GIST: Correlation of risk classifications and outcome.

In clinical practice, there are often discrepancies between the oncological prognosis of gastrointestinal stromal tumors (GIST) and the actual clinical course. This study aimed to check with our collective how reliably the current classifications (Miettinen, Fletcher) predict the prognosis of GIST and to evaluate whether an extension of the classifications by the parameter proliferation activity could make sense. This prospective study enrolled 58 patients who underwent surgery on GIST from 01/2006 to 12/2016. The postoperative course (curation, recurrence, progress) was correlated with the identified risk classification and the proliferative activity. Coincidences with other tumors were strikingly common in patients with GIST (43%). Based on the risk group assignment of GIST, no assessment of the probability of the occurrence of second neoplasia could be derived. Individual patients were under- or over-graduated concerning the assessment of biological behavior based on the standard risk classifications. The inclusion of proliferative activity did not allow for a more precise predictive power - neither to the risk of recurrence and metastasis nor to the development of a second neoplasia. The study showed that there is currently no parameter or logarithm that reliably predicts the biological behavior of GIST. Due to the frequency of coincidence of second neoplasia and (rare) distant metastases, for everyday clinical practice, appropriate staging diagnostic and regular follow-up care should also be used for benign GIST.

[Solid pseudopapillary neoplasms of the pancreas : Diagnostics, surgical treatment and postoperative outcome]. / Solid-pseudopapilläre Neoplasien des Pankreas : Diagnostik, chirurgische Therapie und postoperatives Outcome.

BACKGROUND: Malignant solid pseudopapillary neoplasms (SPN) are rare tumor entities of the pancreas. The prognosis for SPN is generally excellent, although some tumors have malignant potential and tend to metastasize or relapse. OBJECTIVE: The aim was to investigate whether there are histopathological or surgical risk factors that enable the biological potential of SPN to be estimated. PATIENTS AND METHODS: Data from patients with SPN treated in two large German pancreas centers from 2009 to 2018 were evaluated with respect to the occurrence of SPN, surgical management, histopathological tumor characteristics and the postoperative outcome. RESULTS: A total of 22 patients with SPN (17 women, 5 men) were operated on. The median age of the patients was 37 years (range 19-69 years). At the time of surgery 20 patients showed tumor growth limited to the pancreas. A female patient with recurrence of an externally resected SPN had lymph node involvement. Another female patient had a hepatic metastatic recurrence (Union Internationale contre Cancer (UICC) stage IV) of an externally resected SPN. Although all patients survived recurrence-free during the follow-up, this patient developed liver metastases again. The survival rate up to the end of the follow-up (median 43 months; range 1-132 months) of this study was 100%. CONCLUSION: There is a lack of knowledge of the possible parameters that can be used to predict the biological behavior of SPN. Apart from an increased likelihood of recurrence after resection of an SPN recurrence, no clear risk factors could be identified in the examined patient collective that could indicate an increased malignant potential and a possibly poorer outcome. Only a radical surgical resection with lymphadenectomy enables a reliable assessment of the tumor stage and the removal of possibly affected lymph nodes, which could be the cause of a recurrence if left intact.

[Prophylactic Appendectomy: Yes or No?] / Begleitappendektomie: ja oder nein?

Background At more than 50%, appendicitis is the leading cause of acute intra-abdominal disease requiring surgery. In the course of various other operations, prophylactic appendectomy (PA) is frequently performed. Objectives This study examines to what extent PA is justified. Patients and Methods A prospective study was performed in all patients (n = 173) undergoing prophylactic appendectomy in Katharinen Hospital Unna between January 2010 and October 2013. The following variables were analysed: age, gender, type of primary surgery, emergency or elective surgery, complications, lethality, intraoperative and histopathological evaluation of the appendix. In addition, patients were contacted postoperatively with the request to complete a questionnaire. Results Prophylactic appendectomy was carried out without any specific complications. 117 patients (68%) participated in the survey. 15% of these patients had suffered symptoms that could be attributable to irritation of the appendix. With only one exception, all appendectomy specimens revealed pathological findings in the histopathological examination. PA allowed the early diagnosis of 4 adenomas, one neuroendocrine tumour and 6 metastases or manifestations of peritoneal carcinomatosis. Conclusion PA is ethically justifiable, as there are few complications. Moreover, it can help to avoid future appendicitis and allows early detection of malignancies.

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 ß1 (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.

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 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.

Contemporary single-center surgical experiences in redo procedures of the pancreas: improved outcome and reduction of operative risk.

INTRODUCTION: Redo procedures of the pancreas are complex operations associated with significant morbidity and mortality rates. The operative risk may be minimised when indications for redo procedure are well reflected and operation is performed by an experienced surgeon. The aim of this study was to confirm this hypothesis evaluating our experiences with redo procedures. METHODS: We reviewed 28 patients (mean age of 54 years; range 11-75 years) undergoing a redo procedure of the pancreas from January 2004 to June 2008 at our hospital. The term redo procedure was defined as a pancreatic reoperation that was carried out after preceding pancreatic surgery. Relaparotomies following acute complications after pancreatic surgery were not taken into consideration. RESULTS: The following parameters were evaluated: median operative time 332 min (range 160-730 min), median intraoperative blood loss 625 ml (range 300-2,800 ml), median postoperative stay on Intensive Care Unit 20 h (range 0-112 h), median postoperative hospital stay 15 days (range 7-98), morbidity (14%), and mortality (3.6%). CONCLUSIONS: Redo procedures of the pancreas can be performed with low complication rates. In order to achieve a satisfactory outcome, the indication of redo procedures has to be well reflected, and operation may be performed by specialised and experienced surgeons.

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 TP's 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.

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 (beta-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, beta-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.

Intestinal cancer in patients with Crohn's disease.

BACKGROUND: Surveillance of intestinal cancer in Crohn's disease (CD) has often been advocated. To date, no clear evidence exists whether CD patients are at special risk for intestinal cancer. An increased incidence of small bowel adenocarcinoma is suggested. However, recent figures also suggest an increased risk of CD associated colorectal cancer. We report our experience with 10 cases of CD complicated by intestinal adenocarcinoma. MATERIALS AND METHODS: Our institutional database included 330 patients treated for CD between 1988-2005. Data of patients that developed carcinoma within Crohn's lesions of either small or large bowel were analyzed. RESULTS: Ten patients were diagnosed with CD complicated by carcinoma. In nine patients, cancer was present in the colorectum and in one, in Crohn's ileitis. Tumors were in conjunction with fistulae in three and developed within strictures in five patients. Mean age at the time of diagnosis of CD was 43 years. Mean duration of CD until diagnosis of cancer was 14 years. Only five patients were diagnosed for cancer preoperatively. Staging revealed advanced tumors in almost all patients. Mean survival after surgery was 29 months (2-149 months). CONCLUSIONS: Cancer risk in CD and especially in Crohn's colitis may still be underestimated. Delayed diagnosis resulted in a poor prognosis. The value of colonoscopy as surveillance tool is questioned by the fact that in our patients, carcinoma was diagnosed in some patients preoperatively by routine colonoscopy. Therefore, additional markers should be identified to detect CD patients at risk.

Antigen transport and cytoskeletal characteristics of a distinct enterocyte population in inflammatory bowel diseases.

Intestinal antigen uptake is enhanced in inflammatory bowel disease. We analyzed transcellular transport routes of antigens in different compartments of normal enterocytes and atypical intestinal epithelial cells called "rapid antigen uptake into the cytosol enterocytes" (RACE cells). These cells constitute a recently described population of enterocyte-derived cells, which are increased in inflammatory bowel disease. Mucosa of freshly resected specimens were incubated with the antigens ovalbumin or horseradish peroxidase. Ultrastructural labeling patterns of differentiation-dependent proteins, the brush-border enzyme sucrase-isomaltase and the cytoskeleton proteins villin and actin, were determined in enterocytes. Apoptosis was investigated biochemically and ultrastructurally by cleavage of caspase-3. Both antigens were transported to late endosomes and to trans-Golgi vesicles of enterocytes in inflammatory bowel disease and control specimens. Quantitative evaluation revealed a significantly increased transepithelial antigen transport in both compartments of RACE relative to normal enterocytes. Labeling densities for sucrase-isomaltase, villin, and actin were decreased in RACE relative to normal enterocytes. Caspase-3 was not increased in RACE cells relative to controls. RACE cells are characterized by increased antigen transport to late endosomes and the trans-Golgi network, a disassembled cytoskeleton and lower concentrations of proteins that are markers of cell differentiation.

Preoperative steroid administration: effect on morbidity among patients undergoing intestinal bowel resection for Crohns disease.

Long-term steroid therapy may predispose to increased perioperative morbidity in patients undergoing surgery with bowel anastomoses. The aim of our study was to review our data to determine if the steroid dosage is associated with the incidence of early complications after bowel resection in patients with prolonged steroid therapy for Crohns disease (CD). Altogether, 397 patients underwent bowel resection with primary intestinal anastomoses for CD between 1982 and 2000 in our institution. The mortality and morbidity rates, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and length of postoperative hospitalization in patients who were having high-dose (>/= 20 mg of prednisolone per day, n = 73) and low-dose (< 20 mg prednisolone per day, n = 146) steroid therapy for more than 1 month before surgery were compared with those of patients ( n = 177) who were not receiving steroids. Statistical analysis was performed using Fisher's exact test and Student's t-test, with p < 0.05 considered significant. The three groups were similar in terms of gender, duration since first diagnosis, American Society of Anesthesiologists classification, and obesity. Mortality, morbidity, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and average postoperative stay were not statistically different in patients with high-dose, low-dose, or no steroid therapy. The only factor associated with increased morbidity was a low preoperative hemoglobin level. Our results demonstrate that, in patients who are undergoing bowel resection for CD, even high-dose prolonged preoperative systemic steroid therapy is not associated with increased postoperative complications.