Endoscopic evaluation of the pancreatic duct system: opportunities offered by novel technology.

Divisions of Surgery, Karolinska University Hospital, Stockholm, Huddinge, Sweden. Urban.Arnelo@ki.se

The development of front-line endoscopic technology has introduced new opportunities during endoscopic retrograde cholangiopancreatography (ERCP) to single-handedly allow direct inspection of detailed structures of the biliary and even the pancreatic duct. This paper presents a new flexible technology delivered with an outer diameter of 0.9 mm giving an image transmission of 6000 pixels. We report on a case where direct inspection of an alleged duct defect, of potential pathogenetic significance, was considered essential in order to substantiate the subsequent clinical management.

PMID: 17613934 [PubMed - indexed for MEDLINE]

Screening for human cationic trypsinogen (PRSS1) and trypsinogen inhibitor gene (SPINK1) mutations in a Finnish family with hereditary pancreatitis.

Departments of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland. raty.sari@kulumbus.fi

OBJECTIVE: Mutations in the cationic trypsinogen gene (PRSS1) have been linked with hereditary pancreatitis (HP). A change in R122H in the third exon is one of the mutations most frequently associated with HP. A mutation N34S in the serine protease inhibitor Kazal type 1 gene has also been shown to be linked with HP. The purpose of this study was to report on the incidence of PRSS1 and SPINK1 mutations in a Finnish family with HP and to correlate the findings to the clinical symptoms. MATERIAL AND METHODS: The study included 36 individuals from one Finnish family with HP (21 M, 15 F, median age 38 years). All individuals underwent abdominal ultrasound and laboratory tests (glucose, faecal elastase-1 test). Blood samples were taken for mutational analysis of PRSS1 (R122H, N29I and A16V) and SPINK1 (N34S). RESULTS: Ten (28%) individuals were affected by mutations: the most frequent mutation was R122H, affecting 8 (22%) individuals; 2 (6%) individuals were affected by the N34S mutation and none by the other tested mutations (N29I and A16V). Four out of eight (50%) R122H-positive individuals had a diagnosis of chronic pancreatitis without other known aetiologies. Four out of five (80%) male individuals with the R122H mutation also had clinical pancreatitis, whereas none of the three mutation-positive females had any signs or symptoms of chronic pancreatitis. The two individuals with the N34S mutation did not have any signs of chronic pancreatitis. CONCLUSIONS: In the investigated Finnish pedigree with HP, the PRSS1 mutation R122H is linked with chronic disease. Although the SPINK1 mutation (N34S) was also observed in two individuals, it was not linked with the disease.

PMID: 17613931 [PubMed - indexed for MEDLINE]

Synthetic 13C-dipeptide breath test for the rapid assessment of pancreatic exocrine insufficiency in rats.

Fundamental Technology Department, Tokyo Gas Co. Ltd., Tokyo, Japan.

OBJECTIVE: (13)C-breath tests have been investigated in order to assess pancreatic exocrine function using various (13)C-compounds, but they have not been accepted for routine clinical use. One of the barriers to their acceptance is that these tests are time-consuming and require up to several hours for breath collection. The purpose of this study was to design a novel (13)C-compound that would make a rapid (13)C-breath test for assessing exocrine pancreatic function possible. MATERIAL AND METHODS: N-benzoyl-L-tyrosyl-1-(13)C-L-alanine was synthesized, and the characteristics of its cleavage in duodenal juice and in the duodenum of rats were examined. Thereafter, a (13)C-breath test was carried out in which N-benzoyl-L-tyrosyl-1-(13)C-L-alanine was given orally to pancreatic exocrine-insufficient and normal control rats. RESULTS: N-benzoyl-L-tyrosyl-1-(13)C-L-alanine was readily cleaved and liberated 1-(13)C-L-alanine in the duodenal juice. Carboxypeptidase was a major contributor to the cleavage. When N-benzoyl-L-tyrosyl-1-(13)C-L-alanine was injected into the duodenum and orally administered to the rats, the (13)C atom% of CO(2) in breath increased rapidly. This indicated that N-benzoyl-L-tyrosyl-1-(13)C-L-alanine in the duodenum liberated (13)C-Ala on cleavage. (13)C-Ala is absorbed and metabolized to liberate (13)CO(2), which is exhaled. It was shown that the Delta(13)CO(2) ( per thousand) in the N-benzoyl-L-tyrosyl-1-(13)C-L-alanine breath test in the pancreatic exocrine-insufficient rats, in whom the absorption and metabolism of (13)C-Ala was unimpaired, was significantly lower than that in the control rats. CONCLUSIONS: The rate of increase in the Delta(13)CO(2) ( per thousand) in the N-benzoyl-L-tyrosyl-1-(13)C-L-alanine breath test is expected to be proportional to the rate of N-benzoyl-L-tyrosyl-1-(13)C-L-alanine cleavage by pancreatic proteases in the duodenum. We propose the N-benzoyl-L-tyrosyl-1-(13)C-L-alanine breath test as a rapid test for assessing pancreatic exocrine function.

PMID: 17613930 [PubMed - indexed for MEDLINE]

Corticosteroid-binding globulin: a possible early predictor of infection in acute necrotizing pancreatitis.

Department of General Surgery, St. Josef Hospital, Ruhr University Bochum, Germany. c.mueller@klinikum-bochum.de

OBJECTIVE: Infected pancreatic necrosis is the main cause of death in patients with acute pancreatitis, and therefore its early prediction is of utmost importance. Endogenous cortisol metabolism plays a basic role both in the course of acute pancreatitis and in the process of infection. The purpose of this study was to analyze corticosteroid-binding globulin (CBG), total cortisol, calculated free cortisol and adrenocorticotropic hormone as potential early predictors in order to differentiate between infected pancreatic necrosis and sterile pancreatic necrosis in patients with acute pancreatitis. MATERIAL AND METHODS: Serum levels of CBG, total cortisol, calculated free cortisol, and plasma levels of adrenocorticotropic hormone were determined in 109 consecutive patients with acute pancreatitis. C-reactive protein was measured as the control parameter. Thirty-five patients developed necrotizing pancreatitis and 10 developed infection of the necrosis. Blood was monitored for 6 days after the onset of pain; 30 healthy individuals served as controls. RESULTS: Of all parameters only CBG showed a significant difference (p = 0.0318) in its peak levels measured in the first 48 h in patients with sterile (26.5 microg/ml, range 21.3-34.7) and infected (16.0 microg/ml, range 15.2-25.0) necrosis at a cut-off level of 16.8 microg/ml. That difference was further preserved for the first 6 days after onset of pain. CONCLUSIONS: In our group of patients, a decreased CBG level below 16.8 g/ml within the initial 48 h of acute pancreatitis was an early predictor of later infected pancreatic necrosis, with a positive predictive value of 100% and a negative predictive value of 87.5%.

PMID: 17852861 [PubMed - indexed for MEDLINE]

Value of routine clinical tests in predicting the development of infected pancreatic necrosis in severe acute pancreatitis.

Laboratory for Research of the GI Tract, Institute for Biomedical Research, Kaunas University of Medicine, Kaunas, Lithuania.

OBJECTIVE: Fine-needle aspiration (FNA) is the procedure of choice for accurate diagnosis of infected necrosis. However, invasive procedures increase the risk of secondary pancreatic infection and the timing of FNA is still a matter for debate. Our objective was to assess the value of routine clinical tests to determine the minimal risk for infected necrosis, thereby optimizing timing and selection of patients for image-guided FNA. MATERIAL AND METHODS: This prospective, non-randomized study comprised 90 patients with acute necrotizing pancreatitis. The data of 52 patients were used for discriminant function analysis to determine the differences between patients with infected necrosis and those with sterile necrosis. Cut-off points for variables were established using receiver operating characteristic (ROC) curve analysis and logistic regression was performed to determine the risk of infected necrosis. The clinical relevance of the defined diagnostic system was prospectively tested in a further 38 consecutive patients with acute necrotizing pancreatitis (ANP). RESULTS: Discriminant function analysis showed that C-reactive protein (CRP) and white blood cell (WBC) values were significant discriminators between patients with sterile necrosis and those with infected necrosis. Cut-off values of 81 mg/l for CRP and 13 x 10(9)/l for WBC were established. The predicted risk for infected necrosis is approx. 1.4% if both tests are below the defined cut-off values. Consequently, we found FNA unnecessary in this subset of patients, unless otherwise indicated, as this invasive procedure per se carries a certain risk of bacterial contamination. CONCLUSIONS: Routine clinical tests are helpful in diagnosing the development of infected necrosis. Based on the application of classification functions, the timing and selection of patients for image-guided FNA can be optimized.

PMID: 17852884 [PubMed - indexed for MEDLINE]

Early inflammatory response in acute pancreatitis is little affected by body mass index.

Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland. panu.mentula@saunalahti.fi

OBJECTIVE: Obesity is a known risk factor for severe acute pancreatitis (AP), but the mechanism by which it affects the severity of AP is not fully understood. The main objective of this study was to investigate the relationship between obesity and inflammatory markers in AP. MATERIAL AND METHODS: Thirty patients with AP who developed organ failure (Group I) and 87 patients with AP who survived without organ failure (Group II) were studied. Patients' height and weight were measured at admission for calculation of body mass index (BMI). Blood samples were taken at admission for measurement of plasma interleukin (IL)-1beta, IL-6, IL-10, IL-1 receptor antagonist, procalcitonin, C-reactive protein (CRP) and monocyte human leucocyte antigen (HLA)-DR expression. RESULTS: Group I patients had higher BMI values (median 26.2 kg/m2) than Group II patients (25.2 kg/m2), p =0.033. Both CRP values and monocyte HLA-DR expression showed a significant correlation with BMI (Spearman's rank correlation r=0.32, p =0.003 and r= -0.33, p = 0.002, respectively). The correlation between BMI and monocyte HLA-DR expression was significant in Group II patients (r = -0.34, p =0.002) but not in Group I patients (r = -0.02, p >0.05). There was no correlation between BMI and IL-1beta, IL-6, IL-10, IL-1 receptor antagonist or procalcitonin. CONCLUSIONS: BMI did not affect either proinflammatory or anti-inflammatory cytokine levels in early AP. However, in patients with mild AP, BMI correlated positively with CRP levels and inversely with monocyte HLA-DR expression, which might reflect an amplified inflammatory response in these patients. Taken together, acute inflammatory response in AP, which ultimately determines the severity of AP, was little affected by BMI.

PMID: 17852885 [PubMed - indexed for MEDLINE]

Comment in:

Scand J Gastroenterol. 2007 Jun;42(6):667-72.

Early treatment of severe pancreatitis with imipenem: a prospective randomized clinical trial.

Department of Surgery, Haukeland University Hospital, Norway. ola.rokke@ahus.no

OBJECTIVE: The main causes of death in severe pancreatitis are multiorgan failure and septic complications. Prophylactic treatment with effective antibiotics is therefore a tempting therapeutic option. However, there could be side effects such as selection of resistant microbes and fungi. The aim of the present study was to compare the rate of infectious complications, interventions, days in the intensive care unit (ICU), morbidity and mortality in patients with severe pancreatitis randomized to prophylactic therapy with imipenem compared with those receiving no treatment at all. MATERIAL AND METHODS: Seventy-three patients with severe pancreatitis were included in a prospective, randomized, clinical study in seven Norwegian hospitals. The number of patients was limited to 73 because of slow patient accrual. Severe pancreatitis was defined as a C-reactive protein (CRP) level of >120 mg/l after 24 h or CRP >200 48 h after the start of symptoms. The patients were randomized to either early antibiotic treatment (imipenem 0.5 g x 3 for 5-7 days) (imipenem group) (n=36) or no antibiotics (control group) (n=37). RESULTS: The groups were similar in age, cause of pancreatitis, duration of symptoms and APACHE II score. Patients in the imipenem group experienced lower rates of complications (12 versus 22 patients) (p=0.035) and infections (5 versus 16 patients) (p=0.009) than those in the control group. There was no difference in length of hospital stay (18 versus 22 days), need of intensive care (8 versus 7 patients), need of acute interventions (10 versus 13), nor for surgery (3 versus 3) or 30-day mortality rates (3 versus 4). CONCLUSIONS: The study, although underpowered, supports the use of early prophylactic treatment with imipenem in order to reduce the rate of septic complications in patients with severe pancreatitis.

PMID: 17506001 [PubMed - indexed for MEDLINE]

Treatment with anti-factor VIIa in acute pancreatitis in rats: blocking both coagulation and inflammation?

Department of Surgery, Lund University Hospital, Lund, Sweden.

OBJECTIVE: Acute pancreatitis starts as an autodigestive process restricted to the pancreas and progresses to a systemic inflammation via cytokine release into the blood stream. Several inhibitors of the coagulation cascade, including active-site-inactivated factor VIIa, have shown anti-inflammatory properties in other inflammatory models than acute pancreatitis. Free radical scavengers have proven useful in reducing the oxidative damage during hyperinflammatory conditions. The aim of this study was to investigate whether pretreatment with FVIIai would have any effect on the multiple organ dysfunction syndrome (MODS) in severe acute pancreatitis. MATERIAL AND METHODS: Experimental acute pancreatitis was induced by intraductal infusion of taurodeoxycholate in the pancreatic duct. The animals were pretreated with N-acetyl-cysteine and active-site-inactivated factor VIIa. Neutrophil infiltration in the lungs, ileum and colon was quantified by myeloperoxidase activity. Inflammatory markers, IL-6 and MIP-2, were measured using ELISA. RESULTS: Tissue infiltration of neutrophils in the lungs, ileum and colon significantly increased during acute pancreatitis as compared to sham operation. These levels were reduced by pretreatment with N-acetylcysteine and active-site-inactivated factor VIIa. Levels of interleukin-6 and macrophage inflammatory protein-2 increased significantly during acute pancreatitis. Pretreatment with NAC and FVIIai reduced these levels. CONCLUSIONS: Both N-acetylcysteine and active-site-inactivated factor VIIa showed powerful anti-inflammatory properties in experimental acute pancreatitis. As they exert their effects through different physiological mechanisms, they represent potential candidates for future multimodal treatment of acute pancreatitis.

PMID: 17506000 [PubMed - indexed for MEDLINE]

Predictive factors in pancreatic ductal adenocarcinoma: role of the inflammatory response.

Department of Surgery, Lund University Hospital, Lund, Sweden.

OBJECTIVE: Pancreatic ductal adenocarcinoma is a highly lethal disease and most patients are not eligible for curable resection. Estimation of prognosis is essential in order to provide the best individual treatment for patients with pancreatic adenocarcinoma. Prediction of survival by current methods is limited, therefore the objective of this study was to determine possible prognostic factors identified at the time of diagnosis. MATERIAL AND METHODS: All 119 consecutive patients with pancreatic ductal adenocarcinoma receiving palliative treatment at the Department of Surgery, Lund University Hospital from 1999 through 2002 were reviewed retrospectively. Prognostic factors and interventions were analysed statistically. C-reactive protein (CRP) at the time of diagnosis was measured in 109 patients. RESULTS: The overall median survival was 4.4 months. By means of a multivariate analysis it was shown that CRP (p<0.001) and tumour size (p=0.018) were independent predictors of survival. The median survival of patients with normal CRP at the time of diagnosis was 10.8 months versus 4.2 months for those with raised CRP levels (>or=5 mg/l; p<0.001). Chemotherapy was the only intervention associated with a longer survival time (p<0.001 versus no chemotherapy). CONCLUSIONS: The poor prognosis for patients with pancreatic ductal adenocarcinoma was confirmed. CRP proved to be a strong independent predictor of survival. Together with previous reported factors, CRP could serve as a potential tool to determine future treatment strategies for optimal individual palliation.

PMID: 17505998 [PubMed - indexed for MEDLINE]

Comment on:

Scand J Gastroenterol. 2007 Jun;42(6):771-6.

Antibiotic prophylaxis: an ongoing controversy in the treatment of severe acute pancreatitis.

PMID: 17505987 [PubMed - indexed for MEDLINE]

Comment on:

Scand J Gastroenterol. 2006 Jun;41(6):744-50.

Efficacy of s-type stents for the treatment of the main pancreatic duct stricture in patients with chronic pancreatitis.

PMID: 17454869 [PubMed - indexed for MEDLINE]

Endoscopic-ultrasound-guided endoscopic transmural drainage of pancreatic pseudocysts and abscesses.

Endoscopy Unit, Paoli-Calmettes Institute, 232 Boulevard St-Marguerite, 13273 Marseille Cedex 9, France.

OBJECTIVE: Surgery is the traditional treatment for symptomatic pancreatic pseudocysts and abscesses, but morbidity and mortality are still too high. Minimally invasive approaches have been encouraged. The aim of this study was to evaluate the results of the endoscopic-ultrasound-guided (EUS) endoscopic transmural drainage of these pancreatic collections. MATERIAL AND METHODS: In this retrospective review of consecutive cases from a single referral centre, cystogastrostomy and cystoduodenostomy were created with an interventional linear echoendoscope under endosonographic and fluoroscopic control by the endoscopic insertion of straight or double pigtail stents. RESULTS: Fifty-one symptomatic patients (33 men; mean age 58 years) were submitted to 62 procedures from January 2003 to December 2005. EUS-guided drainage was successful in 48 (94%) patients. Only three patients needed surgery. There were two procedure-related complications managed clinically. During a mean follow-up of 39 weeks, recurrence due to migration or obstruction of the stent was 17.7%. All these cases were submitted to a new session of endoscopic drainage. There was no mortality. Complications were more frequent in patients with a recent episode of acute pancreatitis (38.5% versus 10%; p=0.083). The endoscopic approach was not more hazardous for abscesses in regard to complications rate (19% versus 16.6%; p>0.05). In abscesses, a nasocystic drain did not decrease the complications rate (27% versus 13%; p=0.619), but the placement of 2 stents did decrease this rate (18% versus 20%; p>0.05), although increased it in pseudocysts (40% versus 13%; p=0.185). CONCLUSIONS: Endoscopic transmural drainage is a minimally invasive, effective and safe approach in the management of pancreatic pseudocysts and abscesses.

PMID: 17454865 [PubMed - indexed for MEDLINE]

Ultra thin needle histology may have impact in diagnosing chronic pancreatitis.

Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland. juhani.sand@phsp.fi

OBJECTIVE: Diagnosis of chronic pancreatitis is usually based on symptoms, ductal or parenchymal changes in imaging studies and function tests, but seldom on histology. Because the diagnosis of mild chronic pancreatitis is especially difficult, better tools to distinguish between chronic pancreatitis and normal pancreas are needed. Nowadays, cutting needles as thin as the widely used puncture needles are available. Using resected specimens, our aim was to evaluate whether these ultra-thin needles can take samples for histology that would allow verification of the diagnosis of chronic pancreatitis, with reference to a pancreatic wedge biopsy as the "gold standard". MATERIAL AND METHODS: Fifty patients underwent pancreatic resection for various reasons. Two 20 G needle biopsies (outer diameter 0.8 mm, study biopsies) and a 5 x 5-mm wedge biopsy (reference biopsies) were taken from the same site of the specimen, avoiding possible neoplastic areas in the specimen. The samples were analyzed for the presence inflammation and fibrosis, both graded 0-3, as well as for any neoplastic changes without knowledge of the medical history, operative findings or final histology. RESULTS: The reference biopsy showed normal tissue in 19 (38%) patients, chronic pancreatitis in 29 (58%) and only mild fibrosis (Grade 1) in 2 (4%) patients. In one patient the needle biopsy was insufficient for analysis. There was agreement between ultra-thin needle histology and the control specimen in 45/49 (92%) patients (correlation coefficient 0.9). Two biopsies of chronic pancreatitis and one mild fibrosis were misclassified as normal tissue, while one chronic pancreatitis biopsy was misclassified as an adenocarcinoma. The sensitivity of needle biopsy for chronic pancreatitis was 89%, specificity 100% and accuracy 94%. CONCLUSIONS: Ultra-thin needle histology correlates well with the pancreatic wedge biopsy. Thus, these encouraging results warrant further clinical studies of different grades and types of chronic pancreatitis.

PMID: 17454862 [PubMed - indexed for MEDLINE]

Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphism in alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals.

Department of Gastroenterology, Medical University of Lublin, ul. Sikorskiego 1/75, PL-20-814 Lublin, Poland. Lach.halina@wp.pl

OBJECTIVE: To investigate the effects of ADH and ALDH gene polymorphism on the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. MATERIAL AND METHODS: We determined the allele and genotype of ADH2, ADH3 and ALDH2 in 198 subjects: 57 with alcohol cirrhosis, 44 with alcohol chronic pancreatitis and 43 "healthy alcoholics"; 54 healthy non-drinkers served as controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method on white cell DNA. RESULTS: In the population examined the ADH2*1 allele frequency was 97.97%.The tests did not show the ADH2*3 allele. The ADH3*1 allele frequency was 57.07%. The ADH2*1 and the ADH3*1 alleles were statistically more common among patients who abuse alcohol in comparison with the controls. The ADH2*2 allele was not detected in any of the patients with chronic alcohol pancreatitis. The ADH2*1/*1 and the ADH3*1/*1 genotypes were statistically significantly more common among the patients who abuse alcohol than in the control group. All patients were ALDH2*1/*1 homozygotic. Patients with the ADH3*1 allele and the ADH3*1/*1 genotype started to abuse alcohol significantly earlier in comparison to the patients with the ADH3*2 allele and the ADH3*2 /*2 genotype. CONCLUSIONS: In the Polish population examined, the ADH3*1 allele and the ADH3*1/*1 genotype are conducive to the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis. However, the ADH2*2 allele is likely to protect against these conditions. Genetic polymorphism of ALDH2 shows no correlation with alcohol addiction or alcohol cirrhosis and alcohol chronic pancreatitis. The ADH3*1 allele and the ADH3*1/*1 genotype are conducive to alcohol abuse starting at a younger age.

PMID: 17454860 [PubMed - indexed for MEDLINE]

Differential effect of opioids in patients with chronic pancreatitis: an experimental pain study.

Centre for Visceral Biomechanics and Pain, Department of Gastroenterology, University Hospital Aalborg, Denmark.

OBJECTIVE: Animal experiments and clinical observations have indicated a different working profile of oxycodone compared to morphine, and it has previously been shown that oxycodone attenuates visceral pain better than morphine. The objective of this study was to test the effects of oxycodone and morphine on experimental pain in patients with pain caused by chronic pancreatitis. MATERIAL AND METHODS: Ten patients took part in this blinded, cross-over study. The analgesic effects of morphine (30 mg, oral), oxycodone (15 mg, oral) and placebo were tested against multimodal (mechanical, thermal and electrical) experimental pain in the skin, muscles and oesophagus. Pain was assessed at baseline and 30, 60 and 90 min after drug administration. RESULTS: In the skin and muscles, oxycodone was more effective than placebo and morphine on mechanically (skin: F=12.4, p<0.001, muscle: F=11.0, p<0.001) and thermally (skin: F=8.5, p<0.001) evoked pain. In oesophageal heat pain, the effect of morphine was equal to that of placebo, while oxycodone attenuated pain better than both morphine and placebo (F=9.5, p<0.001). Both morphine and oxycodone were more effective in attenuating mechanical pain in the oesophagus than placebo (F=8.6, p<0.001). After electrical stimulation no differences were seen between the opioids and placebo in any tissue studied. CONCLUSIONS: Oxycodone was a stronger analgesic than morphine in several pain modalities in the skin, muscle and oesophagus.

PMID: 17354119 [PubMed - indexed for MEDLINE]

Molecular mechanisms of pancreatic cancer and potential targets of treatment.

Department of Surgery, Lund University Hospital, University of Lund, Lund, Sweden.

PMID: 17354106 [PubMed - indexed for MEDLINE]

Obstructed pancreaticojejunostomy partly explains exocrine insufficiency after pancreatic head resection.

Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland. isto.nordback@pshp.fi

OBJECTIVE: The majority of patients with long-term survival after pancreatic head resection suffer from pancreatic exocrine insufficiency. The objective of this study was to investigate whether this is due to glandular malfunction or obstructed pancreaticojejunal anastomosis. MATERIAL AND METHODS: Twenty-six patients (10 M, 16 F, mean age 61 years, range 34-81 years) were re-examined a median of 52 months (range 3-76 months) after pancreatic head resection and end-to-end invaginated pancreaticojejunostomy. Pancreatic exocrine function was measured by fecal elastase-1 assay. The size of the pancreatic remnant, glandular secretion and the flow through the anastomosis were analyzed with secretin-stimulated dynamic magnetic resonance pancreatography (D-MRP). RESULTS: All patients had pancreatic exocrine insufficiency, 24 (92%) of them having severe insufficiency. Eighteen patients (69%) reported moderate to severe diarrhea. Lowest fecal elastase-1 concentrations were associated with the initial diagnosis of chronic pancreatitis or ductal adenocarcinoma, suggesting preoperative primary or secondary chronic pancreatitis as important determinants. The size of the remnant gland did not correlate with the fecal elastase-1 concentrations. D-MRP failed in three patients. Severe glandular malfunctions were found in 7 (30%) of the 23 successful D-MRP examinations. The anastomosis was totally obstructed in 5 patients (22%) or partially obstructed in 6 (26%) but remained perfectly open in 5 patients (22%). The five patients with perfect anastomoses had the highest measured median fecal elastase-1 activity. CONCLUSIONS: Although late diarrhea and pancreatic exocrine insufficiency may be partly induced already by the disease treated with resection, at least half may be explained by obstructed anastomosis. To obtain better late functional results, improvements may be required in the surgical techniques.

PMID: 17327947 [PubMed - indexed for MEDLINE]

Apoptosis, proliferation and differentiation patterns are influenced by Zebularine and SAHA in pancreatic cancer models.

Institute of Pathology, Landeskliniken Salzburg, Salzburg, Austria.

OBJECTIVE: Pancreatic cancer continues to be an urgent clinical problem. We used the novel DNA methyltransferase inhibitor Zebularine and the histone deacetylase inhibitor SAHA to investigate the epigenetic influence on viability and differentiation of the pancreatic cancer cell lines YAP C, DAN G and Panc-89 in vitro and in vivo. MATERIAL AND METHODS: Cell vitality, proliferation and expression of PDX-1, cytokeratin 7 and 20, chromogranin A, vimentin, bax and bcl-2 were determined on the protein and mRNA level in vitro and in a subcutaneous xenograft model. RESULTS: A time- and dose-dependent increase of apoptosis, paralleled by decreased proliferation, was observed after incubation with single agents or a combination therapy with lower concentrations. This was associated with up-regulation of pro-apoptotic bax and a phenotypic stabilization by the enhanced expression of cytokeratin 7. In vivo, growth of xenografts was delayed with the most pronounced effect in Panc-89 after 1 week of daily intraperitoneal injections of Zebularine paralleled with CK7 up-regulation and down-regulation of dedifferentiation markers. CONCLUSIONS: Epigenetic modulation via inhibition of DNA methyltransferase and histone deacetylase induces apoptosis in human pancreatic cancer cells in vitro and delays xenograft growth in vivo, which is associated with a morphological/molecular phenotypic stabilization. These compounds may therefore be suitable as adjunctive therapeutic agents in the treatment of pancreatic cancer.

PMID: 17190770 [PubMed - indexed for MEDLINE]

Antihypertensive medication and the risk of acute pancreatitis: the European case-control study on drug-induced acute pancreatitis (EDIP).

Department of Internal Medicine, Pharmacoepidemiology Unit, Erasmus MC, Rotterdam, The Netherlands. i.eland@erasmusmc.nl

OBJECTIVE: Angiotensin-converting enzyme (ACE) inhibitors and diuretics have been associated with acute pancreatitis. We quantified the risk of acute pancreatitis associated with the use of antihypertensive medication in the European study on drug-induced acute pancreatitis (EDIP). MATERIAL AND METHODS: The EDIP study is a multicenter population-based European case-control investigation of the association between drug use and acute pancreatitis. Patients between 40 and 85 years of age hospitalized for acute pancreatitis were included in the study between 1 October 1994 and 31 December 1998. For each case, age- and gender-matched community controls were recruited. Detailed information on drug use and potential confounders (e.g. comorbidity, alcohol use) was obtained through a structured interview. RESULTS: In all, 724 patients with acute pancreatitis and 1791 community controls were identified and interviewed. Use of ACE inhibitors in the week prior to the index date was associated with an increased risk of acute pancreatitis (adjusted odds ratio 1.5; 95% CI: 1.1-2.2). The risk of acute pancreatitis associated with ACE inhibitors increased with higher daily doses and was highest in the first 6 months of therapy. Calcium channel blockers increased the risk of acute pancreatitis (adjusted odds ratio 1.5; 95% CI: 1.1-2.1) without an apparent dose- or response relationship. Loop and thiazide diuretic use was not associated with an increased risk of acute pancreatitis. Potassium-sparing diuretics elevated the risk of acute pancreatitis, albeit non-significantly. CONCLUSION: Use of ACE inhibitors is associated with a modest increase in the risk of acute pancreatitis during the first months of treatment.

PMID: 17101581 [PubMed - indexed for MEDLINE]