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Biomedical subjects

R W Busuttil

Publications and source records attributed to R W Busuttil.

At least 199 records · Page 11Linked to original sources
PubMed1992

OKT3 treatment of steroid-resistant rejection in pediatric liver transplant recipients.

Of a total of 187 consecutive liver grafts in 149 pediatric recipients, 59 episodes of steroid-resistant, biopsy-proven rejection (32% of grafts) were treated with OKT3 monoclonal antibody. After 59 OKT3-treated episodes, liver function at the end of treatment was normal in 40%, improved in 35%, and unchanged in 24%. Of 21 partial responses, 12 episodes eventually resolved to yield an overall complete response rate of 59%. CD3-positive T-cells greater than 5% occurred during 61% of OKT3-treated rejection episodes and was associated with impaired efficacy of OKT3 (30% complete response rate). Six grafts were re-treated with OKT3 for rejection and in all CD3-positive T-cells could not be maintained less than 5%. Of the six grafts requiring repeat OKT3, five failed-retreatment and required retransplantation. OKT3 antibodies of low titer were found prior to a second use of OKT3 in 65% of episodes. Patients treated with OKT3 after failing more than two preceding steroid courses had a significantly increased chance of graft loss (57%; p = 0.01). We conclude that this group of pediatric patients appeared less responsive to OKT3 compared to other series combining pediatric and adult recipients, possibly due to a more vigorous immune response in the child.

Antibodies↗
PubMed1992

Serum lipid abnormalities in pediatric liver transplant patients.

UNLABELLED: Little is known about serum lipid abnormalities in pediatric liver transplant recipients. We performed a longitudinal cohort review of 102 outpatient pediatric liver recipients surviving greater than 6 months and immunosuppressed with cyclosporine and prednisone (+/- azathioprine). The median age was 6 years, median months posttransplant 25, and male-to-female ratio 1:1.5. The average cholesterol (mean of individual means) was 177 +/- 45 mg/dl and average triglyceride level 158 +/- 71 mg/dl. The mean percent of cholesterol levels greater than 170 mg/dl and triglyceride levels greater than 140 mg/dl was 47% and 50%, respectively. Age, obesity, sex, and family history of risk factors had no significant effect on cholesterol or triglyceride levels. Bivariate regression analysis showed no meaningful association between cholesterol or triglyceride levels and cyclosporine levels, cyclosporine dose, prednisone dose, or diastolic blood pressure. Triglyceride and cholesterol neither increased nor decreased with time posttransplant. The rate of change of triglyceride or cholesterol could not be predicted by the rate of change of cyclosporine levels (or dose), or prednisone dose. We found no evidence that rises or falls in cholesterol or triglyceride levels coincided with rises or falls in either cyclosporine level or prednisone dose. Cholestasis was significantly associated with increased cholesterol and triglyceride levels (P = 0.05). A multivariate analysis was unable to predict cholesterol or triglyceride levels from three predictors: cyclosporine level, prednisone dose, and liver function. The mean dietary intake of fat and cholesterol was above RDA and exercise patterns were suboptimal in school-aged children. CONCLUSIONS: 50% of children had a mean cholesterol greater than 75th percentile (170 mg/dl); 20% were above the 95th percentile; 56% had a mean triglyceride level greater than 140 mg/dl. By these criteria the majority of pediatric liver transplant patients have lipid abnormalities that may predispose them to atherosclerosis in later life.

Adolescent↗
PubMed1992

Appearance of the tumor marker CA 19-9 in liver transplant patients during rejection episodes.

The tumor marker CA 19-9 was shown to be elevated in liver transplant patients, particularly during rejection. Serial serum samples taken from 24 patients after liver transplantation were examined for tumor markers CA 19-9, SLEX, CEA, and TNF-alpha. During rejection, 85% of the patients had elevated levels of CA 19-9. Patients with early rejection had persistently higher levels than patients without rejection. The serum levels were low in nonrejecting patients compared with those with rejection. Thus, the CA 19-9 marker cannot be considered a specific tumor marker. It may, however, be an indicator of an immune response or it may be a byproduct of an inflammatory reaction to a tumor or a transplant.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1992

Liver resection for primary neoplasms.

Resection is the treatment of choice for almost all hepatic neoplasms. Improvements in operative techniques and perioperative patient management have resulted in low morbidity and mortality. Patients with underlying chronic liver disease in association with hepatic malignancy now can be offered either subsegmental resection or liver transplantation in selected cases. The role of cryosurgery and alcohol injection in patients who are not candidates for resection should become clearer once longer follow-up data are available.

Adenoma, Bile Duct↗
PubMed1992

Hepatic artery thrombosis resulting in gas gangrene of the transplanted liver.

Early hepatic artery thrombosis after orthotopic liver transplantation results in massive injury to hepatocytes and the bile duct epithelium. In the fulminate form, impaired liver synthetic function is expressed by encephalopathy and coagulopathy. Ischemic bile duct injury is associated with the disruption of the biliary anastomosis, bile duct strictures, and intrahepatic bilomas. The inability of the liver macrophages to clear translocated portal blood intestinal pathogens results in persistent bacteremia and sepsis. The major radiologic finding is the radiographic evidence of gas gangrene of the liver graft. Early recognition and correct interpretation of the radiologic findings, immediate removal of the liver graft, and placement of the patient on venous-venous bypass or total hepatic devascularization while a new liver is being procured and retransplantation are the only hope for survival.

Adult↗
PubMed1992

Portosystemic shunt versus orthotopic liver transplantation for the Budd-Chiari syndrome.

We have analyzed the indications and results of shunt operation versus orthotopic liver transplantation (OLT) in 22 patients with Budd-Chiari syndrome (BCS). The underlying cause of the syndrome was similar between the two groups and was related to myeloproliferative disorders or the use of birth control pills in 18 of 22 patients. The results of biopsies of the liver showed centrilobular congestion and necrosis in all candidates who underwent shunting and the presence of fibrosis and cirrhosis in the OLT candidates. The indications for shunts included symptoms related to portal hypertension only and well-preserved synthetic hepatic function. Ten patients were treated with 12 shunt procedures, including mesoatrial (eight patients) and side to side portacaval shunt (four patients). Significant complications after shunt procedure included fulminant (one of ten patients) and progressive (one of ten patients) hepatic failure requiring urgent OLT; one death occurred because of pulmonary sepsis. Indications for OLT were signs of end stage liver expressed by severe portal hypertension and variceal bleeding (four of 14 patients), progressive encephalopathy (seven of 14 patients) and poor synthetic function (bilirubin greater than 3 milligrams per deciliter in eight of 14 patients and albumin less than 3.0 grams per liter, or both, in ten of 14 patients). Fourteen patients were treated with 16 OLT, three patients had retransplantation for primary nonfunction graft (two of 14 patients) or chronic rejection (one of 14 patients). There were two early deaths in the group. With a follow-up period between two months to five years, 12 of 14 patients undergoing OLT are alive, fully functional and have normal liver function tests. Seven of ten patients who had shunts are alive, six are able to maintain normal activity and one has progressive end stage hepatic disease and is not a candidate for OLT. However, the hepatic function continues progressively to be abnormal. Various options are available for the treatment of the syndrome. Portosystemic decompression is effective and should be considered at the early stage of the disease, prior to the development of significant hepatic failure. However, few of the patients will continue to have slow, but progressive hepatic failure and may require OLT. The only effective treatment for end stage hepatic disease secondary to the BCS is OLT.

Actuarial Analysis↗
PubMed1991

Renal ultrasound abnormalities in children with end-stage liver disease--reversal by liver transplantation.

Ultrasound (US) imaging of the kidneys was performed in 43 pediatric patients with end-stage liver disease evaluated for orthotopic liver transplantation. Renal size was increased in 8 patients (19%) and echogenicity of the kidneys was increased in 12 patients (28%). In 12 patients studied after liver transplantation, US revealed normal renal size in all and increased echogenicity in only 2 patients shortly after transplantation. Normalization of renal US findings was also found in 2 patients studied before and after liver transplantation. The glomerular filtration rate varied from 65 to 225 ml/min per 1.73 m2 in 5 patients with abnormal US, and from 74 to 116 ml/min per 1.73 m2 in 3 patients with normal US. Nephromegaly and increased echogenicity on renal US are frequent in children with end-stage liver disease and appear to be mostly reversible by liver transplantation.

Adolescent↗
PubMed1991

OKT3 prophylaxis in liver transplantation.

In a randomized prospective study of liver transplant recipients, we compared prophylaxis with OKT3, steroids, and azathioprine to cyclosporine, steroids, and azathioprine. Seventy-two percent of patients receiving OKT3 prophylaxis were rejection free in the first 14 days compared to 41% in the cyclosporine group (P = 0.02). However, after 14 days through a mean of 6.3 months, the overall incidence of rejection did not differ between the two groups (74% for the cyclosporine group and 48% for the OKT3 group). There was no increase in the rate of infectious complications noted in the OKT3-treated group. Thirty-nine percent of the OKT3-treated patients developed anti-OKT3 antibodies. Eight patients in the OKT3 group required reuse of OKT3 for rejection. Six of these continued to have greater than 10% CD3-positive cells with retreatment. Five were rescued successfully. With a mean survival of greater than 674 +/- 209 days in the OKT3-treated group and 626 +/- 242 days in the cyclosporine-treated group, no overall differences in graft and patient survival, liver function, renal function, late rejection incidence, or infectious complications were evident between the two groups. We conclude that OKT3 offers no long-term benefit compared to cyclosporine prophylaxis and should be reserved for treatment of rejection in patients in whom cyclosporine may be contraindicated.

Adult↗
PubMed1991

Failure of duplex sonography to diagnose hepatic artery thrombosis in a high-risk group of pediatric liver transplant recipients.

Excellent correlation between angiographic findings and duplex sonography has been previously reported in the diagnosis of hepatic artery thrombosis (HAT), the most common technical complication of pediatric orthotopic liver transplantation (OLT). We now report a significant incidence of false-negative sonograms, ie, hepatic artery reported as patent but thrombosed on subsequent angiography. HAT was diagnosed in 10 of 57 pediatric OLT recipients evaluated prospectively by duplex sonography. In 5 patients HAT was diagnosed only by angiography even though arterial wave forms were observed on duplex sonography. Selective angiography demonstrated extensive collateral vessel formation arising from the superior mesenteric artery, the celiac axis, or both. The 5 patients shared very similar clinical courses marked by relapsing bacteremias with multiple enteric organisms, associated with focal infarctions of the liver. Four of the grafts had difficult arterial reconstructions and 3 of 5 had segmental bile duct dilation. We conclude that duplex sonography has proven to be a valuable screening tool in evaluating hepatic artery patency but must be correlated with angiography studies in a high-risk group of pediatric transplant patients characterized clinically by relapsing bacteremia and radiographically by false-negative duplex examinations.

Child↗
PubMed1991

Monoclonal anti-tumor necrosis factor-alpha antibody treatment of rat cardiac allografts: synergism with low-dose cyclosporine and immunohistological studies.

Tumor necrosis factor (TNF) levels have been reported to be elevated during episodes of human renal, hepatic, and cardiac transplant rejection. In addition, we have shown polyclonal anti-TNF antibodies to have immunosuppressive effects. The present study was performed to evaluate the efficacy of a monoclonal anti-TNF-alpha antibody in rat cardiac transplantation as the sole immunosuppressant and in conjunction with low-dose cyclosporine (CsA). We also performed immunohistological studies to localize intragraft TNF and evaluate graft infiltrating cells (GICs), and we measured serum TNF levels by an ELISA. Untreated Buffalo to Lewis heterotopic rat cardiac transplants reject in 10.5 +/- 0.4 days. A 10-day induction course of CsA (2 mg/kg/day, po) prolonged survival to 16.7 +/- 2.7 days (P less than 0.05 vs control), and 10 days of anti-TNF (2000 U/day, ip) prolonged survival to 22.6 +/- 0.8 days (P less than 0.05 vs control). Combination of anti-TNF plus CsA synergistically prolonged graft survival to 40.7 +/- 1.8 days. Three-day courses of anti-TNF were moderately effective (13.7 +/- 0.5 days, P less than 0.05 vs control) and were also synergistic with CsA (27.8 +/- 2.2). Intragraft TNF localization using immunoperoxidase showed extensive perivascular and mononuclear cell staining in control hearts vs minimal staining in anti-TNF-treated groups. Likewise, serum TNF levels were significantly lowered for treated groups vs control (83.1 +/- 14.0 pg/ml for control; 39.5 +/- 13.8 for anti-TNF; and 13.4 +/- 5.4 for anti-TNF + CsA; P less than 0.05 vs control for all groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

PGE1 reduces injury in hepatic allografts following preservation.

Prostaglandins of the E series have been shown to decrease renal and hepatic ischemic injury as well as improve hepatic function in patients with primary nonfunction following transplantation. We wished to determine the effect of prostaglandin E1 (PGE1) on hepatic allograft reperfusion injury in the isolated perfused rat liver (IPRL) model. Livers were harvested from adult male Sprague-Dawley rats and the bile duct, portal vein, and suprahepatic vena cava were cannulated. Control livers were placed immediately on the IPRL apparatus and perfused for 2 hr with a blood-Kreb's solution. Group A and B allografts were stored for 8 hr in heparinized lactated Ringer's solution at 4 degrees C. Group A livers were then perfused with a PGE1 infusion at 0.1 micrograms/kg/min while B livers received a placebo infusion of NS at the same rate. Temperature, pH, and inflow pressures were kept constant. Oxygen consumption, portal flow, and resistance were calculated for each group and found not to be statistically different. LDH, SGOT, superoxide anion (SOA), and bile flow were measured at 30-min intervals. At the end of the 2-hr perfusion, the placebo Group B (N = 5) had LDH, SGOT, and SOA higher than those of either Group A (N = 5) or control (N = 4) livers. The difference between Group A and Group B was significant for SGOT and SOA (P less than 0.05). Bile flow was highest in the control group (24.2 +/- 1.8 microliters/g/30 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗
PubMed1991

Liver transplantation in children.

Although liver transplantation is now accepted as the ideal therapy for end-stage liver disease, relatively few centers have gained a large experience in children, and good results have been elusive. Technical difficulty and a high incidence of graft failure are among the obstacles to success. At the University of California at Los Angeles, 39% of our liver transplants are in the patients who are younger than 18 years. We have analyzed our experience with 103 patients to emphasize factors important to a favorable outcome with the procedure. One hundred twenty-three transplants were performed in 103 children (mean age, 5.2 years; 48% younger than 3 years). No reduced-size grafts were used. Scrupulous attention to technical details of the vascular reconstruction, including frequent use of the supraceliac aorta of the recipient and interrupted suture techniques, ensured construction of sound hepatic artery and portal vein anastomoses at the first operation. Preoperative exchange transfusions were used if the prothrombin time was prolonged beyond 7 seconds, resulting in an average blood loss of only 3.3 volumes. Cyclosporine dosage was maintained in the high therapeutic range for the first 4 weeks, and anti-T-cell antibody (OKT3) was used for rejection (38%). Amphotericin prophylaxis was used for biliary atresia patients with multiple previous operations. Eighty-two of one hundred three patients (80%) are alive. There were no intraoperative deaths. Actuarial survival rates at 6 months, 1 year, and 5 years are 80%, 79%, and 77%, respectively. Survival of patients who underwent transplantation at age less than 1 year is 65% versus 85% at age more than 1 year (p = 0.08). Retransplantation was performed in 19 patients (18%), with a survival rate of 58%. Hepatic artery thrombosis, the most frequent technical complication, occurred in only 16 patients (13%). Survival rates of ABO identical-match versus nonidentical-match grafts were 96% and 60%, respectively (p = 0.02). Graft survival was only 47% if more than one steroid cycle was needed, compared to 75% survival with OKT3 treatment. Despite impairment of renal function (glomerular filtration rate [GFR] less than 80 cc/kg/min) in 54% of patients and hypertension requiring therapy in 27%, 90% of the children demonstrated enhancement of growth, development, and functional status. The following conclusions were made. (1) Pediatric liver transplantation is the treatment of choice for all types of end-stage liver disease and should be considered early. (2) Factors that enhance survival include technical precision, aggressive retransplantation, antifungal chemoprophylaxis and therapy, and judicious immunosuppression with use of OKT3 for rejection.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1991

Liver transplantation for hepatoblastoma. The American experience.

The current role of liver transplantation in treating malignant tumors of the liver is uncertain, except for select histologic types. Pooled data on the results of liver transplantation in 12 children with hepatoblastoma is presented here. One half of the children are alive 24 to 70 (44 +/- 19) months after transplantation with no evidence of recurrence. Three patients (25%) died of tumor recurrence and three (25%) died of other causes. Unifocal and intrahepatic tumors were associated with better prognosis compared to the multifocal tumors and tumors with extrahepatic spread (p = 0.04 and 0.13). Microscopically vascular invasion and the predominance of embryonal and/or anaplastic epithelium were associated with a poor prognosis compared to the tumors with no vascular invasion and with predominantly fetal epithelium (p = 0.08 and 0.1). It is concluded that continued efforts to treat unresectable hepatoblastomas by liver transplantation is justified and the role of adjuvant chemotherapy in improving the results needs to be better defined.

Carcinoma, Hepatocellular↗
PubMed1991

Liver transplantation in patients with portal vein thrombosis and central portacaval shunts.

The authors have analyzed the impact of pre-existing portal vein pathology on the outcome of orthotopic liver transplantation. The incidence was high in patients suffering from chronic active hepatitis, hypercoagulable states, trauma or previous dissection of the porta hepatis, and splenectomy. The existence of portal vein thrombosis (23 patients) or surgical central portosystemic shunt (10 patients) was documented by preoperative Doppler sonogram or angiography (26/33), or operative findings of occluded vein (7/33). Successful thrombectomy and dismantling of portacaval shunts were achieved in most cases (24/33). Only nine patients required the placement of an interposition vein graft to the superior mesenteric vein. The intraoperative course was characterized by increased blood loss and coagulopathy, significantly higher than in patients with a patent portal vein. When compared with all liver transplants, the immediate postoperative complication rate was higher for primary nonfunction (33% versus 8%), re-exploration for intraperitoneal bleeding and hematomas, and morbid infections. Rethrombosis rate of thrombectomized veins or vein graft was low (2/33). The mortality rate was 35% in the presence of portal vein thrombosis (PVT) and 30% for portacaval shuct (PCS), both significantly higher than the 12% for other orthotopic liver transplant (OLT) patients. These results are expected to improve with better patient selection, surgical experience, and anticipation of the complex postoperative course. The authors conclude that PVT or the presence of PCS are not contraindications to orthotopic liver transplantation.

Blood Loss, Surgical↗
PubMed1991

The role of tumor necrosis factor in allograft rejection. III. Evidence that anti-TNF antibody therapy prolongs allograft survival in rats with acute rejection.

We have previously demonstrated that TNF-alpha levels are elevated in liver transplant patients experiencing acute rejection. In addition, prophylactic administration of anti-TNF-alpha or anti-TNF-beta antibodies prolonged graft survival in a rat heterotopic cardiac transplant model. This experiment was designed to evaluate anti-TNF therapy in the treatment of acute allograft rejection. Heterotopic cardiac transplants were performed using Buffalo donors and Lewis recipients. Histologic sections of transplanted grafts from untreated animals revealed significant rejection at day 4 with terminal rejection occurring on day 10.8 +/- 0.4. Animals in the experimental groups received antirejection therapy from postoperative days 4-13. Treatment with cyclosporine at 2 mg/kg/day prolonged graft survival to 16.5 +/- 2.0 days (P = 0.01 versus controls). Administration of polyclonal anti-TNF-alpha in combination with polyclonal anti-TNF-beta increased graft survival to 14.6 +/- 0.4 days (P less than 0.001 versus controls). Use of a monoclonal anti-TNF-alpha antibody was even more effective, with graft survival of 17.4 +/- 0.7 days (P less than 0.001 versus controls). Combination immunotherapy with monoclonal anti-TNF-alpha in conjunction with CsA extended survival to greater than 30 days. In contrast, recombinant TNF-alpha (5 micrograms/day, i.p.) markedly accelerated the time to graft failure (7.4 +/- 0.2 days, P less than 0.001 versus controls). Examination of explanted graft tissue on postoperative day 9 from animals treated with anti-TNF showed decreased mononuclear cell infiltrate when compared to untreated animals. Treatment with TNF-alpha markedly increased the inflammatory process. These results suggest that TNF may play a role in the pathogenesis of acute rejection.

Animals↗