Dag Hoem

Acute pancreatitis in Bergen, Norway. A study on incidence, etiology and severity.

Background: Studies on the incidence and etiology of acute pancreatitis show large regional differences. This study was performed to establish incidence, etiology and severity of acute pancreatitis in the population of Bergen, Norway. Methods: A study of all patients with acute pancreatitis admitted to Haukeland University Hospital over a 10-year period was performed. Information was obtained about the number of patients with acute pancreatitis admitted to the Deaconess Hospital in Bergen. Results: A total of 978 admissions of acute pancreatitis were recorded in these two hospitals giving an incidence of 30.6 per 100 000. Haukeland University Hospital had 757 admissions of acute pancreatitis in 487 patients. Pancreatitis was severe in 20 % (96/ 487) of patients, more often in males (25 %) than in females (14 %). Mortality due to acute pancreatitis was 3 % (16/487). Gallstones were found to be an etiological factor in 48.5 % and alcohol consumption in 19 % of patients. The risk of recurrent pancreatitis was 47 % in alcohol induced and 17 % in gallstone induced pancreatitis. The last five years of the study period, endoscopic sphincterotomy of patients with gallstone pancreatitis, resulted in drop in relapse rate from 33 % to 1.6 %. Conclusion: The incidence of acute pancreatitis was found to be 30.6 per 100 000 with 48.5 % associated with gallstones and 17 % alcohol induced. Incidence of first attack was 20/100 000. Pancreatitis was classified as severe in 20 % of cases with a mortality of 3 %.

Molecular analysis of the EGFR-RAS-RAF pathway in pancreatic ductal adenocarcinomas: lack of mutations in the BRAF and EGFR genes

The vast majority of tumors of the pancreas are ductal adenocarcinomas. This cancer type has an extremely poor prognosis and in many Western countries, it represents the fifth leading cause of cancer-related death. Pancreatic ductal adenocarcinomas exhibit the highest incidence of activating KRAS (Ki-Ras) mutations observed in any human cancer. It was therefore of interest to examine how this pattern would relate to mutations in the BRAF and EGFR genes, which are involved in the same signaling pathway as KRAS. We screened a series of 43 formalin-fixed, paraffin-embedded ductal adenocarcinomas of the pancreas. When DNA was extracted from whole tissue sections, KRAS codon 12 mutations were detected in 67% of the tumors. When cancerous ducts were isolated by laser-assisted microdissection, 91% were positive for KRAS mutations. Although it did not reach statistical significance, there was a trend in our material that survival after diagnosis varied according to KRAS mutation subtype, GTT-positive patients having the best prognosis. No alterations in BRAF exons 11 and 15 or in EGFR exons 18–21 were detected in KRAS-positive or KRAS-negative cases. We therefore conclude that the BRAF and EGFR mutations commonly seen in a variety of human cancers are generally absent from pancreatic ductal adenocarcinomas. Apparently, these tumors depend on no more than one genetic hit in the EGFR-RAS-RAF signaling pathway.

Pain management in chronic pancreatitis.

Introduction Chronic pancreatitis is a disease characterized by a painful progressive destruction of the pancreatic gland [1]. Even though other symptoms may occur pain is the predominant symptom both from the point of view of the patient and of his or her doctor. For an important part of the patient population the pain is so severe that all a patient’s waking hours are devoted to pain control, and the quality of life is low in every respect. Although much has been done to improve our understanding of the pathophysiology of chronic pancreatitis, there is still no therapy that counteracts the inflammatory process of the disease. As patients with chronic pancreatitis can, at best, be only symptom free, but never cured, the treatment continues to be directed against symptoms and complications, of which pain is the most dominant. The management of symptoms should therefore be of prime concern in most patients with chronic pancreatitis.

A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer

BACKGROUND The primary aim of our study was to evaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary aim was to evaluate a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance status, and prolonging survival. METHODS Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30min. Subsequently, patients were treated using a commercial clinical ultrasound scanner for 31.5min. SonoVue® was injected intravenously (0.5ml followed by 5ml saline every 3.5min) during the ultrasound treatment with the aim of inducing sonoporation, thus enhancing therapeutic efficacy. RESULTS The combined therapeutic regimen did not induce any additional toxicity or increased frequency of side effects when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n=10) tolerated an increased number of gemcitabine cycles compared with historical controls (n=63 patients; average of 8.3±6.0cycles, versus 13.8±5.6cycles, p=0.008, unpaired t-test). In five patients, the maximum tumour diameter was decreased from the first to last treatment. The median survival in our patients (n=10) was also increased from 8.9months to 17.6months (p=0.011). CONCLUSIONS It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available equipment with no additional toxicities. This combined treatment may improve the clinical efficacy of gemcitabine, prolong the quality of life, and extend survival in patients with pancreatic ductal adenocarcinoma.

Diabetes and Pancreatic Exocrine Dysfunction Due to Mutations in the Carboxyl Ester Lipase Gene-Maturity Onset Diabetes of the Young (CEL-MODY) A PROTEIN MISFOLDING DISEASE

CEL-maturity onset diabetes of the young (MODY), diabetes with pancreatic lipomatosis and exocrine dysfunction, is due to dominant frameshift mutations in the acinar cell carboxyl ester lipase gene (CEL). As Cel knock-out mice do not express the phenotype and the mutant protein has an altered and intrinsically disordered tandem repeat domain, we hypothesized that the disease mechanism might involve a negative effect of the mutant protein. In silico analysis showed that the pI of the tandem repeat was markedly increased from pH 3.3 in wild-type (WT) to 11.8 in mutant (MUT) human CEL. By stably overexpressing CEL-WT and CEL-MUT in HEK293 cells, we found similar glycosylation, ubiquitination, constitutive secretion, and quality control of the two proteins. The CEL-MUT protein demonstrated, however, a high propensity to form aggregates found intracellularly and extracellularly. Different physicochemical properties of the intrinsically disordered tandem repeat domains of WT and MUT proteins may contribute to different short and long range interactions with the globular core domain and other macromolecules, including cell membranes. Thus, we propose that CEL-MODY is a protein misfolding disease caused by a negative gain-of-function effect of the mutant proteins in pancreatic tissues.

Visualization of CD44 and CD133 in Normal Pancreas and Pancreatic Ductal Adenocarcinomas Non-overlapping Membrane Expression in Cell Populations Positive for Both Markers

Tumor-initiating cells of pancreatic ductal adenocarcinoma (PDAC) have been isolated based on expression of either CD133 or CD44. The authors aimed to visualize pancreatic cells simultaneously expressing both these cell surface markers by employing the same antibodies commonly used in cell-sorting studies. Normal and diseased pancreatic tissue, including 51 PDAC cases, were analyzed. CD44 and CD133 expression was determined by immunohistochemical double staining on formalin-fixed material and subcellular protein distribution evaluated by immunofluorescence/confocal microscopy. In the normal pancreas, CD44 and CD133 were coexpressed in the centroacinar regions but in non-overlapping subcellular compartments. As expected, CD44 was found mainly basolaterally, whereas CD133 was present on the apical/endoluminal membrane. This was also the case in chronically inflamed/atrophic pancreatic tissue and in PDAC. In some malignant ducts, CD44 was found at the apical cell membrane adjacent to but never overlapping with CD133 expression. CD44 level was significantly associated with the patient’s lymph node status. In conclusion, a CD44+/CD133+ cell population does exist in the normal and neoplastic pancreas. The preferentially centroacinar localization of the doubly positive cells in the normal parenchyma suggests that this population could be of particular interest in attempts to identify tumor-initiating cells in PDAC. This article contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Endoscopic sphincterotomy in acute gallstone pancreatitis: a prospective study of the late outcome

OBJECTIVE To describe the outcome after acute biliary pancreatitis in patients treated during the acute attack by endoscopic sphincterotomy without cholecystectomy. DESIGN Prospective observational study. SETTING University hospital, Norway. SUBJECTS 130 patients with gallstones and acute pancreatitis. In 62 patients with common bile duct stones the bile duct was cleared by sphincterotomy and stone extraction. The remaining 68 patients had prophylactic sphincterotomy. Cholecystectomy was not planned later. MAIN OUTCOME MEASURES Incidence of recurrent acute pancreatitis and need for cholecystectomy. RESULTS 21 patients were dead or not available for the follow-up. Consequently 109 patients were followed-up for a median of 39 months (range 23-62). One patient had recurrent pancreatitis. 20 patients had a cholecystectomy later for symptoms related to gallstone disease. Of the rest, 25 patients had moderate or mild gallstone-related symptoms. There was no difference in gallstone-related symptoms between those who had had stones in the bile duct and those who had not. 63 patients had no symptoms related to gallstones. CONCLUSION Endoscopic sphincterotomy during or immediately after acute gallstone pancreatitis resulted in half the patients being free of symptoms during the next three years.

Quantification of pancreatic function using a clinically feasible short endoscopic secretin test.

Objectives Clinical and morphological criteria are not precise enough to diagnose early chronic pancreatitis (CP). We investigated if short endoscopic pancreas function testing as a part of routine upper endoscopy could improve clinical diagnostics. Methods Patients with suspected CP underwent modified secretin-stimulated upper endoscopy (short endoscopic secretin test, or EST). Duodenal juice was collected during 15 minutes starting 30 minutes after stimulation. A modified scoring system for CP after Layer with bicarbonate and fecal elastase 1 (FE1) was used. We tested with receiver operating characteristic curves the diagnostic accuracy of bicarbonate and FE1 and with analysis of variance how precise the 2 parameters can discriminate the groups. Results Fifty-two patients aged 19 to 67 years and 25 healthy controls aged 19 to 64 years were included. Twenty-four patients fulfilled the modified Layer Score for CP or non-CP. The overall accuracy of the EST versus FE1 test was 85%/71%, with positive and negative predictive values of 100%/79% and 80%/69%, respectively. Conclusions Short EST is rapid and easy to perform and can be incorporated in daily routines. We demonstrate that EST is superior to FE1 in the assessment of pancreatic insufficiency and may prove to be useful in diagnosing early or mild CP.

Improving survival following surgery for pancreatic ductal adenocarcinoma--a ten-year experience.

OBJECTIVE Report results following pancreatic surgery at a tertiary referral hospital in Norway, and our experience with the effects of preoperative use of common bile duct stents, the prophylactic efficacy of octreotide, and explore significant survival factors. MATERIAL AND METHODS Prospective observational study of 275 patients during the years 1999-2009. RESULTS Ninety-two ductal adenocarcinomas were operated, and 183 cases were inoperable. Pylorus preserving pancreatico-duodenectomy (PPPD) was performed in 42 cases, a classic Whipple procedure (WP) in 38, distal resection in 6 and total pancreatectomy in 6 patients. Median size of the tumours was 3 cm R(0) resection was obtained in 54 patients. Lymph node metastases were found in 64 patients. 20% experienced postoperative intra-abdominal complications, and 30 days postoperative mortality was 4%. A routine use of somatostatine analogues postoperatively did not reduce the frequency of leakage. Two years survival was 34.6% and 5 years 11.8%, respectively. CONCLUSIONS Patients with ductal adenocarcinomas can be offered potential curative resections with acceptable rates of complication and mortality. Preoperative biliary stenting is still controversial and prophylactic octreotide should be used whenever the anastomosis is considered challenged and in cases of a soft pancreatic remnant. Five years all over survival has improved over the last decade from <5% to >11%.

Nonadhesive Organ Culture of Human Exocrine Pancreatic Cells with Their Stroma

Introduction Studies using explanted tissue have shown that it is possible to keep adult human cells in organ culture with a preserved morphology for up to 1 month as spheres in a nonadhesive organ culture. Aims The current study was to determine whether human exocrine pancreatic cells also can be grown in this manner. Methodology Small tissue samples from organ donors and tumor-free resection rim from patients with pancreatic carcinoma were obtained (n = 16 adults). From each patient, fragments of approximately 300 &mgr;m in diameter were cultured and investigated with light microscopy and scanning and transmission electron microscopy at the time of explantation and after 5, 10, 20, 30, and 40 days of culture. Results Incubation of cultured fragments with vital dyes revealed a viable epithelium. At the time of explantation all the tissue fragments had a rough appearance with an uneven, torn periphery. During the first week of culture the fragments became rounder, with a smooth surface covering the whole circumference. This spheroid morphology persisted for the rest of the 6-week culture period. The fragments were within 1 week covered by a highly differentiated, polarized epithelium with secretory apparatus, apical secretion granules, and microvilli, as well as specialized cell junctions, with the same appearance as acinoductal pancreatic cells of the original tissue. The core of the fragments consisted of connective tissue with vascular elements, fibroblasts, leukocytes, and a few ductal and acinar elements. Transmission electron microscopy of the spheroids revealed a continuous basal lamina underneath the epithelium. Immunostaining for cytokeratin 5, 6, 7, 8, 17, and 18 was strongly positive in the epithelium. Conclusion These results show that normal exocrine pancreatic cells can be grown in vitro in a nonadhesive organ culture with their stroma.