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Drugs are a relatively rare cause of acute pancreatitis, with an estimated incidence of 0.1-2%. Many drugs have been suspected of causing pancreatitis, but the true incidence is not known as the evidence is derived mainly from random case reports. Case reports with the strongest evidence are those that clearly diagnose pancreatitis and exclude common aetiologies, provide the dose and time interval between the start of treatment with the suspected drug and the development of pancreatitis, document response to withdrawal of the drug, and demonstrate recurrent pancreatitis upon rechallenge with the drug. Few data exist on the mechanisms of drug-induced pancreatitis. Certain subpopulations such as children, women, the elderly and patients with advanced HIV infection or inflammatory bowel disease may be at higher risk. The diagnosis of drug-induced pancreatitis is often challenging because there are no unique clinical characteristics to distinguish drugs from other causes of pancreatitis. The majority of cases are mild, but severe and even fatal cases may occur, thus making identification of the offending agent critical. Management of drug-induced acute pancreatitis requires withdrawal of the offending agent and supportive care. Prevention of drug-induced pancreatitis requires an up-to-date knowledge of drugs that have the strongest evidence linking their use to the development of pancreatitis as well as the proposed mechanisms through which they may cause the reaction. In this paper, the epidemiology, diagnosis, management and prevention of drug-induced pancreatitis is reviewed. Drugs and classes of drugs strongly implicated as causing acute pancreatitis, based on well documented case reports, are discussed in detail. [ABSTRACT FROM AUTHOR]

Background and Aims: Peroral endoscopic myotomy (POEM) is becoming the treatment of choice for achalasia. Data beyond 3 years are emerging but are limited. We herein report our 10-year experience, focusing on long-term efficacy and safety including the prevalence, management, and sequelae of postoperative reflux., Methods: This was a single-center prospective cohort study., Results: Six hundred ten consecutive patients received POEM from October 2009 to October 2019, 160 for type 1 achalasia (26.2%), 307 for type II (50.3%), 93 for type III (15.6%), 25 for untyped achalasia (4.1%), and 23 for nonachalasia disorders (3.8%). Two hundred ninety-two patients (47.9%) had prior treatment(s). There was no aborted POEM. Median operation time was 54 minutes. Accidental mucosotomies occurred in 64 patients (10.5%) and clinically significant adverse events in 21 patients (3.4%). No adverse events led to death, surgery, interventional radiology interventions/drains, or altered functional status. At a median follow-up of 30 months, 29 failures occurred, defined as postoperative Eckardt score >3 or need for additional treatment. The Kaplan-Meier clinical success estimates at years 1, 2, 3, 4, 5, 6, and 7 were 98%, 96%, 96%, 94%, 92%, 91%, and 91%, respectively. These are highly accurate estimates because only 13 patients (2%) were missing follow-up assessments. One hundred twenty-five patients (20.5%) had reflux symptoms more than once per week. At a median of 4 months, the pH study was completed in 406 patients (66.6%) and was positive in 232 (57.1%), and endoscopy was completed in 438 patients (71.8%) and showed reflux esophagitis in 218 (49.8%), mostly mild., Conclusions: POEM is exceptionally safe and highly effective on long-term follow-up, with >90% clinical success at ≥5 years., (Copyright © 2021. Published by Elsevier Inc.)

Background & Aims: Endoscopic submucosal dissection (ESD) is widely used in Asia to resect early-stage gastrointestinal neoplasms, but use of ESD in Western countries is limited. We collected data on the learning curve for ESD at a high-volume referral center in the United States to guide development of training programs in the Americas and Europe., Methods: We performed a retrospective analysis of consecutive ESDs performed by a single operator at a high-volume referral center in the United States from 2009 through 2017. ESD was performed in 540 lesions: 449 mucosal (10% esophageal, 13% gastric, 5% duodenal, 62% colonic, and 10% rectal) and 91 submucosal. We estimated case volumes required to achieve accepted proficiency benchmarks (>90% for en bloc resection and >80% for histologic margin-negative (R0) resection) and resection speeds >9cm 2 /hr., Results: Pathology analysis of mucosal lesions identified 95 carcinomas, 346 premalignant lesions, and 8 others; the rate of en bloc resection increased from 76% in block 1 (50 cases) to a plateau of 98% after block 5 (250 cases). The rate of R0 resection improved from 45% in block 1 to >80% after block 5 (250 cases) and ∼95% after block 8 (400 cases). Based on cumulative sum analysis, approximately 170, 150, and 280 ESDs are required to consistently achieve a resection speed >9cm 2 /hr in esophagus, stomach, and colon, respectively., Conclusions: In an analysis of ESDs performed at a large referral center in the United States, we found that an untutored, prevalence-based approach allowed operators to achieve all proficiency benchmarks after ∼250 cases. Compared with Asia, ESD requires more time to learn in the West, where the untutored, prevalence-based approach requires resection of challenging lesions, such as colon lesions and previously manipulated lesions, in early stages of training., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Heller's myotomy (HM) is one of the most effective treatments for esophageal achalasia. However, failures do exist, and the success rate tends to decrease with time. The efficacy of rescue treatments for patients with failed HM is limited. A few small-scale studies have reported outcomes of per-oral endoscopic myotomy (POEM) in these patients. We conducted this study to systematically assess feasibility, safety, and efficacy of POEM on patients who have had HM., Methods: Patients at least 3 months out from POEM were selected from our prospective database: 318 consecutive POEMs performed from October 2009 to October 2016. The efficacy and safety of POEM were compared between the 46 patients with prior HM and the remaining 272 patients., Results: Patients with prior HM had longer disease history, more advanced disease, more type I and less type II achalasia, lower before-POEM Eckardt scores, and lower before-POEM lower esophageal sphincter (LES) pressure (all P < .01). Procedure parameters and follow-up results (clinical success rate, Eckardt score, LES pressure, GERD score, esophagitis, and pH testing) showed no significant difference between the 2 groups. For the 46 HM-POEM patients, no clinically significant perioperative adverse events occurred. Their overall clinical success rate (Eckardt score ≤3 and no other treatment needed) was 95.7% at a median follow-up of 28 months., Conclusion: POEM as a rescue treatment for patients with achalasia who failed HM is feasible, safe, and highly effective. It should be the treatment of choice in managing these challenging cases at centers with a high level of experience with POEM., (Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Achalasia is an uncommon esophageal motility disorder characterized by the selective loss of enteric neurons leading to absence of peristalsis and impaired relaxation of the lower esophageal sphincter. Per-oral endoscopic myotomy (POEM) is a novel modality for the treatment of achalasia performed by gastroenterologists and surgeons. It represents a natural orifice transluminal endoscopic surgery (NOTES) approach to Heller myotomy. POEM has the minimal invasiveness of an endoscopic procedure that can duplicate results of the surgical Heller myotomy. POEM is conceptually similar to a surgical myotomy without the inherent external incisions and post-operative care associated with surgery. Initial high success and low complications rates promise a great future for this technique. In fact, POEM has been successfully performed on patients with end-stage achalasia as an initial treatment reserving esophagectomy for those without good response. The volume of POEMs performed worldwide has grown exponentially. In fact, surgeons who have performed Heller myotomy have embraced POEM as the preferred intervention for achalasia. However, the niche of POEM remains to be defined and long term results are awaited. We describe our experience with POEM having performed the first POEM outside of Japan in 2009, the evolution of our technique, and give our perspective on its future.

Endoscopic therapy for achalasia is directed at disrupting or weakening the lower esophageal sphincter (LES). The two most commonly utilized endoscopic interventions are large balloon pneumatic dilation (PD) and botulinum toxin injection (BTI). These interventions have been extensively scrutinized and compared with each other as well as with surgical disruption (myotomy) of the LES. PD is generally more effective in improving dysphagia in achalasia than BTI, with the latter reserved for infirm older people, and PD may approach treatment results attained with myotomy. However, PD may need to be repeated. Small balloon dilation and endoscopic stent placement for achalasia have only been used in select centers. Per oral endoscopic myotomy is a newer endoscopic modality that will likely change the treatment paradigm for achalasia. It arose from the field of natural orifice transluminal endoscopic surgery and represents a scarless endoscopic approach to Heller myotomy. This is a technique that requires extensive training and preparation and thus there should be rigorous accreditation and monitoring of outcomes to ensure safety and efficacy.

Endoscopic retrograde cholangiopancreatography (ERCP) can fail in 3-10% of the cases even in experienced hands. Although percutaneous transhepatic cholangiography (PTC) and surgery are the traditional alternatives, there are morbidity and mortality associated with both. In this paper, we have discussed the efficacy and safety of endoscopic-ultrasound-guided cholangiopancreatography (EUS-CP) in decompression of biliary and pancreatic ducts. The overall technical and clinical success rates are around 90% for biliary and 70% for pancreatic duct drainage. The overall EUS-CP complication rate is around 15%. EUS-CP is, however, a technically challenging procedure and should be performed by an experienced endoscopist skilled in both EUS and ERCP. Same session EUS-CP as failed initial ERCP is practical and may result in avoidance of additional procedures. With increasing availability of endoscopists trained in both ERCP and EUS, the role of EUS-CP is likely to grow in clinical practice.

Nutritional therapy has an important role in the management of patient with severe acute pancreatitis. This article reviews the endoscopist's approach to manage nutrition in such cases. Enteral feeding has been clearly validated as the preferred route of feeding, and should be started early on admission. Parenteral nutrition should be reserved for patients with contraindications to enteral feeding such as small bowel obstruction. Moreover, nasogastric feeding is safe and as effective as nasojejunal feeding. If a prolonged course of enteral feeding (> 30 d) is required, endoscopic placement of feeding gastrostomy or jejunostomy tubes should be considered.

Background: EUS-guided liver biopsy by Trucut yields variable specimen adequacy at high cost, limiting its utility. A modified EUS-guided technique with reliable adequacy could be a viable alternative to standard techniques in cost-effective clinical settings., Objective: To describe our experience with EUS-guided liver biopsy by 19-gauge FNA, non-Trucut, needle in a cost-effective setting: patients with abnormal liver test results of unclear etiology referred for EUS to exclude biliary obstruction in whom an unrevealing EUS would have prompted a next-step liver biopsy by the referring physician., Design: Prospective case series., Setting: Tertiary-care teaching hospital., Patients: Consecutive patients with abnormal liver tests referred for EUS., Interventions: EUS-guided liver biopsy by 19-gauge FNA needle (non-Trucut)., Main Outcome Measurements: Diagnostic yield, specimen adequacy, and complications. An adequate specimen was defined as a length of 15 mm or longer and 6 or more complete portal tracts (CPTs)., Results: Between July 2008 and July 2011, 22 of 31 consecutive patients meeting inclusion criteria underwent unrevealing EUS with same-session EUS-guided liver biopsy by 19-gauge FNA needle. A median of 2 FNA passes (range 1-3) yielded a median specimen length of 36.9 mm (range 2-184.6 mm) with a median of 9 CPTs (range 1-73 CPTs). EUS-guided liver biopsies yielded a histologic diagnosis and adequate specimens in 20 of 22 patients (91%). Expanded experience led to improved specimen adequacy. There were no complications., Limitation: Small study size., Conclusions: EUS-guided liver biopsy by using a 19-gauge FNA needle appears to be feasible and safe and provides excellent diagnostic yield and specimen adequacy., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background & Aims: Several risk factors have been identified for the development of recurrent Clostridium difficile infection (CDI) that alter host immunity and disrupt colonic flora. Although the function of the appendix has been debated, its active, gut-associated lymphoid tissue and biofilm production indicate potential roles in recovery from initial CDI and protection against recurrent CDI. We investigated whether the presence or absence of an appendix is associated with CDI recurrence., Methods: We reviewed the medical records of adult inpatients with CDI who were admitted to a tertiary-care teaching hospital from 2005 to 2007 to identify those with and without an appendix. The primary dependent variable for statistical analysis was CDI recurrence., Results: In a multivariate analysis of 11 clinical variables, the presence of an appendix was associated inversely with CDI recurrence (P < .0001; adjusted relative risk, .398). Age older than 60 years also was associated with CDI recurrence (P = .0280; adjusted relative risk, 2.44)., Conclusions: The presence of an appendix has a significant and independent, inverse association with CDI recurrence, but this finding requires validation in a prospective study. Assessing the presence or absence of an appendix might be useful in predicting CDI recurrence., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: To study a cohort of patients undergoing 48 h Bravo pH testing receiving deep sedation with propofol., Methods: We retrospectively reviewed the charts of 197 patients (81 male, 116 female) who underwent Bravo esophageal pH monitoring from July 2003 to January 2008. All patients underwent Bravo pH probe placement via esophagogastroduodenoscopy (EGD) and received propofol for sedation. Patients on a proton pump inhibitor (89 patients) were excluded. Acid reflux variables measured included the total, upright, and supine fractions of time at pH < 4 and DeMeester score, and were compared between day 1 and day 2., Results: Of the 108 patients that were included in the study, the most common indication for Bravo pH monitoring was heartburn, with chest pain being the second most common. A signed rank test revealed no statistically significant difference between day 1 and day 2 reflux episodes., Conclusion: Patients who received propofol for sedation for EGD with Bravo pH capsule placement did not experience any significant difference in reflux episodes from day 1 to day 2.

Pancreatic cysts include inflammatory lesions, low-grade neoplasms, and malignant neoplasms. Cystic neoplasms may prompt investigation because of symptoms such as abdominal pain, distension, jaundice, or nausea, but they are usually incidentally discovered. In the older literature, pseudocysts related to acute and chronic pancreatitis accounted for the majority of pancreatic cysts, but it is difficult to differentiate pancreatic cystic neoplasms from pseudocysts even with high-resolution modalities including computed tomography (CT) and magnetic resonance imaging (MRI) scans. Additionally, the more recent literature has shown that small pancreatic cystic lesions are relatively common as incidental findings on cross-sectional imaging examinations that are performed for other reasons, typically in older patients without prior episodes of pancreatitis; these are often low-grade mucinous lesions or occasionally epithelial cysts. Endoscopic ultrasound with fine-needle aspiration has emerged as a prime modality in delineating such cystic lesions. There has been an exponential increase in the more recent literature regarding pancreatic cystic lesions. The purpose of this review article is to provide a concise overview of these pancreatic cystic lesions.

Background: Delayed gastric emptying (DGE) occurs in 14% to 61% of patients after pylorus-preserving pancreaticoduodenectomy, but its pathogenesis is unclear. We hypothesized that DGE may be due to pylorospasm secondary to vagal injuries at operation and may be preventable by the addition of pyloromyotomy., Methods: Patients operated on consecutively between April 2000 and August 2003 were studied. Pyloromyotomy was of the Fredet-Ramstedt type combined with antroplasty. DGE-free recovery was defined as tolerance of a diet for three successive days by postoperative day 8. The symptom of nausea was used as a basis for nasogastric tube removal and diet resumption. A gastric emptying test (GET) with solid food was obtained. Patients with difficulty swallowing were fed via a feeding tube., Results: There were 47 patients. Two patients were excluded because of death (n = 1) and ileus with pancreatic fistula (n = 1). Diagnoses were pancreatic cancer (n = 23), chronic pancreatitis (n = 11), ampullary cancer (n = 5), mucinous cystic neoplasm (n = 5), and duodenal villous adenoma (n = 3). Median times to nasogastric tube removal, start of liquid diet, and start of solid diet were postoperative days 2, 3, and 5, respectively. Two patients had tube feedings. Preoperative GET was abnormal in 51%, and postoperative GET was abnormal in 37%. The average length of stay was 9.5 days (median, 7 days). DGE occurred in only one patient (2.2%). There were no late complications during a 6-month follow-up., Conclusions: The addition of pyloromyotomy to pylorus-preserving pancreaticoduodenectomy is effective in preventing DGE. Results are supportive of the hypothesis that DGE may be caused by operative injuries of the vagus innervating the pyloric region.

A number of genetic mutations have recently been identified that appear to be important in the development of pancreatitis. Point mutations in the cationic trypsinogen gene are capable of initiating pancreatitis. These mutations also provide important insights into the pathophysiology of acute pancreatitis and into potential connections between acute and chronic pancreatitis. Mutations in the genes encoding for the pancreatic secretory trypsin inhibitor and the cystic fibrosis transmembrane conductance regulator more likely work in concert with other genes and environmental factors in affecting disease susceptibility. Although the subject so far has received only a limited amount of study, genetic polymorphisms in a wide range of genes relating to pancreatic function and to regulation of inflammation are likely to play major roles in determining each individual's susceptibility to developing pancreatitis, and its severity if it does develop.

Cytomegalovirus (CMV) can be an important opportunistic infection in HIV-1-infected patients, particularly when the CD4+ T-cell count drops below 50 lymphocytes/mm3. CMV-associated disease, including retinitis, pneumonitis, gastroenteritis, and encephalitis, is estimated to affect up to 40% of AIDS patients. We have studied the cellular immune response to CMV in gut-associated lymphoid tissue (GALT) of HIV-1-infected patients. Two patients with chronic diarrhea of unknown etiology were examined by flexible sigmoidoscopy and upper endoscopy. Biopsy specimens were obtained from lymphoid-associated tissue sites in rectum and duodenum. Both patients were seropositive for CMV IgG, but had not been treated with ganciclovir, and neither had clinical signs of CMV disease. Mononuclear cell cultures were established from GALT and blood and assayed for the presence of CMV-specific CD8+ T cells. CD8+ T-cell phenotype and function were assessed by MHC Class I tetramer staining, using an HLA-A*0201 tetramer complex specific for peptide 495-503 (NLVPMVATV) of CMV lower matrix protein pp65, and by a standard 51Cr release assay. CMV pp65-specific cytotoxic lymphocytes (CTL) were detected in GALT and blood MNC from both patients. These results demonstrate that HIV-1-infected subjects seropositive for CMV, but without active CMV gastrointestinal disease, harbor CMV-specific CTL in intestinal lymphoid tissue. This is the first report of isolation of CMV-specific CTL in GALT and will lead to greater understanding of the pathogenesis of CMV disease in human mucosal tissue.

Acute HIV-1 infection depletes CD4(+) T cells in gut-associated lymphoid tissue (GALT). The failure of containment of local viral replication, and consequent CD4(+) T cell depletion, might be due to delayed mobilization of effector CD8(+) T cells or absence of functioning HIV-1-specific CD8(+) T cell effectors within GALT. No studies have addressed human intestinal HIV-1-specific CD8(+) T cell functions. We sought to determine whether functional HIV-1-specific CTL were present in GALT and whether the repertoire differed from HIV-1-specific CTL isolated from peripheral blood mononuclear cells. From three HIV-1-infected subjects, we isolated HIV-1-specific CD8(+) T cells expressing the mucosal lymphocyte integrin CD103 from GALT. These antigen-specific effector cells could be expanded in vitro and lysed target cells in an MHC class I-restricted manner. HIV-1-specific CTL could be isolated from both duodenal and rectal GALT sites, indicating that CD8(+) effectors were widespread through GALT tissue. The breadth and antigenic specificities of GALT CTL appeared to differ from those in peripheral blood in some cases. In summary, we found HIV-1-specific CD8(+) effector T cells in GALT, despite HIV-1-induced CD4(+) T cell lymphopenia. This suggests that HIV-1-specific CTL in gut tissue can be maintained with limited CD4(+) T cell help., (Copyright 2000 Academic Press.)

This presentation reviews the role of cholecystokinin (CCK) as a contributory factor for the development and progression of acute pancreatitis (AP) and the perspective of CCK receptor antagonists for treatment of AP. High, supraphysiological concentrations of CCK induce AP in various species including man. There is also evidence that physiological increases in plasma CCK deteriorates AP in several animal models. The latter findings support the hypothesis that CCK plays a contributory or permissive role for the development of AP. The majorities of experimental studies show that the prophylactic and therapeutic use of CCK antagonists ameliorates AP. The latter effects were clearly shown for models of biliary AP in which plasma CCK is increased due to a feedback mechanism. However, CCK antagonists also had beneficial effects in models in which plasma CCK is not increased. In animal strains which do not have a CCK-A-receptor due to a genetic abnormality AP induced by a certain noxious factor does not develop to the same severity when compared to animals with a normal CCK-A-receptor. Thus, CCK acts as a permissive or contributory factor for the development and progression of AP. There is also evidence that CCK antagonists have a potential therapeutic benefit. Clinical studies will evaluate their therapeutic potential for patients with AP.

Conclusion: In models of biliary acute pancreatitis, which might resemble the situation in humans, premature activation of trypsinogen inside the pancreas ("autodigestion") occurs and is correlated with the extent of ductal and parenchymal injury. It is accompanied by a critical spending of protease inhibitors and glutathione, compromising important acinar cell defense and maintenance mechanisms., Background: Premature activation of pancreatic digestive enzymes and profound changes of levels of certain biochemical compounds have been implicated in the pathophysiology of acute pancreatitis. Hitherto, little information on their role in biliary acute pancreatitis has been available., Methods: Three types of injury to the pancreaticobiliary duct system of various severity were induced in rats--ligation of the common bile-pancreatic duct, retrograde infusion of electrolyte, or retrograde infusion of taurocholate solution--and were compared to sham-operated animals. Trypsin, trypsin inhibitory capacity (TIC), reduced glutathione (GSH), and other compounds were measured in pancreatic tissue. Histopathology, as well as serum amylase, lipase, and gamma-glutamyl transferase (gamma GT) were assessed., Results: Histopathology and elevated activity of gamma GT in the serum revealed increasing severity of pancreatic injury from sham operation through retrograde duct infusion with taurocholate. GSH was diminished even in macroscopically normal-appearing tissue, but significantly lower in altered (hemorrhagic)-looking sections. Conversely, tissue levels of trypsin were significantly increased. TIC was elevated only in the duct obstruction model, whereas it was reduced in the retrograde duct infusion models.

The pathological activation of zymogens within the pancreatic acinar cell plays a role in acute pancreatitis. To identify the processing site where activation occurs, antibodies to the trypsinogen activation peptide (TAP) were used in immunofluorescence studies using frozen sections from rat pancreas. Saline controls or animals receiving caerulein in amounts producing physiological levels of pancreatic stimulation demonstrated little or no TAP immunoreactivity. However, after caerulein hyperstimulation (5 micrograms. kg-1. h-1) for 30 min and the induction of pancreatitis, TAP immunoreactivity appeared in a vesicular, supranuclear compartment that demonstrated no overlap with zymogen granules. The number of vesicles and their size increased with time. After 60 min of hyperstimulation with caerulein, most of the TAP reactivity was localized within vacuoles >/=1 micrometer that demonstrated immunoreactivity for the granule membrane protein GRAMP-92, a marker for lysosomes and recycling endosomes. Pretreatment with the protease inhibitor FUT-175 blocked the appearance of TAP after hyperstimulation. These studies provide evidence that caerulein hyperstimulation stimulates trypsinogen processing to trypsin in distinct acinar cell compartments in a time-dependent manner.

Although it is widely accepted that trypsinogen activation is an initiating event in the development of acute pancreatitis, its location inside the pancreas is not known. In our studies, acute edematous pancreatitis was induced in rats by one or two intraperitoneal injections of 50 microg cerulein/kg body weight. The pancreas was removed for examination 1 or 2 h after the first and the second cerulein injection, respectively. The cleavage product of trypsinogen activation, trypsinogen activation peptide, was specifically labeled on pancreatic tissue sections by a corresponding antibody, the signal enhanced by a biotin-avidin conjugate, and the site then visualized by coupled peroxidase activity on diaminobenzidine. The sections were examined by light microscopy. Trypsinogen activation peptide, reflecting activation of the pancreatic digestive enzyme trypsinogen, was detected inside pancreatic acinar cells in this animal model of acute pancreatitis. As early as 1 h after the first injection of cerulein, protease activation was seen within the apical pole of acinar cells. Protease activation was increased 2 h after the latter of two injections of cerulein and more evenly distributed within the cells. For the first time morphologic evidence confirms that the activation originates within the acinar cell, rather than from the interstitium or the duct lumen. The location of this activation at the apical site of the acinar cell indicates its origin from subcellular compartments involving the late steps in the secretory pathway.

Stimulation of the exocrine pancreas with cholecystokinin analogues leads to a variety of intraacinar processes, many coupled to energy consumption. It was hypothesized that extensive ATP depletion could play a role in the pathophysiology of acute pancreatitis, especially in the hyperstimulation (cerulein) model. Mice received seven intraperitoneal injections of cerulein at hourly intervals, at doses ranging from physiological (0.1 micrograms/kg) to pharmacological (50 micrograms/kg). A single dose of cerulein induced a 28-33% decrease in ATP, whereas a complete course of injections led to a nadir as low as 45% of the control value. The overall pattern of ATP tissue content during the observed time course was surprisingly similar in all four groups and statistically not different at any time point. Until 12 h, ATP levels in all groups remained below the control value. In contrast, serum amylase and light microscopy reflected a degree of pancreatitis in a close dose-response pattern to the administered cerulein dose. These findings suggest that ATP depletion--although probably facilitating acinar damage--does not seem to play a causal or primary role in the pathophysiology of acute pancreatitis.

Background & Aims: Subcellular redistribution of lysosomal enzymes into the zymogen-enriched fraction (cosedimentation) in pancreatic homogenates occurs after different pancreatic injuries and has been proposed to be the trigger event for acute pancreatitis. This phenomenon is now studied in models of biliary pancreatitis., Methods: The bile-pancreatic duct in rats was either obstructed or retrogradely infused at different degrees of pressure and with solutions of various injurious potential. Controls were untreated or sham operated. Six hours later, the pancreas was analyzed for the total activity of cathepsin B and beta-galactosidase and their distribution among subcellular fractions., Results: In control animals, 17% and 29%, respectively, of these lysosomal enzymes were found in the zymogen fraction. Redistribution occurred after all duct manipulations, including obstruction. In contrast to sham operation and duct obstruction, all modes of duct infusion resulted in marked increases in the total activity of lysosomal enzymes., Conclusions: Increased lysosomal activity in models of biliary pancreatitis might contribute to acinar injury or represent a cellular repair mechanism. Cosedimentation at a certain extent is a physiological event. Redistribution reflects a uniform response to a range of perturbations, some of which do not cause pancreatitis. Thus, it seems unlikely that redistribution is the trigger event for acute pancreatitis.

Octreotide is an effective therapeutic option in controlling secretory diarrhea of varied etiology. However, marked patient-to-patient differences in the antidiarrheal effects necessitate titration of octreotide dose in individual patients to achieve optimal symptom control. A consensus development panel established guidelines for octreotide dose titration in patients with secretory diarrhea. Overall, the panel recommended an aggressive approach in selecting the initial octreotide dose and in making subsequent dose escalations in patients with secretory diarrhea due to gastrointestinal tumors (eg, carcinoids, VIPomas), AIDS, dumping syndrome, short bowel syndrome, radiotherapy, or chemotherapy. To avoid hypoglycemia in patients with diabetes mellitus-associated secretory diarrhea, the panel recommended a low initial octreotide dose and a conservative titration regimen with close monitoring a blood glucose levels. The end point of therapy should focus on a reduction in diarrhea (frequency of bowel movements or stool volume) rather than normalization of hormonal profile. Overall, octreotide is well tolerated; principal side effects are transient injection site pain and gastrointestinal discomfort. For many patients with secretory diarrhea, octreotide therapy is expected to improve the overall health and quality of life and in the long run will lessen health care costs.

Studies in acutely inflamed pancreatic tissue in humans and animals suggest that premature activation of proteases within the gland plays a key role in its pathophysiology. The present study aimed to detect such protease activation in relation to protease inhibition and to changes in the concentrations of the vital cellular compounds ATP and glutathione in pancreatic tissue during caerulein-induced pancreatitis in rats. Within 1 h after supramaximal stimulation by intraperitoneal caerulein injection, pancreatic tissue activities of enzymatically active trypsin and elastase showed significant increases, accompanied by a twofold increase in trypsin inhibitory capacity. Over the same time course pancreatic ATP and glutathione concentrations dropped to 38% and 47%, respectively, after 1 h and reached a nadir of 22% and 28%, respectively, after 4-8 h. Intrapancreatic trypsin activation in this model, despite increasing trypsin inhibitory capacity, indicates concealed liberation of even more protease or enzyme-inhibitor complex instability. It is hypothesized that early acinar glutathione depletion, in part due to diminished ATP, could play a role in the premature activation of digestive enzymes by impairment of the integrity of the cytoskeleton and cell organelles or lowered defense capabilities against oxidant stress, finally leading to acute pancreatitis.

Endoscopic training has become an increasingly important part of training in gastroenterology in recent years. As plans are developed to require 3 years of training in gastroenterology for board eligibility, the outline of a 3-year curriculum is proposed that would incorporate both "basic" training and "advanced" training (where offered) in endoscopy as integral components of a flexible plan designed to suit the needs and capabilities of both trainees and programs.

Background: Hydrocolonic ultrasonography--abdominal ultrasonography in conjunction with the retrograde instillation of water into the colon--has been advocated as an alternative to colonoscopy for detecting colorectal polyps and cancer. We conducted a prospective, blinded trial to evaluate the procedure further., Methods: Fifty-two consecutive patients (50 men and 2 women; average age, 62 years) who were referred for colonoscopy underwent hydrocolonic ultrasonography followed by colonoscopy. The physicians performing colonoscopy were blinded to the ultrasound results. Patients who had a history of colonic polyps or tumors or who had previously undergone flexible sigmoidoscopy or colonoscopy were excluded., Results: Twenty-two patients had normal results on colonoscopy, 26 had polyps, 3 had cancer and polyps, and 1 had cancer alone. Twenty patients had polyps less than 7 mm in diameter, eight had polyps 7 mm or more in diameter, and one had a polyp of unknown size. Hydrocolonic ultrasonography did not detect any cancers and detected only one polyp > or = 7 mm and one polyp < 7 mm in diameter. The overall sensitivity of ultrasonography for identifying any polyp was 6.9 percent, and for identifying a polyp > or = 7 mm, it was 12.5 percent. Ultrasonography suggested the presence of five masses and five polyps that were not confirmed by colonoscopy. Six patients had incomplete ultrasound studies because of discomfort or the inability to retain water. There were two complications: one patient had two vasovagal episodes, and another had diaphoresis., Conclusions: Hydrocolonic ultrasonography was less useful than colonoscopy for detecting colorectal polyps and cancers. The usefulness of the technique in screening for colonic polyps and tumors appears to be limited.

Background/aims: GP2 is the major membrane protein in pancreatic zymogen granules. It is linked to the membrane via a glycosyl-phosphatidylinositol linkage. After cleavage, a significant fraction of GP2 becomes soluble. The present study assessed whether GP2 is a useful serum marker for acute pancreatitis., Methods: Using an anti-GP2 monoclonal antibody, an enzyme-linked immunosorbent assay was developed to measure the serum levels of GP2 in rats with cerulein-induced acute pancreatitis., Results: The anti-GP2 antibody was specific because it did not cross-react with uromodulin, a structurally similar protein to GP2, or to protein extracts from nonpancreatic tissues. Eight hours after the induction of pancreatitis, the serum levels of amylase, lipase, and GP2 peaked. Peak GP2 levels were 4.2 times higher than those of controls. At 24 hours, GP2 was still 70% of the peak level, whereas amylase and lipase were 5.5% and 0.5%, respectively, of their peak levels., Conclusions: GP2 may serve as a potentially valuable marker for clinical acute pancreatitis.

L-Buthionine-[S,R]-Sulfoximine (BSO) decreases glutathione levels in various organs by inhibition of gamma-glutamylcysteine synthetase. We have examined the levels of total glutathione and oxidized glutathione in the pancreas of mice, as well as serum amylase and pancreatic histology, after BSO administration in two different ways. The injection of a single dose of BSO (5 mmol/kg body wt) decreased total glutathione to 10% of the control value. A similar depletion was observed after 24 h of oral administration of a 10 mM BSO solution, without changes in the levels of oxidized glutathione. BSO-induced pancreatic glutathione depletion--even if maintained for up to 14 d--did not cause morphological alterations of the pancreas or hyperamylasemia. Thus pancreatic glutathione depletion in itself does not lead to pancreatitis, although during development of experimental acute pancreatitis, glutathione depletion has been described. BSO might be used in animal models to weaken the glutathione-based acinar defense mechanisms against oxidant stress or to alter other physiologic processes in which glutathione is involved.

In order to reproduce what might occur during the initial phase in some cases of acute alcohol-induced pancreatitis, rabbits were infused with diluted ethanol and low-dose cerulein. The duct permeability was assessed by recovery of fluoresceinated dextran (molecular weight 19,500) in central venous blood following orthograde duct perfusion with this substance in the anesthetized animal. Serum ethanol, lipase, and amylase were measured; pancreatic duct morphology was examined by light microscopy and electron microscopy. ATP and glutathione were measured, as were amylase, trypsinogen/trypsin, cathepsin B, and DNA levels in differential centrifugates. As expected, acinar amylase and trypsinogen showed a significant decrease in the experimental group; cathepsin B activity was similarly diminished. Compared with the control group, the activity of serum amylase and lipase in the experimental group demonstrated a significant increase. However, no differences between saline-infused control animals and the treated group regarding pancreatic duct permeability, continuity of lumen-lining epithelium, ATP and glutathione levels, and the relative subcellular distribution of pancreatic digestive and lysosomal enzymes were observed. Thus, our findings do not support the relevance of some of the most common hypotheses on the pathophysiology of acute pancreatitis in its early stage for at least a certain subgroup of patients with acute alcohol-induced pancreatitis.

In order to reproduce what may occur during the initial phase of biliary acute pancreatitis, the rabbit pancreatic duct was perfused with preincubated mixtures of bile and different digestive enzymes at low physiologic pressure. Permeability of the pancreatic duct system, serum amylase, and histological appearance of pancreatic tissue were studied after orthograde duct perfusion in the anesthetized animal. The ductal permeability was estimated by recovery of fluoresceinated dextran (molecular weight 17,200) in central venous blood following duct perfusion with this substance. Perfusion with preincubated bile failed to increase permeability significantly (11.10 +/- 3.04 nmol/L compared to 5.80 +/- 2.71 nmol/L in the control group), whereas mixtures of bile and trypsin (27.19 +/- 5.21 nmol/L), bile and lipase (16.68 +/- 3.75 nmol/L), and bile and pancreatic juice (13.92 +/- 0.48 nmol/L) caused significant increases (p < 0.05). Similar observations were made regarding serum amylase and histology. Thus, the presence of mixtures of bile with pancreatic enzymes (following their prolonged common incubation) in the absence of elevated pressure, results in an increase in duct permeability for molecules up to the size range of pancreatic enzymes and thereby may contribute to the initiation of acute pancreatitis.

A variety of receptors on pancreatic acinar and duct cells regulate both pancreatic exocrine secretion and intracellular processes. These receptors are potential sites of action for therapeutic agents in the treatment of pancreatitis. Cholecystokinin (CCK) receptor antagonists, which may reduce the level of metabolic "stress" on acinar cells, have been shown to mitigate the severity of acute pancreatitis in a number of models. Not all studies have shown a benefit, however, and differences may exist between different structural classes of antagonists. Because increased pancreatic stimulation due to loss of feedback inhibition of CCK has been proposed to contribute to the pain of some patients with chronic pancreatitis, CCK receptor antagonists could also be of benefit in this setting. Somatostatin and its analogs diminish pancreatic secretion of water and electrolytes and have been effective in treating pancreatic fistulas and pseudocysts. These agents are also being evaluated for their ability to reduce pain in chronic pancreatitis (perhaps by reducing ductal pressure by diminishing secretory volume) and mitigating the severity of acute pancreatitis (possibly by reducing the metabolic load on acinar cells). Recently described secretin receptor antagonists may also have therapeutic value as a means of selectively inhibiting pancreatic secretion of water and electrolytes.

The present studies were done to evaluate the therapeutic potential of several antioxidants and free radical scavengers in three different models of acute pancreatitis. (a) Edematous pancreatitis with acinar cells necrosis was induced by seven hourly intraperitoneal injections of 50 micrograms of caerulein per kg in mice. (b) Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet in mice. (c) Hemorrhagic pancreatitis was induced by retrograde infusion of 0.6 ml of 5% sodium taurocholate into the pancreatic duct in rats. The following antioxidants and free radical scavengers were given at various doses intravenously, subcutaneously, or intraperitoneally before the onset of pancreatitis: Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], superoxide dismutase, catalase, deferoxamine (Desferal), dimethyl sulfoxide, or allopurinol. The severity of pancreatitis was assessed at various times after its onset by determination of serum amylase and pancreatic weight (edema), by grading of histological alterations, and by determination of survival (survival determined in models of hemorrhagic pancreatitis). In general, free radical scavengers and antioxidants ameliorated edema and inflammation to a greater degree than necrosis and the increase in serum amylase. Superoxide dismutase (as did Ebselen in previous studies) exerted beneficial effects on survival in diet-induced pancreatitis in the absence of marked effects on pancreatic necrosis, suggesting that these beneficial effects are due to amelioration of extrapancreatic complications that often contribute to mortality in acute pancreatitis. None of the antioxidants had major beneficial effects in taurocholate-induced hemorrhagic pancreatitis. Thus, formation of free radicals may be important for progression and outcome in diet-induced and, to a lesser degree, in caerulein-induced pancreatitis but not at all in taurocholate-induced pancreatitis. Different models of pancreatitis may, therefore, involve different degrees and mechanisms of free radical formation. Despite the amelioration of edema and the beneficial effects on mortality seen for some antioxidants in some of the models, antioxidants and free radical scavengers appear to have only a limited potential for treatment of acute pancreatitis.

Studies in animal models suggest that oxygen radicals may be important in the pathogenesis of acute pancreatitis. Because glutathione is an essential component of the defense against radical-mediated cellular injury, we investigated whether pancreatic glutathione content is influenced by inducing acute pancreatitis and whether augmenting the intracellular supply of glutathione would alter the course of pancreatitis. Caerulein, a decapeptide cholecystokinin analogue, induces acute necrotizing pancreatitis in mice when given in high doses (50 micrograms/kg per h) over a period of 6 h. The pancreatic glutathione content (total, GSH + GSSG) in mice treated with high-dose caerulein fell to 17% of normal within 4 h of beginning caerulein and recovered toward normal after discontinuing caerulein treatment. Mice treated with glutathione monoethyl ester (20 mmol/kg 1 h before caerulein, 10 mmol/kg 3 and 7 h after starting caerulein) were found to have blunted depletion of pancreatic glutathione, diminished histologic evidence of pancreatitis (necrosis, inflammation, and vacuolization), and lower serum amylase values compared with mice treated with caerulein alone. These findings suggest that the profound depletion of pancreatic glutathione caused by hyperstimulation of the pancreas with caerulein is critically important in the pathogenesis of acute caerulein-induced pancreatitis.

In view of the increasing number of new imaging techniques and serum tumor markers, it is not well established which combination or which order of tests may provide the most information for diagnosis of pancreatic carcinoma. This review determines the diagnostic value of the various tests and evaluates which combination of tests may provide the most information and what may be considered to be a current rational approach to the diagnosis of pancreatic carcinoma. In the present analysis endoscopic retrograde cholangiopancreatography (ERCP) provided a 92% sensitivity that exceeded the 83% and 74% sensitivities calculated for computed tomography (CT) and ultrasound, respectively. The specificity of all three imaging techniques exceeded 90%. Serum determination of CA 19-9 yielded an 83% sensitivity, which was considerably higher than sensitivities of carcinoembryonic antigen and various other tumor markers. The combination of CA 19-9 and ultrasound improved the sensitivity of each test performed alone by 10-15%. Fine-needle biopsy allows diagnosis of pancreatic carcinoma with a sensitivity of 83% and an almost perfect specificity of 99%. On the basis of these data, the combination of ultrasound and determination of CA 19-9 is recommended as the initial tests when pancreatic carcinoma is suspected. CT also must be performed if ultrasound is indeterminant or inconsistent with the clinical evaluation, as well as in patients with negative ultrasound but abnormal CA 19-9. Negative results of CT, ultrasound, and CA 19-9 will exclude pancreatic carcinoma in most patients. A positive ultrasound or CT result usually leads to fine-needle biopsy, which helps avoid most diagnostic laparotomies. ERCP must be performed in patients where ultrasound, CT, and fine-needle biopsy do not clarify the diagnosis. In the majority of patients with pancreatic carcinoma, noninvasive imaging techniques such as ultrasound and CT also allow adequate staging. In some patients, however, laparoscopy and angiography may need to be performed for strategic planning of further therapy. Although modern imaging techniques and serum tumor markers allow diagnosis of pancreatic carcinomas as small as 2-3 cm and help avoid most diagnostic laparotomies, this improvement in diagnostic capability has as yet not significantly improved the prognosis.

The present work evaluates the methodology and standards of acute hemorrhagic-necrotizing pancreatitis induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice. The diet model appears to be a good approximation of severe necrotizing human pancreatitis. Both the gross and histological appearance of the pancreatic and peripancreatic inflammation as well as the clinical and biochemical course of diet-induced pancreatitis resemble human disease. By limiting the period of feeding the diet, one can control the mortality at any desired level between 0 and 100%. Ascites, acidosis, hypoxia and hypovolemia occur in this model as well as in human pancreatitis. The time course of the morphological and biochemical alterations have extensively been studied and are, thus, well defined in this model. Despite the differences in pathogenesis of pancreatitis induced in this model versus human disease, the experimental pancreatitis and clinical pancreatitis share several pathophysiologic features. Therefore, the model is suitable to study pathophysiologic aspects of this disease. The diet model is particularly well suitable to study the potential for new therapeutic substances. The small size of the animals used, however, is a limitation for the evaluation of surgical procedures and of new diagnostic tools. Several pitfalls and problems have to be considered in order to obtain valuable data. The amount of injury produced by the CDE diet depends critically on sex, age and weight of the mice. Special care has to be taken to guarantee that the intake of the CDE diet is identical between different experimental groups. Therefore, each set of experiments needs to include a separate control group of mice which receive the CDE diet without any other special treatment. The potential benefit of an experimental therapy can be assessed by measuring survival, various biochemical and histological features, and alterations in hematocrit, pH and blood gases.

Objective: To determine the efficacy and safety of octreotide for treatment of refractory, profuse diarrhea in patients with the acquired immunodeficiency syndrome (AIDS)., Design: A prospective, open-label study., Setting: Inpatient metabolic units of four university medical centers., Patients: Fifty-one patients infected with human immunodeficiency virus (HIV) who had uncontrolled diarrhea (greater than or equal to 500-mL liquid stool per day) despite treatment with maximally tolerable doses of antidiarrheal medications., Intervention: After initial baseline studies, patients received octreotide, 50 micrograms every 8 hours for 48 hours. If stool volume was not reduced to less than 250 mL/d, the dose of octreotide was increased stepwise to 100, 250, and 500 micrograms., Main Results: Fifty men and one woman (mean age, 36.3 +/- 1.1 years) entered and completed the 28-day protocol (14 days of inpatient therapy and 14 days of outpatient therapy). Stool frequency and volume decreased significantly (6.5 +/- 0.5 stools per day on day 0 compared with 3.8 +/- 0.3 stools per day on day 21 [P less than 0.001] and 1604 +/- 180 mL/d on day 0 compared with 1084 +/- 162 mL/d on day 14 [P less than 0.001], respectively). Twenty-one patients (41.2%) were considered to be partial or complete responders (reduction in daily stool volume by greater than or equal to 50% of initial collections or reduction to less than or equal to 250 mL/d). Of the 21 responders, 14 (67%) had no identifiable pathogens at initial screening compared with 9 of 30 (30%) nonresponders (P less than 0.01)., Conclusion: Patients with AIDS-associated refractory watery diarrhea, especially those without identifiable pathogens, may respond favorably to subcutaneously administered octreotide. This drug deserves further study in a randomized, placebo-controlled trial.

This study evaluated the effects of the seleno-organic substance Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] in two models of acute hemorrhagic and acute edematous pancreatitis. Ebselen is known to catalyze glutathione peroxidase-like reactions and to inhibit lipid peroxidation. Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice for 66 h. Edematous pancreatitis was induced by 7-h subcutaneous injections of 50 micrograms/kg of cerulein in mice. Ebselen was given from the beginning of the CDE diet either as a subcutaneous injection of 100 mg/kg at 6-h intervals or was mixed in with the CDE diet to yield a daily dose of 100 mg/kg of Ebselen. In further experiments, Ebselen was given at various time intervals after the beginning of the CDE diet as subcutaneous injections of 100 mg/kg at 6-h intervals. In the cerulein model, Ebselen was given 5 min prior to each cerulein injection at doses from 10-500 mg/kg. Prophylactic administration of Ebselen given orally or subcutaneously significantly improved survival from 38.5% in the control group of saline-injected CDE-fed mice to 61.9 and 65.0%, respectively. Ebselen also reduced increases in serum amylase and pancreatic weight in the diet model. Therapeutic administration of Ebselen significantly increased survival only when injections were started 20 h after the beginning of the CDE diet (64%), but not when started after 40 h (44%). Similarly, increases in serum amylase and pancreatic weight due to the CDE diet were significantly reduced by Ebselen only when injections were started after 20 h but not when started after 40 h.(ABSTRACT TRUNCATED AT 250 WORDS)