A combination of serum leucine-rich α-2-glycoprotein 1, CA19-9 and interleukin-6 differentiate biliary tract cancer from benign biliary strictures.

BACKGROUND: Biliary tract cancer (BTC) and benign biliary strictures can be difficult to differentiate using standard tumour markers such as serum carbohydrate antigen 19-9 (CA19-9) as they lack diagnostic accuracy. METHODS: Two-dimensional difference gel electrophoresis and tandem mass spectrometry were used to profile immunodepleted serum samples collected from cases of BTC, primary sclerosing cholangitis (PSC), immunoglobulin G4-associated cholangitis and healthy volunteers. The serum levels of one candidate protein, leucine-rich α-2-glycoprotein (LRG1), were verified in individual samples using enzyme-linked immunosorbent assay and compared with serum levels of CA19-9, bilirubin, interleukin-6 (IL-6) and other inflammatory markers. RESULTS: We report increased LRG1, CA19-9 and IL-6 levels in serum from patients with BTC compared with benign disease and healthy controls. Immunohistochemical analysis also demonstrated increased staining of LRG1 in BTC compared with cholangiocytes in benign biliary disease. The combination of receiver operating characteristic (ROC) curves for LRG1, CA19-9 and IL-6 demonstrated an area under the ROC curve of 0.98. In addition, raised LRG1 and CA19-9 were found to be independent predictors of BTC in the presence of elevated bilirubin, C-reactive protein and alkaline phosphatase. CONCLUSION: These results suggest LRG1, CA19-9 and IL-6 as useful markers for the diagnosis of BTC, particularly in high-risk patients with PSC.

Endoscopic ultrasound: diagnostic and therapeutic applications.

Endoscopic ultrasound (EUS) comprises several techniques of performing high-frequency ultrasound via an endoscope placed in the gastrointestinal tract (oesophagus, stomach, duodenum and pancreaticobiliary tree and rectum). It has rapidly become an important tool in the investigation of a variety of lumenal disorders as well as locoregional staging of gastrointestinal malignancies. Needle biopsy of peri-intestinal structures, such as lymph nodes and pancreatic masses, can also be performed under real-time ultrasound control. To date, the utilization of this technology in Australia has been limited by cost constraints and a paucity of training opportunities. EUS continues to be a rapidly growing area in clinical gastroenterology. Recent studies continue to define its role, particularly in the loco-regional staging of a variety of malignancies. In addition, new instruments permit tissue sampling and a variety of therapeutic manoeuvres under direct ultrasound guidance.33; 26-32)

A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn's perianal fistulas.

BACKGROUND & AIMS: To determine accuracy of endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI) for evaluation of Crohn's disease perianal fistulas. METHODS: Thirty-four patients with suspected Crohn's disease perianal fistulas were prospectively enrolled in a blinded study comparing EUS, MRI, and examination under anesthesia (EUA). Fistulas were classified according to Parks' criteria, and a consensus gold standard was determined for each patient. Acceptable accuracy was defined as agreement with the consensus gold standard for > or =85% of patients. RESULTS: Three patients did not undergo MRI; 1 did not undergo EUS or EUA; and consensus could not be reached for 1. Thirty-two patients had 39 fistulas (20 trans-sphincteric, 5 extra-sphincteric, 6 recto-vaginal, 8 others) and 13 abscesses. The accuracy of all 3 modalities was > or =85%: EUS 29 of 32 (91%, confidence interval [CI] 75%-98%), MRI 26 of 30 (87%, CI 69%-96%), and EUA 29 of 32 (91%, CI 75%-98%). Accuracy was 100% when any 2 tests were combined. CONCLUSIONS: EUS, MRI, and EUA are accurate tests for determining fistula anatomy in patients with perianal Crohn's disease. The optimal approach may be combining any 2 of the 3 methods.

Neural network analysis of EUS images to differentiate between pancreatic malignancy and pancreatitis.

BACKGROUND: The differentiation of focal pancreatitis and pancreatic adenocarcinoma is problematic and often resolved only by pancreaticoduodenectomy. EUS is the most sensitive imaging modality for both conditions, yet ultrasonic criteria for distinguishing the two have not been described and differentiation remains difficult. The aims of this study were to develop a self-learning computer program that can analyze EUS images and differentiate malignancy from pancreatitis, and to compare results obtained with this system with EUS interpretation by experienced endosonographers. METHODS: Twenty-one patients with pancreatic cancer and 14 with focal pancreatitis were included. The diagnosis was confirmed histologically in all cases and each patient had undergone EUS. A single EUS image from each procedure was used for computer analysis. The results were compared with the EUS diagnosis reported at the actual procedure as well that of an endosonographer who reviewed videotapes of the procedures. RESULTS: The software program differentiated focal pancreatitis from malignancy with a maximal 89% accuracy. With sensitivity set at 100% for malignancy, the program was 50% specific and accuracy was 80%. Sensitivity and accuracy of the endosonographer's impression at the time of EUS were, respectively, 89% and 85%. A sensitivity of 73% and accuracy of 83% were achieved with blinded interpretation of EUS videotapes. CONCLUSIONS: Analysis of EUS images with computer software programs is feasible and compares favorably with human interpretation. The application of this technology to EUS and other imaging scenarios could be a useful adjunct to diagnostic endoscopy and warrants further investigation.

Optimising outcomes in acute pancreatitis.

Acute pancreatitis is a common cause for presentation to emergency departments. Common causes in Western societies include biliary pancreatitis and alcohol (the latter in the setting of chronic pancreatitis). Acute pancreatitis also follows endoscopic retrograde pancreatography in 5 to 10% of patients, a group that could potentially benefit from prophylactic treatment. Although episodes of pancreatitis usually run a relatively benign course, up to 20% of patients have more severe disease, and this group has significant morbidity and mortality. Therefore, attempts have been made to identify, at or soon after presentation, those patients likely to have a poor outcome and to channel resources to this group. The mainstay of treatment is aggressive support and monitoring of those patients likely to have a poor outcome. Pharmacotherapy for acute pancreatitis (both prophylactic and in the acute setting) has been generally disappointing. Efforts initially focused on protease inhibitors, of which gabexate shows some promise as a prophylactic agent. Agents that suppress pancreatic secretion have produced disappointing results in human studies. Infection of pancreatic necrosis is associated with high mortality and requires surgical intervention. In view of the seriousness of infected necrosis, the use of prophylactic antibacterials such as carbapenems and quinolones has been advocated in the setting of pancreatic necrosis. Similarly, data are accumulating to support the use of prophylactic antifungal therapy. Recently, it has become apparent that the intense inflammatory response associated with acute pancreatitis is responsible for much of the local and systemic damage. With this realisation, future efforts in pharmacotherapy are likely to focus on suppression or antagonism of pro-inflammatory cytokines and other inflammatory mediators. Similarly, animal studies have demonstrated the importance of oxidative stress in acute pancreatitis, although to date there is a paucity of information regarding the efficacy of antioxidants. Although the clinical course for most patients with acute pancreatitis is mild, severe acute pancreatitis continues to be a clinical challenge, requiring a multidisciplinary approach of physician, intensivist and surgeon.

Utility of endoscopic ultrasonography in endoscopic drainage of pancreatic pseudocysts in selected patients.

OBJECTIVES: To determine the effect of endoscopic ultrasonography (EUS) on endoscopic drainage of pancreatic pseudocysts and to determine patency with fistula dilation and placement of multiple stents. PATIENTS AND METHODS: Between September 1995 and January 1999, 19 patients underwent endoscopic drainage of pancreatic pseudocysts, 17 of whom were assessed by EUS before drainage. Radial EUS scanning was used to detect an optimal site of apposition of pseudocyst and gut wall, free of intervening vessels. A fistula was created with a fistulatome, followed by balloon dilation of the fistula tract. Patency was maintained with multiple double pigtail stents. The primary goal of this retrospective study was to determine whether EUS affected the practice of endoscopic drainage of pancreatic pseudocysts. RESULTS: In 3 patients, drainage was not attempted based on EUS findings. In the other 13 patients (14 pseudocysts), creation of a fistula was successful on 13 occasions, and no immediate complications occurred. However, 1 patient subsequently developed sepsis that required surgery. All other patients were treated with balloon dilation, multiple stents, and antibiotics, with no septic complications. Of 14 pseudocysts (in 13 patients), 13 (93%) resolved. CONCLUSIONS: Results of EUS may alter management of patients considered for endoscopic drainage of pancreatic pseudocysts. Endoscopic ultrasonography was useful for selecting an optimal and safe drainage site. The combination of balloon dilation, multiple stents, and antibiotics appears to resolve pancreatic pseudocysts without septic complications.

A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain.

BACKGROUND: Celiac plexus neurolysis, a chemical splanchnicectomy of the celiac plexus, is used to treat pain caused by pancreatic cancer. Most commonly, celiac plexus neurolysis is performed percutaneously under CT or fluoroscopic guidance, but can also be performed with EUS. The aim of this study was to prospectively assess the efficacy of EUS celiac plexus neurolysis in the management of pain caused by pancreatic cancer. METHODS: In this prospective study conducted in a community-based referral hospital, 58 patients with painful and inoperable pancreatic cancer were evaluated at 8 observation points before and after EUS celiac plexus neurolysis for up to 6 months. The following data were collected: age, gender, tumor location, vascular invasion, adjuvant therapy, and laboratory tests including prothrombin time, and complete blood counts were obtained at baseline (before EUS celiac plexus neurolysis); pain scores, morphine use, and adjuvant therapy were assessed at each observation. RESULTS: Pain scores were lower (p = 0.0001) 2 weeks after EUS celiac plexus neurolysis, an effect that was sustained for 24 weeks when adjusted for morphine use and adjuvant therapy. Forty-five of the 58 patients (78%) experienced a decline in pain scores after EUS celiac plexus neurolysis. Chemotherapy with and without radiation also decreased pain after EUS celiac plexus neurolysis (p = 0.002). Procedure-related transient abdominal pain was noted in 5 patients; there were no major complications. CONCLUSIONS: EUS celiac plexus neurolysis is safe and controls pain caused by unresectable pancreatic cancer.

Impact of EUS-guided fine-needle aspiration on lymph node staging in patients with esophageal carcinoma.

BACKGROUND: Preoperative identification of lymph node metastases associated with esophageal carcinoma may influence treatment. EUS is the most accurate method for locoregional staging of these tumors. The impact of EUS-guided fine-needle aspiration (EUS-FNA) on lymph node staging in esophageal carcinoma is unclear. METHODS: From May 1996 to May 1999, 74 patients with esophageal carcinoma underwent preoperative EUS. After October 1998 EUS-guided FNA was performed on nonperitumoral lymph nodes greater than 5 mm in width. The results of EUS with and without FNA were retrospectively reviewed and compared. Final diagnosis was based on surgical results or EUS-guided FNA malignant cytology. Ten of the 74 patients had to be excluded for lack of lymph node stage confirmation. Final diagnosis was obtained in the remaining 64 patients (33 from the EUS only group and 31 from the EUS-FNA group). RESULTS: The results of EUS versus EUS-FNA for lymph node staging were sensitivity 63% versus 93% (p = 0.01), specificity 81% versus 100% (not significant), and accuracy 70% versus 93% (p = 0.02), respectively. Complications comprised 1 patient who developed self-limited bleeding after dilation that did not preclude completion of the EUS (1%, 95% CI [0%, 7%]). CONCLUSIONS: EUS-FNA is more sensitive and accurate than EUS alone for preoperative staging of locoregional and celiac lymph nodes associated with esophageal carcinoma. EUS-FNA of nonperitumoral lymph nodes in patients with esophageal carcinoma is safe and should be routinely performed when treatment decisions will be affected by nodal stage.

Initial experience with a steerable, phased vector array ultrasound catheter in the GI tract.

BACKGROUND: EUS requires a significant capital outlay. The ability to perform high-resolution phased array scanning and Doppler interrogation by using a catheter that interfaces with a standard US console could increase the accessibility of EUS. Recently, an electronic phased-array US catheter was developed for intracardiac use. To date, this technology has not been applied to the GI tract. The aim of this study is to determine the feasibility and imaging characteristics of a new phased array scanning US catheter in the GI tract. METHODS: Swine were placed under general anesthesia. This study used a 100 cm, 10F, torquable catheter with 4-way tip deflection to greater than 90 degrees. The catheter tip houses a phased vector array transducer with variable frequency (5.5-10 MHz) and variable focal distance. It has pulsed/color and power Doppler capability. The probe was passed through a therapeutic flexible sigmoidoscope into the upper GI tract. Acoustic coupling was achieved via a condom filled with water or by gastric water infusion. Needle visualization experiments were performed with a second endoscope (also passed per oral) with a standard EUS-guided fine needle aspiration needle. RESULTS: Acoustic coupling was easily achieved. Resolution of the GI wall into characteristic layers (esophagus 5, stomach 7) was demonstrated. At 5.5 MHz, tissue resolution and Doppler imaging were excellent to greater than 10 cm from the transducer. A 22-gauge EUS-guided fine needle aspiration needle was easily visualized at depth greater than 4 cm. Flow in gastric, hepatic, and pancreatic parenchymal vessels approximately 1 mm diameter was visualized by using power and color Doppler. CONCLUSIONS: This 10F array US catheter is capable of high-resolution two-dimensional imaging of the gut wall as well as high-quality Doppler imaging. The Doppler capabilities of this equipment may have new GI applications.

Acute extraluminal hemorrhage associated with EUS-guided fine needle aspiration: frequency and clinical significance.

BACKGROUND: Complications with EUS-guided fine needle aspiration cytology (EUS-guided FNA) are rare and include perforation, infection, pancreatitis, and intraluminal bleeding. To date, the ultrasound appearance and clinical significance of perilesional bleeding during EUS-guided FNA have not been described. The aim of this study was to analyze the frequency of acute extraluminal hemorrhage associated with EUS-guided FNA. METHODS: From September 1998 to October 1999 EUS-guided FNA was performed during 227 of 1104 EUS procedures. Patient follow-up and complications were recorded and retrospectively analyzed. OBSERVATIONS: Three patients were identified with acute extraluminal hemorrhage at the site of the aspiration during EUS (frequency 1.3%: 95% CI [0%, 2.8%]). The bleeding manifested as an expanding echopoor region adjacent to the sampled lesion. No clinically recognizable sequela arose from the bleeding. All patients were treated with a short course of antibiotics and outpatient observation. Preprocedure coagulation and platelet assessment did not predict which patients were at risk for this complication. CONCLUSION: Acute extraluminal hemorrhage occurring during EUS-guided FNA is a rare complication with a characteristic ultrasound appearance. Recognition of this event might be important to allow the endoscopist to terminate the procedure and thereby minimize the potential for more serious bleeding.

Endoscopic surveillance and ablative therapy for periampullary adenomas.

OBJECTIVES: Periampullary adenomas are an increasingly recognized condition, both in those with familial adenomatous polyposis syndromes (FAP) as well as sporadic cases. Endoscopic management has been advocated for these lesions without differentiating between these two patient groups regarding aim of therapy. The aims of this study were to determine the safety and effectiveness of endoscopic surveillance and ablative therapy of periampullary adenomas in patients with both sporadic and FAP-associated lesions. METHODS: Retrospective analysis of 59 patients with FAP and 32 with sporadic lesions who were all enrolled in a program of endoscopic surveillance and ablative therapy. Median follow-up was 24 months (range, 1-134 months). RESULTS: Ampullary ablative therapy has resulted in return to normal histology in 44 and 34% of sporadic and FAPassociated lesions, respectively. Complications of endoscopic therapy were mild in 12 patients and severe in 3 patients: the latter category involved one occurrence of asymptomatic duodenal stenosis and one occurrence of postcoagulation syndrome--both after Nd-YAG laser therapy-and necrotizing pancreatitis after ampullary biopsy in one patient. Thirteen patients have been referred for surgical intervention. There has been no mortality and no cases of advanced malignancy missed by endoscopy. CONCLUSIONS: Endoscopic surveillance and ablative therapy of periampullary lesions is safe and can be effective, although eradication of ampullary tissue requires multiple ablative sessions.

The role of transabdominal ultrasonography, helical computed tomography, and magnetic resonance cholangiopancreatography in diagnosis and management of pancreatic disease.

Many technical advances have offered enhanced capabilities in noninvasive imaging of the pancreas. Although these technical advances are impressive, current studies do not always define clearly the benefits that these advances will confer in patient management. A critical overview of these imaging modalities is offered here, with respect to diagnosis and patient management. Outcomes from various studies are summarized for modalities including transabdominal ultrasound, computed tomography, magnetic resonance imaging with and without pancreatography, and positron emission tomography.

Management and long-term prognosis of Dieulafoy lesion.

BACKGROUND: The Dieulafoy lesion is an important cause of gastrointestinal (GI) hemorrhage. Optimal treatment and long-term outcome are unknown. This study aimed to characterize the presentation of the Dieulafoy lesion and to summarize the results and report the long-term outcome of endoscopic therapy. METHODS: Data regarding diagnosis, treatment and outcomes were derived from our GI Bleed Team database, patient records and follow-up correspondence. RESULTS: Ninety Dieulafoy lesions were identified in 89 patients after a mean of 1.9 endoscopies. Their mean age was 72 years. Thirty-four percent of lesions were extragastric. Median transfusion requirement was 5 units. Two patients exsanguinated and 3 required surgery; all others were initially successfully treated endoscopically (with or without epinephrine injection): heat probe (71 patients), band ligation (3), hemoclip (1), laser (2), bipolar probe (4), sclerotherapy (2) and epinephrine alone (2). Gastric perforation occurred in 1 patient following sclerotherapy. Thirty-day mortality was 13%, 4 related to hemorrhage and 5 related to comorbidity. During median follow-up of 17 months, 34 patients (42%) died. One patient had recurrent bleeding 6 years after operation. CONCLUSIONS: Dieulafoy lesion is relatively common and often extragastric. Endoscopic therapy is safe and effective. Long-term recurrence was not evident following endoscopic ablation. Follow-up after ablative therapy appears unnecessary.

Interventional treatment of acute and chronic pancreatitis. Endoscopic procedures.

The role of therapeutic endoscopy in the treatment of acute and chronic pancreatitis has expanded dramatically over the past 10 years. Drainage of pseudocysts and even organized pancreatic necrosis when localized are becoming commonplace. Other areas in which therapeutic endoscopy has been shown to be efficacious include severe biliary pancreatitis, pancreatic duct disruptions, strictures, and obstructive calculi. Its role in the management of acute recurrent pancreatitis with presumed Oddi's sphincter dysfunction or pancreas divisum continues to be defined. The cost-effectiveness and minimally invasive nature of endoscopic therapy compared with surgery should ensure the continued development of these techniques. More controlled, prospective data are required.

Alcoholic pancreatitis and polymorphisms of the variable length polythymidine tract in the cystic fibrosis gene.

BACKGROUND: The observation that only a minority of alcoholics develops clinical pancreatic disease has led to a search for a predisposing factor to the disease. One possible predisposing factor is mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene as cystic fibrosis leads to pancreatic injury. We have recently demonstrated that 15 common CFTR mutations are not found in patients with alcoholic pancreatitis. Another common polymorphism of the CFTR gene has recently been implicated in the pathogenesis of idiopathic chronic pancreatitis, the 5T variant of the variable length polythymidine tract in intron 8 (the normal genotypes are 7T and 9T). The 5T variant inhibits transcription of exon 9 resulting in a CFTR protein lacking chloride channel activity. The aim of this study was to determine whether the 5T variant is associated with alcoholic pancreatitis. METHODS: Fifty-two patients with alcoholic pancreatitis were identified using standardized diagnostic criteria. Fifty alcoholics without pancreatitis were also studied as controls. Genomic DNA was extracted from peripheral blood leukocytes and the polythymidine tract of intron 8 was amplified by nested polymerase chain reaction using established primers. The polymerase chain reaction products were digested with MseI, separated by electrophoresis on 15% polyacrylamide gels and genotypes assigned by comparison with known positive controls. RESULTS: The 5T allele we found in only two patients with alcoholic pancreatitis (3.9% of th index group; 95% confidence intervals 0-10%) and in seven alco holic controls. Allele frequencies for 5T, 7T, and 9T in patients with alcoholic pancreatitis were 1.9%, 85.6%, and 12.5%, respectively These did not differ from the allele frequencies in alcoholic controls (7%, 79%, and 14% for 5T, 7T, and 9T, respectively). CONCLUSION: The 5T allele was not associated with alcoholic pancreatitis. Individual susceptibility to this disease remains unexplained.

Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture.

BACKGROUND: The pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells (vitamin A storing cells) play a significant role in the development of fibrosis. AIMS: To determine whether cells resembling hepatic stellate cells are present in rat pancreas, and if so, to compare their number with the number of stellate cells in the liver, and isolate and culture these cells from rat pancreas. METHODS: Liver and pancreatic sections from chow fed rats were immunostained for desmin, glial fibrillary acidic protein (GFAP), and alpha smooth muscle actin (alpha-SMA). Pancreatic stellate shaped cells were isolated using a Nycodenz gradient, cultured on plastic, and examined by phase contrast and fluorescence microscopy, and by immunostaining for desmin, GFAP, and alpha-SMA. RESULTS: In both liver and pancreatic sections, stellate shaped cells were observed; these were positive for desmin and GFAP and negative for alpha-SMA. Pancreatic stellate shaped cells had a periacinar distribution. They comprised 3.99% of all pancreatic cells; hepatic stellate cells comprised 7.94% of all hepatic cells. The stellate shaped cells from rat pancreas grew readily in culture. Cells cultured for 24 hours had an angular appearance, contained lipid droplets manifesting positive vitamin A autofluorescence, and stained positively for desmin but negatively for alpha-SMA. At 48 hours, cells were positive for alpha-SMA. CONCLUSIONS: Cells resembling hepatic stellate cells are present in rat pancreas in a number comparable with that of stellate cells in the liver. These stellate shaped pancreatic cells can be isolated and cultured in vitro.

Metabolism of ethanol by rat pancreatic acinar cells.

It has been postulated that ethanol-induced pancreatic injury may be mediated by the oxidation of ethanol within the pancreas with secondary toxic metabolic changes, but there is little evidence of pancreatic ethanol oxidation. The aims of this study were to determine whether pancreatic acinar cells metabolize significant amounts of ethanol and, if so, to compare their rate of ethanol oxidation to that of hepatocytes. Cultured rat pancreatic acinar cells and hepatocytes were incubated with 5 to 50 mmol/L carbon 14-labeled ethanol (25 dpm/nmol). Ethanol oxidation was calculated from the production of 14C-labeled acetate that was isolated by Dowex ion-exchange chromatography. Ethanol oxidation by pancreatic acinar cells was demonstrable at all ethanol concentrations tested. At an intoxicating ethanol concentration (50 mmol/L), 14C-labeled acetate production (227+/-20 nmol/10(6) cells/h) approached that of hepatocytes (337+/-61 nmol/10(6) cells/h). Phenanthroline (an inhibitor of classes I through III isoenzymes of alcohol dehydrogenase (ADH)) inhibited pancreatic ethanol oxidation by 90%, but 4-methylpyrazole (a class I and II ADH inhibitor), carbon monoxide (a cytochrome P450 inhibitor), and sodium azide (a catalase inhibitor) had no effect. This study has shown that pancreatic acinar cells oxidize significant amounts of ethanol. At intoxicating concentrations of ethanol, pancreatic acinar cell ethanol oxidation may have the potential to contribute to pancreatic cellular injury. The mechanism appears to involve the class III isoenzyme of ADH.