuropathy; (2) seizure; (3) metabolic encephalopathy; and (4) central pontine myelinolysis. All patients showed improvement or resolution of their neurological symptoms after conversion to rapamycin. Two patients died, the first due to a hypoxic event and the second due to central pontine myelinolysis with limited improvement and a family decision to withdraw care. There were no complications directly attributed to rapamycin. Specifically, there were no thrombotic events, wound complications, or biliary leaks. Three patients had a rejection episode that was successfully treated with pulse corticosteroids and low-dose tacrolimus (levels < 5 ng/mL). CONCLUSIONS: Rapamycin can be safely used in OLT recipients with severe neurological symptoms ascribed to or exacerbated by CNIs. Rapamycin monotherapy may be inadequate to control rejection early after transplantation. Rapamycin can be combined with low doses of CNI to prevent rejection.

Arterioportal fistulae following segmental liver transplantation in a child.

We report a case of arterio-portal fistulae in a 12-month-old-child following a segmental liver transplantation. The fistula, probably the result of mass ligature of a vascular pedicle during back table allograft reduction, is to our knowledge the first such case reported. Diagnosed on the third post-operative day, the fistula was successfully managed with transcatheter coil embolization. The child is well and asymptomatic, 33 months after transplantation. In addition to those seen in whole organ transplantation, there are a few complications specifically related to segmental transplantation. These complications, although infrequent, are a direct consequence of the back table liver partition, as in the case herein reported.

Functional venous anatomy for right-lobe grafting and techniques to optimize outflow.

Right-lobe living donor liver transplantation has emerged as an alternative to cadaveric transplantation. An appreciation of the unique anatomy and behavior of the right lobe has emerged and has precipitated technical modifications. Living donors underwent right lobectomy, including preservation of significant inferior hepatic veins. The parenchyma was divided following a plane approximating the right border of the posterior two thirds of the midhepatic vein (MHV), but deviating anteriorly to include the distal one third of the MHV with the graft. Large venous tributaries from segment VIII were preserved. Anastomosis in the recipient was accomplished by means of complete cavoplasty. Significant inferior veins, tributaries to the MHV, and the distal portion of the MHV were reconstructed when technically possible. Forty-eight right-lobe resections and transplantations were performed in the manner described. There were no donor complications attributable to the technique. Forty-six of the 48 recipients are alive, and 44 of the 46 surviving patients have their original graft. Venous tributaries from segment VIII and/or the distal portion of the MHV were reconstructed in only 3 patients. Outflow obstruction was recognized intraoperatively in 2 patients; 1 patient had a caval web excised and the other patient required revision of the main anastomosis. Neither organ was lost. There were no other significant venous complications. The incidence of ascites was the same as that in recipients of whole organs. These methods of parenchymal transection and venous reconstruction resulted in a low rate of complications. The wide anastomosis and collateral pathways between the MHV and right hepatic vein seem to be more critical than reconstruction of tributaries from segment VIII or the distal MHV.

Reconstruction of double hepatic arterial and portal venous branches for right-lobe living donor liver transplantation.

Double hepatic arterial and portal venous branches are common anatomic variations of the isolated right hepatic lobe. Reconstruction of these vessels during transplantation can be challenging because of their small caliber, close proximity to other hilar structures, and abnormal alignment with the native vasculature. Practical techniques for the creation of these anastomoses would simplify the recipient surgery and might minimize the incidence of vascular complications. Alternative methods for management of these structures are summarized. The recipient's proper hepatic artery and its bifurcation are resected for use as an arterial Y-type graft. The donor arteries are individually anastomosed at the bifurcation of the recipient's hepatic artery at the back table. The free end of the Y graft is then replaced at the origin of the gastroduodenal artery using standard branch-patch technique. Reconstruction of a second donor portal branch is similarly facilitated by ex situ placement of a Y-type vascular conduit derived from the recipient's portal vein. Surgical management of these vessels and reconstruction of other hilar structures are noticeably less cumbersome. There have been no short-term vascular complications. The use of autologous vascular conduits with ex situ reconstruction facilitates management of double donor arterial and portal venous branches. The incidence of complications attributable to these methods is expected to be low.

CD-20 expression in post-transplant lymphoproliferative disorders: treatment with rituximab.

B-cell lymphoproliferative disorders are rare but serious complications of solid organ and bone marrow transplantation. We report that these tumors frequently express the CD-20 antigen, and immunotherapy directed at this antigen may be a well-tolerated and effective treatment.

Hyperbaric oxygen therapy for hepatic artery thrombosis after liver transplantation in children.

Early hepatic artery thrombosis (HAT) after pediatric orthotopic liver transplantation (OLT) can cause significant morbidity and mortality, leading to liver failure or septic complications requiring urgent retransplantation. Experimental evidence that hyperbaric oxygen (HBO) may ameliorate hepatic ischemic-reperfusion injury led to this study of HBO in pediatric liver transplant recipients who developed HAT. Children undergoing OLT under primary tacrolimus immunosuppression and University of Wisconsin organ preservation between August 1, 1989, and December 31, 1998, who developed HAT were the basis for this study. Patients who developed HAT between March 1, 1994, and December 31, 1998, were treated with HBO therapy until signs of ischemia resolved (absence of fever, normalizing liver injury test results) or for 2 weeks. The pediatric OLTs performed from August 1, 1989, to February 28, 1994, who developed HAT served as a control group. Primary outcome measures were survival, retransplantation rate, time to retransplantation, incidence of hepatic gangrene, and days to collateral formation. Three hundred seventy-five consecutive pediatric patients underwent 416 OLTs between August 1, 1989, and December 31, 1998. Thirty-one patients (7.5%) developed HAT at a mean time of 8.2 days (range, 1 to 52 days) post-OLT. In 17 patients, HBO treatment was begun within 24 hours of HAT or immediately after the revascularization attempt and performed twice daily for 90 minutes at 2.4 atmospheres pressure. Fourteen patients were treated without HBO. None of the HBO-treated patients developed hepatic gangrene. Eight HBO patients (47%) were bridged to retransplantation at a mean time of 157 days (range, 3 to 952 days) after initial OLT and all survived. Mean time to retransplant in the control group was 12.7 days (range, 1 to 64 days). HBO was well tolerated without significant complications. Although there was no significant difference in survival or retransplantation rates, HBO significantly delayed retransplantation, potentially by hastening the development of hepatic artery collaterals.

Comparative histopathology of hepatic allografts and xenografts in the nonhuman primate.

Liver transplantation was performed in the following groups: Group 1, baboon-to-baboon allografting (n=8) (control group); Group 2, ABO-compatible vervet monkey-to-baboon xenografting (n=8); Group 3, ABO-incompatible vervet monkey-to-baboon xenografting (n=6); Group 4, pig-to-baboon xenografting (n=2); and Group 5, pig-to-rhesus monkey xenografting (n=6). Immunosuppressive therapy (cyclosporine, cyclophosphamide, and methylprednisolone) was begun 2-7 days before liver transplantation (LTx) and continued indefinitely after LTx. The liver grafts were biopsied pre-LTx and subsequently post-LTx at approximately 1 hr, 2-3 hr, 7-10 days, 20-30 days, 60 days, 120 days, and at euthanasia or spontaneous death. There were 19 successful LTxs with grafts functioning from one hour to 123 days. No pig liver (Groups 4 and 5) survived more than 5.5 hr, as there was an immediate severe vascular response after reperfusion, typical of hyperacute rejection (congestion and hemorrhage). Vascular rejection was not seen in allografts (Group 1), but early mild-to-moderate congestion and neutrophil infiltration were present in concordant xenografts (Groups 2 and 3), which were associated with moderate deposition of immunoglobulin, C3, and fibrinogen. Lymphoid cell infiltration, bile duct damage, and portal vein endothelialitis in the portal zones occurred later in both allografts (Group 1) and concordant xenografts (Groups 2 and 3), developing earlier in the presence of ABO-incompatibility (Group 3). In concordant xenografts it was usually followed by fibrosis.

A high incidence of native portal vein thrombosis in veterans undergoing liver transplantation.

The incidence of native portal vein thrombosis (PVT) in liver transplant recipients has been reported to range from 2.1 to 13.8%. We have identified an inordinately high incidence of PVT in a consecutive series of U.S. veterans receiving liver transplants. Between October 1989 and February 1994, 88 consecutive U.S. veterans received 99 orthotopic liver transplants under primary Tacrolimus (Prograf, formerly FK506) based immunosuppression. A number of clinical features were examined in an effort to identify risk factors for PVT and outcome was compared to patients without PVT. Native PVT was present in 23/88 (26%) patients. All of these patients were male U.S. veterans with a mean age of 47 years. When compared to the 65 patients without PVT, we found no significant difference with respect to underlying liver disease, age, Childs-Pugh score (mean = 12), UNOS status as defined prior to April 1995 (95% UNOS 3 or 4), previous abdominal surgery, or liver volume. Median blood loss for patients with PVT (21 units of packed red blood cells) was greater than for those without PVT (14 units, P = 0.04). Portal thrombectomy was performed in 11 patients, 11 patients required mesoportal jump grafts, and 1 patient had an interposition graft. Standard veno-venous bypass was used in 10 patients with single bypass utilized for the remainder. Actuarial patient survival for all patients at 1, 2, and 4 years was 88, 85, and 79%, respectively. There was no significant difference in patients with or without PVT. Patients with PVT had poorer graft survival than patients without PVT (86% vs 65%, 1 year; 81% vs 65%, 2 years; 81% vs 61%, 4 years; P = 0.03); however, this was not related to technical problems with the portal venous inflow. PVT occurred in 26% of U.S. veterans undergoing liver transplantation. These patients had significantly higher operative blood loss and poorer graft survival. The high incidence of postnecrotic cirrhosis in a predominantly male group of patients with advanced disease, as is evident by the high mean Childs-Pugh score and UNOS status, perhaps accounts for our observations.

Secondary organ allografting after a primary "bridging" xenotransplant.

It remains uncertain whether xenotransplantation can sensitize the recipient to alloantigens, rendering subsequent allotransplantation unsuccessful. This is of considerable importance if a xenograft is to be used as a "bridge" to support the patient until a suitable allograft becomes available. When sera from 9 baboons that had received pig or African green monkey heart or liver xenografts were tested against a panel of lymphocytes from 5 or 6 potential donor baboons, positivity was seen in only 1 baboon (and then to only 2 of the potential 5 donors). In 4 baboons that had undergone previous xenotransplants (1 from this series of 9 baboons and 3 others), subsequent organ allografting was not followed by hyperacute, antibody-mediated, or accelerated cellular rejection. We conclude that organ xenotransplantation using discordant or concordant donor species does not prohibit subsequent allotransplantation.

Auxiliary liver allografting and xenografting in the nonhuman primate.

Auxiliary liver transplantation has been performed in the baboon using allografts (n = 8) and concordant xenografts from donor African green monkeys (n = 8). The native portal vein was ligated in all cases and the native common bile duct was ligated in 5 cases. The immunosuppressive therapy used was identical in both the allografts and xenografts and consisted of triple drug therapy (cyclosporine, cyclophosphamide, and methylprednisolone), all at dosages consistent with clinical use. During the determination of the surgical technique to be applied, there were 5 early failures (3 allografts, 2 xenografts), and 2 deaths at 10 and 20 days from multiorgan failure and sepsis, respectively (xenografts). The remaining 9 baboons (5 allografts, 4 xenografts) were electively euthanized at 16-62 days (allografts) and 35-120 days (xenografts). Hyperacute rejection or antibody-mediated rejection was not seen in the grafted livers. Episodes of acute cellular rejection occurred in the majority of animals within the first 30 days and recurred in the longer-term survivors, but could be controlled by bolus therapy with intravenous methylprednisolone. Satisfactory donor liver function was confirmed using a number of tests, including scintigraphy in 3 cases. We conclude that auxiliary liver transplantation using a closely related donor species is feasible in baboons and might be extended to humans with terminal liver failure. A baboon-to-man auxiliary liver graft may serve as a "bridge" until either a human cadaver donor liver became available or native liver function recovers in patients with fulminant hepatic failure.

Treatment of IgA deficiency in liver transplant recipients with human breast milk.

IgA deficiency is associated with high mortality (42% at 120 days) following liver transplantation (OLTx). Most of the mortality has been associated with enteric infections. Mother's milk, or human breast milk (HBM), is a rich source of IgA that is considered to have beneficial effects in terms of protection from microbial translocation and enteric infections. Two IgA-deficient OLTx recipients were given HBM orally for 10 days perioperatively. HBM was given in order to replenish intestinal IgA. Both patients had an excellent infection-free post-operative course. IgA levels in the serum rose from 5 to 10 mg/dl in one patient and from 7 to 30 mg/dl in the other. No complications from HBM administration were observed. We conclude that HBM can be used in IgA-deficient liver transplant recipients to reduce the risk of infectious complications in the post-operative period.

Alternative procedure for failed reconstruction of a right replaced hepatic artery in liver transplantation.

A right replaced hepatic artery (RRHA) arising from the superior mesenteric artery (SMA) is the most frequent variation of the hepatic arterial supply requiring backtable reconstruction. There are several widely used techniques for backtable reconstruction of the RRHA to a single conduit. If these reconstructions fail, due to technical reasons or size discrepancies, an alternative method of rearterialization is needed. We describe six cases in which an RRHA was anastomosed to the donor's gastroduodenal artery (GDA) stump utilizing a loupe magnification technique. In four cases the reconstruction was performed at the time of the backtable procedure and in two after reperfusion and failure of the original RRHA to splenic artery (SA) reconstruction. In all cases, the anastomoses remained patent. All patients had Doppler sonography and two had subsequent arteriograms that verified anastomotic patency. This method of reconstruction is more demanding technically but obviates the awkward 90-degree twist of the hepatic artery when an RRHA is anastomosed to the SA stump.

Survival following organ transplantation in an Oklahoma institution, 1985-1993.

Since 1985, a total of 413 patients have undergone 439 solid organ transplants at the authors' institution. The current actuarial one-year survival rate of patients undergoing heart, kidney, lung, or liver transplantation at our center is 94%, 90%, 87%, and 91%, respectively. Five-year survival of heart and kidney recipients is 80% and 75%, respectively. In view of these excellent results and the excellent quality of life that successful organ transplants provide patients with end-stage organ failure, every possible effort should be made to increase organ donation.

Improved detection of spontaneous bacterial peritonitis with Bactec as compared with conventional culture methods. A prospective study.

Bacteriologic diagnosis of spontaneous bacterial peritonitis is difficult due to the low yield of isolating the bacteria from the ascitic fluid. We prospectively compared the conventional culture method with the nonradiometric Bactec culture system for the detection of bacteria in 20 episodes of spontaneous bacterial peritonitis. The ascitic fluid culture was positive by the conventional culture method in 25% and by Bactec in 79% of the episodes of spontaneous bacterial peritonitis (P = 0.004). Of culture-positive episodes, Gram-negative bacteria were detected by conventional cultures in 20% and by Bactec in 47%. Bactec culture system was significantly better than the conventional cultures for the detection of streptococci (viridans streptococci and Enterococcus fecalis), 33% versus 0 (P < 0.05). Conventional cultures did not detect bacteria that were not also detected by Bactec cultures. In conclusion, the Bactec nonradiometric culture method is superior to conventional cultures for the diagnosis of spontaneous bacterial peritonitis.

High-dose acyclovir compared with short-course preemptive ganciclovir therapy to prevent cytomegalovirus disease in liver transplant recipients. A randomized trial.

OBJECTIVE: To assess the efficacy of high-dose oral acyclovir therapy compared with preemptive, short-course ganciclovir therapy (administered only if cytomegalovirus [CMV] shedding occurred) to prevent CMV disease in liver transplant recipients. DESIGN: A randomized controlled trial. SETTING: Liver transplant center at a university-affiliated Veterans Affairs Medical Center. PATIENTS: 47 consecutive patients having liver transplantation. INTERVENTION: Patients were stratified by their CMV antibody status and the CMV antibody status of the donor and were randomly assigned to one of two treatment groups. Surveillance cultures for CMV (buffy coat and urine) were done every 2 to 4 weeks for 24 weeks in all patients. One group received high-dose oral acyclovir (800 mg four times daily). The experimental group received no acyclovir, but if surveillance cultures were positive, ganciclovir (5 mg/kg intravenously twice daily) was administered for 7 days. MEASUREMENTS: Cytomegalovirus shedding and CMV disease were measured in the two groups. RESULTS: Cytomegalovirus shedding before the onset of CMV disease occurred in 25% (6 of 24) of patients in the acyclovir group compared with 22% (5 of 23) in the experimental group. Cytomegalovirus disease developed in 29% (7 of 24) of the acyclovir group and in 4% (1 of 23) of the experimental group (P < 0.05). No hematologic toxicity occurred with ganciclovir. CONCLUSION: Oral acyclovir is ineffective prophylaxis against CMV in liver transplant recipients. Preemptive, short-course ganciclovir therapy in patients with CMV shedding was well tolerated and provided effective prophylaxis against subsequent CMV disease; this protocol targets the patients at risk for CMV disease and minimizes toxicity and expense.