Sabine Kersting

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.

The JNK inhibitor XG-102 protects against TNBS-induced colitis.

The c-Jun N-terminal kinase (JNK)-inhibiting peptide D-JNKI-1, syn. XG-102 was tested for its therapeutic potential in acute inflammatory bowel disease (IBD) in mice. Rectal instillation of the chemical irritant trinitrobenzene sulfonic acid (TNBS) provoked a dramatic acute inflammation in the colon of 7–9 weeks old mice. Coincident subcutaneous application of 100 µg/kg XG-102 significantly reduced the loss of body weight, rectal bleeding and diarrhoea. After 72 h, the end of the study, the colon was removed and immuno-histochemically analysed. XG-102 significantly reduced (i) pathological changes such as ulceration or crypt deformation, (ii) immune cell pathology such as infiltration and presence of CD3- and CD68-positive cells, (iii) the production of tumor necrosis factor (TNF)-α in colon tissue cultures from TNBS-treated mice, (iv) expression of Bim, Bax, FasL, p53, and activation of caspase 3, (v) complexation of JNK2 and Bim, and (vi) expression and activation of the JNK substrate and transcription factor c-Jun. A single application of subcutaneous XG-102 was at least as effective or even better depending on the outcome parameter as the daily oral application of sulfasalazine used for treatment of IBD. The successful and substantial reduction of the severe, TNBS-evoked intestinal damages and clinical symptoms render the JNK-inhibiting peptide XG-102 a powerful therapeutic principle of IBD.

Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma

CONTEXT Rare solid tumors of the pancreas can be misinterpreted as primary pancreatic cancer. OBJECTIVE The aim of this study was to report our experience in the treatment of patients with rare tumor lesions of the pancreas and to discuss clinical and pathological characteristics in the context of the role of surgery. DESIGN Data from patients of our prospective data-base with rare benign and malignant tumors of the pancreas, treated in our division from January 2004 to August 2010, were analyzed retrospectively. RESULTS One-thousand and ninety-eight patients with solid tumors of the pancreas underwent pancreatic surgery. In 19 patients (10 women, 9 men) with a mean age of 57 years (range: 20-74 years) rare pancreatic tumors (metastasis, solid pseudopapillary tumor, teratoma, hemangioma, accessory spleen, lymphoepithelial cyst, hamartoma, sarcoidosis, yolk sac tumor) were the reason for surgical intervention. CONCLUSION If rare benign and malignant pancreatic tumors, intrapancreatic metastasis, as well as pancreatic malformations or other abnormalities, present themselves as solid masses of the pancreas, they constitute an important differential diagnosis to primary pancreatic neoplasia, e.g. pancreatic ductal adenocarcinoma. Clinical imaging techniques cannot always rule out malignancy, thus operative exploration often remains the treatment of choice to provide the correct diagnosis and initiate adequate surgical therapy.

The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium.

Purpose: The c-Jun N-terminal kinases (JNK) are involved in the activation of T cells and the synthesis of proinflammatory cytokines. Several studies have established the relevance of the JNK pathway in inflammatory bowel diseases. The present study analyzed the therapeutic effect of D-JNKI-1, a specific JNK-inhibiting peptide, in a low-dose dextran sulfate sodium (DSS) model of chronic colitis. Methods: DSS colitis was induced in female C57/BL6 mice by cyclic administration using different concentrations of DSS (1.0% and 1.5%). Mice in the intervention groups received subcutaneous administration of 1 μg/kg D-JNKI-1 on days 2, 12, and 22. They were monitored daily to assess the severity of colitis, body weight, stool consistency, and the occurrence of occult blood or gross rectal bleeding using evaluation of the disease activity index. The animals were sacrificed after 30 days, and the inflamed intestine was histologically evaluated using a crypt damage score. Immunohistochemical quantification of CD4+ and CD8+ cells was also carried out. Results: Administration of 1 μg/kg D-JNKI-1 resulted in a significant decrease in the disease activity index (P = 0.013 for 1.0% DSS; P = 0.007 for 1.5% DSS). As a mild form of colitis was induced, histological examination did not show any distinct damage to the mucosa and crypts. However, expression of CD4+ and CD8+ cells was reduced in mice treated with D-JNKI-1 (not significant). Conclusion: Administration of D-JNKI-1 resulted in a clinical attenuation of chronic DSS colitis, and a therapeutic effect of D-JNKI-1 must therefore be assumed. The decrease in CD4+ and CD8+ cells may reflect the influence of D-JNKI-1 on T-cell activation, differentiation, and migration.

Knockout of the c-Jun N-terminal Kinase 2 aggravates the development of mild chronic dextran sulfate sodium colitis independently of expression of intestinal cytokines TNFα, TGFB1, and IL-6

Introduction The c-Jun N-terminal kinases (JNKs) are involved in signal transduction of inflammatory bowel diseases. The aim of this study was to examine the function of JNKs by using a low-dose dextran sulfate sodium (DSS) model in JNK1 knockout mice (Mapk8−/−), JNK2 knockout mice (Mapk9−/−), and wild-type controls (WT1, WT2). Methods The animals were evaluated daily using a disease activity index. After 30 days, the intestine was evaluated histologically with a crypt damage score. CD4+ and CD8+ cells were quantified using immunofluorescence. Analysis of tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), and transforming growth factor β1 (TGFB1) expression was carried out using LightCycler® real-time polymerase chain reaction. Results Cyclic administration of low-dose DSS (1%) was not able to induce features of chronic colitis in Mapk8−/− WT2 mice. By contrast, DSS administration significantly increased the disease activity index in WT1 and Mapk9−/− mice. In Mapk9−/− mice, the crypt damage score and the number of CD4+ and CD8+ cells as features of chronic colitis/inflammation were also significantly elevated. Expression of TNFα, IL-6, and TGFB1 was not altered by the JNK knockout. Conclusion Administering DSS at a defined low concentration that is unable to induce colitis in WT animals leads to clinically and histologically detectable chronic colitis in Mapk9−/− mice. The reason for this disease-inducing effect resulting from the loss of JNK2 remains to be elucidated. Expression of TNFα, IL-6, and TGFB1 does not appear to be involved; proapoptotic JNK2 may prolong the activity of proinflammatory immune cells, leading to perpetuation of the inflammation.

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.

Amyloidosis of the small intestine following whipple operation is a rare cause of chronic ileus and has to be considered as differential diagnosis

INTRODUCTION When patients who underwent a Whipple operation because of a tumour of the pancreas develop symptoms of chronic ileus several months after surgery, the most common cause is a relapse of tumour growth or a peritoneal carcinomatosis. In this paper we report that secondary amyloidosis of the small intestine can produce similar symptoms and has to be evaluated as a rare differential diagnosis in chronic ileus. CASE REPORTS Three patients (2 men: 82, 70 years old and 1 woman 70 years old) were admitted to our hospital with symptoms of chronic ileus. All of them had undergone a Whipple operation several months (4, 5, 13 months) before. In two patients surgery was performed due to carcinoma in situ and in one patient due to benign cystadenoma of the pancreas. Chronic ileus resulted in relaparotomy in all patients. Surprisingly, the intraoperative situs did not show any tumour growth. Instead severe adhesions of the small intestine were detected. The entire small intestine was covered with a substance that had a similar aspect to sugar icing. Thereby the motility of the small intestine was constricted. An extensive adhaesiolysis and a decompression of the bowel was carried out. By histopathology, amyloidosis was diagnosed using congo red staining. Diffuse amyloid deposits were found on the small intestine. In the postoperative course two patients could be discharged free of complaints after 7 to 9 days in the hospital. One man died four months later, after transfer to a geriatric hospital, because of intestinal atony and a serious senile depression. CONCLUSION Secondary amyloidosis following the Whipple operation is a rare reason for the symptoms of chronic ileus. Surgeons have to keep in mind that amyloidosis is a possible differential diagnosis in addition to relapse of tumour growth and peritoneal carcinomatosis in these patients. Thus, in our opinion, relaparotomy should be undertaken as early as possible because this is the only chance to detect the cause of chronic ileus.

Synchronous lymph node and liver metastasis in a well differentiated gastric endocrine tumour type I.

Abstract Gastric endocrine tumours constitute less than 1% of all (neuro-)endocrine tumours and less than 2% of all gastrointestinal malignancies. They are classified into three groups: well-differentiated endocrine tumours, well-differentiated endocrine carcinoma, poorly-differentiated endocrine carcinoma. We report the rare case of a patient with a metastasising gastric endocrine tumour that histologically revealed all signs of a well-differentiated endocrine tumour.

Knock out der c-Jun N-terminalen Kinase 2 (JNK2) aggraviert die Entwicklung der chronischen DSS Colitis unabhängig von der intestinalen Zytokin-Expression

Background The c-Jun N-terminal kinase 2 (JNK2) is involved in signal transduction of inflammatory bowel diseases (IBD) and regulates the expression of pro-inflammatory cytokines. For this reason, JNK2 is considered as novel target for IBD therapy. The aim of this study was 1.) to examine the function of JNK2 applying a low dose Dextran Sulfate Sodium (DSS) model of chronic experimental colitis in JNK2 knock out mice and 2.) to analyze the expression of JNK2 dependent cytokines. Material and Methods: For induction of a mild chronic colitis, female JNK2 knockout mice (JNK2 ko) and their wildtype controls (WT2) received three cycles of DSS treatment, each consisting of 1.0 % DSS for 5 days, followed by 5 days with water. Control groups of both genotypes received water only (each n = 9). Animals were daily evaluated by a disease activity index (DAI). After 30 days all animals were sacrificed, and the inflamed intestine was histologically evaluated by a crypt damage score (CDS). Analysis of TNFα, IL-6 and TGFβ expression in the colon was carried out using LightCycler® real-time PCR with calibrator-normalized quantification. Statistical analysis was carried out by ANOVA. P-values ≤ 0.05 were considered statistically significant. Results: In WT2 animals, application of 1.0 % DSS did not induce a chronic colitis reflected by a mean DAI of 1.14 (± 0.38) which was not significantly elevated compared to 0.58 (± 0.15) in the H2O control group. In contrast, DSS application in JNK2 ko animals resulted in a chronic colitis with a mean DAI of 2.32 (± 0.28) which was significantly higher compared to the H2O control group with 0.61 (± 0.15) (p ≤ 0.001) and compared to the WT2-DSS group (p ≤ 0.05). The calibrator normalized quantitative real-time PCR did not show any significant differences between the four experimental groups regarding the expression of TNFα, IL-6 and TGFβ. Conclusion: DSS application in a definite concentration (1.0 %), which is unable to induce colitis in wildtype animals, leads to a clinically and histologically detectable chronic colitis in JNK2 ko mice. It remains to be elucidated how inactivation of JNK2 aggravates DSS colitis. However, the JNK2 dependent expression of TNFα, IL-6 and TGFβ does not play a major role. We hypothesize that the functional deletion of the otherwise pro-apoptotic JNK2 prolongs the activity of pro-inflammatory immune cells leading to a perpetuation of the inflammation. Thus inhibition of JNK2 does not represent a reasonable principal in IBD therapy.