Microdialysis in early detection of temporary pancreatic ischemia in a porcine model.

BACKGROUND: Ischemic injury to the pancreas occurs in various clinical conditions. A method for online monitoring of pathophysiological events in pancreatic parenchyma is missing. AIMS: To assess the timing of microdialysis (MD) technique response on temporary changes in pancreatic perfusion, and to evaluate the relationship between MD data and systemic markers of anaerobic metabolism and inflammation. METHODS: In anaesthetized normoventilated pigs, MD probes were placed in right (control) and left (ischemic) pancreatic lobes, respectively. Following the clamping of the vessels, ischemia was verified by tissue oxygen tension (P(ti)O(2)) measurements. RESULTS: P(ti)O(2) decreased within 20 min after the clamping of the vessels, already returning to baseline levels at the first sampling point after the removal of the clamp. MD lactate levels increased, whereas pyruvate and glucose levels decreased at 20 min after the induction of ischemia. These trends continued until the end of ischemia and returned to baseline following reperfusion. Serum lactate, amylase and tumor necrosis factor-alpha levels decreased throughout the protocol time. CONCLUSION: MD data were in concordance with changes in P(ti)O(2), which is indicative of local anaerobic metabolism. MD allowed the detection of pathophysiological processes within the ischemic pancreas at a stage when no elevations of systemic markers of ischemia or inflammation were observed.

133Xe clearance estimates the effect of vasopressin on peritoneal blood flow in rats.

BACKGROUND/AIMS: When assessing the peritoneal microcirculation with invasive methods, interference with the mechanisms of vaso-regulation may occur. The 133Xe clearance technique renders the possibility, by minimal invasiveness, to estimate the influence of a vasoactive agent on the peritoneal microcirculation. METHODOLOGY: Ten to 15MBq of 133Xe were injected in the abdominal cavity in thirty-eight Wistar-FU (W-FU) rats and 35 Lister-Hooded (LH) rats. A NaI (Tl)-scintillation detector registered activity before and during vasopressin infusion. Gamma camera imaging confirmed the washout from the abdominal cavity. The laser Doppler flowmetry technique was used as a comparison. RESULTS: Vasopressin at 0.07 IU/kg/min IV significantly reduced 133Xe-clearance by 37% (p = 0.029) and 52% (p=0.036) and laser Doppler flowmetry by 69% (p=0.0019) and 44% (p=0.0039) in W-FU and LH rats, respectively. A linear correlation between dose of vasopressin and relative decrease in 133Xe clearance was demonstrated in the W-FU rat model (r2=0.98, p=0.023). The 133Xe clearance from the abdominal cavity in rat using a single-compartment model or the slow compartment in a double-compartment model gave reproducible information. CONCLUSIONS: The usefulness of this mini-invasive technique for sequential measurements before and during intervention will render the 133Xe clearance suitable for assessment of blood flow changes in the abdominal cavity.

A comparison between hepatic artery ligation and portal 5-Fu infusion versus 5-Fu intra arterial infusion for colorectal liver metastases.

AIM: A prospective randomized study was executed comparing two regimens of regional therapy for liver metastases from colorectal cancer. METHODS: Eighteen patients were allocated to hepatic artery occlusion for 16 h followed by intraportal 5-fluorouracil (5-Fu) infusion (1000 mg/m(2)) for 5 days every sixth week (HAO). Twenty-one patients received intra-arterial 5-Fu infusion+Leucovorin (100 mg) i.v. for 2 days every second week (HAI). The follow up every third month included CT and CEA. Thirteen patients had limited extrahepatic cancer. At tumor progression regional therapy was stopped and systemic chemotherapy or the best supportive care was administered. RESULTS: The study was discontinued after randomization of 39 patients. No significant difference in survival within patients with and without extrahepatic cancer was present. The mean survival was longer in the HAI group than for the HAO group (19 months versus 13 months, p=0.0147) (median 18 (8-37) versus 12 (2-26). PR and SD were registered in 8/18 in the HAO group and 17/21 patients in HAI group. The median time to progress was 4 (1-22) months versus 7 (1-23) months for the HAO and HAI group, respectively. CONCLUSION: Regional intraarterial infusion with 5-Fu gives significantly better survival than hepatic artery occlusion followed by portal infusion. A limited amount of extrahepatic cancer does not influence survival time. A trial comparing hepatic artery 5-FU infusion and Leucovorin versus the most effective systemic therapy is warranted.

Treatment of non-resectable pancreatic cancer with intraperitoneal 5-FU and leucovorin IV.

AIM: To explore the feasibility of intraperitoneal (IP) 5-fluorouracil (5-FU) and (IV) leucovorin for patients with advanced pancreatic carcinoma. MATERIALS AND METHOD: Thirty patients (11 men), median age 65 (range 36-74 years), with a non-resectable pancreatic carcinoma in stage III (n=2) and IV (n=28) were treated with IP 5-FU 750-1000 mg/m(2)and leucovorin IV 100 mg/m(2)for 2 days every 3rd week. Tumour effect was analysed with repeated computed tomography (CT) scans, performance status was estimated with Karnofsky's index (KI) and morphine consumption, and toxicity assessed using World Health Organization (WHO) criteria. RESULTS: Median survival time was 7 months (range 0-21). There was no difference in survival between patients with different grading, staging or tumour size. Regional and systemic toxicity: The treatment was well tolerated, with no grade III or IV complications or side-effects. The median KI showed a minor reduction during treatment. The median morphine consumption per 24 hours increased from 0 mg (range 0-250) at inclusion, to 70 mg (range 0-540) at exclusion. The median nadir (WBC) was 7.2x10(3)/mm(3)(range 5.2-18.8). All patients had abdominal discomfort and distension during IP installation. CONCLUSION: Intraperitoneal administration of 5-FU is feasible for patients with nonresectable pancreatic carcinoma. The treatment can induce a temporary stabilization of tumour growth and eventually prolong survival without adverse effects.

Antitumour effect of L-2,4 diaminobutyric acid on a hepatoma cell line.

Pharmacological treatment of malignant disease is often insufficient highlighting the need for more efficient treatment based on new principles. We have observed that the amino acid analogue diaminobutyric acid (DAB), accumulates in malignant cells apparently without saturation kinetics, leading to hyperosmosis and subsequently to cell lysis. In the first in vitro part of the present study hepatoma cells were incubated with DAB in miniwells in the presence or absence of physiological amino acids. In the in vivo part malignant cells were inoculated into rat liver after laparotomy. The tumour was treated by continuous infusion of DAB via a catheter, the tip of which was placed in the center of the tumour. DAB had a significant antitumour effect both in vitro and in vivo. The principle of action of DAB as an antitumour agent is unique and therefore would be the ideal partner to practically any other cytostatic drug for a combined treatment to achieve a synergistic effect.

The influence of zymosan and indomethacin on liver and kidney tumor growth. An experimental study in rats.

Zymosan, a non-specific macrophage-stimulating agent, modifies favourably tumour growth in the liver but has minor effect on renal tumours. The mechanism accounting for variation is still to be clarified. The effect of zymosan on liver cancer may be mediated by the macrophage-monocyte system. Kupffer cells are in vitro cytotoxic against colon cancer cell lines. The kidney is sparse in macrophage elements. The prostaglandin synthesis inhibitor, indomethacin, inhibits tumor growth. In Wistar-FU rats inoculated in the liver and the kidney with an adenocarcinoma cell suspension, pretreatment with zymosan (3 mg x 100 g[-1]) significantly reduced both tumour take and liver volume. This effect was attenuated by concomitant administration of indomethacin (0.2 mg x 100 g[-1]). After 2 weeks there was still reduced liver tumour volume. No significant effects on tumour take or growth were observed when the cells were inoculated into the kidney. There was no significant effect of zymosan on an hepatoma in Lister-Hooded rats. Pretreatment with indomethacin had no effect on tumor take or initial growth.

Carboxylic ester hydrolase and amylase in ischemic pancreatitis in the guinea pig.

The observation that an elevated level of pancreatic carboxylic ester hydrolase (CEH) in serum is a more sensitive and specific marker of acute pancreatitis than is elevated serum amylase activity prompted us to explore whether these findings could be confirmed in an experimental model and, if so, to find the explanation behind this difference. We therefore developed a model for ischemic pancreatitis in the guinea pig and a sandwich enzyme-linked immunosorbent assay for determination of CEH in this species. There was a strong correlation between duration of ischemia and severity of pancreatic inflammation and between severity of inflammation and serum CEH level. In contrast, serum amylase was elevated only in animals with the most severe grade of inflammation. Amylase was, however, increased in urine in animals with mild inflammation, but the level did not increase with severity of inflammation. Only one of 31 animals had detectable CEH in urine. In animals with intermediate serum CEH levels the serum and biliary concentrations correlated, indicating that CEH may be cleared by the liver. Amylase was detectable in bile only in animals with high serum levels. The results confirm our observations made in previous clinical studies. A likely explanation for differences in serum levels of CEH and amylase is clearance from the circulation at different rates and, at least partly, via different routes, e.g., the liver and kidney, respectively.

Diagnosis of traumatic pancreatic duct rupture by on-table endoscopic retrograde pancreatography.

We report on two children who sustained blunt abdominal trauma with pancreatic duct rupture diagnosed by ERP (endoscopic retrograde pancreatography). Examinations were done with patients on the operating table anesthetized for laparotomy (on-table ERP). In both patients, duct laceration remained undiagnosed by computerized tomography and ultrasonography. Operative strategy depends on whether the pancreatic duct is lacerated or not. Findings during on-table ERP allow decisions on operative strategy in patients with pancreatic trauma.

The value of routine biochemical tests in discriminating between malignant and benign pancreatic tumours.

The probability that routine hematological laboratory tests of liver and pancreatic function can discriminate between malignant and benign pancreatic tumours, incidentally detected during operation, was investigated. The records of 53 patients with a verified diagnosis of pancreatic carcinoma and 19 patients with chronic pancreatitis were reviewed with regard to preoperative total bilirubin, direct reacting bilirubin, alkaline phosphatase, glutamyltranspeptidase, aminotransferases, lactic dehydrogenase and amylase. Multivariate and discriminant analysis were performed to calculate the predictive value for cancer, using SYSTAT statistical package in a Macintosh II computer. Total and direct reacting bilirubin and glutamyltranspeptidase were significantly higher in patients with pancreatic carcinoma. However, only considerably increased levels of direct reating bilirubin were predictive of pancreatic carcinoma.

Hepatic portal vein gas following endoscopic retrograde cholangiography with sphincterotomy. Case report.

In a 60-year-old woman, endoscopic retrograde choledochography with sphincterotomy was followed by appearance of gas in the portal venous system. Venous bleeding was seen immediately after completion of sphincterotomy. The patient recovered well. Even in the absence of duodenal perforation, sphincterotomy may be complicated by hepatic portal venous gas.

Carboxylic ester hydrolase. A sensitive serum marker and indicator of severity of acute pancreatitis.

When using clinical criteria, both falsely positive and falsely negative diagnoses of acute pancreatitis (AP) are often made. Based on a clinical study, elevated serum levels of the pancreatic lipolytic enzyme carboxylic ester hydrolase (CEH) was recently suggested to be a highly specific marker of acute pancreatitis. To determine the sensitivity of the test for AP, a study on patients with the diagnosis set objectively was necessary. In the present study, AP was diagnosed by contrast-enhanced computed tomography in 64 patients, and histopathological examination of tissue removed at laparotomy in 18 of them. By these criteria, 42 patients suffered from acute interstitial pancreatitis (AIP), and 22 patients from necrotizing pancreatitis (NP). Based on the CEH concentrations in the first serum sample obtained in each patient, the sensitivity of CEH for pancreatitis was 98%. From the second day after admission, CEH levels in patients with NP were significantly higher than in patients with AIP. Furthermore, in patients with NP, CEH values remained at a raised level for the following 10 d, whereas a significant decrease of CEH values was noted in patients with AIP. In contrast, total serum amylase activities were higher in patients suffering of AIP than in patients suffering of NP during the observation period. We conclude, that the sensitivity of the CEH test is very high for AP. CEH concentrations remaining at a high level are suggestive of NP, whereas diminishing CEH levels are suggestive of AIP.

Fine-needle aspiration biopsy of pancreatic masses.

The results of fine-needle aspiration biopsy of pancreatic masses in 79 patients (percutaneous with ultrasonic guidance in 23 and peroperative in 56) were evaluated and correlated to survival (follow-up at least 2 years). The original biopsy diagnosis was malignancy in 41 patients, histologically confirmed in 19, all but two of whom died of cancer within 18 months. None of the 22 patients without histologic verification of the primary malignant cytodiagnosis survived for 18 months. The fine-needle biopsy showed benign cells in 30 patients, in 13 of whom histologic diagnosis was obtained, revealing carcinoma in seven. Six of these seven died within a year, but of the six with histologically benign lesion, five survived for more than 2 years. All 17 patients without histologic verification of benign aspiration biopsy findings survived more than 24 months. The biopsy diagnosis was inconclusive in eight patients. Four of them proved to have carcinoma and died within 18 months. The sensitivity of fine-needle aspiration biopsy of the pancreas was 76% in this study and the predictive value for malignancy was 100%.

Parenteral superoxide dismutase plus catalase diminishes pancreatic edema in sodium taurocholate-induced pancreatitis in the rat.

Scavengers of toxic oxygen reduction products have been reported to reduce the inflammatory reaction in some models of pancreatitis. In a blinded study, the effect of parenteral pretreatment with superoxide dismutase plus catalase was compared with placebo on pancreatitis induced in rats by infusion of 0.25% or 2% sodium taurocholate into the hepatopancreatic duct. The degree of inflammation was assessed by macroscopic examination of the pancreas, dry/wet weight ratios of pancreatic specimens, amylase activity in plasma and peritoneal exudate, the weight of the exudate, and its content of total protein. All parameters were indicative of a more severe inflammation in rats given the higher concentration of sodium taurocholate. The only significant effect of the superoxide dismutase plus catalase treatment was a moderate reduction of the dry/wet weight ratio, i.e., pancreatic edema, in rats given 2% sodium taurocholate. Our results indicate that toxic oxygen reduction products, available for interception by parenterally administered superoxide dismutase plus catalase, are of only minor importance in the pathogenesis of sodium taurocholate-induced pancreatitis in the rat.

Serum levels of the carbohydrate antigen CA-50 in pancreatic disease.

A monoclonal antibody (C 50) was recently produced by immunization with a colorectal cell line defining the tumour associated carbohydrate antigen CA-50. In previous studies CA-50 in serum has been elevated in 60-70% of patients with gastrointestinal carcinomas. This study surveys the serum levels of CA-50, as determined by a radioimmunoassay, in pancreatic disease. Elevated levels of CA-50 were found in 22 of the 24 patients with carcinoma of the exocrine pancreas, in one of eight patients with chronic pancreatitis, and in six of fourteen attacks (41%) of acute pancreatitis. The serum CA-50 antigen, as determined by the assay employed here, has a high sensitivity (92%) for exocrine pancreatic carcinoma. Only patients with malignant disease had CA-50 values exceeding 43 units per ml. In 58% of the patients with pancreatic carcinoma (14/24), CA-50 values surpassed 43 units per ml. In the presence of a pancreatic mass, marked elevation seems to support diagnosis of carcinoma. The low positive predictive value makes the assay unsuitable as a screening test for detection of pancreatic carcinoma in a general population.

Carboxylic ester hydrolase: a serum marker of acute pancreatitis.

By use of an enzyme-linked immunosorbent assay we established serum reference values of carboxylic ester hydrolase, a pancreatic secretory lipolytic enzyme, and explored to see if a raised serum level is indicative of acute pancreatitis. Postoperative elevation of carboxylic ester hydrolase was observed in seven out of ten patients who underwent pancreatic surgery. Serum levels of carboxylic ester hydrolase and amylase were determined in 129 patients admitted due to abdominal emergency conditions. Amylase was elevated in 27 patients, and in 20 of these raised carboxylic ester hydrolase levels affirmed the diagnosis acute pancreatitis. In five out of the seven patients with elevated amylase alone no etiologic factor of acute pancreatitis was found. Another 11 patients had raised carboxylic ester hydrolase levels without concomitant elevation of amylase. In all these patients, a likely cause of pancreatic inflammation was identifiable. Hence, a raised carboxylic ester hydrolase level, even in presence of normal amylase, could be indicative of acute pancreatic inflammation.