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Markus W Büchler

Publications and source records attributed to Markus W Büchler.

At least 19 recordsLinked to original sources
PubMed2007

Expression of extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in pancreatic neoplasm and pancreatic stellate cells.

EMMPRIN (extracellular matrix metalloproteinase inducer, CD147) participates in the progression of various malignancies by stimulating the synthesis of specific matrix metalloproteinases (MMP) from peritumoral fibroblasts. In the present study, the expression and functional role of EMMPRIN was investigated in pancreatic neoplasm. QRT-PCR, immunohistochemistry, immunoblot, and ELISA analyses were used to analyze the expression, localization, and release of EMMRPIN. Silencing of EMMPRIN was performed using siRNA oligonucleotides, and functional consequences were assessed using growth assays, invasion assays, as well as MMP1/MMP2 and VEGF ELISA. EMMPRIN mRNA levels were 2.2-fold increased in pancreatic cancer (n = 52) and 2.0-3.5-fold increased in other pancreatic neoplasm (n = 105), but unchanged in chronic pancreatitis (n = 10) compared to normal pancreatic tissues (n = 9). Strong and predominantly membranous immunostaining was observed in the cancer cells and surrounding stromal cells. EMMPRIN serum levels were also significantly increased in pancreatic cancer patients (n = 44) (4.13 +/- 0.28 ng/ml) with an AUC of 0.97 compared to healthy volunteers (n = 29) (0.95 +/- 0.16 ng/ml; p < 0.0001) and with an AUC of 0.74 compared to chronic pancreatitis patients (n = 20) (2.98 +/- 0.5 ng/ml; p = 0.0021). EMMPRIN silencing did not significantly affect anchorage-dependent or -independent growth of pancreatic cancer cells. In contrast, EMMPRIN silencing in pancreatic stellate cells slightly repressed VEGF and MMP2 levels but strongly increased pro-MMP1 expression under coculture conditions. In conclusion, Increased EMMPRIN expression is present in different pancreatic neoplasm, likely representing a tumor-specific reaction with the potential to modulate the tumor microenvironment rather than a mere reflection of an activated stroma.

Animals↗
PubMed2007

Regulation of differential pro- and anti-apoptotic signaling by glucocorticoids.

More than a quarter of a century ago, the phenomenon of glucocorticoid-induced apoptosis in the majority of hematological cells was first recognized. More recently, glucocorticoid-induced antiapoptotic signaling associated with apoptosis resistance has been identified in cells of epithelial origin, most of malignant solid tumors and some other tissues. Despite these huge amount of data demonstrating differential pro- and anti-apoptotic effects of glucocorticoids, the underlying mechanisms of cell type specific glucocorticoid signaling are just beginning to be described. This review summarizes our present understanding of cell type-specific pro- and anti-apoptotic signaling induced by glucocorticoids. In the first section we give a summary and update of known glucocorticoid-induced pathways mediating apoptosis in hematological cells. We shortly introduce mechanisms of glucocorticoid resistance of hematological cells. We highlight and discuss the emerging molecular evidence of a general induction of survival signaling in epithelial cells and carcinoma cells by glucocorticoids. We provide a model for glucocorticoid-induced resistance in cells growing in a tissue formation. Thus, attachment to the extracellular matrix and cell-cell contacts typical for e.g. epithelial and tumor cells may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with glucocorticoids.

Animals↗
PubMed2007

Impact of interferon-alpha in combined chemoradioimmunotherapy for pancreatic adenocarcinoma (CapRI): first data from the immunomonitoring.

Data from a phase II trial combining chemoradiotherapy with IFN-alpha (CapRI scheme) for adjuvant treatment of pancreatic carcinoma are very encouraging. Therefore, a phase III trial comparing chemotherapy with the chemoradiotherapy with IFN-alpha scheme has been initiated in August 2004. Translational research with a focus on immunomodulation is performed in parallel to the study. Blood and serum samples are taken at various time points. Patients in arm A (chemoradioimmunotherapy) receive a single low-dose-Interferon injection before therapy to investigate the direct effect of IFN-alpha. So far samples from 44 patients have been investigated for surface molecule expression, cytokine levels, natural killer cell cytotoxicity, and antigen-specific Granzyme B release. Patients in arm A showed 1 day after IFN-alpha injection a significant increase in spontaneous cytotoxicity; this effect was fading after repeated injections. Furthermore, cells releasing Granzyme B after stimulation with CA 19.9 and MUC-1 protein increased under therapy. Five days after the first IFN-alpha injection, IL-12 and TNF-alpha serum levels peak. We observed significant increases of monocytes, peripheral dendritic cells, CD40 cells, central and effector memory T cells, and CD8 cells, CD4 cells decreased during therapy. All these effects were only observed in arm A patients and none of them in arm B patients. In conclusion, in a translational research project accompanying a challenging multimodality treatment trial including IFN-alpha, we observed an immediate activation of antigen-presenting cells and natural killer cells followed later on by antigen-specific activation. It will be most interesting if the immunologic data will show a correlation with the clinical course of the patients.

Adenocarcinoma↗
PubMed2006

Preoperative bowel preparation: surgical standard or past?

BACKGROUND: Preoperative bowel preparation is still routinely used prior to colorectal surgery. This concept is based on traditional and personal empiricism and usually not evidence based. The objective of the present review was to reassess this dogma against the background of the highest level of evidence published thus far. METHODS: The Medline database was searched using the search terms 'preoperative', 'bowel' and 'preparation' limited to 'randomized controlled trials' and 'meta-analyses'. Ten randomised controlled trials and seven meta-analyses comparing orthograde bowel cleansing to no preoperative bowel preparation were considered for rates of anastomotic leakages, surgical infections and other types of complications, reoperations and mortality. RESULTS: All the most recent meta-analyses showed a significant increase of anastomotic dehiscences in patients with preoperative orthograde bowel cleansing. Additionally, a trend towards higher rates of surgical infectious complications and re-operations was revealed. Mortality remained unchanged by preoperative orthograde bowel cleansing. CONCLUSION: Routine preoperative orthograde bowel cleansing is no longer justified prior to colorectal surgery in general due to increased risk of anastomotic leakages. Further investigations should focus on different types of bowel preparation in situations where preoperative bowel preparation still may have a role such as total mesorectal resection with low anastomosis and protective ileostomy.

Cathartics↗
PubMed2006

Management of a rare case of fulminant hemobilia due to arteriobiliary fistula following total pancreatectomy.

Hemobilia is a rare cause of acute upper gastrointestinal bleeding and is often associated with a history of hepatic or biliary tract injury, tumor growth, hepatic artery aneurysm, cholecystitis, or hepatic abscess. We report a case of a 76-year-old patient with massive hemobilia due to intrahepatic bleeding from the segment 8 hepatic artery without evidence of a true aneurysm, abscess, or metastatic disease 4 weeks following pylorus-preserving total pancreatectomy for pancreatic cancer. Gastroduodenoscopy suggested hemorrhage from the duodenojejunostomy but failed to achieve hemostasis, and the patient underwent exploratory laparotomy. It was realized intraoperatively that the bleeding originated from the intrahepatic biliary tract. Bleeding was controlled by blocking the right hepatic bile duct with a Fogarty catheter and subsequent transarterial embolization. Computed tomography did not reveal any local liver or vascular pathology. Retrospectively, the cause of delayed profuse hemobilia was most likely a traumatic intrahepatic pseudoaneurysm following endoscopic bile duct stenting 3 weeks before the pancreatectomy. The reported case is exceptional and of particular interest because of the absence of a typical history or cause of hemobilia, preoperative misleading diagnostic results in an altered anatomic situation, and the operative management to achieve bleeding control in this emergency setting.

Acute Disease↗
PubMed2006

Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations.

BACKGROUND: Transforming growth factors betas (TGF-betas) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-betas modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-beta receptor. METHODS: After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed. RESULTS: The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased. CONCLUSION: Our findings indicate that a functional TGF-beta signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.

Acute Disease↗
PubMed2006

Perioperative outcome in sarcoma surgery.

INTRODUCTION: Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of all malignancies. Although disease-specific surgical management is increasingly important, only few data are available for STS. Here, we analyze a single institution setting focusing on perioperative surgical and clinical parameters. METHODS: Prospectively gathered data of all adult patients undergoing surgery for STS including gastrointestinal stroma tumors (GIST) between October 2001 and October 2004. Patients undergoing only biopsy or ambulatory surgery were excluded. Statistical analysis was performed using SAS(R) software and patient's data from a computerized sarcoma registry. RESULTS: 159 patients with a median age of 60.2 years underwent a total of 179 operations. Three major sites of occurrence were notified: the visceral cavity (VIS) (36.3%), the retroperitoneum (RET) (31.3%), and the extremities (EXT) (27.4%). GIST (53.9%) were the most common type in the VIS, liposarcoma (62.5%) in the RET, and either liposarcoma (30.6%) or malignant fibrous histiocytoma (28.6%) in the EXT. Recurrence was treated in more than half of the patients with RET STS, and in almost one third of the EXT lesions, while primary occurrence dominated in the VIS. Median operation times in the VIS, RET, and EXT were 210, 240, and 120 min, respectively. Blood loss was 300, 500, and 50 ml for VIS, RET, and EXT operations. Morbidity was 26.2, 30.4, and 34.7% in VIS, RET, and EXT operations, respectively (reoperation rates were 9.4, 5.4, and 14.3%). Mortality was 1.5, 8.9, and 2.0% for VIS, RET, and EXT. Length of hospital stay in the groups was comparable. CONCLUSION: STS surgery of a single surgical unit contains predominantly VIS, RET, and EXT tumors. The STS subtype varies with location, as does length of operation, blood loss, morbidity, mortality, and reoperation rate. These data are helpful for planning the perioperative management of adult patients with STS and can be used for prognostic analyses.

Aged↗
PubMed2006

Totally laparoscopic versus conventional ileoanal pouch procedure--design of a single-centre, expertise based randomised controlled trial to compare the laparoscopic and conventional surgical approach in patients undergoing primary elective restorative proctocolectomy--LapConPouch-Trial.

BACKGROUND: Restorative proctocolectomy is increasingly being performed minimal invasively but a totally laparoscopic technique has not yet been compared to the standard open technique in a randomized study. METHODS/DESIGN: This is a two armed, single centre, expertise based, preoperatively randomized, patient blinded study. It is designed as a two-group parallel superiority study. Power calculation revealed 80 patients per group in order to recruit the 65 patients to be analysed for the primary endpoint. The primary objective is to investigate intra-operative blood loss and the need for blood transfusions. We hypothesise that intra-operative blood loss and the need for peri-operative blood transfusions are significantly higher in the conventional group. Additionally a set of surgical and non-surgical parameters related to the operation will be analysed as secondary objectives. These will include operative time, complications, postoperative pain, lung function, postoperative length of hospital stay, a cosmetic score and pre-and postoperative quality of life. DISCUSSION: The trial will answer the question whether there is indeed an advantage in the laparoscopic group in regard to blood loss and the need for blood transfusions. Moreover, it will generate data on the safety and potential advantages and disadvantages of the minimally invasive approach.

Adenomatous Polyposis Coli↗
PubMed2006

Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing gammadelta T cell cytotoxicity.

Intestinal cells express MHC related molecules termed MICA/MICB, which are up-regulated under stress and in many gastrointestinal tumors. These molecules can be recognized by the immunoreceptor NKG2D, which is present on NK and gammadelta T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells. The immediate effect of soluble MIC (sMIC) on cellular cytotoxicity of gammadelta T cells is yet not investigated. We determined sMIC levels in sera of patients with pancreatic carcinoma and the expression of MIC on the surface of tumor cells by FACS. The effect of sMIC content in patient serum on cellular cytotoxicity of gammadelta T and NK cells was investigated by cytotoxicity assays. Subsequently, the effect of IFN-alpha treatment on MIC expression, release and cellular cytotoxicity was investigated. Pancreatic carcinoma cells express MIC, and patient sera contain elevated sMIC levels that correlate with tumor stage and differentiation. Furthermore, cellular cytotoxicity of gammadelta T cells and NK cells against pancreatic carcinoma is impaired by sMIC in patient sera which is prevented by sMIC neutralization. Incubation of pancreatic cancer cells with IFN-alpha increases MIC expression without induction of sMIC resulting in enhanced lysis of tumor cells. Our results demonstrate that sMIC impairs NKG2D-mediated immunity against pancreatic carcinoma by directly diminishing cytotoxicity of gammadelta T cells and NK cells. IFN-alpha, which is used in adjuvant treatment of pancreatic carcinoma, might partly act via up-regulation of MIC without induction of sMIC release.

Enzyme-Linked Immunosorbent Assay↗
PubMed2006

Surgical palliation in patients with pancreatic cancer.

BACKGROUND: The aim of palliative strategies in patients with pancreatic cancer is the relief of tumor-associated symptoms such as biliary and duodenal obstruction and tumor growth. Due to high mortality and morbidity rates of surgery, treatment of patients with advanced pancreatic cancer is mainly in the hand of gastroenterologists. RATIONALE: In recent years, surgery of pancreatic cancer in specialized centres developed strongly, which makes it a viable option even in the treatment of advanced disease. CONCLUSION: We advocate for an aggressive strategy in the treatment of pancreatic cancer with surgical exploration and tumor resection whenever possible.

Abdominal Pain↗
PubMed2006

Pancreatic resection for M1 pancreatic ductal adenocarcinoma.

BACKGROUND: Improved safety of pancreatic surgery has led to consideration of more aggressive approaches, such as resection for primary pancreatic ductal adenocarcinoma (PDAC) with metastatic disease (M1). METHODS: A total of 29 patients who underwent pancreatic resection with resection of associated metastatic disease (interaortocaval lymph node dissection, liver resection, and/or multiorgan resections) were retrospectively identified from a database of 316 R0/R1 pancreatic resections for PDAC. An explorative data analysis of perioperative and clinicopathological parameters, and overall survival was performed by Kaplan-Meier estimation, log rank test, and Fisher's exact test. RESULTS: The overall in-hospital mortality and morbidity of R0/R1 pancreatic resections for M1 disease (n = 29) was 0% and 24.1%, compared with 4.2% and 35.2% of R0/R1 pancreatic resections for M0 disease (n = 287). The median overall survival time was 13.8 months (95% confidence interval [CI], 11.4-20.5), and the estimated 1-year overall survival rate was 58.9% (95% CI, 34.8-76.7) for patients with M1 disease. The median survival in those with metastatic interaortocaval lymph nodes was 27 months (95% CI, 9.6-27.0), whereas it was 11.4 months (95% CI, 7.8-16.5) and 12.9 months (95% CI, 7.2-20.5) for those with liver and peritoneal metastases, respectively. CONCLUSIONS: Pancreatic resections with M1 disease can be performed with acceptable safety in highly selected patients. The survival after interaortocaval lymph node resection is comparable to that of other lymph nodes that do not constitute M1 disease. Resection of liver and peritoneal metastases, although safe in this series, cannot be generally recommended until further controlled trials can be conducted.

Adenocarcinoma↗
PubMed2006

Localization of hyperfunctioning parathyroid glands by selective venous sampling in reoperation for primary or secondary hyperparathyroidism.

BACKGROUND: Localization of hyperfunctioning parathyroid glands in patients with previous cervical operations is not always successful with noninvasive methods such as ultrasound, sestamibi scan, or magnetic resonance imaging. The aim of our study was to evaluate the results of selective venous sampling (SVS) of intact parathyroid hormone (PTH) in patients undergoing surgery for primary (75%) or secondary (25%) hyperparathyroidism (HPT). METHODS: Between January 2000 and January 2006, SVS for PTH was performed in 51 consecutive patients with persistent or recurrent HPT or patients with previous cervical explorations. The results of SVS were compared with those of noninvasive localization studies. RESULTS: Successful surgical treatment was achieved in 47 of 51 patients (92%). SVS had a sensitivity of 83.3% for the correct localization of a parathyroid adenoma (79.5%) or hyperplastic parathyroid glands (91.6%). False-positive or indeterminate results of SVS were found in 6% and 2%, respectively, of the patients. Ultrasound detected enlarged parathyroid glands with a sensitivity of 33.3%, and sestamibi scan with a sensitivity of 57.1%. CONCLUSIONS: Compared with noninvasive localization studies, SVS for PTH yielded the best results for recurrent or persistent HPT and for patients with previous neck explorations. SVS is strongly recommended in reoperative surgery for HPT with indeterminate results of noninvasive methods.

Adult↗
PubMed2006

The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis.

BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Abdominal Pain↗
PubMed2006

Autoimmune pancreatitis associated with a large pancreatic pseudocyst.

Pancreatic cystic lesions comprise various entities with different histopathological characteristics and their differential diagnosis is often a challenge for clinicians. Autoimmune pancreatitis (AIP) is usually not considered in the differential diagnosis of cystic lesions, but often mimics the morphological aspects of pancreatic neoplasm. We report the case of a 64-year-old male patient with a cystic pancreatic head lesion (diameter 5 cm) and stenosis of the distal bile duct requiring repeated stenting. Because of the clinical presentation together with moderate elevation of serum CA19-9 and massive elevation of cyst fluid CA19-9 (122.695 U/L; normal range: <37.0 U/L), the patient underwent explorative laparotomy and pylorus preserving partial pancreaticoduodenectomy. Histology revealed surprisingly AIP with an inflammatory pseudocyst. In conclusion, cyst fluid analysis of tumor markers and cyst fluid cytology lack high accuracy to clearly differentiate cystic pancreatic lesions. Although AIP is rarely associated with pseudocysts, the disease has to be considered in the differential diagnosis of cystic pancreatic lesions. Early examination of serum IgG, IgG4 and auto-antibodies might save these patients from unnecessary endoscopical and surgical procedures.

Autoimmune Diseases↗
PubMed2006

Differentially expressed genes in postperfusion biopsies predict early graft dysfunction after liver transplantation.

BACKGROUND: Preservation induced injury is a major contributing factor to early graft dysfunction in liver allograft recipients. We hypothesized that changes in gene expression represent the earliest indicator of ischemia/reperfusion-related injuries measurable in the graft and could be used as prognostic marker for the occurrence of graft-related complications. METHODS: We studied the expression of 67 genes, known to play a role in acute inflammatory processes by real-time polymerase chain reaction in 59 postperfusion biopsies. The level of expression was correlated with the occurrence of graft-related complications. RESULTS: We identified six genes that were significantly correlated with the occurrence of early graft dysfunction (Spearman test, two-tailed; P<0.05). High C-reactive protein (CRP) gene expression levels correlated significantly with the need of therapeutic interventions due to graft-related complications (P=0,011). Furthermore, five genes related to vascular endothelial cell physiology (CTGF, WWP2, CD274, VEGF. and its receptor FLT1) showed significantly reduced expression in the postperfusion biopsies of patients with need of therapeutic interventions due to graft-related complications in the first month (P<0.05). Using a risk score based on the expression of these five genes, complications could be predicted with 96% sensitivity (ROC analysis, specificity: 74%, positive predictive value: 72%, negative predictive value: 96%). CONCLUSION: Quantitative gene expression analysis in postperfusion biopsies may be a valuable tool to prospectively identify patients at risk for early clinical allograft dysfunction after liver transplantation.

Acute Disease↗
PubMed2006

Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease.

Chronic inflammation, fibrosis, atrophy, malignant transformation, and thromboembolic events are hallmarks of chronic pancreatic disease. Extracellular nucleotides have been implicated as inflammatory mediators in many pathological situations. However, there are minimal data detailing expression of ectonucleotidases and type-2 purinergic receptors (P2R) in chronic pancreatitis and pancreatic cancer. We have therefore defined tissue distribution and localization of the CD39 family of ectonucleotidases and associated P2R in human disease. Transcripts of ectonucleotidases (CD39 and CD39L1) together with P2R (P2X7, P2Y2, and P2Y6) are significantly increased in both chronic pancreatitis and pancreatic cancer. CD39 and CD39L1 are preferentially associated with the vasculature and stromal elements in pathological tissues. P2X7 mRNA upregulation was associated with chronic pancreatitis, and heightened protein expression was found to be localized to infiltrating cells. P2Y2 was markedly upregulated in biopsies of pancreatic cancer tissues and expressed by fibroblasts adjacent to tumors. High-tissue mRNA levels of CD39 significantly correlated with better long-term survival after tumor resection in patients with pancreatic cancer. Heightened expression patterns and localization patterns of CD39, P2X7, and P2Y2 infer associations with chronic inflammation and neoplasia of the pancreas. Our data suggest distinct roles for CD39 and P2-purinergic signaling in both tissue remodeling and fibrogenesis with respect to human pancreatic diseases.

Adult↗