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Ruschoff J.,Institute of Pathology Nordhessen | Ruschoff J.,Targos Advance AG | Kerr K.M.,Royal Infirmary | Grote H.J.,Merck KGaA | And 20 more authors.
Archives of Pathology and Laboratory Medicine | Year: 2013

Context.-The addition of cetuximab to first-line chemotherapy substantially prolonged survival in patients with advanced non-small cell lung cancerwhose tumors expressed high levels of epidermal growth factor receptor (EGFR; immunohistochemistry score of ≥200 on a scale of 0-300). Objective.-To evaluate the interobserver reproducibility of this EGFR immunohistochemistry scoring system, based on both the tumor cell membrane staining intensity (graded 0-3) and the percentage of cells staining at each intensity. Design.-In parts 1 (initial feasibility study) and 2 of this 2-part round robin test, sections of different non-small cell lung cancer tissue microarrays were stained in a central reference laboratory. Following reference evaluation, EGFR expression in 30 selected tumor cores was characterized in serial sections by lung cancer pathology specialists. The reproducibility of scoring by different raters was assessed. Analysis of between-rater agreement was based on the allocation of EGFR immunohistochemistry scores into low- (<200) and high- (≥200) EGFR expression groups. Results.-After discussion with raters of the issues impacting reproducibility identified in part 1 and following adjustment of processes, part 2 of the round robin test showed a high interobserver agreement in EGFR immunohistochemistry scoring, with an overall concordance rate of 90.9% and a mean coefficient of 0.812. Specimens with a reference EGFR immunohistochemistry score of lower than 200 and of 200 or higher showed mean concordance rates of 94.7% and 85.6%, respectively. Conclusions.-After appropriate training, assessing EGFR expression by this immunohistochemistry-based method allowed a highly reproducible allocation of non- small cell lung cancers into clinically relevant high- or low-EGFR expression groups. Source

Cejka D.,Medical University of Vienna | Marculescu R.,Medical University of Vienna | Kozakowski N.,Clinical Institute of Pathology | Kozakowski N.,Medical University of Vienna | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Sclerostin serum levels are increased in patients with chronic kidney disease (CKD). Osteoporosis and CKD often occur simultaneously. Currently antisclerostin antibodies are in clinical development for the treatment of osteoporosis. Objective: The objective of this study was to study the renal handling of sclerostin. Design: This was a cross-sectional study. Setting: The study was conducted at a university hospital and outpatient renal clinic. Patients: One hundred twenty men and women with CKD stage 1-5 participated in the study. Intervention: Measurements of sclerostin in urine and serum (ELISA), renal function [estimated glomerular filtration rate (eGFR)], electrolytes, α1-microglobulin, PTH, vitamin D, and markers of bone turnover were conducted. Eight human kidney biopsies were stained for sclerostin using immunohistochemistry. Main Outcome Measure: Urinary excretion of sclerostin was measured. Results: Urinary sclerostin excretion increased with declining eGFR (R = -0.75, P < .001), from 10.4 (±12.7) pmol/L in patients with eGFR greater than 90 mL/min per 1.73 m2 (CKD stage 1) to 117.9 (±65.4) pmol/L in patients with eGFR less than 15 mL/min per 1.73 m2 (CKD stage 5, P < .001). Fractional excretion of sclerostin increased with declining eGFR (R = -0.83, P < .001) from 0.45% (±0.6%) in CKD 1 to 26.3% (±17.6%) in CKD 5 (P < .001). Fractional excretion of sclerostin correlated with fractional excretion of α1-microglobulin (R = 0.82, P < .001). No association between serum sclerostin and fractional excretion of phosphorus was found in a multivariate analysis. Sclerostin was detected in proximal tubular cells, showing a diffuse cytoplasmic staining pattern. Conclusion: Increased sclerostin serum levels in CKD patients are not due to decreased renal elimination. On the contrary, renal elimination increases with declining kidney function. Whether this has consequences on antisclerostin antibody dosing, efficacy, or safety in patients with CKD remains to be determined. (J Clin Endocrinol Metab 99: 248-255, 2014). © Copyright 2014 by The Endocrine Society. Source

Dolak W.,Medical University of Vienna | Raderer M.,Medical University of Vienna | Maresch J.,Medical University of Vienna | Muellauer L.,Medical University of Vienna | And 3 more authors.
Endoscopy | Year: 2011

Mucosa-associated lymphoid tissue (MALT) lymphoma is thought to be a multifocal disease with sometimes synchronous involvement of various mucosal structures. In this study we aimed to evaluate the potential involvement of the small bowel in patients suffering from gastric MALT lymphoma by analyzing the results of enteroscopy, a technique that allows easy and safe access to the small bowel with the potential for histological assessment of biopsy samples. We have retrospectively evaluated 347 enteroscopies and found nine patients with gastric MALT lymphoma who had undergone push enteroscopy with serial biopsies during staging. All patients tolerated enteroscopy without side effects, and no local complications occurred. In eight cases no evidence of duodenal or jejunal involvement was found macroscopically or by histological assessment of biopsies, while in one patient enteroscopy revealed jejunal MALT lymphoma infiltration with macroscopic accentuation of mucosal parts and consecutive histopathological verification more distal than 50cm. This single-center retrospective analysis shows that enteroscopy can provide additional diagnostic information in patients with gastric MALT lymphoma, although the number of patients was small and only one out of nine patients showed hitherto undetected MALT lymphoma deposits. Further studies may quantify the additional diagnostic yield provided by this easy and safe endoscopic method. © Georg Thieme Verlag KG Stuttgart, New York. Source

Bago-Horvath Z.,Clinical Institute of Pathology | Grusch M.,Medical University of Vienna | Lackner A.,Medical University of Vienna | Pirker C.,Medical University of Vienna | And 6 more authors.
Neuroendocrinology | Year: 2012

Background: Epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) are crucial targets in cancer therapy. Combined inhibition of both targets yielded synergistic effects in vitro and in vivo in several cancer entities. However, the impact of EGFR and mTOR expression and combined inhibition in neuroendocrine lung tumors other than small-cell lung cancer remains unclear. Material and Methods: Expression and activation of EGFR/AKT/mTOR pathway constituents were investigated in typical and atypical bronchial carcinoid (AC) tumors and large-cell neuroendocrine lung carcinomas (LCNEC) by immunohistochemistry in 110 tumor samples, and correlated with clinicopathological parameters and patient survival. Cytotoxicity of mTOR inhibitor everolimus and EGFR inhibitor erlotinib alone and in combination was assessed using growth inhibition assay in NCI-H720 AC and SHP-77 LCNEC cells. Cell cycle phase distribution was determined by FACS. Apoptosis-associated activation of caspase-3/7 was measured by Caspase-Glo® assay. Activity status of EGFR and mTOR pathway components was analyzed by immunoblotting. Results: Activation of the EGFR/AKT/mTOR axis could be demonstrated in all entities and was significantly increased in higher grade tumors. Neoadjuvant chemotherapy correlated significantly with p-AKT expression and p-ERK loss. Erlotinib combined with everolimus exerted synergistic combination effects in AC and LCNEC cells by induction of apoptosis, while cell cycle phase distribution remained unaffected. These effects could be explained by synergistic downregulation of phospho-mTOR, phospho-p70S6 kinase and phospho-AKT expression by everolimus and erlotinib. Conclusions: Our study indicates that EGFR and mTOR are clinically important targets in bronchial neuroendocrine tumors, and further in vivo and clinical exploration of combined inhibition is warranted. Copyright © 2012 S. Karger AG, Basel. Source

Schoppmann S.F.,Medical University of Vienna | Jesch B.,Clinical Institute of Pathology | Friedrich J.,Clinical Institute of Pathology | Wrba F.,Clinical Institute of Pathology | And 6 more authors.
American Journal of Surgical Pathology | Year: 2010

The human epidermal growth factor receptor-2 gene (HER-2) encodes for a membrane-bound tyrosine kinase (Her-2), which is overexpressed in various human cancers. Her-2-targeted therapy has recently been shown to be beneficial for patients with advanced gastric cancer. Her-2 protein expression was investigated in 341 esophageal carcinomas [152 squamous cell carcinomas (SCC), 189 adenocarcinomas (AC)], 39 cases of Barrett mucosa, and 11 cases of squamous cell dysplasia. HER-2 gene amplification was assessed by colorimetric in-situ hybridization. Positive Her-2 status was found in 15.3% of ACs and 3.9% of SCCs. Positive Her-2-status was more common in dysplastic Barrett mucosas compared with nondysplastic ones (P=0.04). In 26% of the patients with ACs who had received neoadjuvant chemotherapy (n=39), the Her-2 status of pretherapeutic biopsies was different compared with subsequent surgical specimens. There was no statistically significant correlation between Her-2 status and patients' survival. Although Her-2 overexpression is rare in SCCs, it is found in 15.3% of ACs, where amplification of HER-2 gene and overexpression of Her-2 protein seem to be early events in carcinogenesis. The evaluation of Her-2 status in tumor biopsies and in particular in the context with possible alterations after neoadjuvant treatment can potentially lead to false Her-2-staging. Although Her-2-overexpression in esophageal cancer seems to have no influence on patients' survival, these subtypes of esophageal ACs have to be considered as targets for an anti-Her-2 therapy. © 2010 by Lippincott Williams & Wilkins. Source

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