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Background: RCTs are considered the reference standard in clinical research. However, surgical RCTs pose specific challenges and therefore numbers have been lower than those for randomized trials of medical interventions. In addition, surgical trials have often been associated with poor methodological quality. The objective of this study was to evaluate the evolution of quantity and quality of RCTs in pancreatic surgery and to identify evidence gaps., Methods: PubMed, CENTRAL and Web of Science were searched systematically. Predefined data were extracted and organized in a database. Quantity and quality were compared for three intervals of the study period comprising more than three decades. Evidence maps were constructed to identify gaps in evidence., Results: The search yielded 8210 results, of which 246 trials containing data on 26 154 patients were finally included. The number of RCTs per year increased continuously from a mean of 2·8, to 5·7 and up to 13·1 per year over the three intervals of the study. Most trials were conducted in Europe (46·3 per cent), followed by Asia (35·0 per cent) and North America (14·2 per cent). Overall, the quality of RCTs was moderate; however, with the exception of blinding, all domains of the Cochrane risk-of-bias tool improved significantly in the later part of the study. Evidence maps showed lack of evidence from RCTs for operations other than pancreatoduodenectomy and for specific diseases such as neuroendocrine neoplasms or intraductal papillary mucinous neoplasms., Conclusion: The quantity and quality of RCTs in pancreatic surgery have increased. Evidence mapping showed gaps for specific procedures and diseases, indicating priorities for future research., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: The definition of resection margin (R) status in pancreatic cancer is under debate. Although a margin of at least 1 mm is an independent predictor of survival after resection for pancreatic head cancer, its relevance to pancreatic body and tail cancers remains unclear. This study aimed to validate R status based on a 1-mm tumour-free margin as a prognostic factor for resected adenocarcinoma involving the pancreatic body and tail., Methods: Patients who underwent distal or total pancreatectomy for adenocarcinomas of the pancreatic body and tail between January 2006 and December 2014 were identified from a prospective database. Resection margins were evaluated using a predefined cut-off of 1 mm. Rates of R0, R1 with invasion within 1 mm of the margin (R1 less than 1 mm), and R1 with direct invasion of the resection margin (R1 direct) were determined, and overall survival in each group assessed by Kaplan-Meier analysis. Univariable and multivariable Cox regression analyses were performed to identify predictors of survival., Results: R0 resection was achieved in 107 (23·5 per cent) and R1 in 348 (76·5 per cent) of 455 patients. Among R1 resections, invasion within 1 mm of the margin was found in 104 (22·9 per cent) and direct invasion in 244 (53·6 per cent). The R0 rate was 28·9 per cent after distal and 18·6 per cent after total pancreatectomy. In the total cohort, median survival times for patients with R0, R1 (less than 1 mm) and R1 (direct) status were 62·4, 24·6 and 17·2 months respectively, with 5-year survival rates of 52·6, 16·8 and 13·0 per cent (P < 0·001). In patients who received adjuvant chemotherapy, respective median survival times were 68·6, 32·8 and 21·4 months, with 5-year survival rates of 56, 22 and 16·0 per cent (P < 0·001). In multivariable analysis, R status was independently associated with survival., Conclusion: A cut-off of at least 1 mm for evaluation of resection margins is an independent determinant of survival after resection of adenocarcinomas of the pancreatic body and tail., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Preoperative nutritional status has an impact on patients' clinical outcome. For pancreatic surgery, however, it is unclear which nutritional assessment scores adequately assess malnutrition associated with postoperative outcome., Methods: Patients scheduled for elective pancreatic surgery at the University of Heidelberg were screened for eligibility. Twelve nutritional assessment scores were calculated before operation, and patients were categorized as either at risk or not at risk for malnutrition by each score. The postoperative course was monitored prospectively by assessors blinded to the nutritional status. The primary endpoint was major complications evaluated for each score in a multivariable analysis corrected for known risk factors in pancreatic surgery., Results: Overall, 279 patients were analysed. A major complication occurred in 61 patients (21·9 per cent). The proportion of malnourished patients differed greatly among the scores, from 1·1 per cent (Nutritional Risk Index) to 79·6 per cent (Nutritional Risk Classification). In the multivariable analysis, only raised amylase level in drainage fluid on postoperative day 1 (odds ratio (OR) 4·91, 95 per cent c.i. 1·10 to 21·84; P = 0·037) and age (OR 1·05, 1·02 to 1·09; P = 0·005) were significantly associated with major complications; none of the scores was associated with, or predicted, postoperative complications., Conclusion: None of the nutritional assessment scores defined malnutrition relevant to complications after pancreatic surgery and these scores may thus be abandoned., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Intra-abdominal drains are frequently used after pancreatic surgery whereas their benefit in other gastrointestinal operations has been questioned. The objective of this meta-analysis was to compare abdominal drainage with no drainage after pancreatic surgery., Methods: PubMed, the Cochrane Library and Web of Science electronic databases were searched systematically to identify RCTs comparing abdominal drainage with no drainage after pancreatic surgery. Two independent reviewers critically appraised the studies and extracted data. Meta-analyses were performed using a random-effects model. Odds ratios (ORs) were calculated to aggregate dichotomous outcomes, and weighted mean differences for continuous outcomes. Summary effect measures were presented together with their 95 per cent confidence intervals., Results: Some 711 patients from three RCTs were included. The 30-day mortality rate was 2·0 per cent in the drain group versus 3·4 per cent after no drainage (OR 0·68, 95 per cent c.i. 0·26 to 1·79; P = 0·43). The morbidity rate was 65·6 per cent in the drain group and 62·0 per cent in the no-drain group (OR 1·17, 0·86 to 1·60; P = 0·31). Clinically relevant pancreatic fistulas were seen in 11·5 per cent of patients in the drain group and 9·5 per cent in the no-drain group. Reinterventions, intra-abdominal abscesses and duration of hospital stay also showed no significant difference between the two groups., Conclusion: Pancreatic resection with, or without abdominal drainage results in similar rates of mortality, morbidity and reintervention., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: The International Study Group on Pancreatic Surgery has stated that at least 12 lymph nodes should be evaluated for staging of pancreatic cancer. The aim of this population-based study was to evaluate whether the number of positive lymph nodes refines staging., Methods: Patients who underwent pancreatectomy for stage I-II pancreatic cancer between 2004 and 2012 were identified from the Surveillance, Epidemiology, and End Results database. The predictive value of the number of positive lymph nodes for survival was assessed by generalized receiver operating characteristic (ROC) curve analysis and propensity score-adjusted Cox regression analysis., Results: Some 5036 patients were included, with a median of 18 (i.q.r. 15-24) lymph nodes examined. Positive lymph nodes were found in 3555 patients (70·6 per cent). The median duration of follow-up was 15 (i.q.r. 8-28) months. ROC curve analysis revealed that two positive lymph nodes best discriminated overall survival. Patients with one or two positive lymph nodes (pN1a) and those with three or more positive lymph nodes (pN1b) had an increased risk of overall mortality compared with patients who were node-negative (pN0): hazard ratio (HR) 1·47 (95 per cent c.i. 1·33 to 1·64) and HR 2·01 (1·82 to 2·22) respectively. These findings were confirmed by propensity score-adjusted Cox regression analysis. The 5-year overall survival rates were 39·8 (95 per cent c.i. 36·5 to 43·3) per cent for patients with pN0, 21·0 (18·6 to 23·6) per cent for those with pN1a and 11·4 (9·9 to 13·3) per cent for patients with pN1b disease., Conclusion: The number of positive lymph nodes in the resection specimen is a prognostic factor in patients with pancreatic cancer., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Vascular resection interventions and the associated necessity of a reconstruction for maintenance particularly of hepatic and small intestinal perfusion are important aspects especially for the surgical treatment of pancreatic cancer. An R0 resection is the only curative treatment option for patients with pancreatic cancer. Venous or arterial vascular infiltration by the tumor and the associated resection and reconstruction for complete tumor removal and establishment of a sufficient perfusion of the dependent organs represents one of the greatest challenges in pancreatic surgery. In addition the oncological significance with respect to arterial vascular resections is controversial., Objective: In this review article the indications and technical aspects of vascular resection and reconstruction in the therapy of pancreatic cancer are presented and discussed based on the current literature., Material and Methods: A systematic search of Medline, Embase and the Cochrane Library was carried out to identify studies reporting the results of venous or arterial vascular resection techniques, postoperative morbidity, mortality and patient survival after surgery for pancreatic cancer. Results Pancreatic cancer with vascular infiltration should not principally be seen as non-resectable but must always be checked for the possibility of a curative resection. A decisive factor is the differentiation between venous and arterial vascular involvement. Various safe technical options are available for venous vascular resection, depending on the extent of tumor infiltration. Arterial vascular resections are associated with an increased morbidity and mortality. In selected patients a complete tumor resection and prolonged survival can be achieved by arterial vascular resection.

Pancreatic surgery has undergone significant progress during recent years. Specialised centres with interdisciplinary expertise have led to improved patient care with decreased morbidity and mortality. Regarding evidence-based medicine, consensus definitions on morbidity as well as high-quality studies, systematic reviews and meta-analyses on different topics of pancreatic surgery have been published. In acute pancreatitis paradigms have shifted towards conservative management, in chronic pancreatitis parenchyma-sparing resection techniques have widely become accepted. Management of cystic lesions - especially intraductal papillary mucinous neoplasms (IPMN) - has attracted great interest in surgical practice. In pancreatic cancer treatment not only surgical resection techniques have improved but also the central impact of adjuvant treatment has been demonstrated in large multicentre trials., (Georg Thieme Verlag KG Stuttgart · New York.)

The role of pancreatic acinar cells in initiating necro-inflammatory responses during the early onset of alcoholic acute pancreatitis (AP) has not been fully evaluated. We investigated the ability of acinar cells to generate pro- and anti-inflammatory mediators, including inflammasome-associated IL-18/caspase-1, and evaluated acinar cell necrosis in an animal model of AP and human samples. Rats were fed either an ethanol-containing or control diet for 14 weeks and killed 3 or 24 h after a single lipopolysaccharide (LPS) injection. Inflammasome components and necro-inflammation were evaluated in acinar cells by immunofluorescence (IF), histology, and biochemical approaches. Alcohol exposure enhanced acinar cell-specific production of TNFα, IL-6, MCP-1 and IL-10, as early as 3 h after LPS, whereas IL-18 and caspase-1 were evident 24 h later. Alcohol enhanced LPS-induced TNFα expression, whereas blockade of LPS signaling diminished TNFα production in vitro, indicating that the response of pancreatic acinar cells to LPS is similar to that of immune cells. Similar results were observed from acinar cells in samples from patients with acute/recurrent pancreatitis. Although morphologic examination of sub-clinical AP showed no visible signs of necrosis, early loss of pancreatic HMGB1 and increased systemic levels of HMGB1 and LDH were observed, indicating that this strong systemic inflammatory response is associated with little pancreatic necrosis. These results suggest that TLR-4-positive acinar cells respond to LPS by activating the inflammasome and producing pro- and anti-inflammatory mediators during the development of mild, sub-clinical AP, and that these effects are exacerbated by alcohol injury.

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas constitute an increasingly recognized entity of cystic pancreatic tumors which are characterized by mucin production and epithelial growth within the pancreatic ducts and show a wide spectrum of morphologic variants. They may arise in the main pancreatic duct, its major side branches or in both (mixed type). Furthermore, IPMNs are considered as precursor lesions to pancreatic adenocarcinoma. However, it is not clear what the time course of such potential neoplastic transformation might be and whether all lesions progress to malignant tumors. As currently no diagnostic test can reliably differentiate between benign and malignant tumors the majority of newly diagnosed IPMNs should be surgically resected. According to current treatment guidelines (Sendai criteria), only asymptomatic side branch IPMNs of less than 3 cm in diameter without suspicious radiologic features, such as nodules, thickness of the cystic wall or size progression, should be treated conservatively without the need for surgical resection. Recently, this approach has become controversial due to a relevant number of reported Sendai negative IPMNs which revealed malignant transformation on final histological examination. The focus of this review is on the surgical treatment of IPMNs with regard to the current state of knowledge.

Background: Liver ischaemia after pancreatic resection is a rare but potentially serious complication. The aim of this study was to determine the impact of postoperative liver ischaemia after pancreatic resection., Methods: All consecutive patients undergoing pancreatic resection between January 2007 and August 2008 in the Department of Surgery in Heidelberg were identified retrospectively from a prospectively collected database and analysed with a focus on postoperative hepatic perfusion failure. Laboratory data, computed tomography (CT) findings, symptoms, therapy and outcome were recorded., Results: A total of 762 patients underwent pancreatic resection in the study period. Seventeen patients (2·2 per cent) with a postoperative increase in liver enzymes underwent contrast-enhanced CT for suspected liver perfusion failure. The types of perfusion failure were hypoperfusion without occlusion of major hepatic vessels (6 patients) and ischaemia with arterial (5) and/or portal vein (6) involvement. The overall mortality rate was 29 per cent (5 of 17 patients). Therapy included conservative treatment (7), radiological or surgical revascularization and necrosectomy or resection of necrotic liver tissue (10). Outcome varied from full recovery (4 patients) to moderate systemic complications (6) and severe complications (7) including death. Simultaneous involvement of the portal vein and hepatic artery was always fatal., Conclusion: Postoperative liver perfusion failure is a rare but potentially severe complication following pancreatic surgery requiring immediate recognition and, if necessary, radiological or surgical intervention., (Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background: Pancreatic neuropathy in chronic pancreatitis (CP) and pancreatic cancer (PCa) is characterized by pancreatic neuropathy, i.e. increased neural density and hypertrophy, which are associated with neuropathic pain. To better understand the mechanism of these neuropathic alterations, we aimed at achieving an in-vitro simulation of the intrapancreatic neuroplasticity., Methods: Dissociated myenteric plexus (MP) and dorsal root ganglia (DRG) neurons of newborn rats were treated with normal human pancreas (NP), CP or PCa tissue extracts. Furthermore, MP and DRG neurons were cultured in supernatants from different pancreatic cancer cell lines (PCC) and human pancreatic stellate cells (hPSC) obtained from either CP or PCa tissues. For analysis, the neurite density, outgrowth, neuronal branching capacity and perikaryonal size were quantified., Key Results: Myenteric plexus and DRG neurons grown in CP and PCa tissue extracts built denser networks than in NP extracts. Both neuronal types showed a strong neurite outgrowth, more complex branching pattern and a somatic hypertrophy in CP and PCa extracts. Pancreatic cancer cell supernatants induced a prominent neurite outgrowth, increased neurite density and perikaryonal hypertrophy in MP and DRG neurons. Supernatants of CP-derived hPSC strongly stimulated neurite outgrowth. Glial density in MP cultures was strikingly increased by PCa tissue extracts., Conclusions & Inferences: Intrapancreatic microenvironment in CP and PCa induces neuroplastic alterations under in-vitro conditions, leading to increased neural density and hypertrophy. Thus, due to its neurotrophic attributes, the intrapancreatic microenviroment in CP and PCa seems to be a key player in the generation of pancreatic neuropathy and neuroplasticity.

Background: Preoperative biopsy of pancreatic lesions suspected of malignancy is controversial., Methods: A systematic Medline literature search was carried out. Diagnostic studies reporting quantitative preoperative pancreatic biopsy data were evaluated., Results: The analysis included 53 studies, mostly of a retrospective nature. Despite acceptable rates for sensitivity and specificity, the negative predictive value of percutaneous and endoscopic ultrasonography-guided biopsies was 60-70 per cent. Biopsy results were considered to be essential for directing non-surgical therapy in advanced disease. However, they were of limited value in planning the treatment of resectable solid or cystic tumours, or focal lesions in the setting of chronic pancreatitis., Conclusions: Biopsy of suspected pancreatic malignancies with systemic spread or local irresectability is indicated for planning palliative or neoadjuvant therapy. Preoperative biopsy of potentially resectable pancreatic tumours is not generally advisable, as malignancy cannot be ruled out with adequate reliability., (Copyright (c) 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Cross-sectional imaging based on navigation and virtual reality planning tools are well-established in the surgical routine in orthopedic surgery and neurosurgery. In various procedures, they have achieved a significant clinical relevance and efficacy and have enhanced the discipline's resection capabilities. In abdominal surgery, however, these tools have gained little attraction so far. Even with the advantage of fast and high resolution cross-sectional liver and pancreas imaging, it remains unclear whether 3D planning and interactive planning tools might increase precision and safety of liver and pancreas surgery. The inability to simply transfer the methodology from orthopedic or neurosurgery is mainly a result of intraoperative organ movements and shifting and corresponding technical difficulties in the on-line applicability of presurgical cross sectional imaging data. For the interactive planning of liver surgery, three systems partly exist in daily routine: HepaVision2 (MeVis GmbH, Bremen), LiverLive (Navidez Ltd, Slovenia) and OrgaNicer (German Cancer Research Center, Heidelberg). All these systems have realized a half- or full-automatic liver-segmentation procedure to visualize liver segments, vessel trees, resected volumes or critical residual organ volumes, either for preoperative planning or intraoperative visualization. Acquisition of data is mainly based on computed tomography. Three-dimensional navigation for intraoperative surgical guidance with ultrasound is part of the clinical testing. There are only few reports about the transfer of the visualization of the pancreas, probably caused by the difficulties with the segmentation routine due to inflammation or organ-exceeding tumor growth. With this paper, we like to evaluate and demonstrate the present status of software planning tools and pathways for future pre- and intraoperative resection planning in liver and pancreas surgery.

Background: Ischaemia-reperfusion (IR)-associated microcirculatory changes play a major role in acute post-transplantation pancreatitis. The pathophysiological role of platelets in these events is unknown. The aim of this study was to examine platelet adhesion and function during early reperfusion after pancreatic ischaemia., Methods: Rats were subjected to warm pancreatic ischaemia by cross-clamping of the pancreatic vessels for 1 h. After 1 h of reperfusion, platelet-endothelium interaction was evaluated after platelet separation and staining by fluorescence microscopy. Amylase levels and pancreatic histology were evaluated 24 h after reperfusion. Animals treated according to an identical protocol, but without ischaemia, served as controls., Results: Mild pancreatitis had developed by 24 h after IR; serum amylase levels were significantly higher than those in control animals. The numbers of adherent platelets in capillaries and venules were significantly increased, and platelet velocity in capillaries was significantly decreased, in the IR group compared with controls. There was significantly more oedema and inflammation in pancreatic tissue after IR., Conclusion: Warm ischaemia for 1 h followed by reperfusion for 24 h caused mild pancreatitis in this experimental model. The pancreatic microcirculation was characterized by pronounced platelet-endothelium interaction in capillaries and venules. These results suggest that platelet activation may play an important role in acute post-transplantation pancreatitis., (Copyright (c) 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Aim: Runx transcription factors are important regulators of lineage specific gene expression, cell proliferation, and differentiation. Runx3 expression is lost in a high proportion of gastric cancers, suggesting a tumour suppressive role in this malignancy. This study investigates the expression and localisation of Runx3 in pancreatic tissues., Methods: Quantitative polymerase chain reaction was used to measure Runx3 mRNA. Immunohistochemistry was carried out to localise Runx3 in normal pancreatic tissues, and in primary and metastatic pancreatic ductal adenocarcinoma (PDAC). Basal and transforming growth factor beta1 (TGFbeta1) induced Runx3 expression was analysed in cultured pancreatic cancer cell lines., Results: Runx3 expression was low to absent in normal pancreatic tissues, but increased in a third of cancer tissues. Runx3 was present only in islets in normal pancreas, whereas in pancreatic cancers, Runx3 was detected in the cancer cells of seven of 24 samples analysed. In addition, it was expressed by lymphocytes in six of the 16 cases with lymphocyte infiltration. In pancreatic cancer cell lines, Runx3 mRNA was present in Colo-357 and T3M4 cells, but was low to absent in the other cell lines tested. TGFbeta1 repressed Runx3 mRNA expressed in Colo-357 cells, and had no effect on Runx3 expression in the other pancreatic cancer cell lines., Conclusion: Runx3 expression is restricted to islets in the normal pancreas. In contrast, a considerable proportion of pancreatic tumours express Runx3, and its expression is localised in the tumour cells and in the infiltrating lymphocytes. Thus, Runx3 might play a role in the pathogenesis of PDAC.

Indian hedgehog (IHH) and its receptors patched (PTC) and smoothened (SMO) belong to the hedgehog family of signaling molecules, which are essential for a variety of patterning events during mammalian tIssue development. IHH plays a role in pancreas organogenesis and differentiation, as well as in the regulation of insulin production. In the present study, the expression of IHH and its receptors was analyzed in normal human pancreatic and chronic pancreatitis (CP) tIssues using Northern blotting, immunohistochemistry and Western blotting, and was correlated with clinicopathological parameters. In addition, the effects of inhibition and stimulation of the hedgehog signaling pathway on cell growth were determined in TAKA-1 normal pancreatic ductal cells. IHH mRNA was expressed in the normal human pancreas and CP tIssues, with slightly higher expression levels in CP. Using immunohistochemistry, IHH and its receptors were localized mainly in the islet cells of the normal pancreas. In CP, IHH and its receptors were present in the cells forming tubular complexes and in the islets with a different signal pattern compared with the islets in the normal pancreas. Correlation between diabetic and non-diabetic CP patients revealed no significant difference in IHH, SMO, or PTC immunoreactivity. Inhibition of hedgehog signaling in TAKA-1 pancreatic ductal cells using cyclopamine significantly reduced their growth through cell cycle arrest, while stimulation of the IHH pathway enhanced the growth of these cells. In conclusion, IHH and its receptors are expressed in the normal human pancreas and in CP, yet with a different distribution and cellular localization. IHH signaling may be involved in the pathogenesis of CP, i.e. in the formation and proliferation of tubular complexes and in islet cell dysfunction.

Background and Aim: The aim of this study was to systematically analyse the pattern of regeneration in human acute pancreatitis by testing whether pancreatic stellate cells, their myofibroblastic offspring, and pancreatic ductules are involved in the regenerative process., Patients and Methods: Between January 1994 and November 2000, 24 necrosectomy specimens containing vital tissue were obtained for pathological examination. Formalin fixed tissue samples were routinely processed and immunostained for cytokeratins 7 and 19, smooth muscle actin, desmin, Ki-67, and CD68. Pancreatic tissue from organ donors served as normal controls., Results: Necrosectomy specimens were obtained between 11 and 41 days after the onset of symptoms. In vital areas of necrosectomy samples, spherical hypercellular spheres consisting of loose vascular connective tissue occurred, in part showing duct-like profiles which sprouted from remnant exocrine tissue almost perpendicular to the periphery of the spheres. In normal tissue, only a few stellate cells and myofibroblasts were present around ducts and ductules. In contrast, numerous stellate cells and myofibroblasts were detected in the hypercellular regenerative spheres after acute pancreatitis, both being situated within the loose tissue and forming compact periductular sheaths. Stellate cells/myofibroblasts and ductule cells exhibited increased proliferative activity., Conclusions: Pancreatic stellate cells and their activated myofibroblastic offspring may participate in regeneration after acute necrotising pancreatitis in humans. Time course studies are needed to further strengthen this regeneration concept.

Our purpose was to investigate brain-derived neurotrophic factor (BDNF) in chronic pancreatitis (CP) in comparison with the normal pancreas and to evaluate its association with pain. By immunohistochemistry, in the normal pancreas BDNF immunoreactivity was moderately present in the cytoplasm of most ductal cells and weakly present in most acinar cells, islet cells, nerve fibers (including perineurium), and ganglia cells. In contrast, in CP intense immunostaining of BDNF was present in most cells of ductular complexes and in the perineurium of enlarged nerves. Moderate immunostaining of BDNF was found in degenerating acinar cells and islet cells. In addition, moderate immunoreactivity of BDNF was also detected in most enlarged nerve fibers and intrinsic pancreatic ganglia cells in CP samples. Western blot analysis also revealed 5.6-fold higher BDNF levels in CP samples (P < 0.01) compared with normal pancreas samples. The expression level of BDNF was positively correlated with pain intensity (P < 0.01) and pain frequency (P < 0.01) of CP patients. Furthermore, there was a significant relationship (r = 0.68, P < 0.01) between the BDNF immunostaining and the global pain scores. BDNF is increased in CP. Its association with pain suggests that it functions as a peripheral and central pain modulator, as reported previously in other inflammatory disorders.

Objective: To assess phospholipase A2 isoforms during human and experimental acute necrotizing pancreatitis. Phospholipase A2 isoforms (group I, II, and IV) were examined in acute pancreatitis tissues in humans and rats to determine whether the exocrine pancreas itself is a source of these mediators., Summary Background Data: Phospholipase A2 has important regulatory functions, especially in inflammation., Methods: Using Northern blot analysis and immunohistochemistry, the expression and localization of phospholipase A2 isoforms were analyzed in pancreatic tissue obtained from 21 patients with acute necrotizing pancreatitis and in pancreatic tissues of rats with acute edematous and necrotizing pancreatitis. Rat samples were examined daily for 1 week., Results: In human acute pancreatitis, phospholipase A2-I mRNA expression was 8.9-fold decreased. By contrast, phospholipase A2-II (7.8-fold) and phospholipase A2-IV (8.1-fold) mRNA levels were increased. By in situ hybridization, phospholipase A2-IV was found to be expressed in remaining acinar and ductal cells adjacent to the necrotic areas. Immunostaining revealed moderate to intense phospholipase A2-II immunoreactivity in remaining acinar and ductal cells next to the necrosis. In rat pancreatitis, phospholipase A2-II mRNA levels in the pancreas were unchanged in the early phase (8 hours) but markedly increased after 24 hours, with a fluctuating pattern until day 7., Conclusions: Enhanced expression of phospholipase A2-II and A2-IV isoenzymes in human and experimental acute pancreatitis suggests that these enzymes play a role in modulating the inflammatory reaction in the pancreas. Because phospholipase A2-II and A2-IV mRNA was strongly present in remaining viable pancreatic acinar and ductal cells, the pancreas itself seems to be at least partly a source and a regulator of phospholipase A2-II- and A2-IV-dependent inflammatory reactions in acute pancreatitis.

Pancreatic cancer in many patients is associated with altered glucose metabolism and abnormalities in pancreatic islet hormones at serum and tissue levels. Our previous studies have indicated a tendency of islet cells to differentiate toward ductal cell lineage, but the specificity of these findings for pancreatic cancer was not investigated. In the present study, we examined the immunoreactivity of pancreatic islets to antibodies against tumor-associated antigens DU-PAN-2, TAG-72 and CA19-9 in tissues from the normal pancreas, chronic pancreatitis and pancreatic cancer. Although no immunoreactive islet cells were found in the 12 normal pancreases and 20 chronic pancreatitis patients, 25 of 37 pancreatic cancer tissues showed the expression of these antigens, primarily CA19-9 and TAG-72, where the number of immunoreactive cells varied considerably from case to case. In 4 cases over 50% and in 2 of them more than 75% of the islets showed positive staining of 60-70% of islet cells within each islet. The presence of intrainsular ductular structures expressing the same antigen as the surrounding islet cells suggested transformation of antigen expressing islet cells to ductal cells. All but four islets were within or around the cancer favoring the notion that factors produced by cancer cells are responsible for the altered islet cell differentiation.

Background: Pancreatic resections can be performed with great safety. However, the morbidity rate is reported to be 40-60 per cent with a high prevalence of pancreatic complications. The aim of this study was to analyse complications after pancreatic head resection, with particular attention to morbidity and pancreatic fistula., Methods: From November 1993 to May 1999, perioperative and postoperative data from 331 consecutive patients undergoing pancreatic head resection were recorded prospectively. Data were analysed and grouped according to the procedure performed: classic Whipple resection, pylorus-preserving pancreatoduodenectomy (PPPD) or duodenum-preserving pancreatic head resection (DPPHR)., Results: Pancreatic head resection had a mortality rate of 2.1 per cent; the difference in mortality rate between the three groups (0.9-3.0 per cent) was not significant. Total and local morbidity rates were 38.4 and 28 per cent respectively. DPPHR had a lower morbidity, both local and systemic, than pancreatoduodenectomy. The prevalence of pancreatic fistula was 2.1 per cent in 331 patients, and was not dependent on the procedure or the aetiology of the disease. Reoperations were performed in 3.9 per cent of patients, predominantly for bleeding and non-pancreatic fistula. None of the patients with pancreatic fistula required reoperation or died in the postoperative course., Conclusion: A standardized technique and a continuing effort to improve perioperative management may be responsible for low mortality and surgical morbidity rates after pancreatic head resection. Pancreatic complications occur with Whipple, PPPD and DPPHR procedures with a similar prevalence. Pancreatic fistula no longer seems to be a major problem after pancreatic head resection and rarely necessitates surgical treatment.

Background: Infectious complications in severe pancreatitis are the main factors determining clinical course and outcome. The taurocholate model for acute necrotizing pancreatitis was evaluated for frequency and time course of pancreatic and extrapancreatic bacterial infection., Methods: Sixty-five male Wistar rats were divided into 5 groups of 13 animals each. Specimens for bacteriologic examination were taken, and pancreatitis was induced by intraductal infusion of 3% taurocholate under sterile conditions. Animals were killed 8, 16, 24, or 32 hours thereafter, and bacteriologic examination was performed. A control group of animals with intraductal infusion of 0.9% saline solution were killed after 32 hours., Results: There was no significant pancreatic infection in the control group and in the 8-hour group (1 of 13 rats). Sixteen and 24 hours after induction of pancreatitis, infection and inflammation of the pancreas were found in 77% (10 of 13 rats), and after 32 hours pancreatic infection occurred in 69% (9 of 13 rats). Extrapancreatic bacterial infection after 16 hours occurred in the liver (62%), spleen (62%), and mesenteric lymph nodes (46%). Bacteria infecting the pancreas reflected the bacterial spectrum of the large bowel and terminal ileum before induction of pancreatitis (Escherichia coli [77%], Proteus [43%], Enterococcus [37%], and Staphylococcus [23%])., Conclusions: Pancreatic infection is an early and frequent finding in the taurocholate model of acute necrotizing pancreatitis. Infection occurs between 8 and 16 hours after induction of pancreatitis. The source of infecting bacteria seems to be the large bowel or the terminal ileum. We present a useful model of severe pancreatitis in which to study bacterial translocation, the further route of spread, and therapeutic approaches.

Background & Aims: Cellular infiltrates are present already in early stages of chronic pancreatitis. The mechanisms responsible for their recruitment are unknown. Hence, we determined the differential expression of chemokine genes and their cellular sources in normal and affected pancreatic tissues., Methods: Pancreatic tissues from 23 patients with chronic pancreatitis and from 4 normal controls were subjected to in situ hybridization for detecting messenger RNA (mRNA) of the chemokine genes interleukin 8, ENA-78, MIG, MCP-1, and I-309., Results: Normal pancreatic tissues lack cells expressing mRNA for IL-8, ENA-78, MIG, and MCP-1. In contrast, pancreatic lobuli with mild to moderate signs of tissue alterations strongly expressed MCP-1 mRNA in centroacinar ducts, endothelia, fibroblasts, macrophages, T cells, and occasionally in nerves. Interleukin 8 and ENA-78 mRNA is preferentially detected in centroacinar ducts of pancreatic lobuli with more advanced alterations. Variable numbers of pancreas-infiltrating T cells express MIG mRNA. I-309 mRNA, however, is consistently observed in normal acini and in tissue with mild to moderate signs of tissue alterations., Conclusions: The observed differential expression of distinct chemokine genes in pancreatic parenchyma and infiltrates from patients with chronic pancreatitis strongly suggests an involvement of distinct chemokines in the initiation and perpetuation of disease.

By autoradiography, neurotensin (NT) binding is specifically detectable in pancreatic cancer, but not in the normal pancreas, chronic pancreatitis (CP), or other pancreatic disorders. In the present study, we investigated whether this is due to NT receptor-1 (NTR-1) mRNA up-regulation and whether NTR-1 mRNA could also be used as a specific diagnostic marker and treatment target in pancreatic cancer. Fifteen normal pancreas tissue samples, 20 CP samples, and 30 pancreatic cancer samples were studied. Expression and localization of NTR-1 mRNA was investigated by Northern blot analysis and in situ hybridization. Furthermore, consecutive tissue sections were analyzed for NTR-1 mRNA expression and NT binding. By Northern blot analysis, NTR-1 mRNA expression was 4.4-fold (P < 0.01) and 3.0-fold (P < 0.01) higher in pancreatic cancer and CP tissue samples, respectively, compared with normal controls. There was no difference in NTR-1 mRNA levels between CP and cancer samples (P > 0.05). In pancreatic cancer, the NTR-1 mRNA levels were higher in advanced tumor stage (stages III and IV) than early tumor stage (stages I and II; P < 0.05), but no difference was found between well/moderately differentiated (grades 1 and 2) and poorly differentiated/undifferentiated cancers (grades 3 and 4; P > 0.05). By in situ hybridization, NTR-1 mRNA signals were weakly present in the cytoplasm of acinar and ductal cells of the normal pancreas. Moderate to intense NTR-1 mRNA signals were present in the cytoplasm of acinar cells dedifferentiating into tubular complexes and degenerating acinar cells of CP samples. In the cancer samples, NTR-1 mRNA was moderately to intensely expressed in the cytoplasm of cancer cells. When on consecutive tissue sections NTR-1 mRNA expression was compared with the presence of NTR-1, measured by receptor autoradiography, a correlation was found in carcinomas but not in CP samples, in which no receptors were detectable by autoradiography. The enhanced expression of NTR-1 mRNA in pancreatic cancer cells further suggests that neuroendocrine hormones might modulate pancreas cancer cell behavior. However, its relatively high levels in CP excludes NTR-1 mRNA as a specific parameter for pancreatic cancer and for the differentiation of pancreatic cancer from CP.

Persistent, uncontrolled pain is the most common indication for surgery in chronic pancreatitis. In the presence of an inflammatory mass in the pancreatic head or in pancreatic head-related complications of chronic pancreatitis, resection procedures are inevitable. The Whipple procedure, originally introduced for malignant lesions of the periampullary region, is commonly employed, although it represents surgical over-treatment in a benign pancreatic disorder. In this article, we discuss our long experience with duodenum-preserving pancreatic head resection (Beger procedure) for chronic pancreatitis. Prospective, randomized controlled trials suggest that this organ- and function-preserving procedure should be the gold standard for the surgical treatment of pancreatic head-related complications of chronic pancreatitis.

Background/aim: Genomic imprinting is a chromosomal modification causing differential expression of maternal and paternal alleles. Loss of imprinting (LOI) of IGF-II and H19 has been suggested to be an early oncogenic event in cancerogenesis. Aim of the present study was to describe the status of IGF-II and H19 imprinting in adult human pancreatic tissues., Methods: Allele-specific gene expression was studied using RNA and DNA from human pancreatic cancer, chronic pancreatitis, and normal pancreas tissues heterozygous for ApaI (IGF-II) or RsaI (H19) restriction fragment length polymorphism. Reverse-transcriptase polymerase chain reaction products were digested with either ApaI or RsaI and analyzed on agarose gels to study the status of allelic expression. The expression level of H19 and IGF-II was studied on Northern blots or by polymerase chain reaction., Results: H19 was imprinted in normal pancreas and in chronic pancreatitis. H19 LOI was observed in 1 of 4 informative cancer tissues and was not associated with increased H19 transcript levels. Biallelic expression of IGF-II was found in 6 of 10 informative cancer tissues and in 6 of 9 informative normal tissues. In chronic pancreatitis, the IGF-II gene was imprinted in all informative samples. IGF-II mRNA was not overexpressed in the tissues showing LOI., Conclusion: Low frequencies of H19 LOI and the lack of correlation between biallelic expression and overexpression observed for both H19 and IGF-II suggest that LOI of H19 and IGF-II is not a relevant oncogenic factor during human exocrine pancreatic cancerogenesis.

Experimental chronic pancreatitis is associated with microcirculatory disturbances but can also be induced or aggravated by perfusion changes. Microcirculatory alterations in human chronic pancreatitis are poorly defined. In this clinical study we investigated pancreatic microcirculation in the normal human pancreas and in chronic pancreatitis by laser Doppler flowmetry. Laparotomy was performed on 13 patients with nonpancreatic disease and on nine patients with chronic alcoholic pancreatitis for pancreatic head resection. Blood flow was measured over the pancreatic head, the uncinate process, over the mesenteric vein, the pancreatic corpus, and over the pancreatic tail by laser Doppler flowmetry. Blood flow was highest in the head of a normal pancreas with a mean of 436 +/- 34 perfusion units (PU), 399 +/- 43 PU in the uncinate process, 286 +/- 30 PU in the pancreatic corpus, and 351 +/- 46 PU in the tail of the pancreas. In the normal pancreas, lowest blood flow was measured over the mesenteric vein (228 +/- 23 PU). In chronic pancreatitis, blood flow in the pancreas was significantly decreased across the whole pancreas (p < 0.01). Furthermore flow-wave pattern was altered in chronic pancreatitis as compared with the normal pancreas. The normal human pancreas has a spatial variation in blood flow, correlating with the pancreatic arterial blood supply. In the chronically inflamed human pancreas, blood flow is significantly diminished, with a lower flow toward the pancreatic head.

Macrophage Proinflammatory Human Chemokine-3alpha (Mip-3alpha/LARC/Exodus) belongs to a large family of chemotactic cytokines, which participate in directing inflammatory cell migration and in modulating angiogenesis. Mip-3alpha signals through a recently identified G-protein linked 7-transmembrane receptor, CCR6. In this study, we have characterized the expression of Mip-3alpha and CCR6 in 12 normal and 16 cancerous human pancreatic tissues and in 4 cultured pancreatic cancer cell lines, and assessed the effects of Mip-3alpha on growth and invasion of these cell lines. Pancreatic cancer tissues markedly overexpressed Mip-3alpha in comparison with normal pancreatic samples. By in situ hybridization Mip-3alpha and CCR6 mRNA moieties were present in cancer cells within the tumors. In addition, Mip-3alpha was abundant in the macrophages infiltrating the tumor mass. Mip-3alpha and its receptor CCR6 were expressed in all 4 tested pancreatic cancer cell lines. Mip-3alpha stimulated the growth of one cell line, enhanced the migration of another cell line, and was without effect in the other 2 cell lines. Together, our findings suggest that Mip-3alpha has the potential to act via autocrine and paracrine mechanisms to contribute to the pathobiology of human pancreatic cancer.

Bak is a pro-apoptotic member of the Bcl-2 family whose genes are involved in regulation of programmed cell death. Using in situ hybridization, immunohistochemistry, and Northern blot analysis, we studied the expression of Bak in specimens from 12 normal pancreata and 26 primary pancreatic cancers, and correlated the findings with the clinical and histopathologic data of the patients. By comparison with normal pancreas, Northern blot analysis demonstrated a 2.5-fold increase of Bak messenger RNA expression in the tumor samples (P <0. 001). Elevated levels were found in 15 of the 26 pancreatic cancer tissue specimens. In these samples Bak expression was increased 4.3 fold (P <0.001). No association was detected between Bak expression and tumor stage. In situ hybridization and immunohistochemistry revealed that the tumor cells themselves and the stroma cells expressed only low levels of Bak. In contrast, in regions adjacent to the tumor, which showed chronic inflammation, there was always high expression in the acinar and inflammatory cells, explaining the increased Bak levels found in the tumor samples by means of Northern blot analysis. In the normal pancreas the expression of Bak was generally moderate in the acinar cells and low in the ductal and islet cells. In situ analysis using the terminal deoxynucleotidyl transferase method further showed that there was extensive cell death in the peritumorous areas with chronic inflammation. Taken together, these results suggest that in pancreatic cancer Bak expression and programmed cell death are present in cells that are localized in regions of chronic inflammation surrounding the pancreatic cancer cells but not in the tumor cells themselves, a situation that may facilitate tumor growth and spread.

Postoperative complications following major pancreatic surgery are mainly due to the difficulties of performing a safe and proper anastomosis between the stomach or small bowel and the pancreas. Continuous pancreatic juice secretion and the often soft structure of the pancreatic parenchyma are major risk factors. The present paper summarizes the results of six previously published, placebo-controlled, double-blind trials and one open randomized trial analyzing the efficacy of octreotide in preventing postoperative complications in patients who undergo major pancreatic surgery. Patients were given either octreotide (3x100-150 microg subcutaneously/day) or a placebo perioperatively for 5-7 days starting at least 1 h before operation. The patients were monitored postoperatively for typical postoperative complications such as: leakage of the anastomosis, pancreatic fistula, abscess, fluid collection, shock, sepsis, pulmonary insufficiency, renal insufficiency, bleeding, postoperative pancreatitis, and death. Six of the seven studies showed significantly fewer postoperative complications in the octreotide group in comparison with the placebo group (p<0.05). The effectiveness of octreotide was most apparent in the prevention of secretion-related complications such as fistula, fluid collection and leakage of the anastomosis. These studies demonstrated that inhibition of perioperative pancreatic secretion is a viable treatment concept in patients undergoing major pancreatic surgery. The perioperative and prophylactic application of octreotide in patients who undergo major pancreatic resection reduces the postoperative complication rate significantly.

Objective: Chronic pancreatitis is a painful chronic inflammatory disease of the exocrine pancreas that is associated with the replacement of functional parenchyma by extended fibrosis and with a massive infiltration of T lymphocytes. However, to date further characterization of infiltrating T cells in chronic pancreatitis has not been undertaken., Methods: Using the novel method of multiepitope imaging with fluorochrome-tagged specific monoclonal antibodies, which allows the simultaneous localization and characterization of T cells in tissues, we analyzed the distribution and phenotypes of T cells infiltrating the pancreas in chronic pancreatitis., Results: The mean CD4:CD8 ratio in 10 cases of chronic pancreatitis was 2.4:1. In order of decreasing frequency, the following markers were observed: CD45RO, CD18, TCRgammadelta, and CD103. The lymphocytes, especially of the CD4+ subset, were found mainly in the fibrous stroma, but T cells were also observed periductally. A T-cell subset bearing the phenotype CD8+CD103+, analogous to intestinal intraepithelial lymphocytes, was found intracalating between the cells of the ductal epithelium., Conclusions: Phenotyping of the T lymphocytes in chronic pancreatitis supports the concept of the involvement of cell-mediated cytotoxicity in the pathogenesis of this disease. In addition, intraepithelial lymphocytes were found interspersed between the ductal epithelial cells, pointing to a role of this T-cell subset as a first-line defense against deleterious epithelial events in chronic pancreatitis.

Background & Aims: Feedback regulation of pancreatic enzyme secretion is well established in animals, and their pancreases are able to adapt to intraduodenal inhibition of pancreatic enzymes by proteinase inhibitors such as Camostate (FOY-305; Schwarz GmbH, Monheim, Germany). In this study, we addressed whether similar adaptive changes occur in the human pancreas after 4 weeks of 2 g/day Camostate application., Methods: Before, at the end of, and 2 weeks after 4-week Camostate treatment (four times 500 mg daily), pancreatic changes were analyzed with the use of a secretin-cerulein test, a test-meal stimulation, cholecystokinin plasma measurement, and standardized ultrasonographic investigations of the pancreas., Results: Duodenal trypsin output after secretion stimulation was significantly increased (+44%; P < 0.01) and duodenal bicarbonate output decreased 22% (P < 0.05) after 4 weeks of Camostate application. The size of the pancreatic head (vertical) increased 8% (P < 0.05) at week 4 and decreased to pretreatment values 2 weeks after treatment (week 6). The other three diameters measured (head oblique, body, and tail) showed a similar pattern. Stimulated cholecystokinin plasma levels 15 minutes after application of a standard test meal increased 62% (P < 0.05)., Conclusions: The human pancreas adapts to oral application of the proteinase inhibitor Camostate. These findings support the theory that feedback control of the exocrine pancreas operates in humans.

Conclusions: Adaptive changes in exocrine and endocrine pancreatic function, as well as changes in pancreas size and morphology, were not observed after 4-wk of oral pancreatic enzyme application. These findings suggest that the normal pancreas does not significantly adapt--either morphologically or functionally--to a 4-wk oral application of high-dose pancreatic enzymes., Background: The control of exocrine pancreatic enzyme secretion is not completely understood. Although it has been established that exocrine pancreatic secretion is mainly regulated in the short-term by the amount of pancreatic enzymes in the proximal small intestine, it is not known whether long-term application of pancreatic enzymes causes changes in exocrine pancreatic secretion in humans., Methods: Twelve healthy male volunteers (median age 27 yr) participated in a prospective, randomized, placebo-controlled, double-blind study. Six were placed in the treatment group and six in the placebo group. Over a 4-wk period, the six subjects in the treatment group took 18 capsules of Panzytrat (20,000 units of lipase, 18,000 units of amylase, and 1000 units of protease per capsule) daily. Before (wk 0), 4 wk following pancreatic enzyme application and 2 wk afterward, a secretin-cerulein test was carried out in all subjects to study exocrine pancreatic function (trypsin, chymotrypsin, bicarbonate content, and total pancreatic fluid secretion in the duodenum). One day following the secretin-cerulein test, a standard test meal was given to all subjects to analyze endocrine pancreatic function. Additionally, before starting the treatment, once per week during treatment and 2 wk afterward, an ultrasound examination of the pancreas was carried out to see whether there was any change in pancreas size and morphology., Results: Trypsin content in the duodenal aspirates following simultaneous stimulation with secretin and cerulein after 4 wk of high-dose pancreatic enzyme application was 92% in the treatment group and 82% in the placebo group compared with the wk 0 test results (100%). Two weeks after enzyme application, the secretin/cerulein-stimulated trypsin content was 88% in the treatment group and 107% in the placebo group. None of these changes was statistically significant. The same results were seen for chymotrypsin content, amylase, and bicarbonate content as well as for total pancreatic fluid secretion. Additionally, no change in the endocrine pancreatic function could be observed after 4 wk of pancreatic enzyme treatment. Pancreas ultrasonography revealed no alteration in pancreas size or parenchymal structure during the 4 wk of treatment and the following 2 wk.

Platelet-derived growth factors (PDGF) are mitogenic polypeptides that are involved in cellular proliferation and tissue repair. The expression of PDGFs and type beta PDGF receptor was examined in the normal human pancreas and in chronic pancreatitis, a fibrotic disease associated with fibroblastic proliferation, atrophy, and acinar cell dedifferentiation. In the normal human pancreas, PDGF A chain mRNA levels were relatively abundant, whereas PDGF B chain mRNA levels were not detected, and type beta PDGF receptor mRNA transcripts were present at low levels. In the normal pancreas, PDGF immunoreactivity was present in islet cells, whereas type beta PDGF receptor immunoreactivity was present in acinar cells. In chronic pancreatitis, PDGF A chain mRNA transcripts were also abundant, and 11 of 19 samples exhibited the PDGF B chain mRNA transcript. In addition, there was a significant increase in the mRNA levels of type beta PDGF receptor in the pancreatitis samples by comparison with the normal pancreas (P < 0.001). In chronic pancreatitis tissues, PDGF and type beta PDGF receptor immunoreactivity were present in acinar, ductal, islet, and endothelial cells, fibroblasts, and leukocytes. The concomitant overexpression of PDGFs and of the type beta PDGF receptor points to the existence of autocrine and paracrine PDGF-dependent loops in human chronic pancreatitis.

Objective: To determine if phospholipase A2 (PLA2) type II and type IV mRNA expression and protein are altered in chronic pancreatitis., Summary Background Data: PLA2s have an important regulatory function in several signaling pathways, especially in inflammation. In this study, we examined the expression of three PLA2 isoforms (type I, type II, and type IV) in chronic pancreatitis., Methods: The distribution of PLA2 was studied in 15 pancreas samples obtained from patients with chronic pancreatitis using immunohistochemical, Northern blot, and in situ hybridization techniques. Normal pancreas obtained from healthy organ donors served as control., Results: Northern blot analysis revealed enhanced mRNA levels of PLA2 type II (5.7-fold) and type IV (5.1-fold) in chronic pancreatitis (p < 0.01) versus normal pancreas. In normal pancreas, intense PLA2 type I immunostaining was present in acinar cells, whereas PLA2 type II immunostaining was visible only in some acinar cells. In chronic pancreatitis, PLA2 type II immunostaining was present more frequently and with higher intensity in acinar cells. Furthermore, PLA2 type II immunoreactivity was more abundant in metaplastic ductal cells in the chronic pancreatitis samples. By in situ hybridization, areas with ductal metaplasia in chronic pancreatitis exhibited intense PLA2 type IV mRNA signals. All chronic pancreatitis tissues with concomitantly increased mRNA expression for PLA2 type II and type IV exhibited a higher degree of degeneration, ductal metaplasia, and fibrosis., Conclusions: Upregulation of PLA2 types II and IV in areas with more histologic damage suggests that these PLA2 isoforms might contribute to the morphologic changes that occur in chronic pancreatitis.

Transforming growth factor-beta (TGF-beta) signal transduction is mediated via specific cell surface signaling TGF-beta receptors, most notably the type I ALK5 (TbetaR-I[ALK5]) and the type II (TbetaR-II). We evaluated TbetaR-I(ALK5) and TbetaR-II expression in 41 human pancreatic cancer tissue samples and correlated these findings with clinical data of the patients. Northern blot analysis indicated that, in comparison with the normal pancreas, pancreatic adenocarcinomas exhibited 8.0-fold and 4.5-fold increases (P < 0.01), respectively, in mRNA levels encoding TbetaR-I(ALK5) and TbetaR-II. In situ hybridization showed that both TbetaR-I(ALK5) and TbetaR-II mRNA were highly expressed in the majority of pancreatic cancer cells. Immunohistochemical analysis of TbetaR-I(ALK5) and TbetaR-II revealed positive immunostaining in 73% and 56% of the tumors, respectively. Both receptors were concomitantly present in 54% of the pancreatic cancer samples. The presence of TbetaR-I(ALK5) or TbetaR-II and the concomitant presence of TbetaR-I(ALK5) and TbetaR-II in the cancer cells was associated with advanced tumor stage (P < 0.01). These findings show that in many human pancreatic cancers, increased levels of the two signaling TbetaRs are present. The presence of the signaling TbetaRs in advanced tumor stages indicates a role in disease progression.

Background: Human pancreatic cancers exhibit a high frequency of K-ras mutations., Methods: In this study we used oligonucleotide specific hybridization to compare the frequency of K-ras mutations in genomic DNA samples prepared from 21 normal pancreatic tissues, 26 chronic pancreatitis tissues, and 24 pancreatic cancers., Results: None of the DNA samples from normal or chronic pancreatitis tissues exhibited a K-ras mutation at codons 12 or 13 of K-ras. In contrast, 17 of 24 DNA pancreatic cancers harbored a K-ras mutation. Validity of the methodology was confirmed by genotyping 7 human pancreatic cancer cell lines. Analysis of focal areas of proliferation from 5 chronic pancreatitis and 5 pancreatic cancer samples processed by selective ultraviolet radiation fractionation (SURF), a procedure used to enrich DNA isolation from foci of proliferating cells, revealed complete concordance with total genomic DNA analysis., Conclusions: These findings indicate that the pancreatic parenchyma in patients with chronic pancreatitis most frequently does not possess a K-ras mutation.

Vascular endothelial growth factor (VEGF) is an angiogenic polypeptide that has been implicated in cancer growth. In the present study, we characterized VEGF expression in cultured human pancreatic cancer cell lines and determined whether the presence VEGF in human pancreatic cancers is associated with enhanced neovascularization or altered clinicopathological characteristics. VEGF mRNA transcripts were present in all six tested cell lines (ASPC-1, CAPAN-1, MIA-PaCa-2, PANC-1, COLO-357, and T3M4). Immunoblotting with a highly specific anti-VEGF antibody revealed the presence of VEGF protein in all of the cell lines. Northern blot analysis of total RNA revealed a 5.2-fold increase in VEGF mRNA transcript in the cancer samples in comparison with the normal pancreas. Immunohistochemical and in situ hybridization analysis confirmed the expression of VEGF in the cancer cells within the tumor mass. Immunohistochemical analysis of 75 pancreatic cancer tissues revealed the presence of strong VEGF immunoreactivity in the cancer cells in 64% of the cancer tissues. The presence of VEGF in these cells was associated with increased blood vessel number, larger tumor size, and enhanced local spread but not with decreased patient survival. These findings indicate that VEGF is commonly overexpressed in human pancreatic cancers and that this factor may contribute to the angiogenic process and tumor growth in this disorder.

Urokinase plasminogen activator (uPA) is a serine proteinase that has been suggested to play an important role in cancer invasion and metastasis. It binds to a specific membrane receptor denominated uPA receptor (uPAR). uPA activates plasminogen to form plasmin, which participates in tissue degradation and proteolysis. Binding of uPA to its receptor accelerates UPA's own activation from pro-uPA, enhancing the activity of the uPA/uPAR cascade. Using immunohistochemistry and Northern blot analysis, we analysed the role of uPA and uPAR in 30 human pancreatic cancers. Immunohistochemical analysis demonstrated moderate to strong immunostaining of both factors in most pancreatic cancers. Cancer lesions with signs of invasion exhibited the strongest immunohistochemical signals for both factors. In addition, in desmoplastic areas adjacent to the cancer cells, moderate uPA and uPAR immunoreactivity was detectable. Northern blot analysis revealed a sixfold and a fourfold increase in uPA and uPAR mRNA levels in pancreatic cancer, respectively, in comparison with normal controls (P<0.01). Correlation of the Northern blot data with the clinical parameters of the patients indicated that patients with concomitant overexpression of uPA and uPAR had a shorter post-operative survival (median 9 months; mean+/-s.d. 10.2+/-3.6 months) than patients in whom only one or none of these factors were overexpressed (median 18 months; mean+/-s.d. 20.3+/-8.7 months) (P<0.002). Our data suggest that uPA and uPAR may serve as prognostic markers in human pancreatic cancer and that the marked overexpression of both factors may create an environment that enables pancreatic cancer cells to invade surrounding tissues.

Intrasplenic pseudocyst is a rare form of a late complication of chronic pancreatitis. We report the case of a 30-year-old man with an intrasplenic pseudocyst associated with chronic alcoholic pancreatitis. The patient was admitted with the third acute phase of chronic relapsing pancreatitis. Abdominal US and CT showed a large cyst in the pancreatic tail with involvement of the spleen. ERCP revealed marked irregularities of the main pancreatic duct without communication to the large cyst and a narrowing of the distal common bile duct by chronic pancreatitis of the head of the pancreas. Organ preserving surgical treatment with duodenum- preserving resection of the head of the pancreas combined with distal pancreatectomy and splenectomy was performed. This procedure may be indicated in selected patients to preserve functional pancreatic tissue and prevent diabetes. It should be in the armamentarium of the specialized pancreatic surgeon.

The risk of developing postoperative complications following pancreatic resection depends mainly on how difficult it is to perform a proper pancreaticointestinal anastomosis. We have evaluated the serum pancreolauryl test, a rapid tubeless pancreatic function test, as a simple preoperative predictor of the degree of pancreatic fibrosis. Degree of fibrosis in turn provides an indirect parameter for the difficulties of performing a proper and safe pancreaticointestinal anastomosis. In 35 patients (21 chronic pancreatitis, 14 pancreatic tumors) undergoing major pancreatic resection, we found a negative correlation (r = -0.75, p < 0.001) between the degree of fibrosis at the resection margin and the serum pancreolauryl test results. Patients with chronic pancreatitis had a significantly higher degree of fibrosis at the resection margin (59 +/- 22 vs. 34 +/- 25%; X +/- SD; p < 0.01) and lower fluorescein serum concentrations (2.6 +/- 1.9 vs. 4.3 +/- 2.1 micrograms/ml; X +/- SD; p < 0.01) in comparison with patients with pancreatic tumors. These findings indicate that the degree of pancreatic fibrosis, the difficulties of performing a proper pancreaticointestinal anastomosis, and subsequently the potential risk of postoperative complications can easily be predicted preoperatively.

Major pancreatic resection is still accompanied by considerable morbidity (35%) and mortality (10%). Typical complications, such as pancreatic fistula and abscess, are chiefly associated with exocrine pancreatic secretion. The hormone somatostatin and its analogue octreotide are well known as potent inhibitors of exocrine pancreatic secretion. In two randomised, double-blind, placebo-controlled, multicentre trials we assessed the prophylactic effect of the perioperative inhibition of exocrine pancreatic secretion by octreotide to prevent postoperative complications. Each patient received 3 X 100 micrograms/day octreotide or placebo subcutaneously. A significant reduction in fistula, abscess, fluid collection, sepsis and postoperative pancreatitis occurred with patients undergoing pancreatic resection for cancer. Results were similar in a second study, using the same protocol but recruiting only patients with chronic pancreatitis. A new randomised, controlled multicentre trial is also described, in which 300 patients with severe acute pancreatitis are being treated with or without octreotide in double-blind fashion. The results will clarify the influence of inhibition of exocrine pancreatic secretion by octreotide on the course of acute pancreatitis, and hence its potential, through inhibition of digestive enzyme secretion, as a treatment for acute pancreatitis.

Objective: To investigate the effect of long-acting octreotide (SMS 201-995) on the plasma growth hormone level in preweaning rats and to study the growth and composition of the exocrine pancreas in these rats after stimulation by caerulein- and camostate-induced endogenous cholecystokinin (CCK)., Methods: Wistar rats of both sexes were treated as littermate pairs in two periods of postnatal age, from days 1 to 11 and from days 11 to 21. To stimulate pancreatic growth, caerulein (3 micrograms/kg subcutaneously three times daily) was given from days 1 to 11, and oral camostate (200 mg/kg given once daily) or CCK-8 (10 micrograms/kg subcutaneously three times daily) was administered from days 11 to 21. Octreotide (6 or 15 micrograms/kg subcutaneously twice daily) was administered alone or in combination with caerulein or camostate. The rats were exsanguinated on days 11 or 21, and each pancreas was removed, weighed and analysed., Results: Caerulein stimulated pancreatic growth and raised the trypsin concentration; camostate induced pancreatic hypertrophy and hyperplasia. By day 11, octreotide had decreased the plasma growth hormone level and the basal pancreatic trypsin concentration and content. Given in combination with caerulein, octreotide reduced the growth hormone level and the stimulated trypsin and DNA contents. By day 21, rats treated with octreotide in the camostate group showed a reduced basal pancreatic trypsin concentration and a decreased basal trypsin content (although the changes were not significant). Plasma growth hormone levels were not significantly reduced., Conclusion: The antitrophic pancreatic action of octreotide and its plasma growth hormone-lowering effect were shown in rats during the first 10 days after birth. These effects were less notable from days 11 to 21, a period when CCK receptors increase in number and components of the stimulus-secretion mechanism are mature.

A number of patients with chronic pancreatitis develop an inflammatory enlargement of the head of the pancreas leading to complications such as common bile duct, duodenal, pancreatic duct, and/or vascular obstruction. The duodenum preserving pancreatic head resection has been developed to treat these lesions and to avoid a Whipple procedure in chronic pancreatitis. Between 1972 and 1992 280 patients (231 male, 49 female, mean age 44, range 22-76 years) underwent a duodenum preserving pancreatic head resection for chronic pancreatitis. The indication to operate was a cholestases syndrome in 50% of the patients, a duodenal compression in 36% and an obstruction of the portal vein in 16% of the patients. 94% suffered from pain, 53% had recurrent severe pain attacks and 72% had daily pain. Hospital mortality was 1.1% (3/280). Pancreatic fistula, leakage of pancreatic anastomosis and postoperative bleeding occurred in 4.6%, 1.8% and 3.2% of the patients, respectively. A relaparotomy needed 16 patients (5.7%). With respect to glucose tolerance in the early postoperative period 88% of the patients, showed no change in comparison with the preoperative glucose tolerance analysis. In a long-term follow-up (mean follow-up time was 3.7 years (3 months to 18 years)) 219 patients were included. The late mortality within the follow-up period was 5.0% (11/219). 90% of the patients had no or rare pain in the long-term follow-up. 63% of the patients were full rehabilitated professionally. The duodenum preserving pancreatic head resection represents a new standard procedure which solves most surgical problems in chronic pancreatitis. It does not lead to diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

The c-met proto-oncogene encodes a transmembrane tyrosine kinase receptor (MET) that has the capacity to modulate cell proliferation and differentiation; it is activated by the hepatocyte growth factor. Using a highly specific anti-MET antibody we found mild MET immunoreactivity in acinar, ductal, and islet cells in the normal human pancreas and intense MET immunoreactivity in many of the duct-like cancer cells in 14 of 16 human pancreatic adenocarcinomas. Intense MET immunoreactivity was also evident in the ductal cells in regions adjacent to the cancer cells. Northern blot analysis of total RNA revealed that, by comparison with the normal pancreas, pancreatic cancers exhibited a 7-fold (P < 0.01) increase in c-met mRNA levels. Hepatocyte growth factor mRNA levels were increased 10-fold (P < 0.05) in the same cancers. The concomitant over-expression of c-met and hepatocyte growth factor in human pancreatic cancers suggests that there is excessive activation of c-met-dependent signaling pathways that may contribute to pancreatic cancer cell growth in vivo.

The aim of this study was to determine the concentrations of ciprofloxacin in human pancreatic tissue and juice. Concentrations were measured by high-pressure liquid chromatography (HPLC). Two hundred mg of ciprofloxacin were administered as a short i.v. infusion (30 min). The median ciprofloxacin concentrations 140 min (median) after the start of infusion in pancreatic tissue as well as in pancreatic juice were 0.9 mg/kg (mg/l). The penetration ratio was 1.0 for pancreatic tissue and 0.83 for pancreatic juice. With regard to the minimal inhibitory concentrations (MIC) for the respective bacteria, ciprofloxacin seems to be an appropriate drug for the treatment of septic complications in necrotizing pancreatitis. Future clinical trials are necessary to prove this assumption.