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Biomedical subjects

C B Rosen

Publications and source records attributed to C B Rosen.

At least 19 recordsLinked to original sources
PubMed2007

Clinical Trial of the Pan-Caspase Inhibitor, IDN-6556, in Human Liver Preservation Injury.

Cold ischemia/warm reperfusion (CI/WR) injury remains a problem in liver transplantation. The aim of the current study was to assess the utility of the pan-caspase inhibitor IDN-6556 on CI/WR injury during human liver transplantation. This report is a post hoc analysis of a Phase II, multi-center, randomized, placebo-controlled, double-blinded, parallel group study. Subjects were assigned to four treatment groups: Group 1 (Organ storage/flush: Placebo-Recipient: Placebo); Group 2 (Organ storage/flush: 15 microg/mL-Recipient: Placebo); Group 3 (Organ storage/flush: 5 microg/mL-Recipient: 0.5 mg/kg); and Group 4 (Organ storage/flush: 15 microg/mL-Recipient: 0.5 mg/kg). Liver cell apoptosis was assessed by serum concentrations of the apoptosis-associated CK18Asp396 ('M30') neo-epitope, TUNEL assay and caspase 3/7 immunohistochemistry. Liver injury was assessed by serum AST/ALT determinations. Serum markers of liver cell apoptosis were reduced in all groups receiving drug as compared to placebo. However, TUNEL, caspase 3/7 positive cells and serum AST/ALT levels were only consistently reduced in Group 2 (drug exposed to organ only). This reduction in serum transaminases was significant and observed across the study. In conclusion, IDN-6556 when administered in cold storage and flush solutions during liver transplantation offers local therapeutic protection against CI/WR-mediated apoptosis and injury. However, larger studies are required to confirm these observations.

Adult↗
PubMed2006

Factor XII deficiency acquired by orthotopic liver transplantation: case report and review of the literature.

Transmission of congenital clotting factor deficiencies after orthotopic liver transplantation is rare. There are published reports of liver donor-to-recipient transmission of protein C deficiency with dysfibrinogenemia, protein S, factor VII and factor XI deficiencies. We report a case of transmission of factor XII deficiency with liver transplantation in a patient with Budd-Chiari syndrome. There was a persistent elevation of the activated partial thromboplastin time (aPTT), but no evidence of bleeding while the patient was maintained on warfarin. The presence of a persistently abnormal aPTT may raise suspicion for the presence of a clotting factor deficiency; however, deficiencies of other clotting factors may not be readily apparent on routine blood tests performed in a donor. Being aware of the possibilities of transmission of these inherited deficiencies of coagulation factors will aid in their early detection and management in the transplant donor and recipient.

Diagnosis, Differential↗
PubMed2005

Preoperative dobutamine stress echocardiography, intraoperative events, and intraoperative myocardial injury in liver transplantation.

INTRODUCTION: The appropriate method of screening for coronary artery disease in patients who present for liver transplantation is currently uncertain. METHODS: We assessed the utility of a screening protocol using dobutamine stress echocardiography (DSE) in 119 patients who underwent liver transplantation. Patients with cardiac risk factors had DSE performed, and those with positive results were referred for coronary angiography. Outcome was myocardial injury during liver transplantation determined by an elevation of cardiac troponin T measured after transplantation. RESULTS: Seventy-three patients had DSE performed; eight were reported as positive for inducible ischemia. Seven of these patients underwent coronary angiography, and one had significant coronary artery disease. Postoperative troponin elevation occurred in 14 patients. There was no significant difference in the prevalence of troponin elevation in those patients with positive DSE versus those with negative DSE. No significant difference was identified in the prevalence of troponin elevation when comparing those patients with cardiac risk factors who underwent DSE with those patients with no risk factors and no DSE performed. DSE had a sensitivity of 0.2 and a specificity of 0.9 for myocardial injury. The prevalence of intraoperative hemodynamic instability was significantly higher in patients who had evidence of myocardial injury, but hemodynamic instability was no more common in patients who had a positive DSE. CONCLUSION: When used in accordance with our protocol a positive DSE does not reliably identify patients at high cardiac risk during liver transplantation, but a negative DSE is strongly predictive of no myocardial injury.

Adrenergic beta-Agonists↗
PubMed2001

Recurrent autoimmune hepatitis after orthotopic liver transplantation.

To determine the frequency, risk factors, and consequences of recurrent autoimmune hepatitis after liver transplantation, 41 patients with type 1 disease were monitored after surgery in accordance with a surveillance protocol. Tacrolimus or cyclosporine plus prednisone were administered to each patient, and liver biopsy examinations were performed at least annually according to protocol. Corticosteroid therapy was ultimately discontinued in only 2 patients. Recurrent disease was defined as the presence of lymphoplasmacytic infiltrates in liver tissue in the absence of other causes of allograft dysfunction. Autoimmune hepatitis recurred in 7 patients (17%), and the mean time to recurrence was 4.6 +/- 1 years. Recurrence was asymptomatic in 4 of 7 patients and detected only by surveillance liver biopsy assessment in 2 patients. Histological changes were mild, and there was no progression to cirrhosis during 4.9 +/- 0.9 years of observation. Five-year patient (86% v. 82%; P =.9) and graft (86% v. 67%; P =.5) survival rates were not statistically different between patients with and without recurrent disease. HLA-DR3 or HLA-DR4 occurred more commonly in patients with than without recurrence (100% v. 40%; P =.008) and healthy subjects (100% v. 49%; P =.01). Recurrent disease was unrelated to donor HLA status. In conclusion, recurrence after transplantation for type 1 autoimmune hepatitis is common. Its mild manifestations and favorable prognosis may reflect early detection by a surveillance protocol and/or continuous corticosteroid treatment. HLA-DR3- or HLA-DR4-positive recipients are at risk for recurrence regardless of donor HLA status.

Adult↗
PubMed2001

Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease.

Although nonalcoholic steatohepatitis (NASH) has generally been considered a benign condition, the increasing prevalence and severity of obesity has heightened concerns about the frequency with which NASH progresses to end-stage liver disease. The aim of this study is to determine the frequency, clinical features, and posttransplantation history of decompensated liver disease secondary to NASH. The frequency of NASH as a cause of end-stage liver disease was prospectively determined in patients evaluated for liver transplantation. NASH was considered to be the primary cause of liver disease in patients who had histological evidence of steatohepatitis and in whom chronic liver diseases other than NASH were excluded. Posttransplantation histological characteristics were also determined in patients with NASH and compared with those of patients with pretransplantation diagnoses of cholestatic liver diseases, alcoholic disease, and hepatitis C. Of 1,207 patients evaluated for liver transplantation during the study period, 31 patients (2.6%) had NASH as the primary cause of liver disease. In the same period, 546 liver transplantations were performed, 16 of which (2.9%) were for end-stage disease secondary to NASH. Posttransplantation steatosis was seen in 60% of transplant recipients with NASH versus 5% of those with cholestatic disease, 15% of those with alcoholic disease, and 15% of those with hepatitis C. Steatohepatitis recurred in 33% of transplant recipients with NASH, with progression to cirrhosis in 12.5%. NASH can progress to end-stage liver disease in a minority of affected patients and was the primary cause of liver disease in 2.9% of patients evaluated for liver transplantation at our center. Recurrence of steatosis and NASH is frequent and can be severe after liver transplantation.

Adult↗
PubMed2001

Graft survival in pediatric liver transplantation.

BACKGROUND/PURPOSE: Liver transplantation is standard therapy for children with a variety of liver diseases. The current shortage of organ donors has led to aggressive use of reduced or split grafts and living-related donors to provide timely liver transplants to these children. The purpose of this study is to examine the impact of these techniques on graft survival in children currently treated with liver transplantation. METHODS: Data were obtained on all patients less than 21 years of age treated with isolated liver transplants performed after January 1, 1996 in an integrated statewide pediatric liver transplant program, which encompasses 2 high-volume centers. Nonparametric tests of association and life table analysis were used to analyze these data (SAS v 6.12). RESULTS: One hundred twenty-three children received 147 grafts (62 at the University of Florida, 85 at the University of Miami). Fifty-two (36%) children were less than 1 year of age at time of transplant, and 80 (55%) were less than 2 years of age. Patient survival rate was identical in the 2 centers (1-year actuarial survival rate, 88.4% and 87.1%). Twenty-five (17%) grafts were reduced, 28 (19%) were split, 6 were from living donors (4%), and 88 (60%) were whole organs. One-year graft survival rate was 80% for whole grafts, 71.6% for reduced grafts, and 64.3% for split grafts (P =.06). Children who received whole organs (mean age, 6.1 years) were older than those who received segmental grafts (mean age, 2.5 years; P <.01). Multifactorial analysis suggested that patient age, gender, and use of the graft for retransplant did not influence graft survival, nor did the type of graft used influence patient survival. CONCLUSIONS: The survival rate of children after liver transplantation is excellent independent of graft type. Use of current techniques to split grafts between 2 recipients is associated with an increased graft loss and need for retransplantation. Improvement in graft survival of these organs could reduce the morbidity and cost of liver transplantation significantly in children.

Age Distribution↗
PubMed2000

Comparative allograft histology after liver transplantation for cryptogenic cirrhosis, alcohol, hepatitis C, and cholestatic liver diseases.

BACKGROUND: End-stage liver disease for which no cause can be identified, cryptogenic cirrhosis, is a common indication for liver transplantation. Allograft inflammation and fibrosis have been reported to recur with similar frequencies after liver transplantation for cryptogenic cirrhosis and hepatitis C (HCV). METHODS: We determined sequential posttransplant allograft histology in four groups of recipients: 31 transplanted for cryptogenic cirrhosis, 70 for cholestatic etiologies, 40 for alcoholic liver disease, and 56 for HCV. Modified hepatitis activity index (HAI) and fibrosis stage were determined at 4 months, 1 year, and at most recent biopsy posttransplantation. RESULTS: The prevalence of HAI > or = 2 among cryptogenic recipients was similar to that of cholestatic and alcoholic recipients at 4 months, 1 year, and at most recent evaluation (mean 45+/-17 months posttransplantation). For HCV-infected recipients, the frequency of HAI > or = 2 was more than for cryptogenic recipients at 1 year (52 vs. 29%, P=0.04) and at most recent evaluation (64 vs. 15%, P=0.003). Fibrosis scores for cryptogenic, cholestatic, and alcoholic recipients were similar at all timepoints. The proportion of HCV-infected recipients with fibrosis stage >2 was more than that of cryptogenic recipients at 4 months (29 vs. 12%, P=0.05), 1 years (46 vs. 7%, P=0.0002), and at most recent evaluation (42 vs. 15%, P=0.06). None of the cryptogenic recipients developed cirrhosis. RESULTS: The frequency of elevated HAI and fibrosis stage in recipients who undergo transplantation for cryptogenic cirrhosis is similar to that of recipients who undergo transplantation for cholestatic etiologies and significantly less than that of HCV-infected recipients. Fibrosis stage and HAI are generally stable after transplantation for cryptogenic cirrhosis. These data do not suggest a viral etiology of liver disease in the majority of patients with cryptogenic cirrhosis.

Biopsy↗
PubMed2000

Infusion of donor spleen cells and rejection in liver transplant recipients.

Intact or inactivated donor lymphoid cells have been found to downregulate the alloimmune response in a number of experimental models. We conducted a randomized, prospective, double blind, and placebo-controlled trial to determine whether heat-treated donor spleen cells would affect early rejection after liver transplantation. Donor spleen was obtained during organ procurement for 40 patients undergoing liver transplantation. All patients were treated with cyclosporine, azathioprine and steroids. The patients were randomized after surgery to receive either heat-treated (45 degrees C for 1 h) spleen cells or placebo. Patients underwent protocol biopsies at 1 wk, 4 and 12 months, or as needed. Biopsies were reviewed in a blind fashion and scored according to the Banff consensus criteria. Randomization resulted in 19 patients in the spleen cell group and 21 in the placebo group. One-yr graft survival was 94 and 100%, respectively. Early rejection was more frequent in the spleen cell group (61 vs. 35%, p, not significant). The histopathological rejection activity index at 7 d was also higher for the patients in the spleen cell group: 39% of spleen cell treated patients had a score of 4 or higher as opposed to 5% in the placebo group (p < 0.01). The mean score was 2.9 +/- 2.8 for the spleen cell group versus 1.3 + 1.7 for the placebo group (p = 0.034). It is concluded that heat-treated donor spleen cells given within 24 h after liver transplantation were not clinically beneficial and increased the intensity of rejection in 7-d protocol liver biopsies.

Cell Transplantation↗
PubMed2000

Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation.

In the setting of moderate to severe pulmonary artery hypertension, orthotopic liver transplantation (OLT) may be complicated by pulmonary hemodynamic instability and cardiopulmonary mortality. We retrospectively studied the relationship between cardiopulmonary-related mortality and initial (untreated) pre-OLT pulmonary hemodynamics in 43 patients with portopulmonary hypertension who underwent attempted OLT. Thirty-six patients were reported in 18 peer-reviewed studies, and 7 patients underwent OLT at our institution since 1996. Transplantation procedure outcome, mean pulmonary artery pressure (MPAP), pulmonary vascular resistance (PVR), cardiac output, pulmonary capillary wedge pressure, and transpulmonary gradient (TPG) are summarized. Overall mortality was reported in 15 of 43 patients (35%). Fourteen of the 15 deaths (93%) were primarily related to cardiopulmonary dysfunction. Two deaths were intraoperative, 8 deaths occurred during the transplantation hospitalization, and 4 patients died of cardiopulmonary deterioration posthospitalization. In 4 patients, the transplantation procedure could not be successfully completed. Cardiopulmonary mortality was associated with greater pre-OLT MPAP (49 +/- 14 v 36 +/- 7 mm Hg; P <.005), PVR (441 +/- 173 v 261 +/- 156 dynes.s.cm(-5); P <.005), and TPG (37 +/- 13 v 22 +/- 10 mm Hg; P <.005). MPAP of 50 mm Hg or greater was associated with 100% cardiopulmonary mortality. In patients with an MPAP of 35 to less than 50 mm Hg and PVR of 250 dynes.s.cm(-5) or greater, the mortality rate was 50%. No mortality was reported in patients with a pre-OLT MPAP less than 35 mm Hg or TPG less than 15 mm Hg. Cardiopulmonary-related mortality in OLT patients with portopulmonary hypertension was frequent and associated with significantly increased pre-OLT MPAP, PVR, and TPG compared with survivors. Treated or untreated, we recommend intraoperative cancellation or advise against proceeding to OLT for an MPAP of 50 mm Hg or greater. Patients with an MPAP of 35 to less than 50 mm Hg and PVR of 250 dynes.s.cm(-5) or greater appear to be at high risk for cardiopulmonary-related mortality after OLT. A prospective study is needed to define optimal pretransplantation treatments and pulmonary hemodynamic criteria that minimize OLT mortality associated with portopulmonary hypertension.

Adolescent↗
PubMed2000

Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma.

Orthotopic liver transplantation (OLT) alone for unresectable cholangiocarcinoma is often associated with early disease relapse and limited survival. Because of these discouraging results, most programs have abandoned OLT for cholangiocarcinoma. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Based on these concepts, a protocol was developed at the Mayo Clinic using preoperative irradiation and chemotherapy for patients with cholangiocarcinoma. We report our initial results with this pilot experience. Patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases were eligible. Patients initially received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. 5-FU was then administered continuously through an ambulatory infusion pump until OLT. After irradiation, patients underwent an exploratory laparotomy to exclude metastatic disease. To date, 19 patients have been enrolled onto the study and have been treated with irradiation. Eight patients did not go on to OLT because of the presence of metastasis at the time of exploratory laparotomy (n = 6), subsequent development of malignant ascites (n = 1), or death from intrahepatic biliary sepsis (n = 1). Eleven patients completed the protocol with successful OLT. Except for 1 patient, all had early-stage disease (stages I and II) in the explanted liver. All patients who underwent OLT are alive, 3 patients are at risk at 12 months or less, and the remaining 8 patients have a median follow-up of 44 months (range, 17 to 83 months; 7 of 9 patients > 36 months). Only 1 patient developed tumor relapse. OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma.

Antimetabolites, Antineoplastic↗
PubMed1999

The utility of noninvasive serologic markers in the management of early allograft rejection in liver transplantation recipients.

BACKGROUND: Early allograft rejection after orthotopic liver transplantation (OLT) currently requires a biopsy for diagnosis. Alpha-glutathione S-transferase (alpha-GST) and Pi-glutathione S-transferase (Pi-GST) are potential noninvasive markers of hepatocyte and biliary epithelial cell injury. Our aim was to determine the utility of noninvasive serologic markers in the management of early hepatic allograft rejection. METHODS: Forty-four of 52 consecutive adult patients undergoing primary OLT at the University of Florida were included in the study. All had protocol liver biopsies between days 6 and 8 after OLT. Serum alpha-GST and plasma Pi-GST were determined using a sandwich enzyme immunoassay (Biotrin International, Dublin, Ireland). All biopsy specimens were retrospectively reviewed and scored for rejection and cholestasis. RESULTS: The biopsy specimens were scored for rejection as moderate to severe in 14 patients (group 1) or none to mild in 30 patients (group 2). Group 1 had statistically higher mean levels than group 2 for alpha-GST on days 6, 7, and 9; alanine aminotransferase on days 6 and 9; aspartate aminotransferase (AST) on days 6 and 7; alkaline phosphate (AP) on days 3 through 7, 9, and 10; and gamma-glutamyl transferase on day 3. No differences between groups were seen with Pi-GST or total bilirubin. Between days 6 and 8, the following values were found more frequently in group 1 than group 2: alpha-GST level >15 ng/ml (11/14 vs. 14/30; P<0.01); AST >100 U/L (8/14 vs. 2/30; P=0.002); and AP >120 U/L (14/14 vs. 17/30). Combining AP with either alpha-GST or AST led to improved detection of rejection over any single marker alone. In the first week after the initiation of rejection treatment, alpha-GST was the only marker that accurately predicted response. CONCLUSION: Serum alpha-GST may be useful in the management of early hepatic allograft rejection. A combination of noninvasive markers may be beneficial to diagnose early hepatic allograft rejection.

Adult↗
PubMed1999

Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.

Liver transplantation is the only effective therapeutic option for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC). In this study, we analyzed a single center's experience with 150 consecutive PSC patients who received 174 liver allografts. Mean follow-up was 55 months. Actuarial patient survival at 1, 2, 5, and 10 years was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, whereas graft survival was 83.4%, 83.4%, 79.0%, and 60. 5%, respectively. The main indication for retransplantation was hepatic artery thrombosis, and the major cause of death was severe infection. Patients with PSC had a higher incidence of acute cellular and chronic ductopenic rejection compared to a non-PSC control group. Chronic ductopenic rejection adversely affected patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, were frequent and occurred in 16.2% and 27.2% of patients, respectively. The incidence of recurrent PSC was 20%. A negative impact on patient survival was not seen in patients with either postoperative biliary strictures or recurrence of PSC. Six patients (4%) had cholangiocarcinoma and 1 patient died related to recurrence of malignant disease. Seventy-eight percent of PSC patients had associated inflammatory bowel disease, most commonly chronic ulcerative colitis, which did not adversely impact patient outcome posttransplantation. Nine patients required proctocolectomy after liver transplantation; 5 because of intractable symptoms related to inflammatory bowel disease and 4 due to the development of colorectal carcinoma/high-grade dysplasia. Our data show that liver transplantation provides excellent long-term patient and graft survival for patients with end-stage PSC.

Cause of Death↗
PubMed1998

Delayed graft function after renal transplantation.

BACKGROUND: There is a strong association between delayed graft function (DGF) and reduced graft survival (GS) of cadaveric renal transplants. This study was performed to identify donor characteristics that might predict adverse outcomes. METHODS: We reviewed the folders of 509 consecutive organ donors for 586 renal transplant recipients receiving grafts between 1990 and 1995. A uniform immunosuppression protocol was employed. RESULTS: The factors that did not alter the rate of DGF were procurement year, local versus shared organs, donor gender, race, hypotension, serum creatinine level and trend, blood transfusions, and vasopressor use and dose. The factors that did alter the frequency of DGF were cause of death (P=0.0053), donor age (P=0.0017), cold ischemic time (P=0.0009), anastomotic time (P=0.0012), combined cold ischemic time and anastomotic time (P=0.00018), and body mass index (P=0.009). All of the factors with the exception of body mass index were of comparable import when analyzed by multiple logistic regression. One-year GS of patients without DGF was 93.2%, and the GS of those with DGF was 76.6% (P < 0.0001). However, none of the donor factors correlated with 1-year GS. Seventy-seven donors were the source of paired transplants performed by our program. Sixty percent were concordant for immediate function, 32% were discordant for DGF with equal numbers affecting the first or second graft, and in only 8% did DGF affect both grafts. CONCLUSIONS: Donor factors associated with DGF were increased ischemia, donor age, and cause of death. Although there is a close association between DGF and reduced GS, there is no association between these donor factors and GS. This seeming paradox suggests that unknown variables contribute heavily to early graft outcome.

Adolescent↗
PubMed1997

Hepatic resection for metastatic colorectal cancer results in cure for some patients.

OBJECTIVES: To determine the long-term disease-free and overall survivals for patients undergoing hepatic resection for colorectal cancer metastases and to define significant predictors of improved patients survival. DESIGN: Retrospective review. SETTING: Single tertiary care center. PATIENTS: Two hundred eighty consecutive patients underwent hepatic resection for colorectal cancer metastases at the Mayo Clinic from 1960 to 1987. Fifty patients alive at the completion of the study had a mean follow-up of 11.3 years (median, 121 months). MAIN OUTCOME MEASURES: Disease-free interval following initial hepatic resection and death. RESULTS: The overall 5-year survival of the 280 patients was 27%. Twenty-eight patients were alive at 10 years from the time of hepatic resection, and the 10-year actuarial survival was 20%. Only 2 patients alive and free of disease at 5 years had recurrent disease. For all other patients who were free of disease more than 5 years after hepatic resection and died, the cause of death was not cancer related. No patients characteristics or features of the primary tumor affected survival. Clinical presentation of metastatic disease, configuration of hepatic lesions, the presence of extrahepatic lymph node involvement, and the existence of resectable extrahepatic disease significantly affected long-term patient survival. Need for perioperative blood product transfusion was associated with a lower probability of long-term survival. CONCLUSIONS: Disease-free patient survival beyond 5 years from surgical resection of colorectal cancer metastases to the liver represents patient cure in nearly all instances.

Colorectal Neoplasms↗
PubMed1992

Intermittent jaundice by tumor emboli from intrahepatic cholangiocarcinoma.

Free-floating tumor debris or mucobilia as a cause of intermittent obstruction has been described infrequently. A patient with intermittent jaundice caused by tumor emboli from an intrahepatic polypoid mucinous cholangiocarcinoma is presented. Symptoms of intermittent jaundice and midepigastric pain persisted over 5 years despite an initial cholecystectomy and common bile duct exploration before definitive diagnosis and treatment of an hepatic trisegmentectomy (segments II, III, and IV). Intraductal mucin was confirmed intraoperatively and pathologically as the cause of the obstructive jaundice. The patient remains asymptomatic and without evidence of disease more than 5 years postoperatively. This report of a predominantly mucin-producing intrahepatic cholangiocarcinoma details a rare protracted clinical course of intermittent biliary obstruction from mucus emboli and highlights the possibility of long-term survival after complete resection.

Adenoma, Bile Duct↗