The fate of patients who undergo "preoperative" ERCP to clear known or suspected bile duct stones.

BACKGROUND: There is debate as to whether recurrent biliary complications are more common in patients who do not have elective cholecystectomy after endoscopic retrograde cholangiopancreatography (ERCP) management of common bile duct (CBD) stones. The aim of this study was to determine the fate of patients with intact gallbladders who have had CBD stones removed at ERCP, and to assess their risk of recurrent biliary symptoms. METHODS: We retrospectively identified all patients in our large tertiary center population with intact gallbladders who had an ERCP for CBD stones from December 1999 to March 2002. We determined which patients had subsequent elective cholecystectomy, and the outcomes of patients who did not have elective surgery. RESULTS: 309 patients had CBD stones at ERCP during the study period, of which 139 had intact gallbladders at the time of ERCP. Of these 139 patients 59 had subsequent elective cholecystectomy, 11 by open operation and 48 laparoscopically. Of these 139 patients, 27 had cholecystectomy planned; 47 patients were managed with a wait-and-see strategy, 30 of whom were poor surgical candidates. Of these 47 patients in whom a wait-and-see policy was adopted, 9 (19%) developed complications including recurrent pain and/or abnormal liver function tests (LFTs), recurrent biliary colic, and pancreatitis. Eight of these nine patients were from the poor surgical candidate group. Sphincterotomy had been performed at initial ERCP in all patients. CONCLUSIONS: Over half of our population of 139 patients with CBD stones at ERCP and intact gallbladders had actual or planned elective cholecystectomy. For those patients in whom a decision to wait-and-see was made, almost 20% developed complications. Elective cholecystectomy after a finding of choledocholithiasis is supported by many and is a common strategy in our experience. Recurrent biliary complications are relatively common in those who do not undergo elective cholecystectomy, especially those patients who represent a high operative risk.

Enterogastrone-like effect of peptide YY is vagally mediated in the dog.

Intraluminal fat inhibits gastric secretion through as yet undetermined mechanisms which involve release of one or more hormonal enterogastrones. As intraluminal fat releases Peptide YY (PYY) in amounts sufficient to inhibit meal-stimulated acid secretion, this ileo-colonic peptide exhibits the characteristics required of an enterogastrone. The present study seeks to determine the mechanism by which PYY inhibits acid secretion by examining the effects of PYY on gastric acid stimulated by pentagastrin, histamine, and bethanechol. In addition, effects of PYY on the acid response to sham feeding and distention of a denervated gastric pouch were examined. A dose of PYY (400 pmol X kg-1 X h-1) was employed that reproduced blood levels observed after intestinal perfusion with oleic acid and inhibited the acid secretory response to an intragastric meal by 35 +/- 6%. This same dose of PYY maximally inhibited histamine- and pentagastrin-stimulated acid secretion by 28 +/- 7% (P less than 0.05), and 17 +/- 4% (P less than 0.05), respectively. Although PYY had no effect on bethanechol-stimulated secretion it markedly inhibited the secretory response to sham feeding, maximally reducing secretion by 90 +/- 4% (P less than 0.01). We speculate that PYY acts by inhibiting acetylcholine release from vagal nerve fibers rather than by inhibiting acetylcholine's action on the parietal cell. The demonstration that PYY virtually abolishes cephalic phase acid secretion while having little if any effect on the response to exogenous secretogogues gives PYY unique characteristics among the known hormonal inhibitors of gastric secretion.

Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach.

In humans and dogs, it is known that motilin regulates phase III contractions of migrating motor complex (MMC) in the fasted state. In rats, however, motilin and its receptor have not been found, and administration of motilin failed to induce any phase III-like contractions. Ghrelin was discovered as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R) from the rat stomach. Ghrelin promotes gastric premature phase III (phase III-like contractions) in the fasted state in rats. We hypothesized that endogenous ghrelin regulates spontaneous phase III-like contractions in rats. Strain gauge transducer was sutured on the antrum and a catheter was inserted into the jugular vein. We studied the effects of i.v. administration of ghrelin and a GHS-R antagonist on gastric phase III-like contractions in conscious rats. Plasma level of ghrelin was measured by a radioimmunoassay. Ghrelin augmented spontaneous phase III-like contractions and a GHS-R antagonist significantly attenuated the occurrence of spontaneous phase III-like contractions. During the phase I period, plasma ghrelin level increased to its peak then returned to basal level, subsequently phase III-like contractions were observed. These results suggest that endogenous ghrelin regulates gastric phase III-like contractions in rats.

Laparoscopic distal pancreatectomy with splenic preservation.

BACKGROUND: The technique of distal pancreatectomy has been well described, both with en bloc resection of the spleen and with splenic preservation. Splenic preservation during pancreatic tail resection is desirable when oncologically appropriate, yet it is technically challenging, particularly with laparoscopic approaches. Skeletonization of the splenic artery and vein is associated with longer operative times and greater potential for bleeding. The authors report their experience with splenic preservation during laparoscopic pancreatic resection using ligation of the splenic vessels and preservation of the short gastric vessels. METHODS: A retrospective chart review was performed for all patients who underwent attempted laparoscopic pancreatic resection at Duke University Medical Center from July 2002 to October 2005. Charts were analyzed for demographic information, length of hospital stay, conversion, splenic preservation, and postoperative complications. RESULTS: A total of 12 laparoscopic distal pancreatic resections were attempted for three men and nine women with a mean age was 55.8 years (range, 33-74 years). All 12 patients underwent distal pancreatectomy, 8 with splenic preservation. The spleen was removed from three patients using splenic hilar lesions that prevented splenic salvage. One patient required splenectomy secondary to more than 50% ischemia of the spleen. No patients with preoperatively diagnosed malignancy underwent splenic salvage. The final pathologic diagnosis included neuroendocrine tumors (n = 2), cystic serous (n = 4) and mucinous (n = 2) neoplasms, intraductal papillary mucinous neoplasm (IPMN) (n = 1), pancreatitis (n = 2), and adenocarcinoma (n = 1). Two patients underwent conversion to open surgery for thickened parenchyma secondary to chronic pancreatitis (17%). There were no other conversions. There were three chemical leaks (25%) diagnosed by elevated drain amylase and low volume output, which were managed with intraoperatively placed drains removed at the initial postoperative clinic visit. There were three higher volume leaks (25%) that required extended or percutaneous drainage, with eventual removal. The average blood loss was 215 ml (range, 50-700 ml). The average operative time was 3 h and 41 min (range, 2 h 15 min to 5 h 58 min). The average length of hospital stay was 4 days (range, 2-7 days). CONCLUSION: Splenic preservation should be performed when technically possible to decrease the morbidity of laparoscopic distal pancreatectomy. The choice to ligate the splenic vessels allows for shorter operative times with minimal perioperative morbidity and blood loss while maintaining the spleen.

Impaired gastric motor activity after abdominal surgery in rats.

Postoperative ileus (POI) is a transient bowel dysmotility that occurs following abdominal surgery. Several mechanisms have been proposed such as neural reflex and inflammatory changes. We focused on gastric motility after abdominal surgery in rats. To investigate the time course of gastric motility after surgery, gastric motility was continuously recorded before, during and after surgery. After laparotomy, terminal ileum was manipulated for 10 min. Gastric motility was recorded by a strain gauge transducer implanted on the serosal surface of the stomach. To investigate whether peripheral sympathetic nerve is involved in the pathogenesis of POI, effects of guanethidine and celiac ganglionectomy were tested on the postoperative gastric motility. Although isoflurane anaesthesia reduced the gastric motility to 40%, the motility recovered immediately when isoflurane was withdrawn. Intestinal manipulation reduced the postoperative gastric motility for 3-24 h after surgery, compared with preoperative levels. Guanethidine administration and celiac ganglionectomy restored the impaired gastric motility. Feeding increased the gastric motility in each group. It is suggested that the pathogenesis of postoperative gastric ileus induced by intestinal manipulation involves viscero-sympathetic pathways. Intestinal manipulation causes impaired gastric motility via inhibitory sympathetic efferent pathway. Feeding may improve the postoperative gastric motility.

Percutaneous cervical oesophageal cannulation in the dog for the performance of prolonged oesophageal pH and manometric studies.

Traditional methods for obtaining oesophageal access in experimental animals are unsuitable for prolonged (24 h) oesophageal pH evaluation, a procedure that is commonly employed in the assessment of human patients suspected of having gastroesophageal reflux disease. In the present study, we describe a six-year experience with a technique of percutaneous oesophagostomy for the performance of serial 24 h oesophageal pH and manometric studies involving 62 dogs and a total of 208 oesophageal cannula placement procedures. The results indicate a considerable improvement over previously described techniques with respect to simplicity of surgical technique, associated morbidity, oesophagostomy management, animal conditioning, and avoidance of chemical and excessive physical restraints in animals undergoing oesophageal pH and manometric evaluation.

Role of neuropeptides in the regulation of feeding behavior: a review of cholecystokinin, bombesin, neuropeptide Y, and galanin.

The purpose of this report is to provide a review of four peptides (cholecystokinin, bombesin, neuropeptide Y, galanin) and their role in feeding behavior. Cholecystokinin (CCK) and bombesin (BBS) are considered satiety peptides, and neuropeptide Y (NPY) and galanin (GAL) have been proposed as appetite peptides. For the purposes of this review, satiety refers to the physiological cessation of feeding, and appetite refers to the drive to eat and exists in gradations.

Physiological satiety implications of gastrointestinal antiobesity surgery.

This manuscript reviews the known satiety signals and the impact of antiobesity surgery on these physiological satiety mechanisms. Satiety signals originate from the stomach and small bowel to stop eating behavior. Stomach signals (gastric distension) produce early satiety by releasing hypothalamic cholecystokinin (CCK). The intermeal interval is probably mediated by peripheral CCK released by a threshold level of intraluminal calories. Anti-obesity operations probably rely little on these physiological satiety signals. Gastric balloons and gastroplasty produce nonphysiological gastric distension whereas intestinal bypass causes malabsorption. Gastric bypass combines supramaximal gastric distension with taste aversion from dumping. Future physiological manipulation of the satiety cascade will lead to improve obesity intervention.

Review article: evaluation of drugs in experimental gut distension models.

Distension of the gastrointestinal tract elicits abdominal pain, as well as sensations such as discomfort or fullness. Many patients with irritable bowel syndrome have been reported to show a reduced threshold to the pain or discomfort due to experimental rectal distension. This hypersensitivity of the gut may be characteristics of the irritable bowel, as well as other functional gastrointestinal disorders. Intestinal distension in animals induces a range of responses which have been used as indexes of visceral nociception. This paper reviews a recently introduced canine model used to assess the antinociceptive properties of a novel 5-HT3 receptor antagonist, alosetron.

Management of biliary complications after heart transplantation.

BACKGROUND: Immunosuppression increases the risk of biliary complications in heart transplant recipients. METHODS: Patients undergoing heart transplantation since 1986 who were at risk for cholelithiasis (n = 60) were retrospectively studied. RESULTS: Cholestatic jaundice developed in all patients after the operation because of biliary obstruction from cholelithiasis, cyclosporine toxicity, Imuran toxicity, or Gilbert's disease. The incidence of cholelithiasis or sludge was 42% (n = 25 of 60). Gallstones developed within 1.8 +/- 1.1 years in 17% of patients (n = 8 of 48) with a normal pretransplantation ultrasonogram. Biliary colic or gallstone pancreatitis developed 2 +/- 1.2 years after transplantation in 58% of patients (n = 7 of 12) with asymptomatic gallstones diagnosed before transplantation. The overall incidence of cholecystectomy or cholecystectomy with Roux-en-Y cystojejunostomy was 40% (n = 24). Both open cholecystectomy (n = 5) and laparoscopic cholecystectomy (n = 19) were performed without significant complications. Recovery is significantly more rapid (p < 0.05) after laparoscopic cholecystectomy versus open cholecystectomy (1 week versus 3 weeks). CONCLUSIONS: This analysis indicates that transplant candidates who have gallstones on pretransplantation evaluation or in whom gallstones develop after transplantation should undergo laparoscopic cholecystectomy at the earliest time in their posttransplantation course (i.e., 3 months) regardless of their symptomatic status. Removal of the diseased gallbladder not only simplifies the evaluation of cholestatic jaundice by eliminating the need for multiple ultrasonograms to exclude acute cholecystitis or choledocholithiasis but also safely minimizes the risk of the development of severe biliary complications.

Opposing central and peripheral actions of brain-gut peptides: a basis for regulation of gastric function.

The existence of an increasing number of peptides in both the gut and the brain provides the basis for the concept of a brain-gut axis. However, to date, no unifying hypothesis has been put forward to explain the physiologic significance of this remarkable phenomenon. The present study examines the central and peripheral actions on gastric function of cholecystokinin octapeptide (CCK-8), somatostatin, and bombesin, all of which exist in both the gut and brain. Intravenous infusion of CCK-8, in doses of 50, 100, and 200 pmol X kg-1 X hr-1, caused 28%, 38%, and 52% inhibition, respectively, of the rate of gastric emptying of a liquid meal in dogs. By contrast, the injection of 32, 64, and 128 pmol X kg-1 into the lateral cerebral ventricle of these dogs accelerated gastric emptying by 6%, 26%, and 32%, respectively. Bombesin, which stimulated gastric acid secretion in a dose-dependent manner but which had no effect on the submaximal acid response to pentagastrin when administered peripherally, inhibited in a dose-dependent manner the submaximal response to pentagastrin when given centrally, with a maximal inhibition of 66% +/- 5%, at a dose of bombesin of 180 pmol X kg-1. Similarly, somatostatin-14 caused graded inhibition of pentagastrin-stimulated acid secretion when it was administered peripherally but caused dose-dependent augmentation of the acid response when it was given centrally. Maximal inhibition of 51% of the pentagastrin response occurred with a peripheral dose of somatostatin of 800 pmol X kg-1 X hr-1. By contrast, maximal augmentation of the pentagastrin response of 78% occurred when a dose of 400 pmol X kg-1 of the peptide was injected into the lateral ventricle. We conclude that CCK-8, bombesin, and somatostatin have opposing actions on gastric function when administered centrally and peripherally. We propose that this phenomenon may be common to all neuropeptides of the brain-gut axis and may provide a basis for central regulation of gut function.

The use of somatostatin and its analogs in the treatment of surgical disorders.

Somatostatin is a naturally occurring peptide with a wide spectrum of biologic actions, most of which are inhibitory in nature. It has wide distribution, and within the gastrointestinal tract is is found in the pancreas, the stomach, intestinal mucosa, and myenteric neurons. It appears to function as a classic circulating hormone, as well as both a paracrine or locally acting agent and a neurocrine agent. Because of its inhibitory actions on gut endocrine, secretory, and motor functions, it has potential applicability in the treatment of a variety of disorders of interest to the surgeon. Indeed, it has been used successfully in the management of upper gastrointestinal hemorrhage, secretory diarrhea, short bowel syndrome, pancreatitis, gastrointestinal fistulas, and peptide-secreting tumors of the gut (apudomas). This review discusses physiology, pathophysiology, and therapeutic applications of somatostatin that may be important in surgical practice.

Interactions of vasoactive intestinal polypeptide and cholecystokinin octapeptide on the control of gallbladder contraction.

The gallbladder is supplied by three types of vagal fibers: cholinergic, cholecystokinin (CCK)-ergic, and vasoactive intestinal polypeptide (VIP)-ergic. Most previous studies on the interaction of VIP and CCK on gallbladder contraction have been in vitro. In this study we evaluate this interaction more fully in vivo using six dogs with chronic bile fistula. Dose-response curves were constructed to CCK-8 alone and to VIP alone. The effect of graded doses of VIP on maximal response to CCK-8 was also studied. CCK-8 caused the expected dose-related stimulation of gallbladder contraction, while graded doses of VIP had the opposite effect. VIP also caused a dose-related inhibition of the maximal response to CCK-8, decreasing bilirubin output from 39 +/- 8 to 15 +/- 3 mg/hr (p less than 0.05). The corollary to these findings is that gallbladder tone and contraction is regulated by the interplay of stimulatory cholinergic-CCK-ergic and inhibitory VIP-ergic fibers. Further, a plausible explanation for the variable effects of vagotomy on gallbladder contraction is that variable proportions of these opposing fibers are cut.

Local ampullary resection with careful intraoperative frozen section evaluation for presumed benign ampullary neoplasms.

BACKGROUND: Frozen section evaluation has been reported to be inaccurate in detecting foci of adenocarcinoma within adenomas of the ampulla of Vater, leading many authors to advocate pancreaticoduodenectomy as the method of treatment for these neoplasms. The authors hypothesized that (1) ampullary resection is less morbid than pancreaticoduodenectomy, and (2) frozen section evaluation following ampullary resection is accurate and allows for a selective application of pancreaticoduodenectomy to those with carcinoma or benign lesions too large to be locally resected. METHODS: A retrospective review of a single-surgeon experience was conducted. Thirty-eight patients who underwent ampullary resection and pancreaticoduodenectomy (39 procedures) for benign and malignant ampullary neoplasms were identified. Our technique of step-frozen section analysis is described. RESULTS: Twenty-one ampullary resections were performed for preoperative diagnoses of benign (16) and malignant (5) ampullary neoplasms. Frozen section evaluation accurately predicted the final histology in all patients undergoing ampullary resection. Ampullary resection (vs pancreaticoduodenectomy) was associated with a statistically lower operative time (169 minutes vs 268 minutes), estimated blood loss (192 mL vs 727 mL), mean length of stay (10 days vs 25 days), and overall morbidity (29% vs 78%). CONCLUSIONS: Frozen section evaluation of ampullary neoplasms is accurate. Because ampullary resection is less morbid than pancreaticoduodenectomy and frozen section evaluation is accurate, ampullary resection with frozen section evaluation is our current approach to the treatment of small benign ampullary neoplasms.

Surgical therapy of localized abdominal non-Hodgkin's lymphomas.

Non-Hodgkin's lymphomas may involve a variety of abdominal organs, including the liver, spleen, gastrointestinal tract, and retroperitoneum. The number of organs potentially involved and the noncontiguous mode of spread make non-Hodgkin's lymphoma a difficult tumor to evaluate at the time of laparotomy. To clarify the surgical management of patients with this tumor, we retrospectively reviewed the medical records of 202 patients with histologically proven abdominal lymphomas. Within this group, 36 patients underwent laparotomy before they had chemotherapy or radiation therapy. Ten patients were explored to establish a histologic diagnosis of lymphoma. The remaining 26 patients underwent laparotomy because of presumed benign disease. Twenty patients were found to have localized disease at laparotomy. Patients with localized disease demonstrated significantly better survival than patients with extranodal and nodal involvement (p less than 0.05). Four patients with local resection received no adjuvant therapy and were free of disease a median of 50 months after surgery.

Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo.

BACKGROUND: Directed enzyme pro-drug therapy incorporates the delivery of a gene to a cancer cell that will be specifically expressed and will confer sensitivity to a therapeutic agent. Tumor-specific gene expression can be achieved by coupling the promoter for the carcinoembryonic antigen (CEA) to a gene such as herpes simplex virus thymidine kinase (HSV-tk), which phosphorylates ganciclovir to a potent DNA synthesis inhibitor. METHODS: Retroviral vectors were constructed to contain the CEA promoter coupled to HSV-tk (LN-CEA-TK) and were used to transduce the CEA-expressing pancreatic carcinoma cell line BXPC3. Recombinant pancreatic carcinoma cell lines expressing HSV-tk (BXPC3CEA-TK) were then tested for sensitivity to the toxic effects on ganciclovir after engraftment into severe combined immunodeficient mice. Tumors were generated by subcutaneous inoculation of 20 x 10(6) tumor cells consisting of BXPC3 and/or BXPC3CEA-TK cells in ratios of 100:0, 90:10, 50:50, 10:90, and 0:100. After 3 days mice received daily ganciclovir (0.1 mg/kg) or phosphate-buffered saline solution by intraperitoneal injection and were monitored for tumor growth. RESULTS: All severe combined immunodeficient mice inoculated with BXPC3 or BXPC3CEA-TK cells in any proportion developed large pancreatic tumors. As expected, a significant reduction in tumor size was seen in the BXPC3CEA-TK engrafted mice receiving ganciclovir compared with mice receiving phosphate-buffered saline solution or mice engrafted with only BXPC3. In addition, all animals with any fraction of cells expressing HSV-tk exhibited a significant reduction in tumor growth, including animals with only 10% of cells expressing HSV-tk. CONCLUSIONS: These results suggest the potential utility of directed enzyme pro-drug therapy in patients with CEA-expressing pancreatic carcinoma.

Advances in drug therapy for peptic ulcer disease.

Recently, three new drug types have emerged to treat peptic ulceration. We compared the mechanism of action of omeprazole and somatostatin-14, both inhibitors of gastric acid, with that of tetraprenylacetone, a drug thought to be cytoprotective in the upper gut. Omeprazole and somatostatin-14 caused potent inhibition of meal-stimulated acid secretion in the dog (92% +/- 6% and 97% +/- 1%, respectively). On the other hand, tetraprenylacetone had no significant inhibitory effect on acid secretion (4% +/- 17%). In separate studies, tetraprenylacetone was shown to be a stimulant of gastric bicarbonate secretion in the rabbit, increasing bicarbonate secretion from a basal level of 0 to 86 +/- 28 pmol/2 h. Tetraprenylactone was also found to be a strong stimulant of canine pancreatic bicarbonate secretion. The ability of tetraprenylacetone to stimulate endogenous bicarbonate secretion may explain its ability to heal ulcers both experimentally and clinically.

Primary hypertrophic pyloric stenosis in the adult.

Analysis of 100 consecutive patients with pyloric outlet obstruction revealed that 37% of the obstructions were secondary to peptic ulcer disease and 42% were caused by malignant neoplasm. Only a single patient with primary hypertrophic pyloric stenosis was identified, and whether this lesion is a cause or effect of peptic ulcer disease remains unclear. Similarly, the association of this entity with congenital pyloric stenosis is unknown.

Corticotropin-releasing factor inhibits gastric emptying in dogs: studies on its mechanism of action.

The effects of corticotropin-releasing factor (CRF) on gastric emptying of a saline solution was further investigated in six dogs prepared with gastric fistulas and chronic cerebroventricular guides and in four other dogs with chronic gastric fistulas and pancreatic (Herrera) cannulas. Intravenous infusion of CRF significantly inhibited gastric emptying whereas intracerebroventricular injection of CRF had no effect. Pharmacologic blockade of beta-adrenergic system by propranolol did not modify intravenous CRF induced delay in gastric emptying. Intravenous CRF did not influence basal pancreatic secretion whereas secretin infused stimulated bicarbonate secretion. These results indicate that intravenous but not intracerebroventricular administration of CRF inhibited gastric emptying of a saline solution in dogs. The inhibitory effect of intravenous CRF on gastric emptying is not mediated by the beta-adrenergic nervous system, and not secondary to the release of other peptides that affect both pancreatic secretion and gastric emptying such as cholecystokinin and peptide YY.

Neuropeptide Y functions as a physiologic regulator of cephalic phase acid secretion.

Neuropeptide Y (NPY) has been established as a potent orexigenic peptide, and recent studies suggest that NPY stimulates cephalic phase secretion as well. However, it is not known whether NPY's effects are pharmacologic or physiologic. In order to determine the physiologic significance of NPY, we examined the effects of two putative NPY receptor antagonists, PYX-1 and PYX-2, on sham feeding and gastric acid secretion in dogs. Our results demonstrate that intracerebroventricular (i.c.v.) injection of PYX-1 and PYX-2 at 1000 pmol/kg doses significantly suppresses the gastric acid response to sham feeding in dogs. The volumes sham fed were not significantly altered with i.c.v. administration of the antagonists. Peripheral administration did not affect acid secretion nor sham feeding volumes. Our data suggest that central administration of the novel NPY antagonists, PYX-1 and PYX-2, results in significant suppression of acid secretion in dogs. This supports our hypothesis that NPY functions as a physiologic modulator of cephalic phase acid secretion.