Magnitude of change in alpha-fetoprotein in response to transarterial chemoembolization predicts survival in patients undergoing liver transplantation for hepatocellular carcinoma.

BACKGROUND: Downsizing strategies are often attempted for patients with hepatocellular carcinoma (hcc) before liver transplantation (lt). The objective of the present study was to determine clinical predictors of favourable survival outcomes after transarterial chemoembolization (tace) before lt for hcc outside the Milan criteria, so as to better select candidates for this strategy. METHODS: In this retrospective study, patients with hcc tumours either beyond Milan criteria (single lesion > 5 cm, 3 lesions with 1 or more > 3 cm) or at the upper limit of Milan criteria (single lesions between 4.1 cm and 5.0 cm), with a predicted waiting time of more than 3 months, received carboplatin-based tace treatments. Exclusion criteria for tace included Child-Pugh C cirrhosis or the presence of portal vein invasion or extrahepatic disease on imaging. Only patients without tumour progression after tace underwent lt. RESULTS: Of 160 hcc patients who received liver grafts between 1997 and 2010, 35 were treated with tace preoperatively. The median of the sum of tumour diameters was 6.7 cm (range: 4.8-8.5 cm), which decreased with tace to 5.0 cm (range: 3.3-7.0 cm) at transplantation (p < 0.0004). The percentage drop in alpha-fetoprotein (αfp) was a positive predictor (p = 0.0051) and the time from last tace treatment to transplantation was a negative predictor (p < 0.0001) for overall survival. CONCLUSIONS: The percentage drop in αfp and a shorter time from the final tace treatment to transplantation significantly predicted improved overall survival after lt for hcc downsized with tace. As a serum marker, αfp should be followed when tace is used as a strategy to stabilize or downsize hcc lesions before lt.

Transporting live donor kidneys for kidney paired donation: initial national results.

Optimizing the possibilities for kidney-paired donation (KPD) requires the participation of donor-recipient pairs from wide geographic regions. Initially it was envisaged that donors would travel to the recipient center; however, to minimize barriers to participation and simplify logistics, recent trends have involved transporting the kidneys rather than the donors. The goal of this study was to review outcomes of this practice. KPD programs throughout the United States were directly queried about all transplants involving live donor kidney transport. Early graft function was assessed by urine output in the first 8 h, postoperative serum creatinine trend, and incidence of delayed graft function. Between April 27, 2007 and April 29, 2010, 56 live donor kidneys were transported among 30 transplant centers. Median CIT was 7.2 h (IQR 5.5-9.7, range 2.5-14.5). Early urine output was robust (>100 cc/h) in all but four patients. Creatinine nadir was <2.0 mg/dL in all (including the four with lower urine output) but one patient, occurring at a median of 3 days (IQR 2-5, range 1-49). No patients experienced delayed graft function as defined by the need for dialysis in the first week. Current evidence suggests that live donor kidney transport is safe and feasible.

Recovery of graft function early posttransplant determines long-term graft survival in deceased donor renal transplants.

INTRODUCTION: Because kidneys show remarkable resilience and can recover function, we examined the impact on long-term graft survival in deceased donor renal transplants of both immediate graft function (IGF) and the rate of renal function recovery over the first 3 months after transplantation. METHODS: We included all cadaveric renal transplants from 1990 to 2007 (n = 583). Delayed graft function (DGF) was defined as the need for dialysis in the first 7 days posttransplant. Slow graft function (SGF) and IGF were defined by serum creatinine falls of <20% or >20% in the first 24 hours posttransplant respectively. Recovery of renal function was expressed as either the best creatinine clearance (CrCl) in the first 3 months post-renal transplantation (BCrCl-3mos) as calculated using the Cockcroft-Gault formula or as a percentage of actual versus expected value (as calculated from the donors' CrCl at procurement). RESULTS: There were 140 (23.6%) subjects who received extended criteria donor (ECD) organs. The overall graft survival at 1 and 5 years was 87.8% and 74%, respectively. The 5-year graft survivals for patients with IGF, SGF, and DGF were 85%, 76%, and 54%, respectively (P < .02). ECD kidneys showed twice the DGF rate (49% vs 23%, P < .001). BCrCl-3mos of <30 mL/min displayed a 5-year graft survival of 34%; 30 to 39 mL/min, 72%; 40 to 49 mL/min, 85%; and >50 mL/min, 82% (P < .001). Similarly, a recovery within 90% of expected CrCl in the first 3 months posttransplant correlated with 5-year graft survival of 81%; a recovery of 70% to 90%, with 65%; and a recovery of <70%, with 51% (P < .001). CONCLUSION: Early graft function in the first 3 months showed a significant impact on long-term graft survival after deceased donor renal transplantation.

Liver transplantation for metastases from a bile duct carcinoid.

BACKGROUND: A 29-year-old woman who presented with fatigue and jaundice was found to have an obstructing mass at the bifurcation of the bile duct. The patient underwent a successful left hepatectomy with resection of the bile duct bifurcation and a reconstruction with a right hepaticojejunostomy. Pathology revealed an atypical carcinoid tumour of the left extrahepatic bile duct, with perineural and lymphatic invasion. The patient subsequently developed multiple metastases in the remaining liver. METHODS: In the absence of extrahepatic disease, the patient underwent a successful liver transplant. RESULTS: Two years later she remains disease-free. DISCUSSION: To our knowledge this is the first report of a biliary carcinoid treated with hepatectomy and finally with liver transplantation, with excellent results. The biological behaviour of these rare tumours mandates aggressive surgical management.

The impact of thymoglobulin on renal function and calcineurin inhibitor initiation in recipients of orthotopic liver transplant: a retrospective analysis of 298 consecutive patients.

BACKGROUND: Renal dysfunction remains the Achilles' heel of calcineurin inhibitor (CI)use. The purpose of this study was to assess our institutional, renal-sparing strategy using thymoglobulin (TMG) in recipients of orthotopic liver transplants. METHODS: We performed a retrospective analysis of data from 298 adult recipients who were transplanted between 1991 and 2002. The patients were divided into two groups: those induced with TMG (group 1) and those that were not treated with this agent (group 2). A subgroup analysis was performed of patients with baseline serum creatinine values above 1.5 mg/dL (group 1A received TMG; group 2A did not). All patients received tacrolimus or cyclosporine (CyA) maintenance immunosuppression. RESULTS: Indications and demographics were similar between the two groups. Although there was no difference in patient and graft survivals, there was a statistically significant benefit in the rejection-free graft survival at 1 year for group 1 (51% vs 39%; P =.02). Furthermore, serum creatinine at 6 months was lower for group 1, despite a similar baseline creatinine. Subgroup analysis for patients with baseline abnormal serum creatinines showed that group 1A displayed an improved rejection-free graft survival at 1 month but not at 1 year. CONCLUSIONS: Thymoglobulin induction therapy may allow a delay in the initiation of CI therapy without compromising patient and graft survival, while preventing early rejection, even among patients with baseline renal dysfunction.

Leukoreduction and acute rejection in liver transplantation: an interim analysis.

BACKGROUND: Little is known about the effect of blood transfusions and leukoreduction on acute rejection in liver transplantation. The purpose of this study was to assess the impact of leukoreduction on the occurrence of early rejection episodes in liver transplantation. METHODS: In 1999, mandatory leukoreduction was implemented in our program. Data from 339 consecutive liver transplant recipients were analyzed with attention to the time period as a proxy for leukoreduction, the number of transfusions, the wait list status, the hepatitis B or C status, the recipient age, and the type of immunosuppression. RESULTS: Using an early (6-month) rejection-free graft survival model, we observed that introduction of leukoreduction was independently associated with fewer rejection episodes (P =.001). Despite the lower rejection rate, due to a regimen of tacrolimus and antithymocyte globulin, the effect of implementation of leukoreduction remained significant (P =.021). CONCLUSION: The use of leukoreduction is associated with fewer early rejections, irrespective of the type of immunosuppression. These data support an exploration of the immunomodulatory effect of leukoreduction.

Ureteral implantation technique and urologic complications in adult kidney transplantion.

AIM: To assess the incidence of urological complications and hematuria after adult kidney transplantation using the Lich-Gregoire (LG) versus the Taguchi (T) ureteral implantation technique. METHODS: We performed a retrospective analysis of 212 consecutive kidney transplants from our institution using an access database. RESULTS: Sixty four patients underwent ureteral implantation using the T technique, and the other 148, the LG implantation. Both groups were matched for donor/recipient characteristics and for cold/warm ischemia times. There were 23 urological complications in 17 patients. Twenty-seven patients developed complicated hematuria. The rates of urinary leak and ureteral stones were not different. There was a higher incidence of permanent ureteral strictures using the LG technique (P =.05). T technique was associated more frequently with hematuria, but there was no difference in the length of stay. CONCLUSIONS: We identified an increased incidence of permanent strictures with the LG technique. The rate of hematuria was higher in the T group. Both techniques can be used interchangeably with acceptable rates of urological complications. The simplicity of the T technique has made it the technique of choice in our institution.

Do biliary endoprostheses decrease biliary complications after liver transplantation?

AIM: Most technical complications after orthotopic liver transplantation (OLT) are related to the biliary tree. This report reviews the role of routine intraoperative placement of stents to reduce biliary complications. METHODS: We retrospectively analyzed 396 consecutive OLTs. We reviewed rates of biliary complications after hepaticojejunostomy (HJA) as well as following choledochocholedochostomy (CCA) groups: "experimental" group (routine intraoperative biliary stenting, last 10 months), "recent" control group (nonstented, previous 10 months), "historical" control group (prior to that period of time). RESULTS: All groups were matched for donor/recipient characteristics and for graft cold/warm ischemia time. The overall prevalence of biliary complications was 30.7% after CCA versus 35% after HJA. In the experimental group 21 patients had a 4.8% biliary complication rate compared to the recent control and historical groups, where biliary complication rates were 30% and 32.6%, respectively (P <.05). CONCLUSIONS: The intraoperative use of biliary stents is feasible and appears to decrease the rate of biliary complications. These results support the need for a prospective randomized trial.

Successful outcome after transplantation of a donor liver with focal nodular hyperplasia.

Because of the increasing gap in the number of patients awaiting organ transplantation and the supply of organ donors, reevaluation of donor criteria is an important issue in clinical transplantation. It has become necessary to make maximal use of the currently available donor pool. We describe a case of successful orthotopic liver transplantation in a 57-year-old man with Laënnec's cirrhosis using a liver containing an 8-cm focal nodular hyperplasia (FNH) lesion involving segments II and III and the caudate lobe. The donor liver was procured from a 46-year-old woman declared brain dead after a subarachnoid hemorrhage. Definitive pathological diagnosis was made at laparotomy by obtaining a Tru-cut (Allegiance Health Care Inc, Toronto, Ontario, Canada) core biopsy specimen. The recipient operation was performed uneventfully except for bleeding from the biopsy site. The patient did well postoperatively and was discharged on tacrolimus, mofetil mycophenolate, and prednisone therapy. He continues to thrive 2(1/2) years posttransplantation with no change in the size of the lesion. In well-selected donors, FNH should not be a contraindication for use in transplantation. However, FNH must be differentiated from hepatocellular adenoma. Although FNH has a benign course with little propensity for bleeding and almost no malignant potential, hepatic adenoma is reported to have a 15% to 33% chance of bleeding and rupture with a well-documented potential for neoplastic degeneration, making the liver unsuitable for donation.

Pseudoaneurysm of the superior mesenteric artery after pancreas transplantation treated by endovascular stenting.

Pseudoaneurysm after pancreas transplantation can have serious consequences, including rupture, hemorrhage, and graft loss. We describe a 38-year-old patient who presented with a pseudoaneurysm of the donor superior mesenteric artery 1 month after pancreas transplantation. Selective arteriography was performed and the lesion was repaired with endovascular placement of a 28-mm covered stent. Laparotomy was avoided. The pancreatic graft was continuing to function well 9 months later. As far as we know, this minimally invasive approach was not previously reported. According to published series, pseudoaneurysms often occur secondary to infection and require operative intervention necessitating graft pancreatectomy. Patients can present with serious symptoms including hypotension and shock. Therefore, it is important to detect pseudoaneurysm in a timely manner. Computed tomography and Doppler ultrasound are important diagnostic tools in this regard. We demonstrated the utility of endovascular stenting in the treatment of pseudoaneurysm after pancreas transplantation. When used in a timely manner in well selected patients, endovascular stenting can abrogate the need for operative intervention and its attendant morbidity.

Rejection of pig liver xenografts in patients with liver failure: implications for xenotransplantation.

The pathophysiological state of rejection in liver xenotransplantation is poorly understood. Data from clinical pig liver perfusion suggest that pig livers might be rejected less vigorously than pig hearts or kidneys. Pig livers used in clinical xenoperfusions were exposed to blood from patients with liver failure. We have shown in an animal model that transplant recipients with liver failure are less capable of initiating hyperacute rejection of a xenografted liver than a healthy transplant recipient. The goal of this report is to examine the pathological characteristics of pig livers used in 2 clinical pig liver perfusions and combine this information with in vitro studies of pig-to-human liver xenotransplantation to determine whether the findings in the perfused pig livers could be explained in part by the diminished capacity of the patient with liver failure to respond to xenogeneic tissue. Pathological analysis of the perfused pig livers showed immunoglobulin M deposition in the sinusoids with little evidence of complement activation. Our in vitro studies showed that serum from patients with liver failure caused less injury to pig liver endothelium than serum from healthy subjects. Serum from patients with liver failure had similar levels of xenoreactive antibodies as serum from healthy humans. Incubation of serum from patients with liver failure with pig hepatic endothelial cells generated less iC3b, Bb fragment, and C5b-9 than serum from healthy subjects. We conclude that the altered injury in the perfused pig livers can be attributed to the relative complement deficiency that accompanies liver failure.

Pulmonary injury in recipients of discordant hepatic and renal xenografts in the dog-to-pig model.

Work in our lab demonstrated that the early post-operative course of discordant hepatic and renal xenotransplantation is complicated by a pulmonary injury. The aim of this study was to characterize the nature of this injury, as well as to determine whether endothelin-1 (ET-1) and inducible-nitric oxide synthase (iNOS) are present in this form of pulmonary injury. Dog-to-pig orthotopic liver and kidney xenografts were performed. Pulmonary artery pressures were monitored throughout all procedures. The lungs were stained with monoclonal antibodies for ET-1, endothelin converting enzyme-1, and iNOS. The lungs from pig recipients of hepatic or renal xenografts were compared to lungs from untreated pigs. Pulmonary artery pressures were elevated in recipients of liver xenografts when the suprahepatic caval cross clamp was placed and continued to rise to systolic levels following unclamping. The mean pulmonary artery pressures in recipients of renal and hepatic xenografts rose significantly following revascularization. Pathology in lungs from kidney and liver recipients was similar, showing congestion with peribronchial and septal edema, with diffuse adhesion of PMN to alveolar endothelium. ET-1, endothelin converting enzyme-1 (ECE-1), and iNOS staining was widespread and intense in alveolar and pulmonary arterial endothelium. Discordant xenotransplantation of livers and kidneys is associated with a significant early pulmonary injury that is associated with early PMN infiltration and expression of ET-1 and iNOS.

[A comparative randomized prospective multicenter study of Sandimmune vs Neoral in liver transplantation]. / Etude multicentrique prospective randomisée comparative de Sandimmune vs Néoral en transplantation hépatique.

Despite two decades of use, there are limited data on the best way to administer and monitor cyclosporine for orthotopic liver transplantation (OLT). The present study was undertaken: 1) to establish the safety of a new formulation of cyclosporine, Neoral, 2) to determine if treatment with Neoral will improve the results of liver transplantation and 3) to study the relationship between pharmacokinetic parameters and clinical outcomes after OLT. A double-blind, randomized, comparison of Sandimmune and Neoral was conducted at 5 Canadian centers in 188 consecutive adults undergoing OLT. Patients were induced with intravenous cyclosporine (CsA) then switched to Neoral or Sandimmune. Dose adjustments were made daily, or as needed, to reach a target trough CsA level (C0) of 350 ng/mL in both groups. Pharmacokinetic studies were performed on days 5, 10, 15 and 30 after transplantation. The Neoral group stopped intravenous CsA earlier (p < 0.0001), and these patients required a lower median daily oral dose (p < 0.01) to maintain comparable trough CsA levels. Five Sandimmune patients, but no Neoral patients discontinued the study because of the inability to reach target trough levels of CsA within the prescribed time (p < 0.05). At 4 months, there were no differences between the two groups with respect to patient survival, graft survival or rejection-free survival. The incidence of serious adverse events was also similar and did not correlate with CsA profiles. The Neoral group had a higher area under the drug concentration curve (AUC) and peak CsA levels (Cmax). There was a correlation between freedom from graft rejection and both AUC and Cmax at days 5 and 10 post-transplant. In contrast, there was a poor correlation between C0 and graft rejection. In summary, Neoral appears to be safe and well tolerated by patients. Cmax and/or AUC maybe better markers for monitoring cyclosporine based immunosuppression after liver transplantation.

Successful treatment of post-transplant lymphoproliferative disorder with interferon-alpha and intravenous immunoglobulin.

We report on the use of interferon-alpha (INF-a) and high-dose non-specific intravenous immunoglobulin (IVIg) in 2 patients (a 60-yr-old female and a 65-yr-old male) who developed post-transplant lymphoproliferative disorder (PTLD) 2 and 8 months after heart and liver transplantation, respectively. Both patients had received immunosuppression with ATG, CsA, azathioprine, and prednisone. The first patient did not receive additional immunosuppression with biological agents. The second patient developed 3 steroid-resistant acute rejection episodes requiring OKT3 (cumulative dose 100 mg) and ATG (cumulative dose 3450 mg). The first patient presented with nodules involving the liver, spleen, lungs and nasophar, ynx. The second patient presented with subcutaneous and liver nodules, as well as pert-portal and para-aortic lymphadenopathies. The histological diagnosis was diffuse B-cell PTLD in both patients. Despite reduction of immunosuppression, a progression of lesions was observed in both patients over 5 months and 2 months, respectively. The first patient received INF-alpha (2 x 10(6) IU, s.c. 3 times/wk) and IVIg (0.5 g/kg i.v. every 15 d) for.4 months, while the second patient received the same therapy for 12 and 7 months, respectively. Complete disappearance of all lesions was observed after 3 months of therapy in the first patient and after 7 months of therapy in the second patient, as assessed by CT scan. PTLD remains in remission 47 and 33 months after therapy, respectively. Our preliminary results suggest that the combination of INF-alpha and IVIg can be an effective therapy for PTLD which does not respond to reduction of immunosuppression.

Comparison of neoral dose monitoring with cyclosporine through levels versus 2-hr postdose levels in stable liver transplant patients.

BACKGROUND: We reported that cyclosporine 2-hr postdose levels (C2) correlate better with the AUC0-4 hr than trough levels (C0) in heart transplant patients receiving Neoral. METHODS: We compared Neoral dose adjustment with C0 (group 1: 100-200 ng/ml) vs. C2 (group 2: 700-1000 ng/ml; group 3: 300-600 ng/ml) in 35 stable adult patients >1 year after liver transplantation. The AUC0-4hr was calculated, and simultaneous blood samples were obtained to measure calcineurin inhibition. Clinical benefit was defined as the absence of rejection and no increase in serum creatinine at the 7-month follow-up. RESULTS: C2 correlated better with the AUC0-4 hr than C0 (r=0.92 vs. r=0.40). Neoral dose increased by 17% and 39% in groups 1 and 2, and decreased by 18% in group 3 (P=0.002 vs. group 1 and P=0.0004 vs. group 2). Serum creatinine increased by 2.1% and 16% in groups 1 and 2, and decreased by 5.1% in group 3 (P=0.006 vs. group 2). A clinical benefit was observed in 37.5%, 23%, and 82% of patients in groups 1, 2, and 3 (P=0.03 vs. group 1 and P=0.01 vs. group 2). Calcineurin inhibition was similar in all groups at 2-hr (44+/-17%, 39+/-30%, and 44+/-35%), in spite of different Neoral doses (2.9+/-0.9, 4.0+/-1.8, and 2.6+/-1.3 mg/kg/day) and C2 (857+/-226, 922+/-274, and 588+/-274 ng/ml). CONCLUSIONS: C2 correlated better with the AUC0-4 hr than C0. Neoral dose monitoring with a C2 range of 300-600 ng/ml resulted in a lower dose and greater clinical benefit compared to C0 or a higher C2 in stable liver transplant patients. The correlation between calcineurin inhibition and clinical events deserves further research.