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1.
Am J Transplant ; 14(2): 356-66, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24456026

ABSTRACT

We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.


Subject(s)
Graft Rejection/drug therapy , Graft Survival/drug effects , Immunosuppressive Agents/therapeutic use , Liver Diseases/surgery , Liver Transplantation , Sirolimus/therapeutic use , Tacrolimus/therapeutic use , Adult , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Graft Rejection/etiology , Graft Rejection/mortality , Humans , International Agencies , Liver Diseases/complications , Liver Diseases/mortality , Male , Middle Aged , Prognosis , Prospective Studies , Survival Rate , Time Factors , Transplantation Immunology
2.
Am J Transplant ; 12(3): 694-705, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22233522

ABSTRACT

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.


Subject(s)
Calcineurin Inhibitors , Graft Rejection/prevention & control , Graft Survival/drug effects , Immunosuppressive Agents/administration & dosage , Liver Transplantation , Sirolimus/administration & dosage , Adolescent , Adult , Aged , Cyclosporine/administration & dosage , Female , Glomerular Filtration Rate , Humans , Male , Middle Aged , Prospective Studies , Tacrolimus/administration & dosage , Treatment Outcome
3.
J Clin Gastroenterol ; 30(4): 409-13, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10875470

ABSTRACT

6-mercaptopurine (6-MP) and azathioprine (AZA) are used to treat inflammatory bowel disease (IBD). Side effects include infection, leukopenia, hepatitis, and pancreatitis. The level of thiopurine methyltransferase (TPMT), which metabolizes 6-MP to 6-methylmercaptopurine, may reflect the risk of side effects. We sought to evaluate the relationship between the side effects of these medications and the TPMT level of pediatric patients with IBD. The medical records of our patients who were diagnosed with IBD and who received 6-MP or AZA were reviewed for measured TPMT levels. All red blood cell (RBC) TPMT levels were determined at the Mayo Medical Laboratories, Rochester, MN. The occurrence of leukopenia, elevated aminotransferases, and pancreatitis was evaluated. Twenty-two patients, mean age 13.7 years, received 6-MP or AZA and had TPMT levels measured. The TPMT levels ranged 10.7-27.5 U/mL RBC with a mean of 17.2 +/- 3.2 U/mL RBC. Two children had levels below the accepted norm of 13.8 U/mL RBC. One of these patients (50%) developed both elevation of aminotransferases and leukopenia. Of all, 20 children had normal levels, 3 (15.0%) exhibited side effects: hepatitis (n = 2) and leukopenia (n = 1). We conclude that side effects of 6-MP or AZA occur despite normal TPMT levels.


Subject(s)
Azathioprine/adverse effects , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Immunosuppressive Agents/adverse effects , Mercaptopurine/adverse effects , Methyltransferases/blood , Adolescent , Azathioprine/therapeutic use , Female , Humans , Immunosuppressive Agents/therapeutic use , Male , Mercaptopurine/therapeutic use
4.
J Clin Gastroenterol ; 30(3): 294-8, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10777191

ABSTRACT

Numerous adult studies show a 30-65% response rate to azathioprine (AZA) or 6-mercaptopurine (6-MP) for significant perianal Crohn's disease. The aim of this study was to evaluate whether these drugs healed pediatric perianal Crohn's disease. Records of pediatric Crohn's patients were retrospectively reviewed for significant perianal disease treated with AZA or 6-MP for > or =6 months. The patient's perianal disease was reviewed and evaluated for fistulas, drainage, induration, and tenderness. In addition, the patients were given a score using the Irvine Perianal Disease Activity Index (PDAI). Patients were retrospectively scored upon initiation of treatment and after six months of therapy. Possible scores ranged from 0-20. Twenty patients met the study criteria. Five patients were considered treatment failures. One patient required a colostomy after 1.5 months of therapy, one developed pancreatitis, and three were noncompliant with therapy. Of the remaining 15 patients who were treated for > or =6 months, 67% had an improvement in drainage, 73% in tenderness, 60% in induration, and 40% in fistula closure. The mean Irvine PDAI was 7.67 +/- 2.19 initially and 4.40 +/- 1.72 after six months of therapy. The improvement was statistically significant (p < 0.001). AZA and 6-MP are effective treatments for healing significant perianal Crohn's disease in pediatrics.


Subject(s)
Anus Diseases/drug therapy , Azathioprine/administration & dosage , Crohn Disease/drug therapy , Immunosuppressive Agents/administration & dosage , Mercaptopurine/administration & dosage , Adolescent , Anus Diseases/diagnosis , Chi-Square Distribution , Child , Child, Preschool , Crohn Disease/diagnosis , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Male , Registries , Retrospective Studies , Treatment Outcome
5.
Transplantation ; 68(10): 1617-9, 1999 Nov 27.
Article in English | MEDLINE | ID: mdl-10589967

ABSTRACT

BACKGROUND: Reconstruction of the hepatic artery in infants undergoing liver transplantation presents challenging vascular situations. Microvascular techniques ensure arterial blood flow via small caliber vessels but are insufficient when inflow is poor. In these situations, the use of allogeneic grafts to the supraceliac aorta have been advocated. The development of a pseudoaneurysm at the supraceliac aortic suture line requires urgent repair and restoration of arterial flow to the graft. METHODS: Our study was based on case reports and review of the literature. RESULTS: Definitive diagnosis and successful repair of supraceliac pseudoaneurysm was accomplished in two infants after transplantation. CONCLUSION: We advocate a thoracoabdominal retroperitoneal approach, which provides safe control of the aorta and primary repair or patching of the diseased aortic segment, and also provides access for hepatic revascularization via placement of an infrarenal graft. Thrombosis of the artery and subsequent liver necrosis are indications for retransplantation.


Subject(s)
Aneurysm, False/etiology , Aortic Aneurysm, Abdominal/etiology , Liver Transplantation/methods , Aneurysm, False/diagnosis , Aneurysm, False/surgery , Aortic Aneurysm, Abdominal/diagnosis , Aortic Aneurysm, Abdominal/surgery , Biliary Atresia/surgery , Female , Hepatic Artery/surgery , Humans , Infant , Postoperative Complications , Reoperation , Treatment Outcome
6.
Clin Transpl ; : 223-9, 1999.
Article in English | MEDLINE | ID: mdl-11038641

ABSTRACT

The liver transplant program at the University of Pennsylvania and the Children's Hospital of Philadelphia experienced healthy growth in its clinical activity in the past 5 years. Patterns of referral and patient evaluation were established, care of patients while waiting on the list or being followed after transplantation was streamlined. We are now achieving excellent outcomes while transplanting relatively sicker patients. Innovative surgical procedures are implemented resulting in more efficient utilization of cadaveric and living-donor liver grafts. The protocols that are used for patient care are more standard, yet flexible and accommodate recent advancement in transplantation immunobiology. This progress of the clinical program was enhanced by careful preservation of the academic mission of the institution, which encourages the liver transplant faculty to be involved in NIH-supported clinical and basic science research.


Subject(s)
Liver Transplantation/statistics & numerical data , Adult , Cadaver , Child , Graft Survival , Hospitals, Pediatric , Hospitals, University , Humans , Liver Diseases/classification , Liver Diseases/surgery , Liver Transplantation/mortality , Liver Transplantation/physiology , Living Donors , Philadelphia , Reoperation/statistics & numerical data , Retrospective Studies , Survival Rate , Tissue Donors/supply & distribution , Tissue and Organ Procurement/organization & administration , Waiting Lists
7.
Gastroenterology ; 115(6): 1329-34, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9834258

ABSTRACT

BACKGROUND & AIMS: Clostridium difficile is an important cause of symptomatic diarrhea in pediatric patients. The bacterium produces two toxins, although many laboratories assay for only one. We questioned this diagnostic approach when patients had positive results for C. difficile at our institution, but initially had tested negative at outside laboratories. METHODS: We retrospectively analyzed relative frequencies of C. difficile toxin A alone, toxin B alone, and toxins A and B from pediatric patients with diarrhea. Results were stratified according to toxin detection and patient age. RESULTS: Of 1061 specimens, 276 (26.8%) were positive for C. difficile toxin(s). Fifty-one (18.5%) were positive for toxin A alone, 133 (48.2%) for toxin B alone, and 92 (33.3%) for both toxins. Assaying for toxin B identified C. difficile infection more frequently than did assaying for toxin A (P < 0.0001). The frequency of toxin B detection was significantly higher for older children but not for infants. CONCLUSIONS: Testing for C. difficile toxin A or toxin B alone will result in more frequent misdiagnosis than testing for both toxins. This practice may lead to inappropriate further invasive investigations in children, although this finding may not be applicable to adults.


Subject(s)
Bacterial Toxins , Clostridioides difficile , Clostridium Infections/diagnosis , Diarrhea/diagnosis , Diarrhea/microbiology , Adolescent , Child , Child, Preschool , Humans , Infant , Retrospective Studies , Sensitivity and Specificity
11.
J Clin Gastroenterol ; 23(3): 174-6, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8899496

ABSTRACT

Uncut Collis-Nissen fundoplication for complicated gastroesophageal reflux was performed in 102 children (46 girls; age 5.6 +/- 4.2 years). Five patients developed intractable emesis postoperatively (average 11 +/- 5 months after surgery) and were found to have two independent luminal openings at the gastroesophageal junction seen on upper endoscopy but not demonstrable on upper GI. The defect was presumed to occur from breakdown of the original staple line on the lesser gastric curve. The condition was successfully repaired in all patients by including a new staple line and rewrapping of the stomach. Practitioners should be aware of this previously unreported complication post uncut Collis-Nissen fundoplication and that this condition may not be excluded by a normal upper GI study.


Subject(s)
Fundoplication/adverse effects , Gastroesophageal Reflux/surgery , Surgical Stapling/adverse effects , Child , Child, Preschool , Female , Fundoplication/methods , Gastroscopy , Humans , Male , Postoperative Complications/surgery , Vomiting/etiology
12.
J Pediatr Surg ; 31(6): 840-2, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8783118

ABSTRACT

Inflammatory myofibroblastic tumor is a rare gastrointestinal neoplasm. The authors report the case of a 5-year-old girl who initially presented with gastric outlet obstruction secondary to an inflammatory myofibroblastic tumor along the lesser gastric curvature. A subtotal gastrectomy and wedge resection of a left hepatic lobe nodule were performed. Obstructive jaundice developed one month postoperatively. Computerized tomography, percutaneous transhepatic cholangiography, and selective celiac and mesenteric arteriography showed a mass that involved the left hepatic lobe, with concomitant high-grade biliary obstruction and portal venous encasement. Percutaneous biliary drainage was performed. During laparotomy, the tumor was found to be unresectable, and the patient was referred to the Liver Transplant Service at The Children's Hospital of Philadelphia. A total hepatectomy with temporary portocaval shunt was performed, leaving the inferior vena cava in situ. At the back table, an ex vivo left trisegmentectomy was performed, followed by reimplantation of the posterior segment of the right hepatic lobe. The reimplanted liver segment functioned poorly, and completion hepatectomy with portocaval shunt was performed 24 hours postoperatively, because of severe coagulopathy, intraabdominal bleeding, and hemodynamic instability. The patient's condition stabilized, and she was listed for urgent liver transplantation. The anhepatic state was managed with intermittent plasmapheresis. She had transplantation 72 hours later, and was discharged from the hospital 3 weeks postoperatively after an uneventful recovery. She remains disease-free and has normal liver function 8 months after transplantation.


Subject(s)
Liver Neoplasms/surgery , Liver Transplantation/methods , Neoplasm Recurrence, Local/surgery , Neoplasms, Muscle Tissue/surgery , Stomach Neoplasms/pathology , Child, Preschool , Female , Humans , Inflammation , Liver Neoplasms/secondary , Neoplasms, Muscle Tissue/secondary , Plasmapheresis , Reoperation , Stomach Neoplasms/surgery
17.
J Pediatr Gastroenterol Nutr ; 13(3): 285-9, 1991 Oct.
Article in English | MEDLINE | ID: mdl-1791505

ABSTRACT

Cholestasis develops in many infants supported with extracorporeal membrane oxygenation. We prospectively investigated the role of hemolysis and di-(2-ethylhexyl) phthalate exposure in the development of this cholestasis. Both di-(2-ethylhexyl) phthalate levels and hemolysis, as measured by maximum free hemoglobin, were significantly (p less than 0.025) associated with the degree of cholestasis. Other clinical and laboratory factors that may contribute to cholestasis were also investigated and not found to be related to the degree of cholestasis. We speculate that hemolysis during extracorporeal membrane oxygenation support produces a large bilirubin load whose excretion is inhibited by mechanisms similar to the inspissated bile syndrome and/or by di-(2-ethylhexyl) phthalate. This would result in a predominantly direct hyperbilirubinemia with little evidence of hepatocellular or canalicular injury.


Subject(s)
Cholestasis/etiology , Diethylhexyl Phthalate/adverse effects , Extracorporeal Membrane Oxygenation/methods , Hyperbilirubinemia/etiology , Analysis of Variance , Hemoglobins/analysis , Hemolysis/drug effects , Humans , Infant , Prospective Studies , Regression Analysis
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