Howard R. Doyle

Baboon-to-human liver transplantation

Our ability to control both the cellular and humoral components of xenograft rejection in laboratory experiments, together with an organ shortage that has placed limits on clinical transplantation services, prompted us to undertake a liver transplantation from a baboon to a 35-year-old man with B virus-associated chronic active hepatitis and human immunodeficiency virus infection. Liver replacement was performed according to conventional surgical techniques. Immunosuppression was with the FK 506-prednisone-prostaglandin regimen used routinely for hepatic allotransplantation, to which a daily non-myelotoxic dose of cyclophosphamide was added. During 70 days of survival, there was little evidence of hepatic rejection by biochemical monitoring or histopathological examination. Products of hepatic synthesis, including clotting factors, became those of the baboon liver with no obvious adverse effects. Death followed a cerebral and subarachnoid haemorrhage that was caused by an angioinvasive aspergillus infection. However, the underlying cause of death was widespread biliary sludge that formed in the biliary tree despite a seemingly satisfactory choledochojejunostomy. During life and in necropsy samples, there was evidence of the chimerism that we believe is integral to the acceptance of both xenografts and allografts. Our experience has shown the feasibility of controlling the rejection of the baboon liver xenograft in a human recipient. The biliary stasis that was the beginning of lethal infectious complications may be correctable by modifications of surgical technique. In further trials, the error of over-immunosuppression should be avoidable.

Effect of Donor Age and Sex on the Outcome of Liver Transplantation

We correlated donor and recipient factors with graft outcome in 436 adult patients who underwent 462 liver transplants. Donor variables analyzed were age, gender, ABO blood group, cause of death, length of stay in the intensive care unit, use of pressors or pitressin, need for cardiopulmonary resuscitation, terminal serum transaminases, and ischemia time. Recipient variables analyzed were age, gender, primary diagnosis, history of previous liver transplant, ABO blood group, cytotoxic antibody crossmatch, United Network for Organ Sharing (UNOS) status, and waiting time (except for the cross-match results, they were all known at the time of the operation). The endpoint of the analysis was graft failure, defined as patient death or retransplantation. Using multivariate analysis, graft failure was significantly associated with donor age, donor gender, previous liver transplantation, and UNOS 4 status of the recipient. The effect of donor age became evident only when they were older than 45 years. Livers from female donors yielded significantly poorer results, with 2-year graft survival of female to male 55% (95% CI, 45% to 67%); female to female, 64% (95% CI, 54% to 77%); male to male, 72% (95% CI, 66% to 78%); and male to female, 78% (95% CI, 70% to 88%). The only donors identified as questionable for liver procurement were old (> or = 60 years) women in whom the adverse age and gender factors were at least additive. However, rather than discard even these livers, in the face of an organ shortage crisis, their individualized use is suggested with case reporting in a special category.

Hepatic Retransplantation--an analysis of risk factors associated with outcome.

Hepatic retransplantation is controversial because the results are inferior to primary transplants and organs are so scarce. To determine the factors that are associated with poor outcome within the first year following retransplantation, we performed a multivariate analysis, using stepwise logistic regression, of 418 hepatic retransplantations performed at a single institution from November 1987 to December 1993. The minimum follow-up was 1 year. Seven variables were found to be independently associated with subsequent graft failure (defined as either patient death or retransplantation): donor age (odds ratio 2.2 for each 10-year increase over age 45, 95% CI 1.3 to 3.7), female donor sex (odds ratio 1.7, 95% CI 1.05 to 2.7), recipient age (odds ratio 1.6 for each 10-year increase over age 45,95% CI 1.2 to 2.8), need for preoperative mechanical ventilation (odds ratio 1.8, 95% CI 1.1 to 2.9), pretransplant serum creatinine (odds ratio 1.24 for each increase of 1 mg/dl, 95% CI 1.1 to 1.4), pretransplant total serum bilirubin (odds ratio 1.4 for each 10-mg/dl increase over 15 mg/dl, 95% CI 1.1 to 1.8), and the primary immunosuppressant, using tacrolimus as the reference category (odds ratio for cyclosporine-based immunosuppression 3.9, 95% CI 2.3 to 6.8). Although not part of the logistic regression model, the timing of retransplantation was also found to be important, with the overall probability of failure increasing from 0.58 on day 0 to a peak of 0.8 on day 38 and decreasing slowly after that. The implications of these results regarding the appropriateness of retransplantation are discussed.

Long-term results after liver transplantation for primary hepatic epithelioid hemangioendothelioma

AbstractBackground: Hepatic epithelioid hemangioendothelioma (PHEHE) is a multifocal, low-grade malignant neoplasia characterized by its epithelial-like appearance and vascular endothelial histogenesis. The outcome of 16 patients treated with orthotopic liver transplantation (OLT) is the subject of this report. Methods: A retrospective study of 16 patients with HEHE (7 men, 9 women) with ages ranging from 24 to 58 years (mean 37 ± 10.6 years). Follow-up intervals ranged from 1 to 15 years (median of 4.5 years). Results: Actual patient survival at 1, 3, and 5 years was 100, 87.5, and 71.3%, respectively. Disease-free survival at 1, 3, and 5 years was 81.3, 68.8, and 60.2%, respectively. The 90-day operative mortality was 0. Involvement of the hilar lymph nodes or vascular invasion did not affect survival. The 5-year survival of HEHE compares favorably with that of hepatocellular carcinoma at the same stage (stage 4A): 71.3 versus 9.8% (p=0.001) Conclusions: The long-term survival obtained in this series justifies OLT for these tumors even in the presence of limited extrahepatic disease.

Early death or retransplantation in adults after orthotopic liver transplantation: Can outcome be predicted?

Early, reliable outcome prediction after a liver transplant would help improve organ use by minimizing unnecessary retransplantations. At the same time, early intervention in those cases destined to fail may ameliorate the high morbidity and mortality associated with retransplantation. The purpose of this study was to analyze several parameters that have been identified in the past as being associated with patient and graft outcome, and to try to develop a model that would allow us to make predictions based on data available in the early postoperative period. A total of 148 patients were followed in a prospective, observational study. Graft failure was defined as patient death or retransplantation within 3 months of surgery. Preoperative variables studied included patient demographics, need for life support, presence of ascites, serum bilirubin, serum albumin, prothrombin time, serum creatinine, and the results of the cytotoxic crossmatch. During the first 5 postoperative days, standard measurements included serum transaminases, serum bilirubin, ketone body ratio, prothrombin time, factor V, and serum lactate. Oxygen consumption was measured shortly after surgery, once the patients had rewarmed to 36 degrees C. There were 131 successful transplants (88.5%) and 17 failures (11.5%). Most of the variables studied were found to be associated with outcome (by univariate analysis) at different points in the early postoperative period. However, receiver operating characteristic curve analysis showed that the predictive ability of even the best parameter was not adequate to make decisions on individual patients. Multivariate analysis, using stepwise logistic regression, yielded a model with an overall accuracy of 92.7%. Again, receiver operating characteristic curve analysis suggested that this model did not achieve the discriminating power needed for routine clinical use. We are still not able to accurately predict outcome in the early posttransplant period. We must be very careful when evaluating parameters, or scoring systems, that are said to accomplish this. It is especially important in this era of cost containment, with its renewed pressures to guide therapy based on our perceived understanding of a patients future clinical course.

Predicting outcomes after liver transplantation. A connectionist approach.

ObjectiveThe authors sought to train an artificial neural network to predict early outcomes after orthotopic liver transplantation. Summary Background DataReliable prediction of outcomes early after liver transplantation would help improve organ use and could have an impact on patient survival, but remains an elusive goal. Traditional multivariate models have failed to attain the sensitivity and specificity required for practical clinical use. Alternate approaches that can help us model clinical phenomena must be explored.One such approach is the use of artificial neural networks, or connectionist models. These are computation systems that process information in parallel, using large numbers of simple units, and excel in tasks involving pattern recognition. They are capable of adaptive learning and self-organization, and exhibit a high degree of fault tolerance. MethodsTen feed-forward, back-propagation neural networks were trained to predict graft outcomes, using data from 155 adult liver transplants. The data included information that was available by the second postoperative day. Ten separate training and testing data subsets were prepared, using random sampling, and the ability of the different networks to predict outcomes successfully was evaluated using receiver operating characteristic (ROC) curve analysis. ResultsFour of the networks showed perfect discrimination, with an area under the ROC curve (Az) of 1.0. Two other networks also had excellent performance, with an Az of 0.95. The sensitivity and specificity of the combined networks was 60% and 100%, respectively, when using an output neuron activation of 0.6 as the cutoff point to decide class membership. Lowering the cutoff point to 0.14 increased the sensitivity to 77%, and lowered the specificity to 96%. ConclusionsThese results are encouraging, especially when compared to the performance of more traditional multivariate models on the same data set. The robustness of neural networks, when confronted with noisy data generated by nonlinear processes, and their freedom from a priori assumptions regarding the data, make them promising tools with which to develop predictive clinical models.

Orthotopic Liver Transplantation in High-Risk Patients: Risk Factors Associated with Mortality and Infectious Morbidity

BACKGROUND One of the most controversial areas in patient selection and donor allocation is the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing liver transplantation under primary tacrolimus-based immunosuppression. METHODS Twenty-eight pre-liver transplant, operative, and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplants in 130 veterans (98% male; mean age, 47.3 years). RESULTS Eighty-two percent of the patients had postnecrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% United Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit (P=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (P<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with mortality by univariate analysis. Underlying liver disease, cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, ischemia time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV had a trend towards higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppression, posttransplant dialysis, and subsequent transplantation were significant independent predictors of mortality (P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis (P=0.0001), pretransplant creatinine, donor age, median blood loss, intensive care unit length of stay, additional immunosuppression, and biopsy-proven rejection (P<0.05 for all). By multivariate analysis, intensive care unit length of stay and additional immunosuppression were significant independent predictors of infectious morbidity (P<0.03). HCV recurrence was of borderline significance (P=0.07). CONCLUSIONS Biologic and physiologic parameters appear to be more powerful predictors of mortality and morbidity after liver transplantation. Both donor and recipient variables need to be considered for early and late outcome analysis and risk assessment modeling.

Assessing risk in liver transplantation: Special reference to the significance of a positive cytotoxic crossmatch

OBJECTIVE The authors determined the impact of a positive cytotoxic crossmatch on the outcome of liver transplantation. SUMMARY BACKGROUND DATA Liver allografts rarely undergo hyperacute rejection, but transplants performed across a positive cytotoxic crossmatch tend to follow a different clinical course, with higher intraoperative blood use, postoperative graft dysfunction, and, in some cases, graft loss. How this affects overall graft survival has not been determined. METHODS The authors provide a retrospective analysis of 1520 liver transplants performed between November 1989 and December 1993, with a minimum follow-up of 1 year. All cases had a cytotoxic crossmatch using serum pretreated with dithiothreitol. RESULTS There were 1390 negative crossmatch and 130 positive crossmatch cases. There was no difference in overall graft survival, although early survival rates were lower in the positive crossmatch group, with the maximum difference at 6 months: 0.76 (95% confidence interval, 0.74-0.78) for a negative crossmatch versus 0.68 (95% confidence interval, 0.61-0.77) for a positive crossmatch. These differences become negligible by the 2-year mark. Using stepwise logistic regression, the authors identified seven variables independently associated with outcome: 1) donor age, 2) donor gender, 3) prior liver transplant, 4) medical urgency status, 5) ischemia time, 6) indication for transplantation, and 7) primary immunosuppressant. CONCLUSIONS The cytotoxic crossmatch is not statistically associated with overall graft survival after liver transplantation. However, early failure rates are higher in the positive crossmatch cases, a difference that disappears by the second year.

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.

Reducing Variance of Committee Prediction with Resampling Techniques

Algorithms for reducing variance in neural network prediction using committee and resampling techniques bootstrap and cross-validation are presented. Their effectiveness is tested on data sets with different levels of noise and on medical diagnosis data sets. The methods are most effective when the noise level in the data is high or the size of the learning set is small, which consequently produces high variance. The algorithms will not be of much help in cases where the error of prediction is mainly due to bias. An increase in bias is observed due to smaller effective learning size in the bootstrap and crossvalidation committee. The impact of increased bias on the performance ranges from negligible to completely undermining the benefit of reducing the variance.