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R M Ghobrial

Publications and source records attributed to R M Ghobrial.

At least 19 recordsLinked to original sources
PubMed2006

Split liver transplantation.

Seventy-five thousand Americans develop organ failure each year. Fifteen percent of those on the list for transplantation die while waiting. Several possible mechanisms to expand the organ pool are being pursued including the use of extended criteria donors, living donation, and split deceased donor transplants. Cadaveric organ splitting results from improved understanding of the surgical anatomy of the liver derived from Couinaud. Early efforts focused on reduced-liver transplantation (RLT) reported by both Bismuth and Broelsch in the mid-1980s. These techniques were soon modified to create both a left lateral segment graft appropriate for a pediatric recipient and a right trisegment for an appropriately sized adult. Techniques of split liver transplantation (SLT) were also modified to create living donor liver transplantation. Pichlmayr and Bismuth reported successful split liver transplantation in 1989 and Emond reported a larger series of nine split procedures in 1990. Broelsch and Busuttil described a technical modification in which the split was performed in situ at the donor institution with surgical division completed in the heart beating cadaveric donor. In situ splitting reduces cold ischemia, simplifies identification of biliary and vascular structures, and reduces reperfusion hemorrhage. However, in situ splits require specialized skills, prolonged operating room time, and increased logistical coordination at the donor institution. At UCLA over 120 in situ splits have been performed and this technique is the default when an optimal donor is available. Split liver transplantation now accounts for 10% of adult transplantations at UCLA and 40% of pediatric transplantations.

Adult↗
PubMed2006

Prevalence and risk factors for diabetes mellitus in moderate term survivors of liver transplantation.

The prevalence and risk factors for diabetes mellitus after liver transplantation are not well understood. Thus, we sought to identify independent risk factors for the development of diabetes after liver transplantation using currently accepted medical criteria. We studied the prevalence and risk factors in 253 adult recipients transplanted at UCLA between January 1998 and December 2002. Analysis of the retrospective data was performed using demographic, immunosuppression and liver disease variables. Factors found to be significant on a univariate analysis were further studied in a multivariate analysis. There were 158 men and 95 women in our study. The mean age was 51.4 +/- 11.0 years. The mean [+/- standard deviation (SD) pretransplant body mass index was 26.7 (+/-5.1). Most patients were transplanted for hepatitis C (HCV). The prevalence of diabetes after transplantation was 17.8%. In a multivariate analysis only gender [odds ratio (OR) = 0.37; p = 0.02] was independently predictive of the development of diabetes. This study in a large liver transplant recipient population identifies male gender as an independent risk factor for the development of diabetes. Follow-up studies are needed to assess the impact of diabetes, and its intervention on post-transplant morbidity and mortality.

Diabetes Mellitus↗
PubMed2005

Donor MHC class I peptides in conjunction with self-epitopes induce donor-specific tolerance in a dose-dependent manner but unable to abrogate chronic rejection.

Understanding specific tolerance mechanisms is a primary goal of transplantation science. We have previously shown that hosts treated with MHC class I protein have donor sequences in the alpha1-helix of the alpha1 domain on a background of self-epitopes, resulting in the development of donor-specific tolerance. However, the nature of class I alloantigenic determinants that regulate the alloimmune response remains unclear. The alpha1-helical sequence of RT1.A,1 which shares RT1.A(u) sequences, was substituted in the RT1.A(a) molecule to produce the composite [alpha1h(l/u)]-RT1.A(a) MHC class I allochimeric molecule. Immunodominant epitopes were identified within the hypervariable region of the alpha1 domain of RT1.A(a) (ACI), RT1.Al (Lewis, LEW), and RT1.A(u) (Wistar Furth [WF]). To clarify the mechanisms of tolerance development through presentation of donor-type immunogenic epitopes and cryptic self-epitopes we used synthetic peptides corresponding to donor immunogenic determinants with peptides derived from recipient self-sequences (RT1.A(a)--aa 10 to 49 P1 and 91 to 120 P3; and P2 RT1.A(l/u) 50 to 90). ACI recipients of LEW and WF cardiac allografts were injected through the portal vein (PV) at day 0 with four doses (2, 0.5, 0.25, and 0.125 mg/rat) of three peptide mixtures in conjunction with subtherapeutic CsA (10 mg/kg for 3 days). Allograft survival was strongly dose-dependent. Only low-dose regimens were consistent in tolerance induction, but such therapy did not abrogate development of chronic rejection (CR), unlike allochimeric therapy with soluble MHC class I protein. Different effects of protein or synthetic peptide therapies on development of CR suggest that development of specific tolerance is an active immunologic process and it depends on the form of allogeneic epitopes presented.

Animals↗
PubMed2005

Identification of early tolerance regulator genes induced by allochimeric therapy using microarray-based genomewide scan.

We have demonstrated that peri- or postoperative delivery of allochimeric [a1h(u)]-RT1.A(a) class I major histocompatibility complex molecules with donor-type (RT1A(u)) immunogenic epitopes presented in recipient-type (RT1A(a)) sequences induced donor-specific tolerance in ACI (RT1a) recipients of WF (RT1u) heart allografts. A genomic scan during the early posttransplant period was performed to elucidate the underlying operative mechanisms. A rat genome study after transplantation was carefully designed using Affymetrix Rat Genome 230 2.0 Array. The allochimeric treatment group is 3-day cyclosporine (CsA)-treated ACI recipients that accepted Wistar Furth RT1u cardiac allografts with postoperative dosage of allochimeric molecules, while the control is 3-day CsA-treated ACI recipients of WF cardiac allografts. All the samples were harvested 5 days after heart transplant as the early stage of tolerance detection. Following array data normalization and modeling, we compared the above two treatment groups and identified a total of 250 tolerance regulator genes induced by allochimeric molecules only.

Animals↗
PubMed2003

Biliary complications after adult living donor liver transplantation.

We evaluated the causes and outcomes of biliary complications occurring after adult living donor liver transplantation (ALDLT) in a large patient cohort. Among 46 patients who underwent ALDLT at two different centers early bile duct complications occurred in 11 recipients (23.9%), consisting of leakage from the anastomotic site or from the cut surface of the liver. T-tube-associated biliary complications occurred in four patients. Late complications, primarily anastomotic strictures, occurred in 15 patients (32.6%) at 6.7+/-3.5 months after transplantation. Surgical intervention was generally required for early biliary complications but rarely necessary for late complications. No graft loss was caused by biliary complications. Thus, ALDLT is accompanied by a high rate of biliary complications, which in our series have been of low severity. However, long-term effects on graft function are not yet known.

Adult↗
PubMed2003

Treatment for recurrent hepatitis C.

Hepatitis C virus (HCV) has become the leading cause for orthotopic liver transplantation (OLT) worldwide. OLT for HCV has been associated with good survival outcomes. HCV recurrence has been universally documented in allograft recipients within the 1st year post-transplantation. Slow but steady progression of recurrent disease has resulted in allograft failure in a small number of patients in the short-term and may cause allograft destruction in a larger number of patients in the long-term. A pressing need has therefore developed to identify antiviral regimens to treat or prevent recurrent disease. Unfortunately, current antiviral therapy has limited efficacy and is associated with multiple adverse events. Therefore, a concerted effort has been directed toward identification of the patient populations who are most susceptible to the deleterious effects of recurrent disease or those who are most likely to benefit from antiviral treatment. These patient populations may therefore be selected for antiviral therapeutic intervention. Unsuccessful antiviral therapy or the development of allograft may be an indication for retransplantation (re-OLT), a procedure that is not widely accepted since it is associated with high morbidity and mortality. Nevertheless, the appropriate and timely utilization of re-OLT may achieve good results in selected patients. This chapter will outline the current understanding and the results of medical and surgical therapeutic options for recurrent HCV following OLT.

Antiviral Agents↗
PubMed2001

Early graft function after pediatric liver transplantation: comparison between in situ split liver grafts and living-related liver grafts.

BACKGROUND: The systematic application of living-related and cadaveric, in situ split-liver transplantation has helped to alleviate the critical shortage of suitable-sized, pediatric donors. Undoubtedly, both techniques are beneficial and advantageous; however, the superiority of either graft source has not been demonstrated directly. Because of the potential living-donor risks, we reserve the living donor as the last graft option for pediatric recipients awaiting liver transplantation. Inasmuch as no direct comparison between these two graft types has been performed, we sought to perform a comparative analysis of the functional outcomes of left lateral segmental grafts procured from these donor sources to determine whether differences do exist. METHODS: A retrospective analysis of all liver transplants performed at a single institution between February 1984 and January 1999 was undertaken. Only pediatric (<18 years) recipients of left lateral segmental grafts procured from either living-related (LRD) or cadaveric, in situ split-liver (SLD) donors were included. A detailed analysis of preoperative, intraoperative, and postoperative variables was undertaken. Survival was estimated using the Kaplan-Meier method, and comparison of variables between groups was undertaken using the t test of Wilcoxon rank sum test. RESULTS: There were no significant differences in the preoperative variables between the 39 recipients of SLD grafts and 34 recipients of LRD grafts. The donors did differ significantly in mean age, ABO blood group matching, and preoperative liver function testing. Postoperative liver function testing revealed significant early differences in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, prothrombin time, and alkaline phosphatase, with grafts from LRD performing better than those from SLD. SLD grafts also had significantly longer ischemia times and a higher incidence of graft loss owing to primary nonfunction and technical complications (9 vs. 2, P<0.05). However, six of these graft losses in the SLD group were because of technical or immunologic causes, which, theoretically, should not differ between the two groups. Furthermore, these graft losses did not negatively impact early patient survival as most patients were successfully rescued with retransplantation (30-day actuarial survival, 97.1% SLD vs. 94.1% LRD, P=0.745). In the surviving grafts, the early differences in liver function variables normalized. CONCLUSIONS: Inherent differences in both donor sources exist and account for differences seen in preoperative and intraoperative variables. Segmental grafts from LRD clearly performed better in the first week after transplantation as demonstrated by lower liver function variables and less graft loss to primary nonfunction. However, the intermediate function (7-30 days) of both grafts did not differ, and the early graft losses did not translate into patient death. Although minimal living-donor morbidity was seen in this series, the use of this donor type still carries a finite risk. We therefore will continue to use SLD as the primary graft source for pediatric patients awaiting liver transplantation.

Adult↗
PubMed2001

Allochimeric class I MHC molecules prevent chronic rejection and attenuate alloantibody responses.

BACKGROUND: We have shown that treatment with molecularly engineered, allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigens bearing donor-type Wistar-Furth (WF, RT1.Au) amino acid substitutions for host-type ACI (RTI.Aa) sequences in the alpha1-helical region induces donor-specific tolerance to cardiac allografts in rat recipients. This study examined the effect of allochimeric molecules on the development of chronic rejection. METHODS: Allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigenic extracts (1 mg) were administered via the portal vein into ACI recipients of WF hearts on the day of transplantation in conjunction with subtherapeutic oral cyclosporine (CsA, 10 mg/kg/day, days 0-2). Control groups included recipients of syngeneic grafts and ACI recipients of WF heart allografts treated with high-dose CsA (10 mg/kg/day, days 0-6). RESULTS: WF hearts in ACI rats receiving 7 days of CsA exhibited myocardial fibrosis, perivascular inflammation, and intimal hyperplasia at day 80. At day 120, these grafts displayed severe chronic rejection with global architectural disorganization, ventricular fibrosis, intimal hyperplasia, and progressive luminal narrowing. In contrast, WF hearts in rats treated with [alpha1 hl/u]-RT1.Aa molecules revealed only mild perivascular fibrosis, minimal intimal thickening, and preserved myocardial architecture. Alloantibody analysis demonstrated no IgM alloantibodies in all groups. An attenuated, but detectable, anti-WF IgG response was present in recipients receiving allochimeric molecules, with IgG1 and IgG2a subclasses predominating. Immunohistochemical analysis of allografts demonstrated minimal T cell infiltration and IgG binding to vascular endothelium. CONCLUSION: Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.

Amino Acid Sequence↗
PubMed2001

Technical challenges of hepatic venous outflow reconstruction in right lobe adult living donor liver transplantation.

A right lobe graft that is drained by the right hepatic vein (RHV) is obtained by transecting the liver on the right side of the middle hepatic vein (MHV). On occasion, a small RHV that only drains a portion of the right lobe, with the predominant outflow achieved by the MHV, is encountered. If such variation is not recognized while performing right lobe liver transplantation and the RHV only is used for reconstruction, venous outflow obstruction with subsequent graft congestion and eventual graft failure will occur. Additionally, preservation of the main MHV and its branch drainage of the left lobe is crucial to avoid outflow blockage to the remaining segment 4 in the donor. We report 4 cases showing a variant type of small RHV and large MHV branch that drain not only segments 5 and 8, but also segments 6 and 7. These variations were simultaneously associated with a large-caliber inferior RHV that also required reconstruction. The methods used to diagnose such anatomic variations and the techniques for reconstruction in the donor and recipient are described.

Adult↗
PubMed2001

Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature.

Cholangiocellular carcinoma (CCC) is a biliary malignancy that frequently presents in advanced unresectable stages. The role of liver transplantation (LT) as a surgical modality is unclear. The goal of this study is to evaluate outcomes of patients with CCC undergoing LT. A retrospective analysis of all patients undergoing LT was undertaken. Only those patients with the pathological diagnosis of CCC were included on the study. Patients were divided into two groups based on primary tumor location: extrahepatic (EH)-CCC and intrahepatic (IH)-CCC. The Kaplan-Meier method was used to calculate overall and recurrence-free survival. Log-rank analysis was used to determine the significance of prognostic variables. Twenty-five patients were identified: 9 patients with EH-CCC (5 patients, Klatskin-type; 2 patients, the middle third; and 2 patients, the distal third) and 16 patients with IH-CCC. Mean age was 47.1 +/- 10.6 years. There were 14 men and 11 women. Tumor stage was local (stages I and II; n = 9) or advanced (stages III and IV; n = 16). Overall and disease-free survival rates were 71% and 67% at 1 year and 35% and 32% at 3 years, respectively. Analysis of variables showed statistically significant improved outcomes (P < .05) for the absence of contiguous organ invasion at LT, small tumor size, and single tumor foci. This study indicates that early survival after LT for CCC is acceptable. Three-year disease-free survival is achieved in approximately 30% of patients. These outcomes can be improved by applying strict selection criteria based on prognostic variables identified in this study.

Adult↗
PubMed2001

A 10-year experience of liver transplantation for hepatitis C: analysis of factors determining outcome in over 500 patients.

OBJECTIVE: To determine the factors affecting the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV) and to identify models that predict patient and graft survival. SUMMARY BACKGROUND DATA: The national epidemic of HCV infection has become the leading cause of hepatic failure that requires OLT. Rapidly increasing demands for OLT and depleted donor organ pools mandate appropriate selection of patients and donors. Such selection should be guided by a better understanding of the factors that influence the outcome of OLT. METHODS: The authors conducted a retrospective review of 510 patients who underwent OLT for HCV during the past decade. Seven donor, 10 recipient, and 2 operative variables that may affect outcome were dichotomized at the median for univariate screening. Factors that achieved a probability value less than 0.2 or that were thought to be relevant were entered into a stepdown Cox proportional hazard regression model. RESULTS: Overall patient and graft survival rates at 1, 5, and 10 years were 84%, 68%, and 60% and 73%, 56%, and 49%, respectively. Overall median time to HCV recurrence was 34 months after transplantation. Neither HCV recurrence nor HCV-positive donor status significantly decreased patient and graft survival rates by Kaplan-Meier analysis. However, use of HCV-positive donors reduced the median time of recurrence to 22.9 months compared with 35.7 months after transplantation of HCV-negative livers. Stratification of patients into five subgroups, based on time of recurrence, revealed that early HCV recurrence was associated with significantly increased rates of patient death and graft loss. Donor, recipient, and operative variables that may affect OLT outcome were analyzed. On univariate analysis, recipient age, serum creatinine, donor length of hospital stay, donor female gender, United Network for Organ Sharing (UNOS) status of recipient, and presence of hepatocellular cancer affected the outcome of OLT. Elevation of pretransplant HCV RNA was associated with an increased risk of graft loss. Of 15 variables considered by multivariate Cox regression analysis, recipient age, UNOS status, donor gender, and log creatinine were simultaneous significant predictors for patient survival. Simultaneously significant factors for graft failure included log creatinine, log alanine transaminase, log aspartate transaminase, UNOS status, donor gender, and warm ischemia time. These variables were therefore entered into prognostic models for patient and graft survival. CONCLUSION: The earlier the recurrence of HCV, the greater the impact on patient and graft survival. The use of HCV-positive donors may accelerate HCV recurrence, and they should be used judiciously. Patient survival at the time of transplantation is predicted by donor gender, UNOS status, serum creatinine, and recipient age. Graft survival is affected by donor gender, warm ischemia time, and pretransplant patient condition. The authors' current survival prognostic models require further multicenter validation.

Adult↗
PubMed2001

A cost-effectiveness analysis of biliary anastomosis with or without T-tube after orthotopic liver transplantation.

Biliary reconstruction continues to be a major source of morbidity following orthotopic liver transplantation. We wished to determine if choledochocholedochostomy without a T-tube was associated with fewer biliary complications and was less costly than choledochocholedochostomy with a T-tube. A retrospective cohort study of patients who underwent liver transplantation was performed. Patients were stratified into two groups: group I had bile duct reconstruction with T-tube and group II did not have a T-tube. The results were interpreted on an intention-to-treat analysis. We identified 147 adult patients who underwent initial liver transplantation. There were 76 patients in group I and 71 patients in group II. There were no statistical differences between the two groups regarding underlying cause of liver disease, patient age, gender or United Network for Organ Sharing status. As the decision to use a T-tube was made at the time of surgery, the two groups may not be strictly comparable. The mean hospital stay was longer in group I (31.1 +/- 27.9d) than in group II (18.8 +/- 15.5d) (p = 0.001). Biliary complications were statistically more frequent in patients from group I patients (25/76, 32.9%) than in patients from group II (11/71, 15.5%) (p = 0.01). There was a trend for the costs associated with diagnostic and therapeutic procedures for the management of biliary complications to be greater for group I than for group II, although this was not statistically significant (p = 0.235). Our study suggests choledochocholedochostomy without T-tube reconstruction is the preferred strategy for biliary reconstruction in orthotopic liver transplantation. It is not only associated with fewer biliary complications, but also less costly than using choledochocholedochostomy over a T-tube. Randomized prospective studies are needed to confirm our results.

Anastomosis, Surgical↗
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

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↗