Infusion of donor leukocytes to induce tolerance in organ allograft recipients.

To further enhance chimerism, 229 primary allograft recipients have received perioperative intravenous infusion of a single dose of 3 to 6 X 10(8) unmodified donor bone marrow (BM) cells/kg body weight. In addition, 42 patients have been accrued in a concurrent protocol involving multiple (up to three) sequential perioperative infusions of 2 x 10(8) BM cells/kg/day from day 0-2 posttransplantation (PTx). Organ recipients (n = 133) for whom BM was not available were monitored as controls. The infusion of BM was safe and except for 50 (18%), all study patients have optimal graft function. Of the control patients, allografts in 30 (23%) have been lost during the course of follow-up. The cumulative risk of acute cellular rejection (ACR) was statistically lower in the study patients compared with that of controls. It is interesting that, 62% of BM-augmented heart recipients were free of ACR (Grade > or = 3A) in the first 6 months PTx compared to controls. The incidence of obliterative bronchiolitis was also statistically lower in study lung recipients (3.8%) compared with the contemporaneously acquired controls (31%). The levels of donor cell chimerism were at least a log higher in the peripheral blood of majority of the study patients compared with that of controls. The incidence of donor-specific hyporeactivity, as determined by one-way mixed leukocyte reaction, was also higher in those BM-augmented liver, kidney, and lung recipients that could be evaluated compared to controls.

Immune status of recipients following bone marrow-augmented solid organ transplantation.

It has been postulated that the resident "passenger" leukocytes of hematolymphoid origin that migrate from whole organ grafts and subsequently establish systemic chimerism are essential for graft acceptance and the induction of donor-specific nonreactivity. This phenomenon was augmented by infusing 3 x 10(8) unmodified donor bone-marrow cells into 40 patients at the time of organ transplantation. Fifteen of the first 18 analyzable patients had sequential immunological evaluation over postoperative intervals of 5 to 17 months, (which included 7 kidney (two with islets), 7 liver (one with islets), and one heart recipient). The evolution of changes was compared with that in 16 kidney and liver nonmarrow controls followed for 4 to 5 months. The generic immune reactivity of peripheral blood mononuclear cells (PBMC) was determined by their proliferative responses to mitogens (PHA, ConA). Alloreactivity was measured by the recipient mixed lymphocyte reaction (MLR) to donor and HLA-mismatched third-party panel cells. Based on all 3 tests, the recipients were classified as donor-specific hyporeactive, intermediate, and responsive; patients who were globally suppressed made up a fourth category. Eight (53%) of the 15 marrow-treated recipients exhibited progressive modulation of donor-specific reactivity (3 hyporeactive and 5 intermediate) while 7 remained antidonor-responsive. In the nonmarrow controls, 2 (12.5%) of the 16 patients showed donor-specific hyporeactivity, 10 (62.5%) were reactive, and 4 (25%) studied during a CMV infection had global suppression of responsiveness to all stimuli.

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report.

BACKGROUND: Tacrolimus (Tac) and mycophenolate mofetil (MMF) are newly approved immunosuppressive agents. However, the safety and efficacy of the combination of MMF and Tac in primary liver transplantation has not been determined. METHODS: An Institutional Review Board-approved, open-label prospective randomized protocol was initiated to study the efficacy and toxicity of Tac and steroids (double-drug therapy) versus Tac, steroids, and MMF (triple-drug therapy) in primary adult liver transplant recipients. Both groups of patients began on the same doses of Tac and steroids. Patients randomized to triple-drug therapy also received 1 g of MMF twice a day. RESULTS: Between August 1995 and January 1997, 200 patients were enrolled, 99 in double-drug therapy and 101 in triple-drug therapy. All patients were followed until May 1997, with a mean follow-up of 12.7 months. During the study period, 28 of 99 patients in double-drug therapy received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 61 patients in triple-drug therapy discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. By an "intention-to-treat analysis," the actuarial 1-year patient survival rate was 85.1% in double-drug therapy and 83.1% in triple-drug therapy (P=0.77). The actuarial 1-year graft survival rate was 80.2% for double-drug therapy and 79.2% for triple-drug therapy (P=0.77). Forty-one patients (41.4%) in double-drug therapy and 32 (31.7%) in triple-drug therapy had at least one episode of rejection, but this was not statistically significant (P=0.15). The mean maintenance dose of corticosteroids was slightly lower in triple-drug compared with double-drug therapy. CONCLUSION: Patient and graft survival rates were similar in both groups. There was a trend to a lower incidence of rejection, reduced nephrotoxicity, and a lesser amount of maintenance corticosteroids in triple-drug therapy compared with double-drug therapy.

Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence.

BACKGROUND: Alcoholic liver disease has emerged as a leading indication for hepatic transplantation, although it is a controversial use of resources. We aimed to examine all aspects of liver transplantation associated with alcohol abuse. METHODS: Retrospective cohort analysis of 123 alcoholic patients with a median of 7 years follow-up at one center. RESULTS: In addition to alcohol, 43 (35%) patients had another possible factor contributing to cirrhosis. Actuarial patient and graft survival rates were, respectively, 84% and 81% (1 year); 72% and 66% (5 years); and 63% and 59% (7 years). After transplantation, 18 patients (15%) manifested 21 noncutaneous de novo malignancies, which is significantly more than controls (P=0.0001); upper aerodigestive squamous carcinomas were overrepresented (P=0.03). Thirteen patients had definitely relapsed and three others were suspected to have relapsed. Relapse was predicted by daily ethanol consumption (P=0.0314), but not by duration of pretransplant sobriety or explant histology. No patient had alcoholic hepatitis after transplantation and neither late onset acute nor chronic rejection was significantly increased. Multiple regression analyses for predictors of graft failure identified major biliary/vascular complications (P=0.01), chronic bile duct injury on biopsy (P=0.002), and pericellular fibrosis on biopsy (P=0.05); graft viral hepatitis was marginally significant (P=0.07) on univariate analysis. CONCLUSIONS: Alcoholic liver disease is an excellent indication for liver transplantation in those without coexistent conditions. Recurrent alcoholic liver disease alone is not an important cause of graft pathology or failure. Potential recipients should be heavily screened before transplantation for coexistent conditions (e.g., hepatitis C, metabolic diseases) and other target-organ damage, especially aerodigestive malignancy, which are greater causes of morbidity and mortality than is recurrent alcohol liver disease.

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report.

BACKGROUND: Tacrolimus (TAC) and mycophenolate mofetil (MMF) are currently approved immunosuppressants for prevention of rejection in liver transplantation (LTx). They have different modes of action and toxicity profiles, but the efficacy and safety of MMF in primary liver transplantation with TAC has not been determined. METHODS: An Institutional Review Board-approved, open-label, single-center, prospective randomized trial was initiated to study the efficacy and toxicity of TAC and steroids (double-drug therapy (D)) versus TAC, steroids, and MMF (triple-drug therapy (T)) in primary adult LTx recipients. Both groups of patients were started on the same doses of TAC and steroids. Patients randomized to T also received 1 gm MMF twice a day. RESULTS: Between August 1995 and May 1998, 350 patients were enrolled at a single center-175 in the D and 175 in the T groups. All patients were followed until May 1998, with a mean follow-up of 33.8+/-9.1 months. Using an intention-to-treat analysis, the 1-, 2-, 3-, and 4-year patient survival was 85.1%, 81.6%, 78.6%, and 75.8%, respectively, for D and 87.4%, 85.4%, 81.3%, and 79.9%, respectively, for T. The 4-year graft survival was 70% for D and 72.1% for T. Although the rate of acute rejection in the first 3 months was significantly lower for T than for D (28% for triple vs. 38.9% for double, P=0.03), the overall rate of rejection for T at the end of 1 year was not significantly lower than for the D (38.9% triple vs. 45.2% double). The median time to the first episode of rejection was 14 days for D versus 24 days for T (P=0.008). During the study period, 38 of 175 patients in D received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 103 patients in the T discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. The need for corticosteroids was less after 6 months for T and the perioperative need for dialysis was lower with use of MMF. CONCLUSION: This final report confirms similar patient survival and graft survival up to 4 years with a trend towards fewer episodes of rejection, lower need for steroids, and better perioperative renal function. However, the complex nature of LTx patients and their posttransplantation course prevents the routine application of MMF.

Liver transplantation with cavoportal hemitransposition in the presence of diffuse portal vein thrombosis.

BACKGROUND: Orthotopic liver transplantation is possible even in the presence of recipient portal vein thrombosis, provided that hepatopetal portal flow to the graft can be restored. On rare occasions this is not possible due to diffuse thrombosis of the portal venous system. In these cases, successful liver transplantation has been considered impossible. Portocaval transposition was introduced in the pretransplantation era to study the effect of systemic venous flow on the liver and has been used in three patients for the treatment of glycogen storage disease. We used portocaval hemitransposition (portal perfusion with inflow from the inferior vena cava) in liver transplantation when portal inflow to the graft was not feasible. We are reporting the collective experience of nine patients from four liver transplant centers. METHODS: Cavoportal hemitransposition was used in nine patients. In seven of these cases, the technique was used during the original transplant (primary group). In two cases, it was used after the portal inflow to the first transplant had clotted (secondary group). RESULTS: Five of seven patients in the primary group are alive after intervals of 6-11 months. The two patients in the rescue group died. In the successful cases, liver function and histology were indistinguishable from those of conventional liver transplantation. Ascites disappeared within 3-4 months and the patients were able to return to their normal activities. Postoperative variceal bleeding necessitated splenectomy and gastric devascularization in one case and splenic artery embolization in another case. Bleeding was controlled in both these cases. Splenectomy and gastric devascularization were performed prophylactically in one patient with a history of variceal bleeding in order to prevent this complication after transplantation. CONCLUSION: Portocaval hemitransposition maybe useful in liver transplantation when hepatopetal flow to the liver graft cannot be established by other techniques. Rescue after failure of conventional technique was not possible in two patients.

Hepatitis G virus coinfection in hepatitis C virus-infected liver transplant recipients.

BACKGROUND: In this study, we determined the prevalence of hepatitis G virus (HGV) infection in end-stage hepatitis C virus (HCV)-related liver disease and examined the influence of HGV coinfection on the outcome of liver transplantation. METHODS: HGV was detected by reverse transcriptase-polymerase chain reaction and Southern blotting in sera drawn from 159 patients who were known to be HCV infected before transplantation. Patients were followed up for a mean of 28.4 months after transplantation. RESULTS: Forty-one (25.3%) patients were HGV positive and the prevalence of HGV infection was similar for different HCV genotypes. Both HGV-positive and -negative groups had similar survival, recurrence rates, inflammatory activity scores, and degree of fibrosis at the time of recurrence. CONCLUSION: Infection with HGV is common in end-stage HCV-infected patients presenting for liver transplantation. It influences neither the outcome of liver transplantation nor the recurrence of hepatitis in the graft.

Role of nuclear medicine in liver transplantation.

Orthotopic liver transplantation is now a very well-established technique for treating patients with end-stage liver disease. Since 1967, more than 26,000 liver transplants have been performed, including 15,000 in the United States. The overall 1-year survival rate is approximately 80% and 5-year survival is 70%. Nuclear imaging plays an important role in the management of liver transplant recipients before and after liver transplantation. The evaluation of candidates potentially includes liver-spleen scan for liver volume, multiple gated acquisition scan, adenosine or stress thallium study, bone scan, and quantitative ventilation perfusion scan for hepatopulmonary syndrome. In the post-transplant phase, the deconvolution analysis (which corrects for the problem of recirculation) is a promising tool for diagnosing rejection, although its role in the transplant population has to be established. A variety of nuclear medicine techniques are helpful in the postoperative diagnosis of biliary complications. By performing a semiquantitative analysis to discriminate hepatocyte dysfunction from biliary disease and measuring hepatocyte extraction fraction by deconvolution analysis and excretion, (T1/2 values measured by the nonlinear list squares technique) have been very promising.

Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system.

BACKGROUND: Hepatic resection for metastatic colorectal cancer provides excellent longterm results in a substantial proportion of patients. Although various prognostic risk factors have been identified, there has been no dependable staging or prognostic scoring system for metastatic hepatic tumors. STUDY DESIGN: Various clinical and pathologic risk factors were examined in 305 consecutive patients who underwent primary hepatic resections for metastatic colorectal cancer. Survival rates were estimated by the Cox proportional hazards model using the equation: S(t) = [So(t)]exp(R-Ro), where So(t) is the survival rate of patients with none of the identified risk factors and Ro = 0. RESULTS: Preliminary multivariate analysis revealed that independently significant negative prognosticators were: (1) positive surgical margins, (2) extrahepatic tumor involvement including the lymph node(s), (3) tumor number of three or more, (4) bilobar tumors, and (5) time from treatment of the primary tumor to hepatic recurrence of 30 months or less. Because the survival rates of the 62 patients with positive margins or extrahepatic tumor were uniformly very poor, multivariate analysis was repeated in the remaining 243 patients who did not have these lethal risk factors. The reanalysis revealed that independently significant poor prognosticators were: (1) tumor number of three or more, (2) tumor size greater than 8 cm, (3) time to hepatic recurrence of 30 months or less, and (4) bilobar tumors. Risk scores (R) for tumor recurrence of the culled cohort (n = 243) were calculated by summation of coefficients from the multivariate analysis and were divided into five groups: grade 1, no risk factors (R = 0); grade 2, one risk factor (R = 0.3 to 0.7); grade 3, two risk factors (R = 0.7 to 1.1); grade 4, three risk factors (R= 1.2 to 1.6); and grade 5, four risk factors (R > 1.6). Grade 6 consisted of the 62 culled patients with positive margins or extrahepatic tumor. Kaplan-Meier and Cox proportional hazards estimated 5-year survival rates of grade 1 to 6 patients were 48.3% and 48.3%, 36.6% and 33.7%, 19.9% and 17.9%, 11.9% and 6.4%, 0% and 1.1%, and 0% and 0%, respectively (p < 0.0001). CONCLUSIONS: The proposed risk-score grading predicted the survival differences extremely well. Estimated survival as determined by the Cox proportional hazards model was similar to that determined by the Kaplan-Meier method. Verification and further improvements of the proposed system are awaited by other centers or international collaborative studies.

Intermittent subcutaneous opioids: using an algorithm.

Nurses and patients prefer the administration of injections via an indwelling subcutaneous cannula. Patients undergoing intermediate and minor surgery need improved pain relief. The algorithm provides a safe and acceptable mechanism for administering subcutaneous opioids more frequently.