CD166/ALCAM expression is characteristic of tumorigenicity and invasive and migratory activities of pancreatic cancer cells.

BACKGROUND: CD166, also known as activated leukocyte cell adhesion molecule (ALCAM), is expressed by various cells in several tissues including cancer. However, the role of CD166 in malignant tumors is controversial, especially in pancreatic cancer. This study aimed to clarify the role and significance of CD166 expression in pancreatic cancer. METHODS: We performed immunohistochemistry and flow cytometry to analyze the expression of CD166 in surgical pancreatic tissues and pancreatic cancer cell lines. The differences between isolated CD166+ and CD166- pancreatic cancer cells were analyzed by invasion and migration assays, and in mouse xenograft models. We also performed quantitative RT-PCR and microarray analyses to evaluate the expression levels of CD166 and related genes in cultured cells. RESULTS: Immunohistochemistry revealed high expression of CD166 in pancreatic cancer tissues (12.2%; 12/98) compared with that in normal pancreas controls (0%; 0/17) (p = 0.0435). Flow cytometry indicated that CD166 was expressed in 33.8-70.2% of cells in surgical pancreatic tissues and 0-99.5% of pancreatic cancer cell lines. Invasion and migration assays demonstrated that CD166- pancreatic cancer cells showed stronger invasive and migratory activities than those of CD166+ cancer cells (p<0.05). On the other hand, CD166+ Panc-1 cells showed a significantly stronger colony formation activity than that of CD166- Panc-1 cells (p<0.05). In vivo analysis revealed that CD166+ cells elicited significantly greater tumor growth than that of CD166- cells (p<0.05) in both subcutaneous and orthotopic mouse tumor models. mRNA expression of the epithelial-mesenchymal transition activator Zeb1 was over-expressed in CD166- cells (p<0.001). Microarray analysis showed that TSPAN8 and BST2 were over-expressed in CD166+ cells, while BMP7 and Col6A1 were over-expressed in CD166- cells. CONCLUSIONS: CD166+ pancreatic cancer cells are strongly tumorigenic, while CD166- pancreatic cancer cells exhibit comparatively stronger invasive and migratory activities. These findings suggest that CD166 expression is related to different functions in pancreatic cancer cells.

Total pancreatectomy and autologous islet cell transplantation as a means to treat severe chronic pancreatitis.

Autologous islet cell transplantation after near-total or total pancreatic resection can alleviate pain in patients with severe chronic pancreatitis and preserve endocrine function. From February 2000 to February 2003, a total of 22 patients, whose median age was 38 years, underwent pancreatectomy and autologous islet cell transplantation. Postoperative complications, metabolic studies, insulin usage, pain scores, and quality of life were recorded for all of these patients. The average number of islet cells harvested was 245,457 (range 20,850 to 607,466). Operative data revealed a mean estimated blood loss of 635 ml, an average operative time of 9 hours, and a mean length of hospital stay of 15 days. Sixty-eight percent of the patients had either a minor or major complication. Major complications included acute respiratory distress syndrome (n=2), intra-abdominal abscess (n=1), and pulmonary embolism (n=1). There were no deaths in our series. All patients demonstrated C-peptide and insulin production indicating graft function. Forty-one percent are insulin independent, and 27% required minimal amount of insulin or a sliding scale. All patients had preoperative pain and had been taking opioid analgesics; 82% no longer required analgesics postoperatively. Pancreatectomy with autologous islet cell transplantation can alleviate pain for patients with chronic pancreatitis and preserve endocrine function.

The impact of post-procedure interpretation of ERCP X-ray films by radiologists on patient care: should it be routine or selective?

BACKGROUND: Review of ERCP x-ray films by radiologists is routine, but the utility of this practice is unproven. The aim of this study was to assess whether the routine post-procedural interpretation of ERCP films by radiologists alters patient management. METHODS: A retrospective analysis of 212 ERCPs followed by a prospective analysis of 112 ERCPs was performed. Comparative ductogram interpretations were categorized as: I, complete agreement; II, minor findings reported only by the radiologist; III, findings reported only by the endoscopist; and IV, major findings reported only by the radiologist that altered or should have altered management. RESULTS: In the retrospective analysis, 289 ductograms were identified, and interpretations were classified as: category I, 73%; category II, 16%; category III, 10.7%; and category IV, 0.3%. In the prospective study, interpretations of 167 ductograms were analyzed and classified as follows: category I, 84%; category II, 11%; category III, 5%; category IV, none. CONCLUSIONS: Post-procedure interpretation of ERCP spot x-ray films by radiologists adds little to patient management. Selective consultation with radiologists would appear to be more appropriate than review by radiologists of ERCP spot x-ray films on a routine basis.

Prevalence and predictors of severity as defined by atlanta criteria among patients presenting with acute pancreatitis.

INTRODUCTION: Effective triage of patients with acute pancreatitis is dependent on the ability to accurately predict a severe course. Predictors (e.g., APACHE II score of >8) have been tested against wide-ranging definitions of severity (prevalence, 15%-40%). To ensure uniformity in defining a severe course of acute pancreatitis, the Atlanta symposium of 1992 adopted all-encompassing criteria (local complications, systemic complications, need for surgery, or death). AIMS: To assess the prevalence of each Atlanta criteria for severe acute pancreatitis and to determine the sensitivity, specificity, and positive and negative predictive values of the APACHE II score as a predictor of these criteria for severe acute pancreatitis. METHODOLOGY: We reviewed records of patients admitted to the University of Cincinnati Medical Center (Cincinnati, OH, U.S.A.) between 1994 and 1998 with acute pancreatitis. Exclusion criteria included referral from an outside hospital, immunocompromised state, and chronic pancreatitis. RESULTS: Seventy-four consecutive patients met our inclusion criteria. Ten patients (13.5%) had a severe course. Seven patients developed only local complications. Three patients had systemic complications. Pancreatic surgical intervention was required in four patients. No deaths occurred. An APACHE II score of >8 exhibited 50% sensitivity and 69% specificity (positive predictive value, 20%; negative predictive value, 89%). All patients with systemic complications and two of seven patients with only local complications had an APACHE II score of >8. CONCLUSIONS: The prevalence of severity among our nonreferred patients with acute pancreatitis was less than previously reported. The APACHE II scoring system exhibited reasonable sensitivity in predicting systemic complications and/or the need for surgery, with a low positive predictive value. This most certainly is a function of the low pretest probability of severe pancreatitis. Future studies attempting to identify predictive systems that triage patients in a more cost-effective manner should restrict their analysis to Atlanta criteria other than local complications.

IAP Guidelines for the Surgical Management of Acute Pancreatitis.

During 2002 the International Association of Pancreatology developed evidenced-based guidelines on the surgical management of acute pancreatitis. There were 11 guidelines, 10 of which were recommendations grade B and one (the second) grade A. (1) Mild acute pancreatitis is not an indication for pancreatic surgery. (2) The use of prophylactic broad-spectrum antibiotics reduces infection rates in computed tomography-proven necrotizing pancreatitis but may not improve survival. (3) Fine-needle aspiration for bacteriology should be performed to differentiate between sterile and infected pancreatic necrosis in patients with sepsis syndrome. (4) Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention including surgery and radiological drainage. (5) Patients with sterile pancreatic necrosis (with negative fine-needle aspiration for bacteriology) should be managed conservatively and only undergo intervention in selected cases. (6) Early surgery within 14 days after onset of the disease is not recommended in patients with necrotizing pancreatitis unless there are specific indications. (7) Surgical and other forms of interventional management should favor an organ-preserving approach, which involves debridement or necrosectomy combined with a postoperative management concept that maximizes postoperative evacuation of retroperitoneal debris and exudate. (8) Cholecystectomy should be performed to avoid recurrence of gallstone-associated acute pancreatitis. (9) In mild gallstone-associated acute pancreatitis, cholecystectomy should be performed as soon as the patient has recovered and ideally during the same hospital admission. (10) In severe gallstone-associated acute pancreatitis, cholecystectomy should be delayed until there is sufficient resolution of the inflammatory response and clinical recovery. (11) Endoscopic sphincterotomy is an alternative to cholecystectomy in those who are not fit to undergo surgery in order to lower the risk of recurrence of gallstone-associated acute pancreatitis. There is however a theoretical risk of introducing infection into sterile pancreatic necrosis. These guidelines should now form the basis for audit studies in order to determine the quality of patient care delivery.

Acute pancreatitis in children.

OBJECTIVES: Currently, there is no scoring system for predicting severity in acute pancreatitis in children. Our intent was to evaluate the performance of existing scoring systems in children, to develop a system for children, and to examine the etiology of acute pancreatitis in children. METHODS: A chart review of children with acute pancreatitis was conducted at six centers, three serving as criterion centers and three as validation centers. Ranson and Glasgow scores were calculated for each admission. Additional clinical data were collected, and parameters correlating with severity were incorporated into a new scoring system. Performance characteristics were calculated for each system. RESULTS: A total of 301 admissions were reviewed, 202 in the criterion group and 99 in the validation group. Eight parameters were included in a new scoring system for children. The parameters were as follows: age (<7 yr), weight (<23 kg), admission WBC (>18,500), admission LDH (>2,000), 48-h trough Ca2+ (<8.3 mg/dl), 48-h trough albumin (<2.6 g/dl), 48-h fluid sequestration (>75 ml/ kg/48 h), and 48-h rise in BUN (>5 mg/dl). When the cut-off for predicting a severe outcome was set at 3 criteria, the new system had better sensitivity versus Ranson and Glasgow scores (70% vs 30% and 35%, respectively) and a better negative predictive value (91% vs 85% and 85%). The specificity (79% vs 94% and 94%) and positive predictive value (45% vs 57% and 61%) fell slightly. CONCLUSION: The new scoring system performs better in this group than do existing systems.

Elucidation of vasoactive intestinal peptide pharmacophore for VPAC(1) receptors in human, rat, and guinea pig.

Vasoactive intestinal peptide (VIP) is a neurotransmitter involved in a number of pathological and physiological processes. VIP is rapidly degraded and simplified stable analogs are needed. VIP's action was extensively studied in rat and guinea pig. However, it is largely unknown whether its pharmacophore in these species resembles human. To address this issue we investigated the VIP pharmacophore for VPAC(1) (the predominant receptor subtype in cancers and widely distributed in normal tissues) by using alanine and D-amino acid scanning. Interaction with rat, guinea pig, and human VPAC(1) was assessed using transfected Chinese hamster ovary (CHO) and PANC1 cells and cells possessing native VPAC(1). Important species differences existed in the VIP pharmacophore. The human VPAC(1) expressed in CHO cells, which were used almost exclusively in previous studies, differed markedly from the native VPAC(1) in T47D cells. The most important amino acids for determining affinity are His(1), Asp(3), Phe(6), Arg(12), Arg(14), and Leu(23). Ser(2), Asp(8), Asn(9), Thr(11), Val(19), Asn(24), Ser(25), Leu(27), and Asn(28) are not essential for high-affinity interaction/activation. [Ala(2,8,9,11,19,24,25,27,28)]VIP, which contained 11 alanines, was synthesized and it was equipotent to VIP at VPAC(1) receptors in all species and was metabolically stable. Our results show in any design of simplified VIP analogs for VPAC(1) it will be important to consider species differences and it is essential to use transfected systems that reflect the native receptor's pharmacophore. Last, with our results a simplified, metabolically stable VIP analog was identified that should be useful as a prototype for design of selective agonists/antagonists that could be useful therapeutically.

Lack of benefit of intravenous synthetic human secretin in the treatment of autism.

The objective of this study was to determine if an intravenous infusion of synthetic human secretin improves language and behavioral symptoms in children with autism. Forty-two children with the diagnosis of autism were randomized to one of two groups in this double-blind cross-over trial. One group received 2 IU/kg of intravenous synthetic human secretin at the first visit, followed by an equal volume of intravenous saline placebo at week 6. The other group received treatments in the reverse order. All children were evaluated at weeks 1, 3, 6, 9, and 12 with standardized assessments of language, behavior, and autism symptomatology. There were no significant differences in the mean scores on any measure of language, behavior, or autism symptom severity after treatment with secretin compared to treatment with placebo. The results of this study do not support secretin as a treatment for autism.

Recurrent Acute Pancreatitis.

Patients with recurrent acute pancreatitis should be treated with the same supportive and symptom-oriented measures as those with acute pancreatitis. The need for specific treatment depends on the cause of the pancreatitis. Patients should discontinue alcohol use, putative causative medications, and exposure to toxins or helminths in endemic areas. Metabolic abnormalities need to be corrected, and appropriate treatment should be initiated for associated infections, autoimmune diseases, vasculitis, and hypercoagulable states. For patients with gallstone pancreatitis, endoscopic retrograde cholangiopancreatography is indicated if biliary obstruction persists or if cholangitis is present. Elective cholecystectomy may be performed in appropriate patients; otherwise, consider biliary sphincterotomy and ursodeoxycholic acid for prevention of recurrent attacks. Transpapillary stenting or sphincterotomy of the minor papilla benefits some patients with pancreas divisum and no other explanation for recurrent pancreatitis. Surgical sphincteroplasty is reserved for those failing endoscopic treatment. Biliary sphincterotomy benefits more than 50% of patients with sphincter of Oddi dysfunction and recurrent acute pancreatitis. Some authors advocate pancreatic sphincter manometry and sphincterotomy for persistent pancreatic segment hypertension in patients who have recurrent pancreatitis after biliary sphincterotomy. In patients with pancreatic duct strictures, transpapillary stent placement serves as a short-term measure; most patients ultimately require surgery.