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R W Busuttil

Publications and source records attributed to R W Busuttil.

At least 55 records · Page 3Linked to original sources
PubMed2001

Liver transplantation at Dumont-UCLA Transplant Center: an experience with over 3,000 cases.

Liver transplantation has seen extraordinary advances over the past 2 decades and now represents the only life-saving therapy for many patients with decompensated liver disease, regardless of etiology. As the indications for transplantation expand, the patient waiting list continues to grow, while the number of available donors each year remains relatively constant. As a result, there is a marked shortage of donor organs, prolonging the waiting time and thereby increasing the mortality of patients while waiting for OLT. At UCLA, we are actively pursuing novel approaches to increase retrieval of transplant organs. The use of in-vivo split-liver transplantation represents an effective technique to safely expand the number of organs and also provides a size-matched organ for pediatric patients. Living-donor liver transplantation represents a significant surgical achievement in an effort to expand the critical shortage of donor organs. However, the added risk imposed on a healthy individual by the use of this technique raises serious bio-ethical concerns. Although the results of OLT have improved substantially, most of the current recipient morbidity and mortality results from recurrence of disease, infectious complications, rejection, PNF, and technical complications. The development of effective pharmacological agents to prevent disease recurrence, as well as improvements in immunosuppression therapy will be important issues in the upcoming decade.

Academic Medical Centers↗
PubMed2000

The effect of immunosuppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a serious complication associated with the use of chronic immunosuppression for solid organ transplantation. This study represents a retrospective analysis of UCLA's experience with PTLD in all pediatric liver transplant recipients between 1984-1997. We assessed the clinical presentation, risk factors, incidence density, immunological characteristics, management, and outcome of patients who developed PTLD when receiving either primary cyclosporin A (CsA) or tacrolimus. METHODS: A total of 251 children received primary CsA therapy of which 70 required OKT3 for steroid resistant rejection and 29 required tacrolimus rescue for OKT3 resistance and/or chronic rejection. One hundred forty one children received tacrolimus as primary therapy. Sixty patients who survived for less than 6 months after transplantation were excluded from the study. RESULTS: The total incidence density (ID) rate of PTLD was 1.8+/-0.4 per 100 patient-years (30/392). The overall ID rate of PTLD in the CsA group was 0.93+/-0.2 per 100 patient-years (15/251). Within this group of primary CsA-treated patients, the ID rate of PTLD was 0.49+/-0.1 without OKT3 or tacrolimus, 0.67+/-0.2 with OKT3, and 6.42+/-1.1 with tacrolimus rescue. The overall PTLD ID rate in the primary tacrolimus-treated patients was 4.86+/-1.2 per 100 person-years (15/141). There was a 5-fold increase in the ID rate of PTLD in the primary tacrolimus group when compared to the comparable, primary CsA group (P<0.001). The mean time to PTLD was 5-fold longer (49.7+/-20.7 months) in the CsA group when compared to the CsA/tacrolimus rescue group (9.8+/-3 months, P<0.05) or the tacrolimus primary group (12.6+/-5.1 months, P<0.05). Five patients had monoclonal disease in the CsA group, but only one in the tacrolimus group (P<0.05). Clinical presentations with enlarged lymph nodes, fevers, malaise, anorexia, weight loss, hypoalbuminemia, and gastrointestinal blood loss were common. Mortality was 20%, three patients died in each group. CONCLUSION: The use of primary tacrolimus therapy was associated with a significant 5-fold higher rate of PTLD when compared to those treated with primary cyclosporine. Early diagnosis, decrease and/or discontinuation of potent immunosuppressive agents may contribute to decrease morbidity and mortality of this entity.

Adolescent↗
PubMed2000

Regulatory cells potentiate the efficacy of IL-4 gene transfer by up-regulating Th2-dependent expression of protective molecules in the infectious tolerance pathway in transplant recipients.

We have previously shown that the tolerant state in allograft recipients can be maintained and perpetuated by an "infectious" T cell-dependent regulatory mechanism. Hence, 1) treatment of LEW rats with RIB-5/2, a CD4 nondepleting mAb, produces indefinite survival of LBNF1 cardiac allografts; 2) donor-specific tolerance can be then transferred by spleen cells into new cohorts of test allograft recipients; and 3) putative regulatory CD4+ Th2-like cells are instrumental in this tolerance model. We now report on studies aimed at exposing mechanisms underlying the infectious tolerance pathway, with emphasis on the interactions between intragraft adenovirus-IL-4 gene transfer and systemic infusion of regulatory cells from tolerant hosts. Unlike individual treatment regimens, adjunctive therapy with adenovirus-IL-4 and suboptimal doses of regulatory spleen cells was strongly synergistic and extended donor-type test cardiac allograft survival to about 2 mo. RT-PCR-based expression of intragraft mRNA coding for IL-2 and IFN-gamma remained depressed, whereas that of IL-4 and IL-10 reciprocally increased selectively in the combined treatment group, data supported by ELISA studies. In parallel, only adjunctive treatment triggered intragraft induction of molecules with anti-oxidant (HO-1) and anti-apoptotic (Bcl-xL/Bag-1) but not with pro-apoptotic (CPP-32) functions, both in the early and late posttransplant phases. Hence, systemic infusion of regulatory cells potentiates the effects of local adenovirus-IL-4 gene transfer in transplant recipients. Th2-driven up-regulation of protective molecule programs at the graft site, such as of anti-oxidant HO-1 and/or anti-apoptotic Bcl-xL and Bag-1, may contribute, at least in part, to the maintenance of the infectious tolerance pathway in transplant recipients.

Adenoviridae↗
PubMed2000

Quinupristin/Dalfopristin therapy for infections due to vancomycin-resistant Enterococcus faecium.

The efficacy and safety of quinupristin/dalfopristin for treatment of infections due to vancomycin-resistant Enterococcus faecium were evaluated in 24 hospitalized patients with documented infections (19 bacteremias, 5 localized infections) caused by vancomycin-resistant E. faecium that was susceptible to quinupristin/dalfopristin in vitro. Patients received iv quinupristin/dalfopristin at a dosage of either 7.5 mg/kg every 8 h or 5 mg/kg every 8 h. A favorable clinical response (cure or improvement) occurred in 19 (83%) of 23 evaluable patients; bacteriologic eradication occurred in 17 (74%) of 23 evaluable patients. A favorable clinical response was observed in 12 (80%) of 15 patients who were treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h and in 7 (88%) of 8 patients treated with 5 mg/kg of quinupristin/dalfopristin every 8 h. Two of four treatment failures were associated with a decrease in the in vitro susceptibility of vancomycin-resistant E. faecium to quinupristin/dalfopristin. Superinfections developed in 6 patients (26%), but only one was caused by Enterococcus faecalis that was resistant to quinupristin/dalfopristin. Myalgias and arthralgias were the only adverse events related to quinupristin/dalfopristin. These conditions occurred in 8 (33%) of 24 patients and were dose-related (8 cases in 16 patients treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h, no cases in 8 patients treated with 5 mg/kg every 8 h). Mortality associated with vancomycin-resistant E. faecium infection was 17% (4 of 23 patients), whereas mortality from other causes was 52% (12 of 23 patients). These results suggest that quinupristin/dalfopristin is effective as treatment for vancomycin-resistant E. faecium infections in critically ill patients with serious underlying conditions. Except for myalgias and arthralgias at higher dosages, the drug is well-tolerated.

Adolescent↗
PubMed2000

Fas ligand gene transfer prolongs rat renal allograft survival and down-regulates anti-apoptotic Bag-1 in parallel with enhanced Th2-type cytokine expression.

BACKGROUND: Fas ligand (FasL) induces apoptosis of cells bearing Fas receptor, and may play a role in the acquisition of immune privilege. We have previously shown that adenovirus (Ad)-mediated FasL gene transfer significantly prolongs survival in a strongly major histocompatibility complex-incompatible rat kidney allograft model. This study analyzes putative mechanisms of FasL-mediated effects, with particular emphasis on Th1 and Th2 immune activation and Bag-1 expression, a Bcl-2-binding anti-apoptotic protein. METHODS: Kidney transplants were performed in Wistar-Furth to Lewis rat combination. Donor kidneys were perfused in situ with Ad-FasL or Ad-beta-Gal, and then transplanted. Kidney allografts were harvested at days 2, 7, and 56 and were evaluated by hematoxylin and eosin and immunohistochemical staining. The expression of FasL, Bag-1, and Th1/Th2 cytokine genes was assessed by Northern blots, Western blots, and competitive template reverse-transcriptase polymerase chain reaction, respectively. RESULTS: Intragraft expression of FasL was enhanced, whereas that of anti-apoptotic Bag-1 gene was diminished throughout, in Ad-FasL-transduced well-functioning renal allografts, compared with Ad-beta-Gal-treated rejecting controls. In parallel, the expression of mRNA coding for IL-2 and IFN-gamma remained depressed, whereas that of IL-4 and IL-10 reciprocally and progressively increased in the Ad-FasL animal group. CONCLUSIONS: Prolonged survival in Ad-FasL-transduced rat renal allograft model correlates with down-regulation of Bag-1, a novel anti-apoptotic gene, and preferential Th2-type cytokine elaboration profile at the graft site. Because Th1-like cells are sensitive to FasL-mediated cytotoxic effects, T-cell apoptosis may preferentially spare Th2-like cells, with resultant prolonged graft survival.

Animals↗
PubMed2000

Fibronectin-mononuclear cell interactions regulate type 1 helper T cell cytokine network in tolerant transplant recipients.

Fibronectin (FN), expressed primarily by macrophages, endothelial cells, and smooth muscle cells, represents an integral feature of the rejection response in transplant recipients. Here we demonstrate a unique pattern of cellular FN expression in rat recipients of cardiac allografts rendered tolerant in an infectious manner with either nondepleting CD4 mAb or regulatory spleen cells. Unlike in rejecting controls, cellular FN in tolerant hosts was restricted to the graft vessels and no vascular cell adhesion molecule-1 or intercellular adhesion molecule-1 expression could be found, supporting the role of FN in leukocyte sequestration at the graft site. The lack of myocardial FN in tolerant rats, despite dense macrophage infiltration, correlated with profound depression of Th1 (interleukin-2 and interferon-gamma) cytokines. Treatment with CD4-depleting mAb prevented tolerance induction and restored myocardial expression of FN in parallel with marked increase in the expression of interleukin-2 and interferon-gamma mRNA/protein. Furthermore, connective segment-1 peptide-facilitated adjunctive blockade of FN-alpha4beta1 interactions in recipients conditioned with CD4 depleting mAb, significantly depressed intragraft expression of interleukin-2 and interferon-gamma mRNA/protein. Hence, the lack of FN associated with infiltrating leukocytes plays an important role in the maintenance of tolerance in transplant recipients by depressing local expression of Th1 cytokines that otherwise facilitate acute graft rejection.

Animals↗
PubMed2000

Advances in pediatric liver and intestinal transplantation.

BACKGROUND: Significant progress has been made with liver and intestinal transplantation in pediatric patients. Shortage of whole-organ cadaveric grafts has resulted in a high mortality rate for children awaiting transplantation. New surgical procedures such as split-liver transplantation and living-related liver transplantation have evolved over the last decade to maximize donor utilization in pediatric patients. METHODS: In this article we review the current indications and contraindications for liver and intestinal transplantation in children, the surgical innovations to expand an exceedingly small cadaveric liver pool, postoperative management, and the impact on patient and graft survival. RESULTS: Reduced-size liver transplantation provides children with much needed small grafts; however, split-liver transplantation may eliminate the need for reduced-size and living-related liver transplantation except in urgent situations. CONCLUSION: Liver transplantation is a durable procedure that provides excellent long-term survival. The use of living-related and split-liver transplantation has dramatically reduced the waiting periods for children and improved survival. In the past decade significant progress has been made with intestinal transplantation owing to improvements in surgical technique, immunosuppressive agents, and early identification and treatment of postoperative complications.

Adult↗
PubMed2000

Surgical advances in liver transplantation. Living related and split donors.

Surgical innovations to expand an exceedingly small cadaveric liver pool have paved the way for the more complex procedure of adult-to-adult living donation. Although reduced-size liver transplant (RSLT) has provided children and small adults with much needed small size grafts, discarding a part of the liver can no longer be justified in the current era of severe organ shortage. Split liver transplantation may eliminate the need for RSLT and may replace adult-to-adult pediatric donation except in urgent situations. Adult-to-adult living donation is a formidable undertaking that tremendously impacts adult recipients. Adult-to-adult living donation should be approached cautiously to ensure the safety of living donors. Expansion of adult living donation can only be achieved when ethical issues of donation are resolved and long-term donor safety is established.

Adult↗
PubMed2000

Successful orthotopic liver transplantation for lamivudine-associated YMDD mutant hepatitis B virus.

YMDD hepatitis B virus (HBV) mutants emerge in more than one third of patients treated with lamivudine. The development of escape mutants potentially limits the efficacy of this new therapy for chronic HBV infection. Transplant centers may be hesitant to perform orthotopic liver transplantation (OLT) in patients with progressive liver disease who develop the YMDD mutant because of concerns of graft reinfection. We describe a 56-year-old man with chronic liver disease caused by HBV who successfully underwent OLT after the emergence of a YMDD mutant and progressive liver disease. Perioperatively, he received high-dose intravenous hepatitis B immune globulin (HBIG) treatment with continued lamivudine treatment. Thirty-two months after OLT, there was no evidence of HBV reinfection with the use of lamivudine and high-dose HBIG. Our experience suggests that the emergence of a YMDD HBV mutant is not a contraindication to OLT. The combination of lamivudine and high-dose HBIG can protect against reinfection of the hepatic allograft with the YMDD HBV escape mutant.

Hepatitis B virus↗
PubMed2000

An efficacy and cost-effectiveness analysis of combination hepatitis B immune globulin and lamivudine to prevent recurrent hepatitis B after orthotopic liver transplantation compared with hepatitis B immune globulin monotherapy.

Orthotopic liver transplantation (OLT) for hepatitis B virus (HBV) infection was limited until recently by poor graft and patient outcomes caused by recurrent HBV. Long-term immunoprophylaxis with hepatitis B immune globulin (HBIG) dramatically improved post-OLT survival, but recurrent HBV still occurred in up to 36% of the recipients. More recently, combination HBIG and lamivudine has been shown to effectively prevent HBV recurrence in patients post-OLT. The aim of the current study is to determine long-term outcome and cost-effectiveness of using combination HBIG and lamivudine compared with HBIG monotherapy in patients who undergo OLT for HBV. A retrospective chart review identified 59 patients administered combination HBIG and lamivudine and 12 patients administered HBIG monotherapy as primary prophylaxis against recurrent HBV. Lamivudine, 150 mg/d, was administered orally indefinitely. HBIG was administered under a standard protocol (10,000 IU intravenously during the anhepatic phase, then 10,000 IU/d intravenously for 7 days, then 10,000 IU intravenously monthly) indefinitely. A decision-analysis model was developed to evaluate the potential economic impact of prophylaxis against HBV with combination therapy compared with monotherapy. Recurrent HBV was defined as the reappearance of hepatitis B surface antigen (HBsAg) after its initial disappearance post-OLT. In the combination-therapy group, no patient redeveloped serum HBsAg or HBV DNA during mean follow-ups of 459 and 416 days, respectively. In the monotherapy group, 3 patients (25%) had reappearance of HBsAg in serum during a mean follow-up of 663 days. Combination therapy resulted in a dominant, cost-effective strategy with an average cost-effectiveness ratio of $252,111/recurrence prevented compared with $362,570/recurrence prevented in the monotherapy strategy. Combination prophylaxis with HBIG and lamivudine is highly effective in preventing recurrent HBV, may protect against the emergence of resistant mutants, and is significantly more cost-effective than HBIG monotherapy with its associated rate of recurrent HBV.

Adolescent↗
PubMed2000

Endoscopic management of biliary leaks after T-tube removal in liver transplant recipients: nasobiliary drainage versus biliary stenting.

This study presents the long-term sequelae of endoscopic retrograde cholangiopancreatography (ERCP)-managed biliary leakage in patients who underwent orthotopic liver transplantation (OLT) and compares the relative efficacy, safety, and charges of nasobiliary drainage (NBD) versus biliary stenting (BS). We identified all orthotopic liver transplant recipients from January 1, 1993, to December 31, 1997, who had undergone ERCP for biliary leakage. Clinical outcome and charges were calculated on an intention-to-treat basis according to initial endoscopic therapy. Of the 1,166 adult OLTs performed during the study period, 442 patients underwent elective T-tube removal. ERCP was attempted in 69 patients (16%) who developed biliary leakage after T-tube removal. Three patients (5%) in whom initial ERCP was unsuccessful underwent surgery. NBD and BS were used as primary therapy in 45 (68%) and 21 patients (32%), respectively. Three patients initially treated with NBD required reendoscopy or surgery compared with 6 patients initially treated with BS (P <.05). Although not statistically significant, there was a trend toward greater expense in the BS group compared with the NBD group. ERCP is a safe and effective method of managing biliary leakage after T-tube removal in orthotopic liver transplant recipients. However, our results suggest NBD is the preferred method because recurrent leaks were more common in patients treated initially with BS. With prompt use of ERCP, surgery is rarely needed for this complication of OLT.

Bile↗
PubMed2000

Adult-to-adult living-donor liver transplantation: a critical analysis.

Adult-to-adult living-donor liver transplantation is the most recent achievement in the evolution of strategies to increase donor organ supply. Justification of the procedure has evolved from increased organ-waiting times, wait-list morbidity and mortality of adult transplant candidates. Successful application of adult-to-adult living-donor liver transplantation mandates unique surgical, medical, and donor considerations as these procedures predispose to unique complications resulting from anatomic variations, technical considerations, and the transplantation of "partial" grafts. Additionally, because the magnitude of the donor operation is greater and potentially fraught with serious short and long term morbidity and possibly mortality, the utilization of living-donors for adult liver transplantation raises bio-ethical concerns heretofore not encountered. This review explores the current state of adult-to-adult living-donor liver transplantation.

Adult↗
PubMed2000

Predictors of survival after In vivo split liver transplantation: analysis of 110 consecutive patients.

OBJECTIVE: To determine the factors that influence patient survival after in vivo split liver transplantation (SLT). SUMMARY BACKGROUND DATA: Split liver transplantation is effective in expanding the donor pool, and its use reduces the number of deaths in patients awaiting orthotopic liver transplantation. Early SLTs were associated with poor outcomes, and acceptance of the technique has been slow. A better understanding of the factors that influence patient and graft survival would be useful in widening the application of SLT. METHODS: During a 3.5-year period, 55 right and 55 left lateral in vivo split grafts were transplanted in 102 pediatric and adult recipients. The authors' in vivo split technique has been previously described. Median follow-up was 14.5 months. Recipient, donor, and surgical variables were analyzed for their effect on patient survival after SLT. RESULTS: Overall survival rates of patients who received an SLT were not significantly different from those of patients who received whole organ transplants. Survival of left lateral segment recipients, at median follow-up time, was 76% versus 80% in patients receiving a trisegment. Fifty of 102 patients (49%) were high-risk urgent recipients (United Network for Organ Sharing [UNOS] status 1 and 2A) and 52 (51%) were nonurgent recipients (UNOS status 2B, 3). High-risk recipients had a survival rate significantly lower than that of nonurgent recipients. By univariate comparison, two variables-UNOS status and number of transplants per patient-were significantly associated with an increased risk of death. Preoperative recipient mechanical ventilation, preoperative prothrombin time, donor sodium level, donor length of hospital stay, and warm ischemia time approached significance. The type of graft (right vs. left) did not reduce the survival rate after transplantation. Multivariate logistic regression analysis identified UNOS status and length of donor hospital stay as independent predictors of survival. CONCLUSIONS: Patient survival of in vivo SLT is not significantly different from that of whole-organ orthotopic liver transplantation. The variables affecting outcome of in vivo SLT are similar to those in whole-organ transplantation. in vivo SLT should be widely applied to expand a severely depleted donor pool.

Adolescent↗
PubMed2000

Development and evaluation of the Liver Disease Quality of Life instrument in persons with advanced, chronic liver disease--the LDQOL 1.0.

OBJECTIVES: Assessment of health-related quality of life (HRQOL) outcomes in studies of liver disease and liver transplantation is necessary. Reliable and valid disease-targeted HRQOL measures are thus needed. The objective of this study was to develop a reliable and valid self-report HRQOL instrument for ambulatory adults with chronic liver disease. METHODS: The Liver Disease Quality of Life instrument, LDQOL 1.0 (an HRQOL measure that uses the SF-36 as a generic core and 12 disease-targeted multi-item scales) was administered in a multicenter, cross-sectional field test to 221 ambulatory adults with advanced, chronic liver disease referred for primary liver transplantation evaluation. Disease-targeted scales included liver disease-related symptoms, liver disease-related effects on activities of daily living, concentration, memory, sexual functioning, sexual problems, sleep, loneliness, hopelessness, quality of social interaction, health distress, and self-perceived stigma of liver disease. We estimated the internal consistency reliability (Cronbach's alpha) for multi-item scales and construct validity. RESULTS: Interial consistency reliability coefficients were excellent, ranging from 0.62 to 0.95, with 19 of 20 scales >0.70. Multitrait scaling analysis provided strong support for item discrimination across scales, and exploratory factor analysis demonstrated distinguishable physical, mental, and social health dimensions. Significant associations were found between worse HRQOL and worse Child-Pugh class, worse self-rated liver disease severity, and increased number of disability days. CONCLUSIONS: The results of this multicenter field test provide support for the reliability and validity of the LDQOL 1.0 as an HRQOL outcome measure for individuals with chronic liver disease.

Chronic Disease↗
PubMed1999

Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Among persons who receive solid organ transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective. OBJECTIVE: To evaluate the efficacy and safety of prophylactic fluconazole in liver transplant recipients. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-affiliated transplantation center. PATIENTS: 212 liver transplant recipients who received fluconazole (400 mg/d) or placebo until 10 weeks after transplantation. MEASUREMENTS: Fungal colonization, proven superficial or invasive fungal infection, drug-related side effects, and death. RESULTS: Fungal colonization increased in patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003). CONCLUSIONS: Prophylactic fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.

Adolescent↗