Dominique Sülberg

Indications and early outcomes for total pancreatectomy at a high-volume pancreas center.

Background. This study aimed to analyse the most common current indications for total pancreatectomy (TP) at a high-volume pancreas center. Method. Prospectively collected data on indications and short-term outcome of all TPs performed from January 2004 until June 2008 were analysed. Results. The total pancreatectomies (TP) were 63, i.e., 6.7% of all pancreatic procedures (n = 948). Indications for TP were classified into 4 groups: tumors of advanced stage, n = 23 (36.5%), technical problems due to soft pancreatic tissue, n = 18 (28.6%), troubles due to perioperative surgical complications, n = 15 (23.8%), and therapy-resistant pain due to chronic pancreatitis, n = 7 (11.1%). Surgical complications occurred in 23 patients (36.5%). The mortality in elective TP was 6.25%. Median postoperative stay was 21 days. Mortality, morbidity and the other perioperative parameters differed substantially according to the indication for pancreatectomy. Conclusion. Total pancreatectomy is definitely indicated for a limited range of elective and emergency situations. Indications can be: size or localisation of pancreatic tumor, trouble, technical diffuculties and therapy-refractory pain in chronic pancreatitis. A TP due to perioperative complications (troubles) after pancreatic resections is doomed by extremely high morbidity and mortality and should be avoided.

Comparative analysis of cell death induction by Taurolidine in different malignant human cancer cell lines

BackgroundTaurolidine (TRD) represents an anti-infective substance with anti-neoplastic activity in many malignant cell lines. So far, the knowledge about the cell death inducing mechanisms and pathways activated by TRD is limited. The aim of this study was therefore, to perform a comparative analysis of cell death induction by TRD simultaneously in different malignant cell lines.Materials and methodsFive different malignant cell lines (HT29/Colon, Chang Liver/Liver, HT1080/fibrosarcoma, AsPC-1/pancreas and BxPC-3/pancreas) were incubated with increasing concentrations of TRD (100 μM, 250 μM and 1000 μM) for 6 h and 24 h. Cell viability, apoptosis and necrosis were analyzed by FACS analysis (Propidiumiodide/AnnexinV staining). Additionally, cells were co-incubated with the caspase Inhibitor z-VAD, the radical scavenger N-Acetylcystein (NAC) and the Gluthation depleting agent BSO to examine the contribution of caspase activation and reactive oxygen species in TRD induced cell death.ResultsAll cell lines were susceptible to TRD induced cell death without resistance toward this anti-neoplastic agent. However, the dose response effects were varying largely between different cell lines. The effect of NAC and BSO co-treatment were highly different among cell lines - suggesting a cell line specific involvement of ROS in TRD induced cell death. Furthermore, impact of z-VAD mediated inhibition of caspases was differing strongly among the cell lines.ConclusionThis is the first study providing a simultaneous evaluation of the anti-neoplastic action of TRD across several malignant cell lines. The involvement of ROS and caspase activation was highly variable among the five cell lines, although all were susceptible to TRD induced cell death. Our results indicate, that TRD is likely to provide multifaceted cell death mechanisms leading to a cell line specific diversity.

[Distal pancreatectomy: radical or spleen-preserving?].

During recent years, spleen-preserving distal pancreatectomy (SPDP) has broadened the operative spectrum in pancreatic surgery. The rationale for spleen-preserving procedures comprises prevention of overwhelming postsplenectomy infection syndrome (OPSI) and possibly an advantage regarding reduced carcinogenesis. Although there are no prospective randomized trials, SPDP and distal pancreatectomy with splenectomy (DPSx) seem to be equivalent in terms of blood loss, operative time, mortality and frequency of reoperation. Concerning pancreatic fistulas and other major surgical complications, current data from the literature are conflicting. Long-term effects of SPDP, such as development of gastric varices due to portal hypertension, are still insufficiently investigated. However, SPDP should always be considered in patients with benign tumors of the pancreatic tail and chronic pancreatitis. Spleen-preserving distal pancreatectomy can also be combined with resection of the splenic vessels (DPSx-SVx) if the blood supply of the spleen via the small gastric vessels and the gastro-epoploic arcade is sufficient. In the presence of malignant tumors, DPSx is necessary for oncological reasons.

Technical aspects of pancreatoenteric anastomosis

Advances in pancreatic surgery during the last two decades have resulted in significant improvement of patient outcome leading to mortality rates as low as 3-5% following Whipples procedure in specialized centers. However, morbidity remains considerably high at 30-50% which is primarily caused by insufficiency of the pancreato-enteric anastomosis which becomes manifested as a pancreatic fistula. Therefore, numerous studies have aimed to identify the ideal pancreatic anastomosis. The most frequently used techniques comprise end-to-end duct-to-mucosa pancreaticojejunostomy, end-to-end invagination pancreatojejunostomy as well as end-to-side pancreatogastrostomy. In randomized controlled trials the frequency of pancreatic fistulas ranges between 4% and 20% depending on the particular technique. However, no single technique was able to demonstrate a significant superiority in several independent studies. The heterogeneity of definitions for pancreatic fistula represents the main problem in evaluating and comparing clinical studies on pancreato-enteric anastomosis. However, recent clinical trials applied commonly accepted definitions for pancreatic fistula as well as precise study endpoints to address the question of the ideal pancreatic anastomosis.ZusammenfassungFortschritte in der Pankreaschirurgie haben in den letzten beiden Jahrzehnten die Letalitätsraten nach Whipple-Operationen in spezialisierten Zentren auf Werte unter 3–5% sinken lassen. Dennoch bleibt die Morbidität, die vor allem durch Insuffizienzen der pankreatoenterischen Anastomose verursacht und als Pankreasfistel klinisch manifest wird, mit 30–50% immer noch sehr hoch. In zahlreichen Studien wurde daher versucht die „ideale Pankreasanastomose“ zu identifizieren. Zu den am häufigsten verwendeten Methoden gehören die End-zu-Seit-Duct-to-Mucosa-Pankreatikojejunostomie, die End-zu-End-Invaginations-Pankreatojejunostomie und die End-zu-Seit-Pankreatogastrostomie. In kontrolliert randomisierten Studien wurden je nach Anastomosentechnik Pankreasfistelraten zwischen 4% und 20% erreicht, ohne dass eine individuelle Methode in mehreren unabhängigen Studien einen signifikanten Vorteil aufweisen konnte. Ein großes Problem bei der Bewertung der Studien stellt die Heterogenität der Definitionen für eine Pankreasfistel dar. Allerdings bemühen sich jüngere Studien hier um die Verwendung allgemein anerkannter Definitionen und klarer Studienendpunkte, um zukünftig die Frage nach der „idealen Pankreasanastomose“ zu beantworten.AbstractAdvances in pancreatic surgery during the last two decades have resulted in significant improvement of patient outcome leading to mortality rates as low as 3–5% following Whipple’s procedure in specialized centers. However, morbidity remains considerably high at 30–50% which is primarily caused by insufficiency of the pancreato-enteric anastomosis which becomes manifested as a pancreatic fistula. Therefore, numerous studies have aimed to identify the ideal pancreatic anastomosis. The most frequently used techniques comprise end-to-end duct-to-mucosa pancreaticojejunostomy, end-to-end invagination pancreatojejunostomy as well as end-to-side pancreatogastrostomy. In randomized controlled trials the frequency of pancreatic fistulas ranges between 4% and 20% depending on the particular technique. However, no single technique was able to demonstrate a significant superiority in several independent studies. The heterogeneity of definitions for pancreatic fistula represents the main problem in evaluating and comparing clinical studies on pancreato-enteric anastomosis. However, recent clinical trials applied commonly accepted definitions for pancreatic fistula as well as precise study endpoints to address the question of the ideal pancreatic anastomosis.

Gene expression analysis of cell death induction by Taurolidine in different malignant cell lines

BackgroundThe anti-infective agent Taurolidine (TRD) has been shown to have cell death inducing properties, but the mechanism of its action is largely unknown. The aim of this study was to identify potential common target genes modulated at the transcriptional level following TRD treatment in tumour cell lines originating from different cancer types.MethodsFive different malignant cell lines (HT29, Chang Liver, HT1080, AsPC-1 and BxPC-3) were incubated with TRD (100 μM, 250 μM and 1000 μM). Proliferation after 8 h and cell viability after 24 h were analyzed by BrdU assay and FACS analysis, respectively. Gene expression analyses were carried out using the Agilent -microarray platform to indentify genes which displayed conjoint regulation following the addition of TRD in all cell lines. Candidate genes were subjected to Ingenuity Pathways Analysis and selected genes were validated by qRT-PCR and Western Blot.ResultsTRD 250 μM caused a significant inhibition of proliferation as well as apoptotic cell death in all cell lines. Among cell death associated genes with the strongest regulation in gene expression, we identified pro-apoptotic transcription factors (EGR1, ATF3) as well as genes involved in the ER stress response (PPP1R15A), in ubiquitination (TRAF6) and mitochondrial apoptotic pathways (PMAIP1).ConclusionsThis is the first conjoint analysis of potential target genes of TRD which was performed simultaneously in different malignant cell lines. The results indicate that TRD might be involved in different signal transduction pathways leading to apoptosis.

Appendicitis in the elderly. CRP value as decision support for diagnostic laparoscopy

BACKGROUND The diagnosis of acute appendicitis in the elderly bears many pitfalls due to a broad range of differential diagnoses and uncommon clinical presentation. This may result in late detection of appendicitis leading to poor outcome. The aim of this study was to examine the characteristics of appendicitis in elderly patients in order to facilitate early diagnosis. MATERIALS AND METHODS All patients who underwent appendectomy in our institution were prospectively recorded over a 30 month period. Data on patients age (>60 years versus < or =60 years), clinical findings, the inflammatory parameters leucocytes and C-reactive protein (CRP) and histological-findings (perforated versus non-perforated) were collected. Statistical analysis was carried out by ROC analysis, chi(2) and t-tests. RESULTS In the examination period 403 patients underwent appendectomy and 11.2% (n=45) were older than 60 years. These patients were characterized by significantly more frequent perforations compared to those patients < or =60 years (35.6% versus 7.0%, p< or =0.05), peritonitis (42.2% versus 9.5%, p< or =0.05), conversion to open surgery (23% versus 5%, p< or =0.005), longer postoperative hospital stay (9.2 days versus 4.3 days, p< or =0.05) and a higher complication rate (28.9% versus 3.6%, p< or =0.005). CRP values in patients >60 years were on average 123.2 mg/l and significantly higher than in patients < or =60 years (35.5 mg/l, p< or =0.005). The ROC analysis resulted in a CRP cut-off value of 101.9 mg/l for patients >60 years for the existence of a perforation with a specificity of 72.4% and a sensitivity of 81.3% (AUC 0.811). CONCLUSIONS The CRP value showed a strong correlation with respect to the grade of inflammation and perforation. In conclusion, elderly patients with symptoms of appendicitis and a CRP value higher than 102 mg/l should undergo early diagnostic laparoscopy.

Anastomosentechniken am Pankreas

Advances in pancreatic surgery during the last two decades have resulted in significant improvement of patient outcome leading to mortality rates as low as 3-5% following Whipples procedure in specialized centers. However, morbidity remains considerably high at 30-50% which is primarily caused by insufficiency of the pancreato-enteric anastomosis which becomes manifested as a pancreatic fistula. Therefore, numerous studies have aimed to identify the ideal pancreatic anastomosis. The most frequently used techniques comprise end-to-end duct-to-mucosa pancreaticojejunostomy, end-to-end invagination pancreatojejunostomy as well as end-to-side pancreatogastrostomy. In randomized controlled trials the frequency of pancreatic fistulas ranges between 4% and 20% depending on the particular technique. However, no single technique was able to demonstrate a significant superiority in several independent studies. The heterogeneity of definitions for pancreatic fistula represents the main problem in evaluating and comparing clinical studies on pancreato-enteric anastomosis. However, recent clinical trials applied commonly accepted definitions for pancreatic fistula as well as precise study endpoints to address the question of the ideal pancreatic anastomosis.ZusammenfassungFortschritte in der Pankreaschirurgie haben in den letzten beiden Jahrzehnten die Letalitätsraten nach Whipple-Operationen in spezialisierten Zentren auf Werte unter 3–5% sinken lassen. Dennoch bleibt die Morbidität, die vor allem durch Insuffizienzen der pankreatoenterischen Anastomose verursacht und als Pankreasfistel klinisch manifest wird, mit 30–50% immer noch sehr hoch. In zahlreichen Studien wurde daher versucht die „ideale Pankreasanastomose“ zu identifizieren. Zu den am häufigsten verwendeten Methoden gehören die End-zu-Seit-Duct-to-Mucosa-Pankreatikojejunostomie, die End-zu-End-Invaginations-Pankreatojejunostomie und die End-zu-Seit-Pankreatogastrostomie. In kontrolliert randomisierten Studien wurden je nach Anastomosentechnik Pankreasfistelraten zwischen 4% und 20% erreicht, ohne dass eine individuelle Methode in mehreren unabhängigen Studien einen signifikanten Vorteil aufweisen konnte. Ein großes Problem bei der Bewertung der Studien stellt die Heterogenität der Definitionen für eine Pankreasfistel dar. Allerdings bemühen sich jüngere Studien hier um die Verwendung allgemein anerkannter Definitionen und klarer Studienendpunkte, um zukünftig die Frage nach der „idealen Pankreasanastomose“ zu beantworten.AbstractAdvances in pancreatic surgery during the last two decades have resulted in significant improvement of patient outcome leading to mortality rates as low as 3–5% following Whipple’s procedure in specialized centers. However, morbidity remains considerably high at 30–50% which is primarily caused by insufficiency of the pancreato-enteric anastomosis which becomes manifested as a pancreatic fistula. Therefore, numerous studies have aimed to identify the ideal pancreatic anastomosis. The most frequently used techniques comprise end-to-end duct-to-mucosa pancreaticojejunostomy, end-to-end invagination pancreatojejunostomy as well as end-to-side pancreatogastrostomy. In randomized controlled trials the frequency of pancreatic fistulas ranges between 4% and 20% depending on the particular technique. However, no single technique was able to demonstrate a significant superiority in several independent studies. The heterogeneity of definitions for pancreatic fistula represents the main problem in evaluating and comparing clinical studies on pancreato-enteric anastomosis. However, recent clinical trials applied commonly accepted definitions for pancreatic fistula as well as precise study endpoints to address the question of the ideal pancreatic anastomosis.

Oral administration of the anti-proliferative substance taurolidine has no impact on dextran sulfate sodium induced colitis-associated carcinogenesis in mice

Background: New chemopreventive strategies for ulcerative colitis (UC)-associated dysplasia and cancer have to be evaluated. Taurolidine (TRD) has anti-inflammatory, anti-proliferative and anti-neoplastic properties with almost absent toxicity. The aim of the study was to determine whether TRD decreases dysplasia in the well-characterized Dextran Sulfate Sodium – Azoxymethane (DSS-AOM) animal model for UC-associated carcinogenesis. Material and Methods: The DSS-AOM model of carcinogenesis was induced in female inbred C57BL/6 mice. Half of the mice were treated with TRD, the other served as control. After 100 days macroscopic, histological and immunhistochemical (β-Catenin, E-Cadherin, SOX9, Ki-67, Cyclin-D1) examination of the colon was performed. Results: Incidence, multiplicity, grading and growth pattern of adenomas did not differ significantly between TRD and control group. In all animals, inflammatory changes were absent. Immunhistochemistry revealed increased expression of Ki-67, β-catenin, SOX9 and Cyclin-D1 in adenomas compared to normal mucosa – without significant difference between TRD and control treatment. Conclusion: Oral administration of TRD has no impact on DSS-induced colitis-associated carcinogenesis. However, SOX9 and Cyclin-D1 representing key members of the Wnt pathway have not yet been described in the DSS-AOM model of carcinogenesis – underlining the importance of this oncogenic pathway in this setting.

Anastomosentechniken am Pankreas@@@Technical aspects of pancreatoenteric anastomosis

Advances in pancreatic surgery during the last two decades have resulted in significant improvement of patient outcome leading to mortality rates as low as 3-5% following Whipples procedure in specialized centers. However, morbidity remains considerably high at 30-50% which is primarily caused by insufficiency of the pancreato-enteric anastomosis which becomes manifested as a pancreatic fistula. Therefore, numerous studies have aimed to identify the ideal pancreatic anastomosis. The most frequently used techniques comprise end-to-end duct-to-mucosa pancreaticojejunostomy, end-to-end invagination pancreatojejunostomy as well as end-to-side pancreatogastrostomy. In randomized controlled trials the frequency of pancreatic fistulas ranges between 4% and 20% depending on the particular technique. However, no single technique was able to demonstrate a significant superiority in several independent studies. The heterogeneity of definitions for pancreatic fistula represents the main problem in evaluating and comparing clinical studies on pancreato-enteric anastomosis. However, recent clinical trials applied commonly accepted definitions for pancreatic fistula as well as precise study endpoints to address the question of the ideal pancreatic anastomosis.ZusammenfassungFortschritte in der Pankreaschirurgie haben in den letzten beiden Jahrzehnten die Letalitätsraten nach Whipple-Operationen in spezialisierten Zentren auf Werte unter 3–5% sinken lassen. Dennoch bleibt die Morbidität, die vor allem durch Insuffizienzen der pankreatoenterischen Anastomose verursacht und als Pankreasfistel klinisch manifest wird, mit 30–50% immer noch sehr hoch. In zahlreichen Studien wurde daher versucht die „ideale Pankreasanastomose“ zu identifizieren. Zu den am häufigsten verwendeten Methoden gehören die End-zu-Seit-Duct-to-Mucosa-Pankreatikojejunostomie, die End-zu-End-Invaginations-Pankreatojejunostomie und die End-zu-Seit-Pankreatogastrostomie. In kontrolliert randomisierten Studien wurden je nach Anastomosentechnik Pankreasfistelraten zwischen 4% und 20% erreicht, ohne dass eine individuelle Methode in mehreren unabhängigen Studien einen signifikanten Vorteil aufweisen konnte. Ein großes Problem bei der Bewertung der Studien stellt die Heterogenität der Definitionen für eine Pankreasfistel dar. Allerdings bemühen sich jüngere Studien hier um die Verwendung allgemein anerkannter Definitionen und klarer Studienendpunkte, um zukünftig die Frage nach der „idealen Pankreasanastomose“ zu beantworten.AbstractAdvances in pancreatic surgery during the last two decades have resulted in significant improvement of patient outcome leading to mortality rates as low as 3–5% following Whipple’s procedure in specialized centers. However, morbidity remains considerably high at 30–50% which is primarily caused by insufficiency of the pancreato-enteric anastomosis which becomes manifested as a pancreatic fistula. Therefore, numerous studies have aimed to identify the ideal pancreatic anastomosis. The most frequently used techniques comprise end-to-end duct-to-mucosa pancreaticojejunostomy, end-to-end invagination pancreatojejunostomy as well as end-to-side pancreatogastrostomy. In randomized controlled trials the frequency of pancreatic fistulas ranges between 4% and 20% depending on the particular technique. However, no single technique was able to demonstrate a significant superiority in several independent studies. The heterogeneity of definitions for pancreatic fistula represents the main problem in evaluating and comparing clinical studies on pancreato-enteric anastomosis. However, recent clinical trials applied commonly accepted definitions for pancreatic fistula as well as precise study endpoints to address the question of the ideal pancreatic anastomosis.

Genexpressionsanalyse in unterschiedlichen malignen Tumorzelllinien nach Apoptose-Induktion durch Taurolidin mittels cDNA-Microarray

Background: Taurolidine (TRD) was initially used as an anti-infective agent. Recently, TRD has been shown to have apoptosis inducing properties, but the mechanism of action is largely unknown. The aim of this study was to examine the function of TRD in different malignant cell lines on gene expression level. Material and Methods: Five different malignant cell lines, HT29 (colon), Chang Liver (liver), HT1080 (fibrosarcoma), AsPC-1 and BxPC-3 (pancreas) were incubated with increasing concentrations of TRD (100, 250, und 1000 μM) for 6h and 24h. Proliferation rate as well as proportions of viable, apoptotic and necrotic cells were determined by BrdU-Assay and FACS analysis (AnnexinV/ Propidiumiodide staining), respectively (four consecutive passages). Gene expression analysis was carried out by Agilent cDNA-Microarray to indentify genes which displayed conjoint regulation in all cell lines. Furthermore, candidate genes were subjected to Ingenuity Pathways Analysis® to elucidate signal transduction pathways. Results: Incubation with TRD resulted in a significant dose dependent reduction of viable cells after 6 h and 24 h – leading to viable cells between 25.7 % (HT1080) and 66.2 % (HT29). Among all concentrations, TRD 250 μM in all cell lines showed the strongest effects in terms of reduction of viable cells, enhancement of apoptotic cells (FACS analysis) and inhibition of proliferation (BrdU assay). Among the cell death associated genes with the strongest regulation in gene expression (factor x45–x8), pro-apoptotic transcription factors (EGR1, FOS, FosB), pro-apoptotic proteins of the GADD family (GADD45B, GADD45A, GADD34), cell cycle regulators (E2F3, E2F6) as well as pro-apoptotic proteins of the Bcl-2 family (PMAIP1) were identified. Conclusion: This is the first conjoint analysis of potential target genes of TRD which was performed simultaneously in different malignant cell lines. The results indicate that TRD might be involved in different signal transduction pathways leading to apoptosis.