Randomized, placebo-controlled, double-blind study of the efficacy of lanreotide 30 mg PR in the treatment of pancreatic and enterocutaneous fistulae.

OBJECTIVE: Continuous intravenous infusion of somatostatin improves the natural course of digestive fistulae. Lanreotide 30 mg PR is a synthetic analogue of somatostatin with pharmacological activity extending to at least 10 days after intramuscular administration. Its effectiveness was assessed in patients with simple externalized digestive fistulae in a randomized, doubleblind, placebo-controlled study. METHODS: Patients demonstrating a reduction of at least 50% of fistula output within 72 hours after a first double-blind intramuscular injection of lanreotide or placebo were considered to be responders (primary end point) and continued the double-blind treatment to a maximum of 6 injections at 10-day intervals. Other endpoints included fistula closure rate and time to closure. Blind was lifted for nonresponders, and those initially on placebo were then treated with open-label lanreotide. RESULTS: Following the first double-blind injection, 35 of 54 patients (64.8%) on lanreotide were responders versus 20 of 53 (37.7%) on placebo, ie, a 3.1 times higher response likelihood on lanreotide compared with placebo (P = 0.006). Group mean reduction of fistula output at 72 hours was 45.1% and 8.9%, respectively (P = 0.005). Lanreotide compared with placebo had no effect on closure rate which averaged 77% but median time to fistula closure was shorter on lanreotide, based on Kaplan-Meier analysis, although no statistical significance was achieved. CONCLUSION: Compared with placebo, intramuscular lanreotide 30 mg PR significantly decreases digestive fistulae output at Day 3 and shortens time to fistula closure by 9 days. ClinicalTrials.gov registration number: NCT00729313.

Upregulation of DNA repair genes in active cirrhosis associated with hepatocellular carcinoma.

Phenotypic changes in injured livers involve complex network of genes whose interplays may lead to fibrosis and cirrhosis, a major risk of hepatocellular carcinoma. Gene expression profiles in fibrotic livers were analyzed by using cDNA microarray, hierarchical clustering and gene ontology. Analyses of a major cluster of upregulated genes in cirrhosis identified a new set of genes involved in DNA repair and damage. The upregulation of DNA repair genes was confirmed by real-time quantitative polymerase chain reaction and associated with necroinflammatory activity (P<0.001). Increased DNA repair activity in cirrhosis with inflammatory activity may reflect increased DNA damages as a consequence of chronic liver injury.

Accuracy of preoperative imaging methods in a retrospective series of 14 patients with operated intraductal papillary mucinous tumors of the pancreas.

UNLABELLED: Accuracy of preoperative imaging methods for the diagnosis of intraductal papillary mucinous tumor of the pancreas (IPMT) is not well known. AIMS: To compare diagnostic accuracy of various preoperative imaging methods with pathology data following surgical resection. PATIENTS AND METHODS: Fourteen consecutive patients underwent pancreatic surgical resection for IPMT between January 1988 and May 2002. Imaging methods included endoscopic retrograde cholangiopancreatography and/or magnetic resonance cholangiopancreatography and/or endoscopic ultrasonography. Results of preoperative morphological examinations were compared with histopathological findings from surgical specimens. RESULTS: IPMT was located to the pancreatic head or body in 72% of patients and involved the main pancreatic duct (MPD) in 79% of cases Carcinoma was diagnosed in 35% of the cases. Sensitivity of imaging methods varied from 64 to 80% to accurately locate the tumor and from 73 to 80% in distinguishing between types involving the MPD or the accessory ducts. Planned surgical resection based on preoperative imagery correlated with final surgery in 57% of the patients. Histological study of whole pancreas specimens revealed lesions in undilated ducts, and also dilated ducts without histological lesions. CONCLUSION: The sensitivity of preoperative imaging methods is moderate in defining intraductal extension of IPMT. Duct dilatation is not predictive of histological involvement by tumors and ducts may be pathological without dilatation.

Hypothermic storage and cryopreservation of hepatocytes: the protective effect of alginate gel against cell damages.

Hepatocyte-based therapy has been proposed as an alternative to organ transplantation in the treatment of liver disorders. In the clinical context, a major issue is the constant supply of quality assurance-controlled hepatocytes, thereby requiring their cold storage in good conditions. We have analyzed the protective effects of alginate entrapment of rat hepatocytes after either 24 or 48 h of hypothermic storage or cryopreservation on the cell viability, cell yield, both mitochondrial and other cytoplasmic functional activities, and apoptosis. Decrease in viability, as evaluated by the MTT inclusion test, was 4% and 13% (24 h at 4 degrees C), 15% and 33% (48 h at 4 degrees C), and 9% and 19% (liquid nitrogen) for entrapped and free suspended hepatocytes, respectively. Viable cell yields were 86 +/- 8% and 51 +/- 6% for cryopreserved entrapped and free suspended hepatocytes, respectively. The mitochondrial (MTS assay), 7-ethoxyresorufin O-deethylase (EROD), and glutathione-S-transferase (GST) activities were better preserved in entrapped than in free suspended hepatocytes. Both hypothermic storage and cryopreservation were found to induce early caspase-3-like activities, being always much lower in entrapped hepatocytes, particularly after cryopreservation (98.4 +/- 42.4 vs. 6.4 +/- 4.0 fluorescence arbitrary units/hours/microg protein). Thus, cold-induced apoptosis in hepatocytes can be significantly reduced following their entrapment within alginate gel beads and this is associated with an improvement of both their viability and function.

The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery.

In a randomized, double-blinded study, we evaluated the analgesic effect of ketamine in the management of pain in a surgical intensive care unit after major abdominal surgery. Patients received morphine patient-controlled analgesia with either placebo (Group M) or ketamine (Group K). Morphine was administered with initial loading doses of 2 mg until the visual analog scale (VAS) score was <30 and thereafter with bolus doses of 1 mg and a lockout time of 7 min. Ketamine was administered with an initial bolus of 0.5 mg/kg followed by a perfusion of 2 micro g x kg(-1) x min(-1) during the first 24 h and 1 micro g x kg(-1) x min(-1) during the following 24 h. The 4-h cumulative morphine doses were measured over 48 h. The VAS scores at rest and at mobilization were measured every 4 h during 48 h. A total of 101 patients were enrolled, and 93 were analyzed (41 in Group K and 52 in Group M). VAS scores at rest and at mobilization were similar. The cumulative consumption of morphine was significantly smaller in Group K (P < 0.05). We concluded that small doses of ketamine were a valuable adjunct to opioids in surgical intensive care unit patients after major abdominal surgery.

Reduced encephalopathy in pigs with ischemia-induced acute hepatic failure treated with a bioartificial liver containing alginate-entrapped hepatocytes.

OBJECTIVE: To analyze the effects of an extracorporeal bioartificial liver containing alginate bead-entrapped hepatocytes on pigs with ischemia-induced acute hepatic failure. DESIGN: Prospective animal study. SETTING: University and INSERM laboratory. SUBJECTS: Fifteen Large White/Pietrin female pigs weighing 20-30 kg. INTERVENTIONS: Acute hepatic failure was induced by end-to-side portocaval shunt and ligature of the whole porta hepatitis. The bioartificial liver was in a thermostabilized column, containing a fluidized bed of alginate beads that embedded porcine hepatocytes, connected to a plasmapheresis system. Intracranial pressure; survival; ammonia, total bilirubin, aminotransferases, alkaline phosphatase, and lactate concentrations; and clotting factors were studied. The groups were pigs with acute hepatic failure (group 1, n = 4), pigs with acute hepatic failure treated with bioartificial liver containing empty beads (group 2, n = 4), or porcine hepatocytes (group 3, n = 5). MEASUREMENTS AND MAIN RESULTS: In group 1, survival of pigs averaged 10.9 +/- 1.0 hrs; intracranial pressure reached 32.3 +/- 3.8 mm Hg and was associated with coma and cerebral edema. After connection to the bioartificial liver, the survival of acute hepatic failure pigs was 12.1 +/- 1.4 hrs in group 2 and 14.8 +/- 2.5 hrs in group 3. In group 3, intracranial pressure and bilirubin concentrations were reduced significantly compared with both group 1 and group 2. Neither signs of encephalopathy nor cerebral edema was observed in any animal of group 3. In all animals, plasma ammonium, aminotransferases, alkaline phosphatase, and lactate concentrations increased and clotting factors decreased with no significant differences between the three groups. Autopsy revealed a total necrosis of the liver, which was histologically confirmed. CONCLUSIONS: The ischemia-induced model of acute hepatic failure in pigs is reproducible and provides measurable clinical and biological features. A bioartificial liver containing alginate bead-entrapped hepatocytes improves the signs of encephalopathy in pigs with ischemia-induced acute hepatic failure, suggesting that the bioartificial liver can clear out toxic compounds that are released from necrotic livers.

Follow-up by one- and two-dimensional NMR of plasma from pigs with ischemia-induced acute liver failure treated with a bioartificial liver.

Hepatic encephalopathy may occur following acute hepatic failure (AHF), which results in the release of toxic compounds from the injured liver. These compounds, which induce cerebral edema, are not well characterized, yet. The aim of this study was to evaluate the potential interest of NMR spectroscopy in the follow-up of different plasma compounds in pigs with ischemia-induced fulminant hepatic failure treated or not with a bioartificial liver (BAL), which has been previously shown to improve the neurological status of the animals. Qualitative analysis of pig plasma was achieved by one-dimensional-(1)H CPMG, two-dimensional homonuclear (1)H-(1)H TOCSY CPMG and heteronuclear (1)H-(13)C HSQC sequences. Semi-quantitative analysis of selected plasma metabolites along the disease evolution was carried out on pigs with ischemia-induced AHF treated with the BAL containing alginate beads with or without hepatocytes. A quantitative longitudinal follow-up was performed on characteristic metabolites via a one-dimensional CPMG sequence, including choline, glutamine, N-acetyl-glucosamine (NAG), pyruvate and trimethylamine-N-oxide (TMAO). The concentrations of choline and TMAO increased from the beginning to the end in animals treated with the BAL containing alginate beads without hepatocytes. Treatment of pigs with BAL containing hepatocytes resulted in an improvement of survival, the plasma concentrations of choline and TMAO being decreased in three out of five animals. Thus, NMR spectroscopy is a useful approach for the identification of toxic compounds which are involved in hepatic encephalopathy associated with AHF. These compounds can be cleared by a BAL resulting in the improvement of survival and neurological parameters of the animals.