Mismatch repair deficiency, chemotherapy and survival for resectable gastric cancer: an observational study from the German staR cohort and a meta-analysis.

PURPOSE: In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings. METHODS: Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis. RESULTS: MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13-3.37, P = 0.63) and 1.44 (95% CI 0.66-3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14-0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89-1.58, P = 0.26). CONCLUSION: Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

Comparison of biological and alloplastic meshes in ventral incisional hernia repair.

PURPOSE: The aim of our retrospective analysis was to compare the results of incisional hernia repair by porcine small intestinal submucosa-derived (SIS) meshes with those obtained by alloplastic polypropylene-based (PP) meshes in comparable surgical indications by matched-pair design. We hypothesized that in incisional hernia, SIS mesh repair is associated with fewer recurrences and SSO than PP mesh repair in incisional hernias. METHODS: Twenty-four matched pairs (SIS vs. PP mesh repair between 1 January 2005 and 31 December 2013) were identified by matching criteria: gender, age, comorbidities, body mass index, EHS hernia classification, mesh implantation technique, CDC wound classification, and source of contamination/primary surgery leading to incisional hernia. Minimal follow-up time was 24 months. Means and standard deviations were compared by paired t test; categorial data were compared by McNemar's test. Poisson's distribution and negative binominal distribution were employed to detect significant correlation. RESULTS: There were no statistically significant differences between both groups in the pre- and perioperative factors and the follow-up times. There were significantly more wound complications (19 vs. 12, p = 0.041), longer hospital stay (22.0 ± 6.3 vs. 12.0 ± 3.1 days, p = 0.010), and significantly more recurrent hernias (25 vs. 12.5%, p = 0.004) after SIS mesh repair. Both the Poisson's distribution and the negative binominal distribution unveiled significantly more complication points (3-6 vs. 1-2) per month after SIS mesh repair. CONCLUSION: There is no advantage of SIS meshes compared to PP meshes in incisional hernia repair with different degrees of wound contamination in this matched-pair analysis. Further prospective and randomized trials or at least registry studies such as the EHS register with standardized and defined conditions are warranted.

A Step-by-Step Clinical Approach for the Management of Neuroendocrine Tumours.

Neuroendocrine tumours (NET) are rare neoplasms, but the incidence is permanently increasing. Most of the NETs are slow proliferating and clinically silent, and for that reason, they are often diagnosed at a stage with advanced disease. The complexity and diversity of the NET-biology require the treatment of patients in specialised centres to guarantee a qualified, multidisciplinary treatment planning. At our institution, we developed an interdisciplinary model for the assessment and treatment of NET. The aim was to adapt the guidelines to the clinical practice, exchange of current knowledge, and a tailored approach to the individual patient. In our team are included medical professionals from pathology, radiology, oncology, gastroenterology, oncological surgery, and nuclear medicine. In this paper, we describe step-by-step a procedural algorithm for the management of patients with neuroendocrine tumours, focusing on midgut-NETs in terms of therapy.

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract.

BACKGROUND: Biliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC. METHODS: Relative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival. RESULTS: SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865-0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631-0.873). CONCLUSIONS: SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.

[Surgical Therapy and Prognostic Factors for Carcinoma of Vater's Papilla]. / Chirurgische Therapie und prognostische Faktoren des Papillenkarzinoms.

BACKGROUND: Carcinoma of ampulla of Vater are rare tumours of the GI-tract with an improved prognosis compared to other periampullary tumours. Analysis of survival and prognostic factors are limited due to the low incidence of the carcinoma. The intention of this study in patients with papillary carcinoma was to evaluate short- and long-term survival and to identify prognostic factors for pancreatectomy and reconstruction using pancreatogastrostomy as treatment of carcinoma of Vater's ampulla. PATIENTS AND METHODS: Between 1989 and 2008 76 patients with a carcinoma of the ampulla of Vater were treated by oncological resection followed by pancreatogastrostomy. Various factors such as demographics, perioperative factors, histopathological findings as well as short- and long-term survival were evaluated retrospectively. Data were analysed statistically using Kaplan-Meier estimates of survival with log-rank test and uni- and multivariate analysis with Cox regression. RESULTS: The overall 5-year survival was 46 %, the 10-year survival 26 % for resected patients. By univariate analysis we could demonstrate that lymph node metastasis is the only predictor for outcome. In the multivariate analysis, age, sex, grading and especially lymph node status were a significant predictor for the survival of patients. CONCLUSION: In the current patient cohort lymph node status was the most important independent predictor of outcome after resection of carcinoma of Vater's papilla.

[Laparoscopic coincidental finding in a case of incomplete ileus: adenocarcinoma of the small intestine as first manifestation of Crohn's disease]. / Laparoskopischer Zufallsbefund bei inkomplettem Ileus: Adenokarzinom des Dünndarms als Erstmanifestation eines Morbus Crohn.

The case-study reminds of adenocarcinoma of the small intestine as a rare complication of Crohn's disease. A few more than 100 of these cases have been published. Epidemiological studies concerning small bowel carcinoma showed consumption of sugar and carbohydrates as pathogenetic factors, other conditions like ileostoma, ileumconduit, Crohn's disease and coeliac disease have been identified to some extent. An adenoma-carcinoma sequence as in large intestine carcinoma has been discussed. Immunohistochemical and oncogenetic findings failed to demonstrate any result of practical clinical value. Diagnosis of early stages of adenocarcinoma of the small intestine is very difficult and thus might be impossible to differentiate from exacerbation or progressive stenosis of preexisting Crohn's disease. If non-invasive diagnostic measures (ultrasound, small bowel enema, CT-scan, intestinoscopy, radiography, NMR-Sellink, capsule-endoscopy) fail to clear the situation a diagnostic laparoscopy or even laparotomy should not be delayed. This constitutes the only chance to discover early stages which can possibly be cured in accordance with oncosurgical principles. Otherwise the prognosis remains poor with a high percentage of late stages and a 5-year-survival-rate between 20 and 50 percent.

Ribosomal subunit kinase-2 is required for growth factor-stimulated transcription of the c-Fos gene.

Ribosomal subunit kinases (Rsk) have been implicated in the regulation of transcription by phosphorylating and thereby activating numerous transcription factors, such as c-Fos, cAMP responsive element binding protein (CREB), and nuclear receptors. Here we describe the generation and characterization of immortalized embryonic fibroblast cell lines from mice in which the Rsk-2 gene was disrupted by homologous recombinant gene targeting. Rsk-2-deficient (knockout or KO) cell lines have no detectable Rsk-2 protein, whereas Rsk-1 expression is unaltered as compared with cell lines derived from wild-type control mice. KO cells exhibit a major reduction in platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF)-1-stimulated expression of the immediate-early gene c-Fos. This results primarily from a reduced transcriptional activation of the ternary complex factor Elk-1 and reduced activation of the serum response factor. The reduced Elk-1 activation in KO cells occurs despite normal activation of the mitogen-activated protein kinase pathway and normal PDGF- and IGF-1-stimulated Elk-1 phosphorylation. By contrast, PDGF- and IGF-1-stimulated phosphorylation and transcriptional activation of CREB is unaltered in KO cells. Thus Rsk-2 is required for growth factor-stimulated expression of c-Fos and transcriptional activation of Elk-1 and the serum response factor, but not for activation of CREB or the mitogen-activated protein kinase pathway in response to PDGF and IGF-1 stimulation.