Intravenously administered human epidermal growth factor in the rat. Biliary excretion and influences on pancreatic secretion.

BACKGROUND/AIM: Epidermal growth factor (EGF) is known to exert mitogenic effects in different tissues, including the digestive tract and pancreas. EGF is also found in high concentrations in pancreas. Infusion of human EGF has been shown to induce proliferation of cells in exocrine pancreas, and to increase the thickness of the small intestine. The aim of this study was to investigate the influence of intravenously administered human EGF on pancreatic and biliary secretions in the rat. MATERIALS AND METHODS: Rats were fasted overnight and were given human EGF intravenously, either as a bolus dose of 5 microg or as a continuous infusion in increasing doses from 0.5 to 10 microg/h. Bile and pancreatic juice were either collected together or separately. The concentration of human EGF in bile and pancreatic juice was measured. RESULTS: After a bolus dose of EGF increased bile/pancreatic secretion was seen after 60 and 90 min when the bile and pancreatic secretions were not separated. Continuous infusion of EGF increased the joint secretion rate of bile and pancreatic juice in a dose-dependent manner. No effect on secretion rate was seen when bile and pancreatic juice were collected separately. After intravenous infusion of human EGF a 1,000-fold increase of human EGF excretion was found in bile but not in pancreatic juice. CONCLUSION: Intravenously administered human EGF was excreted in high concentrations in bile and increased the secretion rate of pancreatic juice when collected together with bile. The results suggest that EGF, at least partly, exerts its effect on the pancreas and the proximal gastrointestinal tract after excretion with bile and stimulates pancreatic secretion via this route.

The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease.

BACKGROUND: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. PATIENTS AND METHODS: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. RESULTS: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. CONCLUSIONS: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.

Transhepatic intravascular ultrasound for evaluation of portal venous involvement in patients with cancer of the pancreatic head region.

The aim of this study was to evaluate the ability of intravascular ultrasound to diagnose tumor involvement of the portal and the superior mesenteric veins using the preoperative percutaneous, transhepatic approach, and to compare the findings with those made at concomitant direct portography, surgery, and histopathological examination. Ten patients with a preoperative diagnosis of a resectable tumor in the pancreatic head region were examined with percutaneous transhepatic portography (PTP) and intravascular ultrasound (IVUS). The surgeon's intraoperative evaluation and the histopathological examination in combination revealed tumor involvement of the portal or superior mesenteric veins in six of the ten patients. Percutaneous transhepatic portography suggested tumor involvement of the veins in six patients but two of the examinations were false positive and another two were false negative. Intravascular ultrasound showed signs of tumor involvement in eight patients. The examination was, however, false positive in two patients, but there were no false negatives. Complications of the percutaneous transhepatic procedure occurred in six patients including severe pain, bleeding, and related death. Percutaneous transhepatic IVUS of the portal vein may be a useful tool in the preoperative selection of the subgroup of patients with tumor of the pancreatic head region that could benefit from surgery. There is a need for technical improvement as well as studies with larger patient series to definitely decide the role of the technique.

Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial.

OBJECTIVE: To assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. SUMMARY BACKGROUND DATA: Pancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies. METHODS: ESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status. RESULTS: Of 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. CONCLUSIONS: Resection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.

Effect of selective denervation of the rat pancreas on pancreatic endocrine function.

The purpose of this study was to investigate the influence of selective denervation of the rat pancreas on hormone secretion and on peripheral insulin sensitivity. Thirteen rats, 7 denervated and 6 sham operated, received an intravenous glucose challenge for 30 min. The basal plasma levels of insulin, glucagon and glucose did not differ between the two groups. An augmented insulin response to glucose was detected in the denervated group, whereas the glucagon response was unaffected. Glucose tolerance was marginally improved. Twenty-four rats, 12 denervated and 12 sham operated, received a constant infusion of glucose, insulin, epinephrine and propranolol in order to inhibit the endogenous insulin release and thus evaluate insulin sensitivity. No significant change in insulin sensitivity could be detected during our experimental conditions. We conclude that selective denervation brings about an increased insulin response to glucose, probably by interrupting a catecholaminergic negative tone on the beta-cell. The sympathectomized animals did not disclose any apparent changes in peripheral insulin sensitivity.

Differential roles of endogenous nitric oxide on neural regulation of basal exocrine pancreatic secretion in intact and denervated pancreas.

BACKGROUND: Autonomic nerves and humoral factors regulate pancreatic secretion. Nerves containing nitric oxide (NO) synthase (NOS) are in close proximity and located within cholinergic, adrenergic and sensory nerve bundles. Yet, the interactive mechanisms between various nerve populations remain elusive. AIMS: To evaluate the role of endogenous NO in basal exocrine pancreatic secretion in the extrinsically denervated rat pancreas. METHODS: Male Sprague-Dawley rats were assigned to 2 groups of 11 animals. The first group of sham-operated animals served as controls. In the second group extrinsic pancreatic innervation was surgically interrupted. One week later, after selective catheterization of the celiac axis and the bile-pancreatic duct, the animals received intra-arterial infusions of NG-nitro-L-arginine (L-NNA; 0.48 mg/kg b.w./h) followed by intra-arterial infusions of L-arginine (110 mg/kg b.w./h). Total protein and amylase were measured in bile-pancreatic secretions collected at 15-min intervals. RESULTS: In controls, total protein and amylase output showed a biphasic secretion pattern with an increase during L-NNA infusion followed by a decrease when the infusion ceased and further augmentation 1 h later. In denervated animals, L-NNA caused a sustained decrease in pancreatic secretion followed by an increase 1 h later. Infusion of L-arginine at the time of maximum decrease slowed the second phase of protein and amylase output in sham-operated rats, but accentuated the onset of secretion in denervated animals. CONCLUSION: Inhibition of endogenous NO release was shown to increase baseline secretion in the intact pancreas. Superposition of extrinsic denervation on neural NOS-blockade decreased basal exocrine secretion, indicating that intra-pancreatic NO release is regulated by extra-pancreatic nerves.

Acute taurodeoxycholate-induced pancreatitis in the rat is associated with hyperCCKemia.

BACKGROUND: Cholecystokinin (CCK) has been suggested to be involved in the development and course of acute pancreatitis. In the present study we measured plasma CCK concentrations in acute experimental pancreatitis (AEP) in the rat, and evaluated the role of circulating CCK levels on the initial pancreatic damage in pancreatitis. METHODS: Endogenous hyperCCKemia was induced by surgical biliodigestive shunt (BDS) and exogenous hyperCCKemia by infusion of CCK-8S. The CCK-A receptor antagonist devazepide was used to antagonize the effect of CCK. Pancreatitis was induced by pancreatic duct infusion of sodium taurodeoxycholate 4 wk after the BDS operation or 1 wk after the start of the infusions. Nonpancreatitic sham- and BDS-operated rats, respectively, were used as control animals as were groups of otherwise untreated rats with pancreatitis. The animals were sacrificed 6 h after induction of pancreatitis. Concentrations of CCK were determined in plasma as were protein and amylase levels in the pancreas and peritoneal exudates. The extent of pancreatic necroses was assessed microscopically. RESULTS: Pancreatitis caused an 11-20-fold increase of circulating CCK as measured after 6 h. In pancreatitic rats with induced hyperCCKemia, there was a further marked increase of plasma CCK. Pancreatic weight and edema, protein and amylase contents, and extent of necroses were the same regardless of the level of plasma CCK. Devazepide had no influence on the studied pancreatic parameters. CONCLUSION: We conclude that acute taurodeoxycholate-induced pancreatitis in the rat is associated with elevated plasma CCK concentrations. There seems, however, not to be any correlation between the degree of hyperCCKemia and the extent of initial pancreatic damage.

Operations for extrahepatic bile duct cancers: are the results really improving?

OBJECTIVE: To find out if our results for the treatment of extrahepatic bile duct cancer have improved we reviewed our latest patients as a comparison to a previously reported series from this department. DESIGN: Retrospective study. SETTING: Tertiary referral centre, Sweden. SUBJECTS: 102 patients who presented with extrahepatic bile duct cancer 1979-1995. MAIN OUTCOME MEASURES: Morbidity, mortality, and short and long term survival. RESULTS: 16 patients had various types of resection, which were radical in 14 according to the surgeon and in 10 according to the pathologist. One patient (6%) died in hospital, and 1 (44%) developed complications. 13 patients had other operations that did not involve resection, 23 had laparotomy alone, 61 had biliary drainage either by percutaneous transhepatic cholangiography (PTC) or endoscopy, and 10 had no active treatment. One patient of the 16 (6%) who had resections has survived for more than five years and another one is still alive after 40 months. CONCLUSION: Long term survival has not improved for patients with extrahepatic bile duct cancer in our hospital during the last decades.

Is there still an indication for pancreatic duct drainage in chronic pancreatitis?

Pain in chronic pancreatitis is supposed to be multifactorial in origin. Pancreatic duct/tissue hypertension is today proved in patients with chronic pancreatitis and pain. Duct drainage reportedly normalizes pancreatic duct/tissue pressure and reduces pain in 70% of the patients. Also, duct drainage by endoscopy may relieve pain. Surgical duct decompression is parenchyma-preserving and even suggested to prevent further progress of exocrine insufficiency. Recent experience indicates that such operations are pain-relieving not only in patients with dilated ducts but also in those with small duct disease.

[Guidelines for management of patients with acute pancreatitis]. / Riktlinjer för handläggning av patienter med akut pankreatit.

During recent years new concepts and methods have been introduced in the management of acute pancreatitis. Severity and risk of complications show wide variation. Outcome is also dependent on the physician's experience and on his local resources. In this light the Swedish Society of Upper Abdominal Surgery has elaborated national guidelines for management. Attention is paid to diagnosis, severity assessment and etiology. Furthermore, guidelines are offered for treatment of mild and severe pancreatitis, as well as for the management of pseudocysts. The role of multidisciplinary intensive care specialist teams in the management of severe disease is emphasized. The guidelines are supported by the Swedish Society of Gastroenterology, the Swedish Society of Gastroenterology, the Swedish Society of Anesthesiology and Intensive Care and by experts from other Nordic countries.

Effects of intraluminal trypsin and bile on the exocrine and endocrine pancreas after pancreaticobiliary diversion and biliodigestive shunt.

Pancreaticobiliary diversion (PBD) and biliodigestive shunt (BDS) cause long-standing hypercholecystokininemia followed by pancreatic hyperplasia. These changes have been suggested to be due to the lack of intraluminal trypsin and bile, respectively, in the upper small intestine. The aim of these experiments was to study the effect of restoration of intraluminal trypsin and bile on plasma levels of cholecystokinin (CCK) and the changes found in exocrine and endocrine pancreas after PBD and BDS. Male Sprague-Dawley rats were used. PBD was done in 16 rats, eight of which had trypsin dissolved in 50 mM sodium bicarbonate (SB), and eight had SB only by gastric intubation twice daily. BDS was done in another 16 rats, eight of which had bile dissolved in SB, and eight had SB in a similar manner. Sham-operated rats had SB and served as controls. After 4 weeks, the rats were killed, and the concentrations of circulating CCK, gastrin, glucose, glucagon, and insulin were determined. The pancreas was removed, weighed, and analyzed for contents of water, protein, and DNA. In another study, PBD-operated rats got trypsin in varying dosages or trypsin and taurocholate in combination for 2 weeks before death. The concentrations of plasma CCK and glucagon were elevated after both PBD and BDS. PBD decreased the concentration of gastrin in plasma. PBD caused an increase of pancreatic weight and the contents of protein and DNA. Trypsin substitution to PBD-operated rats did not affect plasma CCK or glucagon levels, but the PBD-induced increases in weight and DNA content were counteracted by trypsin. Higher dosages of trypsin did not further influence the effects seen after PBD. Pancreatic weight and DNA content were increased after BDS. Bile administration completely abolished the increase in plasma CCK and glucagon, as well as the gain in pancreatic weight, and reduced the increase in pancreatic DNA. Substitution with bile to BDS-operated rats abolished the increase in the plasma levels of CCK and glucagon, as well as the trophic effects on the pancreas. Trypsin substitution to PBD-operated rats partly reversed the trophic effects on the pancreas but not the hormonal changes in plasma. Thus the trophic effects on the pancreas exerted by BDS seem to be dependent on the lack of bile in the upper small intestine, whereas the effects of PBD only partly are a consequence of the absence of intraluminal trypsin.

Pancreaticogastrostomy after subtotal pancreatectomy for cancer.

BACKGROUND: Failure of the pancreaticodigestive anastomosis after pancreatoduodenectomy is still a major clinical problem. Pancreaticogastrostomy has recently been suggested to be associated with a low risk of leakage. The aim of this report was to add to previously reported experience. METHODS: Data on the postoperative course were prospectively registered in 19 patients operated on with subtotal pancreatectomy because of periampullary cancer. They all had a duct-to-mucosa pancreaticogastrostomy. RESULTS: There were no recognizable leakages from the pancreaticogastrostomy. However, the overall postoperative complication rate was 47% (9/19), the most common complications being delayed gastric emptying (26%, 5/19), wound infection (21%, 4/19), and wound rupture (11%, 2/19). Excluding delayed gastric emptying, the rate of intra-abdominal complications was 16% (3/19). There was 1 in-hospital death. CONCLUSION: The results support the opinion that pancreaticogastrostomy can be done with a low risk of leakage.

Pancreatic biopsy: why? When? How?

For final diagnosis of pancreatic cancer histologic or cytologic confirmation is needed. Tissue or cell material can be achieved by percutaneous puncture as part of the preoperative workup. During operation core-needle, incisional, and wedge biopsies or fine-needle aspiration cytology (FNAC) can be chosen. Sensitivity and diagnostic accuracy are high for both histologic and cytologic examinations, and false-positive results are exceptional, giving a specificity of 100% in most published series. The complication rate is low, also for knife biopsies in recent reports, provided biopsy of seemingly normal tissue is avoided. Percutaneous puncture is currently restricted to patients found to have advanced disease and who are not candidates for laparotomy. Microscopic confirmation is required in all patients in whom chemotherapy, radiotherapy, or both are planned. However, for attempted radical surgery per se, biopsy is not mandatory if the clinical suspicion of cancer is high and the surgical team has documented low postoperative mortality and morbidity rates.

Subtotal pancreatectomy for cancer can be safe in the elderly.

OBJECTIVES: Evaluation of safety of subtotal pancreatectomy for cancer in elderly patients (70 years of age or more) and of long term survival compared with younger patients. DESIGN: Retrospective study of information recorded prospectively in the departmental database. SETTING: University hospital, Sweden. SUBJECTS: 74 consecutive patients who underwent subtotal pancreatectomy for cancer between 1985 and 1993. MAIN OUTCOME MEASURES: Postoperative mortality and morbidity, and long term survival. RESULTS: The diagnosis was pancreatic cancer in 41, cancer of the papilla of Vater in 17, cancer of the bile duct in 7, juxtapapillary duodenal cancer in 5, and 4 other pancreatic head tumours. There were no differences in sex, first symptom, preoperative weight loss, radicality according to the pathology report, tumour size, grade of differentiation or presence of lymph node metastases between the two groups. The rate of postoperative complications was the same for both groups, as was the amount of intraoperative bleeding, operation time, and length of hospital stay including stay at the intensive care unit (ICU). Hospital mortality was 4% for the younger and 7% for the elderly (p = 0.61). The long term survival was the same in the two age groups both when all patients were included and when patients with pancreatic cancer were analysed separately. CONCLUSION: Subtotal pancreatectomy for cancer can be done safely in the elderly which is why chronological age alone is not a contradiction to resection of a periampullary or pancreatic head malignancy provided that the patients are carefully selected.

Pancreatic growth after pancreatico-biliary diversion does not increase the capacity to secrete amylase.

BACKGROUND/AIM: Cholecystokinin (CCK) stimulates secretion and evokes a hyperplastic response in the rat pancreas. The aims of this study were to measure the effect of chronic hyperCCKemia induced by pancreatico-biliary diversion (PBD) on pancreatic enzyme concentrations, on amylase secretion by dispersed acinar cells, and on the CCK-stimulated secretion of pancreatic juice in PBD-operated rats. MATERIAL AND METHODS: Forty-five Sprague-Dawley male rats had either PBD or sham operation 4 weeks before sacrifice or additional experiments. In the first study, 25 rats (13 PBD and 12 sham-operated rats) were either freely fed or fasted overnight before sacrifice. The pancreas was dissected out, weighed and analyzed. In the second study, the rats (6 PBD and 7 sham-operated rats) were fasted overnight before pancreatic acini were prepared. Secretion of amylase during stimulation of acini with CCK-8S and carbachol was measured. In the third study (5 sham-operated and 4 PBD rats), the rats were fasted overnight before basal and CCK-stimulated secretion was measured in vivo. RESULTS: PBD-operated rats showed a threefold increase in pancreatic wet weight with increased contents of DNA, protein and water. The concentration of pancreatic amylase was 7-12% of that found in control animals. The concentrations of trypsin and lipase were also lowered. Stimulation of dispersed pancreatic acini with CCK-8S or carbachol resulted in secretion of amylase to a similar extent in PBD and sham-operated rats. There was no difference in the secretion of pancreatic juice in response to CCK, but although the output of amylase from PBD-operated rats increased with CCK, it remained at a low level throughout the study period. CONCLUSION: PBD evoked hyperplastic changes in the rat pancreas and decreased the concentrations of amylase, trypsin and lipase. However, the capacity of acinar cells to secrete amylase remained intact. The stimulated pancreatic secretion was not changed in volume, but the output of amylase was low in PBD-operated rats. The findings are consistent with the idea that the enlargement of the pancreas following PBD does not improve the secretory capacity.