Publications (31)125.14 Total impact
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Article: T-Tube or no T-tube in the reconstruction of the biliary tract during orthotopic liver transplantation: systematic review and meta-analysis.
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ABSTRACT: The routine use of a T-tube in reconstruction of the biliary tree during orthotopic liver transplantation (OLT) is controversial. A systematic review of the literature on the use of a T-tube in reconstruction of the biliary tree was performed. Retrospective studies were only reviewed, whereas prospective randomized studies were included in the meta-analysis. An analysis of 196 studies revealed that 91 studies investigated the use of a T-tube in OLT. Fifteen retrospective studies compared different groups and were thus considered relevant; 6 prospective studies were identified, of which 5 were randomized controlled trials with a total of 639 patients. The results of the randomized controlled trials were meta-analyzed. The odds ratio (OR) for biliary complications was 1.15 [95% confidence interval (CI) = 0.28-4.72], and this revealed that there were no differences in the rate of overall biliary complications whether or not a T-tube was used (Z = 0.19, P = 0.85). A detailed analysis of the biliary complications revealed that biliary leaks developed in 24 patients in the T-tube group versus 22 patients in the no-T-tube group (OR = 1.17, 95% CI = 0.4-3.47, Z = 0.29, P = 0.77). Biliary strictures were significantly more common in the group of patients who underwent reconstruction without a T-tube (14 versus 31 events; OR = 0.46, 95% CI = 0.23-0.9, Z = 2.26, P = 0.02). In conclusion, although reconstruction of the biliary tree with a T-tube prevents the occurrence of biliary strictures and may have the potential to reduce long-term morbidity with respect to late strictures, there is no clear evidence in favor of using a T-tube during OLT.Liver Transplantation 06/2010; 16(6):705-17. · 3.39 Impact Factor -
Article: Nerve growth factor and artemin are paracrine mediators of pancreatic neuropathy in pancreatic adenocarcinoma.
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ABSTRACT: To further characterize the neurotrophic attributes of pancreatic cancer (PCa). PCa is characterized by neuropathic alterations which are resulting in pancreatic pain. To further characterize pancreatic neuropathy, we aimed: to analyze whether neuropathic alterations in PCa are only limited to the tumor-core or whether they are similarly encountered in neural structures in the noncancerous pancreas, to demonstrate whether PCa features neurotrophic attributes and finally to identify responsible neurotrophic molecules. Nerve density and area were quantified in normal pancreas (NP, n=45), histologically "normal" pancreas next to pancreatic cancer (NNPCa, n=61) and PCa (n=97). Growth-associated protein-43, nerve growth factor (NGF), and Artemin expressions were assessed by Immunohistochemistry, Western-Blot, and quantitative real time polymerase chain reaction-analyses. Isolated myenteric plexus of newborn rats were exposed to NP, NNPCa, and PCa tissue extracts and supernatants of Panc1 and T3M4 cancer cells with or without Artemin and NGF depletion, followed by neurite density analysis. Dense neural networks and enlarged nerves were not only detected in PCa but were also present in NNPCa. Growth-associated protein-43, NGF, and Artemin expressions were absent/weak in NP, but increased in both NNPCa and PCa and were closely associated with intrapancreatic neuropathy. PCa and NNPCa tissue extracts and Panc1/T3M4 supernatants noticeably increased neurite density in myenteric plexus-cultures, which were attenuated by depletion of NGF and Artemin. The neurotrophic effects of PCa extend into the peritumoral "normal" pancreatic areas without neuro-cancer interactions. The neurotrophic characteristics of PCa can be mimicked by in vitro analyses and reveal NGF and Artemin as potential key players in the generation of pancreatic neuropathy in PCa.Annals of surgery 05/2010; 251(5):923-31. · 7.90 Impact Factor -
Article: Pancreatic neuropathy results in "neural remodeling" and altered pancreatic innervation in chronic pancreatitis and pancreatic cancer.
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ABSTRACT: Chronic pancreatitis (CP) and pancreatic cancer (PCa) are characterized by intrapancreatic neuropathic alterations, including increased neural density and hypertrophy, pancreatic neuritis and neural invasion (NI) by cancer cells in PCa. The aim of this study was to identify the influence of these neuropathic changes on the quality of pancreatic innervation, intrapancreatic glia, and visceral pain. Pancreatic nerve fiber qualities were characterized by immunohistochemical visualization of various markers, including those for sympathetic (tyrosine hydroxylase, TH) and cholinergic innervation (choline acetyltransferase, ChAT), as well as the glial transcription factor, Sox10, and the neuroepithelial progenitor cell marker, Nestin, in normal pancreas (NP, n=16), CP (n=20), and PCa (n=20) patients. The neural immunoreactivity scores of these markers were correlated with the severity of intrapancreatic neuropathic changes and with abdominal pain sensation of patients. Pancreatic sympathetic innervation was significantly reduced in CP and PCa, whereas parasympathetic innervation did not show major changes. Nestin neuro-immunoreactivity was stronger, and Sox10-immunoreactivity was weaker in CP and PCa than in NP. Pancreatic sympathetic and cholinergic innervation was noticeably decreased in patients with severe pancreatic neuritis, NI by cancer cells, or abdominal pain. Moreover, the neural immunoreactivity for Sox10 and Nestin also varied with intrapancreatic neuropathic alterations and abdominal pain. The quality of intrapancreatic nerve fibers and the activation state of intrapancreatic glia in CP and PCa are strikingly different from those in normal pancreas. This novel phenomenon of "neural remodeling" shows how pancreatic neuropathic pain and "visceral neuropathy" are associated with altered pancreatic innervation in CP and PCa.The American Journal of Gastroenterology 07/2009; 104(10):2555-65. · 7.28 Impact Factor -
Article: Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis.
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ABSTRACT: The chemokine fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis (CP) is characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of fractalkine and CX3CR1 were investigated in CP (n=61) and normal pancreas (NP, n=21) by QRT-PCR, western blot and immunohistochemistry analyses. Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68. To investigate the influence of fractalkine on pancreatic fibrogenesis, human pancreatic stellate cells (hPSCs) were isolated from patients with CP, incubated with fractalkine and then Collagen-1 and alpha-smooth muscle actin (alpha-SMA) expressions were measured. CX3CR1, but not fractalkine, mRNA was overexpressed in CP. In contrast, the protein levels of both CX3CR1 and fractalkine were upregulated. Neuro-immunoreactivity for fractalkine and CX3CR1 was strongest in patients suffering from severe pain and pancreatic neuritis. Long-term suffering from CP was noticeably related to increased neural immunoreactivity of fractalkine. Furthermore, fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased fractalkine expression, whereas in vitro fractalkine had no significant impact on collagen-1 and alpha-SMA expressions in hPSCs. Therefore, pancreatic fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP.Laboratory Investigation 02/2009; 89(3):347-61. · 3.64 Impact Factor -
Article: Neural invasion in pancreatic cancer: a mutual tropism between neurons and cancer cells.
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ABSTRACT: Neural invasion by pancreatic cancer cells (PCC) worsens the prognosis and frequently limits curative resection. We established a novel in-vitro model in which T3M4-PCCs were co-cultured with either isolated myenteric plexus cells (MP) or dorsal root ganglia (DRG) of newborn rats within a three-dimensional extracellular matrix gel. The close vicinity of MP or DRG to T3M4-PCCs induced early morphologic changes on T3M4-PCCs at the migration front prior to the migration process with elongated and neurite-targeting PCCs, compared to round and non-grouping at the non-migrating front. T3M4-PCCs built cancer-cell clusters around the DRG or MP, a process which was accelerated by increasing number of T3M4-PCCs or neurons. These findings indicate that neuro-cancer interactions start prior to PCC migration and induce evident changes in cancer and nerve biology. These findings can be reproduced within the introduced 3D in-vitro migration assay which allows investigation in the early pathogenesis of neural PCC invasion.Biochemical and Biophysical Research Communications 09/2008; 374(3):442-7. · 2.48 Impact Factor -
Article: Pancreatic neuropathy and neuropathic pain--a comprehensive pathomorphological study of 546 cases.
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ABSTRACT: Chronic pancreatitis (CP) and pancreatic adenocarcinoma (PCa) are characterized by intrapancreatic neural alterations and pain. Our aims were to: (a) Investigate whether neuropathic changes like pancreatic neuritis, increased neural density, and hypertrophy are phenomena only in CP or whether they are also evident in other pancreatic disorders as well, (b) study possible variations in neural cancer cell invasion among malignant pancreatic tumors, and (c) explore whether these neuropathic changes contribute to pain sensation. Neuropathic changes were studied in PCa (n=149), in CP (n=141), in pancreatic tumors (PTm) including serous/mucinous cystadenomas, invasive/noninvasive intraductal papillary mucinous neoplasias, benign/malignant neuroendocrine tumors, ampullary cancers (n=196), and in normal pancreas (n=60). The results were correlated with GAP-43 expression, tissue inflammation, pancreatic neuritis, neural invasion, fibrosis, desmoplasia, pain, and patient survival. Increased neural density and hypertrophy were only detected in PCa and CP and were strongly associated with GAP-43 over expression and abdominal pain. The severity of pancreatic neuritis was strongest in PCa and was closely linked to changes in neural density and hypertrophy. The aggressiveness of neural cancer cell invasion was most prominent in PCa and was related to neuropathic changes, desmoplasia, and pain. Severe and enduring pain were strongly associated with poor prognosis in PCa patients. Enhanced neural density and hypertrophy are only typical features of CP and PCa among all investigated pancreatic disorders. Such neuropathic changes, including damage to nerves by inflammatory and/or cancer cells, seem to enhance and generate pancreatic neuropathic pain.Gastroenterology 09/2008; 136(1):177-186.e1. · 11.68 Impact Factor -
Article: Is there an advantage in performing a pancreas-preserving total duodenectomy in duodenal adenomatosis?
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ABSTRACT: Duodenal adenomatosis is a premalignant condition often not treatable by local resection or endoscopy. An option for treatment is a pylorus-preserving (pp)-Whipple resection. Since the introduction of pancreas-preserving total duodenectomy (PPTD), the question has arisen whether a pp-Whipple resection is still needed to treat duodenal adenomatosis. In a 5-year period 23 PPTDs were performed for duodenal adenomatosis. In a matched-pairs analysis the outcome following PPTD (16 patients with a follow-up longer than 12 months) was compared with pp-Whipple. Hospital mortality in all 23 patients was 4.3% and total morbidity 30% after PPTD. Operation time, intensive care and hospital stay, morbidity, and mortality were comparable between the matched paired groups (16 patients). Patients with PPTD had significantly lower intraoperative blood loss. No PPTD patient required pancreatic enzyme substitution, compared with 12 patients after pp-Whipple. Quality-of-life analysis in PPTD patients revealed no difference compared to a normal control population and the pp-Whipple group. PPTD is a safe surgical procedure for duodenal adenomatosis that avoids pancreatic head resection, provides high quality of life, and shows advantages over the pp-Whipple procedure.American journal of surgery 07/2008; 195(6):741-8. · 2.36 Impact Factor -
Article: Perioperative and follow-up results after central pancreatic head resection (Berne technique) in a consecutive series of patients with chronic pancreatitis.
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ABSTRACT: Many patients require surgery for chronic pancreatitis (CP). By combining the essences of the Beger and the Frey procedures, a hybrid procedure was developed: central pancreatic-head resection (CPHR) (Berne technique). A prospective evaluation of 100 consecutive patients who underwent CPHR for CP between January 2002 and December 2006 was performed. Long-term follow-up, including quality-of-life (QOL) assessment, was carried out. The hospital mortality rate was 1%; the surgical morbidity rate was 16%; and the relaparotomy rate was 6%. Mean surgery time was 295 +/- 7 minutes; mean intraoperative blood loss was 763 +/- 75 mL; and the mean postsurgical hospital stay was 11.4 +/- .8 days. After a median follow-up of 41 months, pain was improved in 55% of patients; weight increase occurred in 67% of patients; and insulin-dependent diabetes mellitus developed in 22% of the patients. Comparison of QOL parameters with a German adult control population showed no statistically significant differences. CPHR is a safe surgical option to resolve CP-associated problems. Long-term follow-up QOL after CPHR shows results comparable with date published data after the Beger and the Frey procedures.American journal of surgery 06/2008; 196(3):364-72. · 2.36 Impact Factor -
Article: Duodenum-preserving pancreatic head resection--a randomized controlled trial comparing the original Beger procedure with the Berne modification (ISRCTN No. 50638764).
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ABSTRACT: A prospective, randomized study was performed to evaluate two variations of the duodenum-preserving pancreatic head resection (DPPHR), either with (Beger procedure) or without (Berne modification) the division of the pancreas anterior to the portal vein, in patients with chronic pancreatitis. Randomized, controlled, patient-blinded trial of patients with inflammatory pancreatic head tumors. The primary endpoint was the duration of surgery. Other a priori-ordered endpoints were length of ICU stay, postoperative complication, length of hospital stay, and quality of life after 24 months. Sixty-five patients were randomized to the Berne or Beger procedures. The Berne modification could be performed faster (46 minutes difference, P < .05). The median length of stay on the ICU was one day in both groups (P = .97) but the median hospital stay was shorter in the Berne group (11 (8-39) versus 15 (8-47); P = .015). The quality of life two years after surgery did not differ significantly between the two groups (EORTC-QLQ-C30, Beger 65.6% vs. Berne 71.3%, P = .371). Three patients who had received the Berne procedure were reoperated on during the follow-up period due to ongoing pancreatitis and bile duct obstruction (P = .22). The Berne technique is technically simpler compared with the original Beger procedure, reflected in its significantly shorter operation times and hospital stays. The quality of life is similar after both procedures. The Berne modification of DPPHR adds to our panel of surgical procedures that can be applied with effective early and late outcomes.Surgery 05/2008; 143(4):490-8. · 3.10 Impact Factor -
Article: Factors influencing survival after bypass procedures in patients with advanced pancreatic adenocarcinomas.
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ABSTRACT: Patients with occult metastasis or locally nonresectable pancreatic cancer found during surgical exploration have a limited life expectancy. We sought to define markers in these patients that could predict survival and thus aid decision making for selection of the most appropriate therapeutic palliative option. In a prospective 4-year single-center study, 136 consecutive patients with obstructive pancreatic cancer and intraoperative diagnosis of nonresectable or disseminated pancreatic cancer underwent a palliative surgical bypass procedure. Potential factors predicting survival were evaluated. Ninety-eight patients had metastatic disease and 38 locally advanced disease. Surgical morbidity rate was 16 %, re-operation rate 1%, and overall in-hospital mortality 4%. Univariate analysis showed American Society of Anesthesiologists (ASA) score, pain, operation time, presence of metastasis, and levels of leukocytes, albumin, C-reactive protein (CRP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 were associated significantly with survival. The multivariate analysis identified ASA score, presence of liver metastasis, pain, CA 19-9, and CEA levels as independent indicators for poor survival. Patients with none or 1 of these risk factors had a median survival of 13.5 months, whereas patients with 4 or 5 risk factors had a median survival of 3.5 months. The clinical markers identified predict poor outcome for patients with palliative bypass surgery and therefore aid the appropriate selection of either surgical bypass or endoscopic stenting in these patients.American journal of surgery 03/2008; 195(2):221-8. · 2.36 Impact Factor -
Article: Pancreatic pain.
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ABSTRACT: Abdominal pain is an important clinical symptom in pancreatic diseases. There is increasing evidence that pain in chronic pancreatitis and pancreatic cancer is triggered by pancreatic neuropathy. Damage to intrapancreatic nerves seems to support the maintenance and exacerbation of neuropathic pain. In chronic pancreatitis, intrapancreatic nerves are invaded by immune cells. This observation led to the hypothesis that neuro-immune interactions play a role in the pathogenesis of chronic pancreatitis and the accompanying abdominal pain syndrome. Similarly, pancreatic cancer cells infiltrate the perineurium of local nerves, which may in part explain the severe pain experienced by the patients. Furthermore, perineural invasion extending into extrapancreatic nerves may preclude curative resection and thus often leads to local recurrence. In recent years, the involvement of a variety of neurotrophins and neuropeptides in the pathogenesis of pancreatic pain was discovered. This review summarises recent data on the mechanisms of neuropathy and pain generation in pancreatic disorders.Baillière' s Best Practice and Research in Clinical Gastroenterology 02/2008; 22(1):31-44. · 2.46 Impact Factor -
Article: Resection of primary pancreatic cancer and liver metastasis: a systematic review.
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ABSTRACT: Resection of liver metastases for locally resectable pancreatic cancer has rarely been performed. Recently, promising results regarding morbidity and mortality as well as long-term survival have been shown. Thus, we conducted a systematic review of the literature on pancreatic cancer resection with associated liver metastasis resection. There are 3 case reports and 18 studies including less than 10 patients. Only three studies are larger series with 10 or more patients in whom pancreatic resections and hepatic metastasectomies were performed. Here, morbidity and mortality ranged from 24.1 to 26% and from 0 to 4.3%, respectively. Median survival was reported to be between 5.8 and 11.4 months. In total, all identified studies included 103 patients in whom a metastasis resection was performed. Liver metastasis resection for locally resectable pancreatic cancer can be performed in selected cases with low morbidity and mortality. Overall survival in cases with one or few liver metastases which are concomitantly resected seems to be comparable to cases without evidence of metastasis. Therefore, randomized controlled clinical trials will have to be initiated to determine the value of such resections and to identify factors which will allow for selection of patients in whom the extension of the resectability criteria might confer a survival benefit.Digestive surgery 02/2008; 25(6):473-80. · 1.37 Impact Factor -
Article: Is there still a role for total pancreatectomy?
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ABSTRACT: To evaluate the perioperative and long-term results of total pancreatectomy (TP), and to assess whether it provides morbidity, mortality, and quality of life (QoL) comparable to those of the pylorus-preserving (pp)-Whipple procedure in patients with benign and malignant pancreatic disease. TP was abandoned for decades because of high peri- and postoperative morbidity and mortality. Because selected pancreatic diseases are best treated by TP, and pancreatic surgery and postoperative management of exocrine and endocrine insufficiency have significantly improved, the hesitance to perform a TP is disappearing. In a prospective study conducted from October 2001 to November 2006, all patients undergoing a TP (n = 147; 100 primary elective TP [group A], 24 elective TP after previous pancreatic resection [group B], and 23 completion pancreatectomies for complications) were included, and perioperative and late follow-up data, including the QoL (EORTC QLQ-C30 questionnaire), were evaluated. A matched-pairs analysis with patients receiving a pp-Whipple operation was performed. Indications for an elective TP (group A + B) were pancreatic and periampullary adenocarcinoma (n = 71), other neoplastic pancreatic tumors (intraductal papillary mucinous neoplasms, neuroendocrine tumors, cystic tumors; n = 34), metastatic lesions (n = 8), and chronic pancreatitis (n = 11). There were 73 men and 51 women with a mean age of 60.9 +/- 11.3 years. Median intraoperative blood loss was 1000 mL and median operation time was 380 minutes. Postoperative surgical morbidity was 24%, medical morbidity was 15%, and mortality was 4.8%. The relaparotomy rate was 12%. Median postoperative hospital stay was 11 days. After a median follow-up of 23 months, global health status of TP patients was comparable to that of pp-Whipple patients, although a few single QoL items were reduced. All patients required insulin and exocrine pancreatic enzyme replacements. The mean HbA1c value was 7.3% +/- 0.9%. In this cohort study, mortality and morbidity rates after elective TP are not significantly different from the pp-Whipple. Because of improvements in postoperative management, QoL is acceptable, and is almost comparable to that of pp-Whipple patients. Therefore, TP should no longer be generally avoided, because it is a viable option in selected patients.Annals of Surgery 01/2008; 246(6):966-74; discussion 974-5. · 7.49 Impact Factor -
Article: Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer.
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ABSTRACT: Neural alterations and aberrantly expressed nerve-specific factors promoting tumor progression are known to contribute to pancreatic cancer's extremely poor prognosis. Despite hints that axon guidance factor semaphorin 3A (SEMA3A) may function as a tumor inhibitor, its clinical importance and therapeutic potential have not yet been explored. The present study investigated the role of SEMA3A and its receptors-plexins A1-A4 (PLXNA1-A4) and neuropilin-1 (NRP1)-in pancreatic cancer. QRT-PCR and immunohistochemical analyses revealed overexpression of SEMA3A, NRP1 and PLXNA1 in metaplastic ducts, malignant cells and nerves of cancerous specimens, and showed that elevated levels of corresponding mRNA (6.8-fold, 2.0-fold and 1.5-fold, respectively) clearly correlated with negative clinicopathological manifestations such as shorter survival (SEMA3A and PLXNA1) and a lesser degree of tumor differentiation (NRP1) in Stages I-III patients. High SEMA3A expression in pancreata of Stage IV M1 patients and in peritoneal metastases, and consequent functional studies indicated that poor clinical outcome might be related to the ability of SEMA3A to promote dissemination and invasiveness of pancreatic cancer cells through activation of multiple pathways involving Rac1, GSK3b or p42/p44 MAPK, but not E- to N-cadherin switch, MMP-9 or VEGF induction. Thus, this study is the first to quantify expression of the SEMA3A system in human malignancy and to show that overexpression of SEMA3A by nerves and transformed cells leads to a SEMA3A-rich environment which may favor malignant activities of tumor cells. Furthermore, negative clinicopathological correlations suggest that SEMA3A might represent a novel intervention target but not a treatment option for pancreatic cancer patients.International Journal of Cancer 01/2008; 121(11):2421-33. · 5.44 Impact Factor -
Article: Acinar cell membrane disruption is an early event in experimental acute pancreatitis in rats.
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ABSTRACT: To test the hypothesis that disruption of acinar cell membranes is the earliest event that takes place after the onset of acute pancreatitis. Cerulein and taurocholate pancreatitis were induced in rats. Furthermore, stimulation with different doses of bombesin, pilocarpine, and cerulein was performed. Five to 180 minutes after initiation of treatment, animals were killed. Disruption of cell membranes was detected by the penetration of the experimental animal's own albumin or immunoglobulin G (IgG) into acinar cells by immunocytological localization. Tissue was further analyzed by electron microscopy and electron microscopic immunostaining. Animals with pancreatitis displayed significantly greater antialbumin and anti-IgG immunostaining in the cytoplasm of acinar cells and in vacuoles in comparison with controls, confirming membrane disruption. This was not detectable after stimulation with bombesin, pilocarpine, and nonsupramaximal doses of cerulein. The first changes were seen after 5 minutes of induction of pancreatitis. Results were verified by electron microscopy and electron microscopic immunohistochemistry. The penetration of albumin and IgG into acinar cells indicates that wounding of their plasma membrane occurs at the onset of acute pancreatitis. Disruption of the membranes could be expected to allow the influx of calcium ions, causing massive intracellular alterations, and exit of molecules, such as enzymes from acinar cells.Pancreas 12/2007; 35(4):e30-40. · 2.39 Impact Factor -
Article: Cannabinoids in pancreatic cancer: Correlation with survival and pain
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ABSTRACT: Cannabinoids exert antiproliferative properties in a variety of malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). In our study, we quantitatively evaluated the immunoreactivity for cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors as well as for the endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MGLL). Furthermore, quantitative real-time RT-PCR for CB1, CB2, FAAH and MGLL in normal pancreas and pancreatic cancer tissues was performed. Levels of endocannabinoids were determined by liquid chromatography/mass spectrometry. Immunoreactivity scores and QRT-PCR expression levels were correlated with the clinico-pathological (TNM, survival, pain) status of the patients. Evaluation of endocannabinoid levels revealed that these remained unchanged in PDAC compared to the normal pancreas. Patients with high CB1 receptor levels in enlarged nerves in PDAC had a lower combined pain score (intensity, frequency, duration; p = 0.012). There was a significant relationship between low CB1 receptor immunoreactivity or mRNA expression levels (p = 0.0011 and p = 0.026, respectively), or high FAAH and MGLL cancer cell immunoreactivity (p = 0.036 and p = 0.017, respectively) and longer survival of PDAC patients. These results are underlined by a significant correlation of high pain scores and increased survival (p = 0.0343). CB2 receptor immunoreactivity, CB2 receptor, FAAH and MGLL mRNA expression levels did not correlate with survival. Therefore, changes in the levels of endocannabinoid metabolizing enzymes and cannabinoid receptors on pancreatic cancer cells may affect prognosis and pain status of PDAC patients. © 2007 Wiley-Liss, Inc.International Journal of Cancer 10/2007; 122(4):742 - 750. · 5.44 Impact Factor -
Article: The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis.
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ABSTRACT: Chronic pancreatitis is characterised by severe abdominal neuropathic pain, perineural inflammatory cell infiltrations and intrapancreatic neural growth. Artemin was recently shown to eliminate neuropathic pain and reverse neurochemical damage after nerve injury. The role of artemin and its receptor GFRalpha3 was investigated in patients with chronic pancreatitis. Expression of artemin and its receptor GFRalpha3 was studied in chronic pancreatitis (n = 66) and normal (n = 22) pancreatic tissues by quantitative reverse transcription-polymerase chain reaction (QRT-PCR) and western blot analysis. Artemin expression was correlated with pain and pathomorphological changes (inflammation, perineural inflammatory cell infiltration, neural alterations and fibrosis). Immunohistochemistry was used to localise artemin and GFRalpha3 in the tissues. To detect sources of artemin, primary human pancreatic stellate cells (hPSCs) were isolated and analysed by QRT-PCR and immunocytology analysis. In chronic pancreatitis, artemin and GFRalpha3 were significantly overexpressed and located in smooth muscle cells of arteries, Schwann cells and neural ganglia. Increased levels of artemin mRNA correlated with pain severity, inflammation, perineural inflammatory cell infiltration, neural density and hypertrophy. Furthermore, the severity of fibrosis was positively related with artemin expression and neural alterations. Activated hPSCs expressed low basal levels of artemin mRNA which were upregulated by exposure to transforming growth factor (TGF)beta1. Overexpression of artemin in chronic pancreatitis might function as a compensatory upregulation in order to repair neural damage incurred by ongoing pancreatic inflammation. Upregulation of TGFbeta1 seems not only to increase pancreatic fibrosis but also to contribute to neural alteration by stimulating artemin expression in hPSCs. However, overexpression of endogenous artemin does not seem to be sufficient to prevent pain in chronic pancreatitis.Gut 05/2007; 56(4):534-44. · 10.11 Impact Factor -
Article: Increase in substance P precursor mRNA in noninflamed small-bowel sections in patients with Crohn's disease.
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ABSTRACT: Neuropeptides, such as substance P (SP), are mediators of neurogenic inflammation and play an important role in inflammatory disorders. To further investigate the role of the SP pathway in inflammatory bowel disease (IBD), we analyzed the following in normal intestinal tissue specimens and in tissue specimens from patients with Crohn's disease (CD) and ulcerative colitis (UC): neurokinin receptor-1 (NK-1R); its isoforms (NK-1R-L and NK-1R-S); its ligand SP, encoded by preprotachykinin-A (PPT-A); and the SP-degradation enzyme, neutral endopeptidase (NEP). Real-time quantitative reverse transcription-polymerase chain reaction was used to simultaneously determine the expression of NK-1R-L, NK-1R-S, and PPT-A. Protein levels of NK-1R and NEP were determined by immunoblot analysis. In noninflamed small-bowel tissue samples of CD patients, PPT-A mRNA expression was significantly increased, whereas there was no difference between inflamed or noninflamed UC and normal intestinal tissue samples. Examining subgroups of diverse intestinal segments from CD and UC samples with various levels of inflammation revealed no differences in NK-1R-L and NK-1R-S mRNA expression, whereas there was a tendency toward overall lower NK-1R-S mRNA copy numbers. Immunoblot analysis showed upregulation of NK-1R protein levels in cases of IBD, with more pronounced enhancement in cases of CD than in UC. For NEP, there were no differences in protein levels in normal, CD, and UC intestinal tissues. These observations suggest a contribution of SP and its receptor, NK-1R, in the local inflammatory reaction in IBD and particularly in ileal CD. Moreover, significant upregulation of PPT-A mRNA in the noninflamed ileum of these patients suggests an influence of inflamed intestines on their healthy counterparts.American journal of surgery 05/2007; 193(4):476-81. · 2.36 Impact Factor -
Article: Distal pancreatectomy: risk factors for surgical failure in 302 consecutive cases.
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ABSTRACT: The objective of this study was to identify potential risk factors for mortality and morbidity after distal pancreatectomy, with special focus on the formation of pancreatic fistula. Distal pancreatectomy can be performed with low mortality and acceptable morbidity rates. Pancreatic fistulas, occurring in 10% to 20% of cases, remain a problem that contributes significantly to morbidity, length of stay, and overall costs. From November 1993 to February 2006, perioperative and postoperative data of 302 consecutive patients were recorded. Univariate and multivariate analyses of potential risk factors for morbidity and for the formation of pancreatic fistula were performed. The surgical techniques used for closure were categorized into 4 groups: 1) anastomosis, 2) seromuscular patch, 3) closure by suture, and 4) closure using a stapling device. Indications for resection were pancreatic tumors in 62% of patients, nonpancreatic tumors in 23%, chronic pancreatitis in 12%, and others in 3%. The spleen was preserved in 24% of patients. The morbidity and mortality rates for distal pancreatectomy in this series were 35% and 2%, respectively. The prevalence of pancreatic fistula was 12%. Univariate and multivariate analyses indicated that closure using a stapling device and an operating time >or=480 minutes were associated with a higher incidence of pancreatic fistula (odds ratio = 2.6 and 4.2, respectively). Overall morbidity was mainly influenced by the extent of resection (multivisceral vs. conventional; odds ratio = 1.7). Pancreatic leak remains a common complication after distal pancreatectomy. Our series suggests that stapler closure of the pancreatic remnant is associated with a significantly higher fistula rate.Annals of Surgery 04/2007; 245(4):573-82. · 7.49 Impact Factor -
Article: Pancreaticojejunostomy versus pancreaticogastrostomy: systematic review and meta-analysis.
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ABSTRACT: Pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG) are the commonly preferred methods of anastomosis after pancreaticoduodenectomy (PD). The ideal choice of anastomosis remains a matter of debate. Articles published until end of March 2006 comparing PJ and PG after PD were searched. Two reviewers independently assessed quality and eligibility of the studies and extracted data for further analysis. Meta-analysis was performed with a random-effects model by using weighted odds ratios. Sixteen articles were included; meta-analysis of 3 randomized controlled trials (RCT) revealed no significant difference between PJ and PG regarding overall postoperative complications, pancreatic fistula, intra-abdominal fluid collection, or mortality. On the contrary, analysis of 13 nonrandomized observational clinical studies (OCSs) showed significant results in favor of PG for the outcome parameters with a reduction of pancreatic fistula and mortality in favor of PG. All OCSs reported superiority of PG over PJ, most likely influenced by publication bias. In contrast, all RCTs failed to show advantage of a particular technique, suggesting that both PJ and PG provide equally good results. This meta-analysis yet again highlights the singular importance of performing well-designed RCTs and the role of evidence-based medicine in guiding modern surgical practice.American journal of surgery 03/2007; 193(2):171-83. · 2.36 Impact Factor
Top co-authors
Top Journals
Institutions
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2007–2010
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Technische Universität München
- Chirurgische Klinik und Poliklinik - Allgemein-, Viszeral- und Transplantationschirurgie
München, Bavaria, Germany
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2003–2009
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Universität Heidelberg
- Institute of Pathology (Mannheim)
Heidelberg, Baden-Wuerttemberg, Germany
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1996
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Universität Ulm
Ulm, Baden-Wuerttemberg, Germany
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