Trastuzumab-based therapy has been shown to confer overall survival benefit in HER2-positive patients with advanced gastric cancer in a large multicentric trial (ToGA study). Subgroup analysis identified adenocarcinomas of the stomach and gastroesophageal (GE) junction with overexpression of HER2 according to immunohistochemistry (IHC) as potential responders. Due to recent approval of trastuzumab for HER2 positive metastatic gastric and GE-junction cancer in Europe (EMEA) HER2 diagnostics is now mandatory with IHC being the primary test followed by fluorescence in situ hybridization (FISH) in IHC2+ cases. However, in order to not miss patients potentially responding to targeted therapy determination of a HER2-positive status for gastric cancer required modification of scoring as had been proposed in a pre-ToGA study. To validate this new HER2 status testing procedure in terms of inter-laboratory and inter-observer consensus for IHC scoring a series of 547 gastric cancer tissue samples on a tissue microarray (TMA) was used. In the first step, 30 representative cores were used to identify specific IHC HER2 scoring issues among eight French and German laboratories, while in the second step the full set of 547 cores was used to determine IHC HER2 intensity and area score concordance between six German pathologists. Specific issues relating to discordance were identified and recommendations formulated which proved to be effective to reliably determine HER2 status in a prospective test series of 447 diagnostic gastric cancer specimens.
Gene expression profiles provide important information about the biology of breast tumors and can be used to develop prognostic tests. However, the implementation of quantitative RNA-based testing in routine molecular pathology has not been accomplished, so far. The EndoPredict assay has recently been described as a quantitative RT-PCR-based multigene expression test to identify a subgroup of hormone–receptor-positive tumors that have an excellent prognosis with endocrine therapy only. To transfer this test from bench to bedside, it is essential to evaluate the test–performance in a multicenter setting in different molecular pathology laboratories. In this study, we have evaluated the EndoPredict (EP) assay in seven different molecular pathology laboratories in Germany, Austria, and Switzerland. A set of ten formalin-fixed paraffin-embedded tumors was tested in the different labs, and the variance and accuracy of the EndoPredict assays were determined using predefined reference values. Extraction of a sufficient amount of RNA and generation of a valid EP score was possible for all 70 study samples (100%). The EP scores measured by the individual participants showed an excellent correlation with the reference values, respectively, as reflected by Pearson correlation coefficients ranging from 0.987 to 0.999. The Pearson correlation coefficient of all values compared to the reference value was 0.994. All laboratories determined EP scores for all samples differing not more than 1.0 score units from the pre-defined references. All samples were assigned to the correct EP risk group, resulting in a sensitivity and specificity of 100%, a concordance of 100%, and a kappa of 1.0. Taken together, the EndoPredict test could be successfully implemented in all seven participating laboratories and is feasible for reliable decentralized assessment of gene expression in luminal breast cancer.
Several etiopathogenetic factors responsible for carcinogenesis in the operated stomach have been proposed in the literature, but exact proof is still lacking. An experimental assay was planned to determine the pathogenetic roles of surgical trauma, of duodenogastric reflux, and of carcinogen application and its effects. Five different techniques of gastric surgery were performed on a collective of 466 Wistar rats: Billroth I resection, Billroth II resection, Billroth II plus gastroenterostomy with Roux-en-Y technique, Billroth II plus Braun's anastomosis, and gastroenterostomy without resection. Forty-two animals were left unoperated as controls. The appropriate date for autopsy was determined by general clinical observation and random endoscopic and radiologic examinations, and eventually fixed on the 56th postoperative week.Carcinomas developing in the resected stomach were found in animals with and without carcinogen exposure. The actual rate of carcinoma incidence was strongly dependent on the surgical procedure chosen for the respective group. The lowest carcinoma incidence (0%) was found in gastroenterostomy without Roux-en-Y anastomosis, the highest rate (70% without carcinogen, 50% with carcinogen application) in gastroenterostomy alone.Tumor development was found to be connected with alterations of the physiological environment induced by the surgical intervention; a direct association between duodenogastric reflux and tumorigenesis can be postulated. The results of the present study are interpreted with an emphasis on reflux-preventing techniques for gastric surgery that should be included in clinical routine.
Currently, early detection of breast cancer offers the most promising possibility to optimize the diagnosis and treatment of breast cancer and, as a result, reduce breast cancer mortality and improve health related quality of life in women.
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