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Biomedical subjects

Ronald W Busuttil

Publications and source records attributed to Ronald W Busuttil.

At least 19 recordsLinked to original sources
PubMed2007

Postresection hepatic failure: successful treatment with liver transplantation.

Postoperative liver failure (PLF) is a rare but often fatal complication of major hepatic resection. Use of orthotopic liver transplantation (OLT) for PLF remains undefined. We conducted a retrospective review of 435 patients who underwent hepatic resection between 1990 and 2004; 9 of them (2.0%) developed PLF. Indications for resection included primary hepatic malignancies (8), colonic metastases (2), and echinococcic cyst (1); all resections were multisegmental, 6 were extended, and 2 were lobectomies. A total of 7 patients underwent OLT at a mean of 25 days after resection. Patients developing PLF had significantly lower preoperative platelet counts and significant elevations of total bilirubin, direct bilirubin, prothrombin time, and international normalized ratio (INR) by postoperative day 2. Pathological cirrhosis and extended right lobectomy were associated with significantly increased risk of PLF. Following OLT, there were no in-hospital deaths, but 1 patient required retransplantation for primary nonfunction. Mean survival with and without OLT was 42.2 and 1.4 months, respectively (P = 0.03). Following OLT, 1- and 5-yr patient survivals were 88% and 40%, respectively; 1- and 5-yr graft survivals were 75% and 34%, respectively. In conclusion, patients with low platelets, biopsy-proven cirrhosis, or those undergoing extended resection are at increased risk for PLF. OLT for PLF has significant morbidity but allows salvage of an otherwise fatal condition.

Adult↗
PubMed2006

Basal rather than induced heme oxygenase-1 levels are crucial in the antioxidant cytoprotection.

Heme oxygenase-1 (HO-1) overexpression protects against tissue injury in many inflammatory processes, including ischemia/reperfusion injury (IRI). This study evaluated whether genetically decreased HO-1 levels affected susceptibility to liver IRI. Partial warm ischemia was produced in hepatic lobes for 90 min followed by 6 h of reperfusion in heterozygous HO-1 knockout (HO-1(+/-)) and HO-1(+/+) wild-type (WT) mice. HO-1(+/-) mice demonstrated reduced HO-1 mRNA/protein levels at baseline and postreperfusion. This corresponded with increased hepatocellular damage in HO-1(+/-) mice, compared with WT. HO-1(+/-) mice revealed enhanced neutrophil infiltration and proinflammatory cytokine (TNF-alpha, IL-6, and IFN-gamma) induction, as well as an increase of intrahepatic apoptotic TUNEL(+) cells with enhanced expression of proapoptotic genes (Bax/cleaved caspase-3). We used cobalt protoporphyrin (CoPP) treatment to evaluate the effect of increased baseline HO-1 levels in both WT and HO-1(+/-) mice. CoPP treatment increased HO-1 expression in both animal groups, which correlated with a lower degree of hepatic damage. However, HO-1 mRNA/protein levels were still lower in HO-1(+/-) mice, which failed to achieve the degree of antioxidant hepatoprotection seen in CoPP-treated WT. Although the baseline and postreperfusion HO-1 levels correlated with the degree of protection, the HO-1 fold induction correlated instead with the degree of damage. Thus, basal HO-1 levels are more critical than the ability to up-regulate HO-1 in response to the IRI and may also predict the success of pharmacologically induced cytoprotection. This model provides an opportunity to further our understanding of HO-1 in stress defense mechanisms and design new regimens to prevent IRI.

Animals↗
PubMed2006

Incisional hernia after liver transplantation.

BACKGROUND: Incisional hernia is a potential complication of orthotopic liver transplantation (OLT), with various options for repair. STUDY DESIGN: We conducted a retrospective review of a series of adult patients with incisional hernias after OLT to identify risk factors and to compare methods of repair. RESULTS: Incisional hernia repair was performed in 44 of 959 patients (4.6%) who underwent OLT from 1999 to 2005. Mean age at time of OLT was 53 years, and 73% were men. One or more complications of OLT occurred in 33 patients (75%) and included reoperation for bile leak or hemoperitoneum (34%), pulmonary problems (27%), early acute rejection (7%), and severe ascites and retransplantation (5% each). Incisional hernia was diagnosed at 419 days (range 62 to 1,524 days) and repaired at 471 days (range 109 to 1,581 days) after OLT. Presentation included pain or discomfort (78%) and incarceration or strangulation (5%); 17% were asymptomatic. Herniorrhaphy techniques included fascial repair with onlay polypropylene mesh reinforcement (n=25, 57%); fascial repair only (n=15, 34%); or inlay mesh sewn to fascial edges (n=4, 9%). Complications of repair included recurrence in seven patients (16%) and wound infection and seroma in one patient each. Recurrence occurred in five patients with primary repair and two with mesh techniques (33% versus 6%, p=0.04). CONCLUSIONS: Incisional hernia is a late complication of OLT for which male gender and early post-OLT complications are risk factors. Repair is safe when undertaken after acute problems have resolved and is best accomplished using mesh reinforcement of autologous tissue.

Adult↗
PubMed2006

CD4+ T regulatory cell induction and function in transplant recipients after CD154 blockade is TLR4 independent.

Although the role of CD4(+) T regulatory cells (Treg) in transplantation tolerance has been established, putative mechanisms of Treg induction and function in vivo remain unclear. TLR4 signaling has been implicated in the regulation of CD4(+)CD25(+) Treg functions recently. In this study, we first examined the role of recipient TLR4 in the acquisition of operational CD4(+) Treg following CD154 blockade in a murine cardiac transplant model. Then, we determined whether TLR4 activation in allograft tolerant recipients would reverse alloimmune suppression mediated by CD4(+) Treg. We document that donor-specific immune tolerance was readily induced in TLR4-deficient recipients by a single dose of anti-CD154 mAb, similar to wild-type counterparts. The function and phenotype of CD4(+) Treg in both wild-type and TLR4 knockout long-term hosts was demonstrated by a series of depletion experiments examining their ability to suppress the rejection of secondary donor-type test skin grafts and to inhibit alloreactive CD8(+) T cell activation in vivo. Furthermore, TLR4 activation in tolerant recipients following exogenous LPS infusion in conjunction with donor-type skin graft challenge, failed to break Treg-mediated immune suppression. In conclusion, our data reveals a distinctive property of CD4(+) Treg in tolerant allograft recipients, whose induction and function are independent of TLR4 signaling.

Animals↗
PubMed2006

CXCR3+CD4+ T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury.

Ischemia-reperfusion injury (IRI), an innate immune-dominated inflammatory response, develops in the absence of exogenous Ags. The recently highlighted role of T cells in IRI raises a question as to how T lymphocytes interact with the innate immune system and function with no Ag stimulation. This study dissected the mechanism of innate immune-induced T cell recruitment and activation in rat syngeneic orthotopic liver transplantation (OLT) model. Liver IRI was induced after cold storage (24-36 h) at 4 degrees C in University of Wisconsin solution. Gene products contributing to IRI were identified by cDNA microarray at 4-h posttransplant. IRI triggered increased intrahepatic expression of CXCL10, along with CXCL9 and 11. The significance of CXCR3 ligand induction was documented by the ability of neutralizing anti-CXCR3 Ab treatment to ameliorate hepatocellular damage and improve 14-day survival of 30-h cold-stored OLTs (95 vs 40% in controls; p < 0.01). Immunohistology analysis confirmed reduced CXCR3+ and CD4+ T cell infiltration in OLTs after treatment. Interestingly, anti-CXCR3 Ab did not suppress innate immune activation in the liver, as evidenced by increased levels of IL-1beta, IL-6, inducible NO synthase, and multiple neutrophil/monokine-targeted chemokine programs. In conclusion, this study demonstrates a novel mechanism of T cell recruitment and function in the absence of exogenous Ag stimulation. By documenting that the execution of innate immune function requires CXCR3+CD4+ T cells, it highlights the critical role of CXCR3 chemokine biology for the continuum of innate to adaptive immunity in the pathophysiology of liver IRI.

Amino Acid Sequence↗
PubMed2006

Hepatocellular carcinoma: microwave ablation with multiple straight and loop antenna clusters--pilot comparison with pathologic findings.

The purpose of this study was to evaluate the clinical implementation of triangular and spherical designs for simultaneous multiple-antenna ablation of human hepatocellular carcinoma (HCC) with a recently engineered microwave coagulation system. Institutional review board approval and informed consent were obtained, and the study was compliant with HIPAA requirements. Nine patients (five men, four women; age range, 53-79 years; mean age, 66.2 years) with resectable HCC (diameter, 2.9-6.0 cm; mean, 4.2 cm) underwent intraoperative ultrasonography-guided tumor ablation followed by resection and pathologic examination. Standard single-straight (n = 2), triangular triple-straight (n = 4), and spherical triple-loop (n = 3) antenna configurations produced mean estimated coagulation volumes of 16.7, 51.7, and 54.3 cm(3), respectively, during a single concurrent 5-10-minute ablation cycle. The triple-loop configuration yielded the most uniformly round ablation shape. Simultaneous activation of multiple straight or loop antennae is a potentially promising technique for rapid and effective treatment of large HCCs.

Aged↗
PubMed2006

Molecular characterization of rat leukocyte P-selectin glycoprotein ligand-1 and effect of its blockade: protection from ischemia-reperfusion injury in liver transplantation.

P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial tethering of leukocytes to activated platelets and endothelium. We report molecular cloning and characterization of the rat PSGL-1 gene. A neutralizing Ab was generated, and its binding epitope was mapped to the N-terminal binding region of rat PSGL-1. We examined the effects of early PSGL-1 blockade in rat liver models of cold ischemia, followed by ex vivo reperfusion or transplantation (orthotopic liver transplantation (OLT)) using an anti-PSGL-1 Ab with diminished Fc-mediated effector function. In the ex vivo hepatic cold ischemia and reperfusion model, pretreatment with anti-PSGL-1 Ab improved portal venous flow, increased bile production, and decreased hepatocellular damage. Rat pretreatment with anti-PSGL-1 Ab prevented hepatic insult in a model of cold ischemia, followed by OLT, as assessed by 1) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic-pyruvic transaminase levels), and ameliorated histological features of ischemia/reperfusion injury, consistent with extended OLT survival; 2) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P-selectin, ED-1, CD3, and OX-62 cells; 3) inhibited expression of proinflammatory cytokine genes (TNF-alpha, IL-1beta, IL-6, IFN-gamma, and IL-2); and 4) prevented hepatic apoptosis accompanied by up-regulation of antiapoptotic Bcl-2/Bcl-xL protective genes. Thus, targeting PSGL-1 with a blocking Ab that has diminished Fc-mediated effector function is a simple and effective strategy that provides the rationale for novel therapeutic approaches to maximize the organ donor pool through the safer use of liver transplants despite prolonged periods of cold ischemia.

Amino Acid Sequence↗
PubMed2006

Long-term analysis of combined liver and kidney transplantation at a single center.

OBJECTIVE: To analyze use of combined liver and kidney transplantation (CLKT) for patients with chronic primary diseases of both organs and for patients with hepatorenal syndrome. DESIGN: Retrospective case series. SETTING: Multiorgan transplantation service in a large university medical center. PATIENTS: A total of 98 patients underwent 99 CLKTs during a 16-year period; 76 had primary renal diseases, and 22 had hepatorenal syndrome. Patients receiving isolated liver and kidney transplants were analyzed for comparison. MAIN OUTCOME MEASURES: Patient and graft survival, rejection rates, and need for hemodialysis before and after transplantation. RESULTS: Overall patient survival was 76%, 72%, and 70% at 1, 3, and 5 years, respectively; liver graft survival was 70%, 65%, and 65%; and kidney graft survival was 76%, 72%, and 70%. No risk factors analyzed for recipients or donors were associated significantly with early posttransplantation mortality or graft loss. In 28 patients who received monoclonal antibody induction therapy with interleukin 2 blockers, there were significantly fewer episodes of acute liver rejection. For patients with hepatorenal syndrome, CLKT did not confer a survival advantage over liver-only transplantation (1-year patient survival was 72% vs 66%; P = .88). The 1-year acute kidney rejection rate in the adult CLKT group was 14% vs 23% in a 5-year cadaveric renal transplantation cohort (P<.01). CONCLUSIONS: First, CLKT is indicated in patients with dual organ disease and achieves excellent results. Second, CLKT for hepatorenal syndrome is indicated in patients receiving hemodialysis for longer than 8 weeks and confers advantages in patient survival and use of hospital resources. Third, the liver is immunoprotective for the kidney.

Adolescent↗
PubMed2006

Preoperative characteristics and intraoperative transfusion and vasopressor requirements in patients with low vs. high MELD scores.

Recent changes in organ allocation based on the model for end-stage liver disease (MELD) prioritize the most ill patients on the waiting list for liver transplantation. While patients undergoing liver transplantation in the MELD era are more acutely ill, the impact of the policy changes on perioperative management has not been completely assessed. We retrospectively reviewed the records of 124 primary adult liver transplant patients. Patients were divided into low (< or = 30) and high MELD (>30) score groups. Preoperative characteristics and intraoperative management were compared between the 2 groups. Patients with high MELD scores had lower baseline hematocrit and fibrinogen levels and were more likely to require ventilatory and vasopressor support before transplantation. Intraoperative transfusion requirements and use of vasopressors were also significantly increased in patients with high MELD scores compared to patients with low MELD scores. In conclusion, these data suggest that pretransplant MELD scores provide important information for perioperative management of patients undergoing liver transplantation.

Adult↗
PubMed2006

Portocaval hemitransposition in pediatric liver transplant recipients: a single-center experience.

Few studies have reported a series of patients who have undergone portocaval hemitransposition at the time of orthotopic liver transplantation (OLT). Furthermore, no series report the outcome of pediatric patients who required the procedure. This work analyzes the experience with portocaval hemitransposition in the pediatric liver transplant population at a single center since the initial description of the procedure. We carried out a retrospective analysis of all pediatric liver transplants performed in our institution during the 8-year period from January 1, 1997, to December 31, 2004. Of 320 pediatric patients who received OLT during the study period, 7 underwent portocaval hemitransposition (2.2%). Five of the patients had biliary atresia. Four grafts were whole cadaveric livers, while the remaining 4 were left lateral segments from either in situ cadaveric split (n = 3) or living donation (n = 1). One patient received a whole cadaveric allograft and was retransplanted with a segment 2/3 graft; in both cases portocaval hemitransposition was utilized. Average warm ischemia time was 54 +/- 16 minutes. Three patients had primary nonfunction of the allograft; 2 were retransplanted with successful outcome, and the remaining patient died before retransplantation. Another patient died from recurrent disease. Four of 7 are long-term survivors and demonstrate good liver function as long as 8 years posttransplant. In conclusions, long-term survival is possible following OLT with portocaval hemitransposition in pediatric patients. However, rates of primary graft nonfunction can be high. Appropriate selection of recipient and type of donor graft are essential for good outcomes. Portocaval hemitransposition should be used cautiously and as a last resort to establish portovenous inflow.

Adult↗
PubMed2006

Collagenase and surgical disease.

Collagen types I, II, and III are the most abundant extracellular matrix (ECM) proteins. Collagenase is a member of the matrix metalloproteinase (MMP) family of enzymes, and is the principal enzyme involved with collagen degradation. Cellular-ECM interactions are vitally important to tissue structure and function. In this review, we summarize recent work that highlights the role of collagenase in ECM remodeling and repair, and further report that alterations of collagenase expression, function, and/or regulation are found in many diverse disease states, including aortic aneurysms, tumor invasiveness and their metastases, and hernias. Collagenase is intimately involved in many surgical diseases, and represents a potential target for therapy.

Animals↗
PubMed2006

Optimal utilization of donor grafts with extended criteria: a single-center experience in over 1000 liver transplants.

OBJECTIVE: Severely limited organ resources mandate maximum utilization of donor allografts for orthotopic liver transplantation (OLT). This work aimed to identify factors that impact survival outcomes for extended criteria donors (ECD) and developed an ECD scoring system to facilitate graft-recipient matching and optimize utilization of ECDs. METHODS: Retrospective analysis of over 1000 primary adult OLTs at UCLA. Extended criteria (EC) considered included donor age (>55 years), donor hospital stay (>5 days), cold ischemia time (>10 hours), and warm ischemia time (>40 minutes). One point was assigned for each extended criterion. Cox proportional hazard regression model was used for multivariate analysis. RESULTS: Of 1153 allografts considered in the study, 568 organs exhibited no extended criteria (0 score), while 429, 135 and 21 donor allografts exhibited an EC score of 1, 2 and 3, respectively. Overall 1-year patient survival rates were 88%, 82%, 77% and 48% for recipients with EC scores of 0, 1, 2 and 3 respectively (P < 0.001). Adjusting for recipient age and urgency at the time of transplantation, multivariate analysis identified an ascending mortality risk ratio of 1.4 and 1.8 compared to a score of 0 for an EC score of 1, and 2 (P < 0.01) respectively. In contrast, an EC score of 3 was associated with a mortality risk ratio of 4.5 (P < 0.001). Further, advanced recipient age linearly increased the death hazard ratio, while an urgent recipient status increased the risk ratio of death by 50%. CONCLUSIONS: Extended criteria donors can be scored using readily available parameters. Optimizing perioperative variables and matching ECD allografts to appropriately selected recipients are crucial to maintain acceptable outcomes and represent a preferable alternative to both high waiting list mortality and to a potentially futile transplant that utilizes an ECD for a critically ill recipient.

Adult↗
PubMed2006

Effect of nonviral factors on hepatitis C recurrence after liver transplantation.

OBJECTIVE: Hepatitis C (HCV) is now the most common indication for orthotopic liver transplantation (OLT). While graft reinfection remains universal, progression to graft cirrhosis is highly variable. This study examined donor, recipient, and operative variables to identify factors that affect recurrence of HCV post-OLT to facilitate graft-recipient matching. METHODS: Retrospective review of 307 patients who underwent OLT for HCV over a 10-year period at our center. Recurrence of HCV was identified by the presence of biochemical graft dysfunction and concurrent liver biopsy showing diagnostic pathologic features. Time to recurrence was the endpoint for statistical analysis. Five donor, 6 recipient, and 2 operative variables that may affect recurrence were analyzed by univariate comparison and Cox proportional hazard regression models. RESULTS: Recurrence-free survival in the 307 study patients was 69% and 34% at 1 and 5 years, respectively. Four predictive variables related to either donor or recipient characteristics were identified. Advanced donor age, prolonged donor hospitalization, increasing recipient age, and elevated recipient MELD scores were found to increase the relative risk of HCV recurrence. Examination of HLA disparity between donors and recipients demonstrated no correlation between class I or class II mismatches and recurrence-free survival. CONCLUSIONS: We have identified donor and recipient characteristics that significantly predict hepatitis C recurrence following liver transplantation. These factors are identifiable before transplant and, if considered when matching donors to HCV recipients, may decrease the incidence of HCV recurrence after OLT. A change in the current national liver allocation system would be needed to realize the full value of this benefit.

Adult↗
PubMed2006

Intraoperative hypokalemia in pediatric liver transplantation: incidence and risk factors.

In this retrospective study of 268 children undergoing liver transplantation, we investigated the incidence of intraoperative potassium (K+) disturbances and the risk factors for hypokalemia in the preperfusion and postreperfusion periods. Overall, hypokalemia was the predominant disturbance, occurring in 72.0% of pediatric patients during liver transplantation. Hypokalemia was more common during the postreperfusion period than the prereperfusion period. Hyperkalemia, though a commonly cited complication, was infrequent during pediatric liver transplantation. Using multivariate logistic regression analysis, baseline serum K+ < or =3.5 mmol/L, base excess >5 mmol/L, and creatinine < or =0.5 mg/dL were found to be predictors for hypokalemia in the prereperfusion period; and body weight < or =15 kg, K+ < or =3.5 mmol/L, fresh-frozen plasma transfusion >90 mL/kg, and absence of ascites at surgery were independent predictors for hypokalemia in the postreperfusion period. These findings support the use of K+ replacement to maintain normokalemia and avoid the potential complications related to hypokalemia in pediatric liver transplantation, especially in children with the risk factors for hypokalemia.

Adolescent↗
PubMed2006

The status of liver transplantation for hepatitis C.

The hepatitis C virus (HCV) infects 3% of the world's population, or approximately 170 million people. Most of those acutely infected progress to chronic infection and are unresponsive to existing antiviral treatment. Over a 20-year period, chronic HCV infection leads to cirrhosis and the sequelae of end-stage liver disease, including hepatic encephalopathy, ascites, variceal haemorrhage and hepatocellular carcinoma. Orthotopic liver transplantation (OLT) is the optimal treatment for decompensated HCV cirrhosis, but is limited by organ availability and universal graft reinfection. This review discusses the results with OLT for HCV from the Dumont-UCLA Liver Transplant Center and discusses future directions in the management of HCV.

Animals↗
PubMed2006

Intraoperative triple antenna hepatic microwave ablation.

OBJECTIVE: Microwave ablation is emerging as a new treatment option for patients with unresectable hepatic malignancies. This two-center study shows the results of a phase 1 clinical trial of patients with known hepatic masses who underwent synchronous triple antenna microwave ablation before elective hepatic resection. SUBJECTS AND METHODS: Intraoperative microwave ablation was performed before hepatic resection. Hepatic lesions were targeted using real-time intraoperative sonography with three microwave antennas positioned in a triangular configuration. Microwave ablation was performed at 45 W for 10 minutes. Hepatic resection was then completed in the standard fashion. Gross specimens were sectioned and measured to determine tumor and ablation sizes. Representative areas were stained with H and E stain and vital histochemical nicotinamide adenine dinucleotide (NADH) stain. RESULTS: Ten patients with a mean age of 64 years (range, 48-79 years) were treated. Tumor histology included colorectal carcinoma metastases and hepatocellular carcinoma. The mean maximal tumor diameter was 4.4 cm (range, 2.0-5.7 cm). The mean maximal ablation diameter was 5.5 cm (range, 5.0-6.5 cm), while the average ablation zone volume was 50.8 cm3 (range, 30.3-65.5 cm3). Gross and microscopic examinations of areas after microwave ablation showed clear coagulation necrosis, even surrounding large hepatic vessels (> 3 mm in diameter). A marked thermallike effect was observed with maximal intensity closest to the antenna sites. NADH staining confirmed the uniform absence of viable tumor in the ablation zone. CONCLUSION: This study shows the feasibility of using multiple microwave antennas simultaneously in the treatment of liver tumors intraoperatively. Additional percutaneous studies are currently under way to investigate the safety and efficacy in treating nonsurgical candidates.

Aged↗