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Kaemmerer D.,Zentralklinik Bad Berka | Trager T.,Zentralklinik Bad Berka | Trager T.,Friedrich - Schiller University of Jena | Hoffmeister M.,University Hospital of Tuebingen | And 5 more authors.
Oncotarget | Year: 2015

Introduction: Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC). Methods: SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21-49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data. Results: Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors. Conclusion: We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies.


Warth A.,University of Heidelberg | Fink L.,Institute of Pathology and Cytology | Fisseler-Eckhoff A.,Horst Schmidt Hospital | Jonigk D.,Leibniz University of Hanover | And 8 more authors.
Virchows Archiv | Year: 2013

Evaluation of proliferative activity is a cornerstone in the classification of endocrine tumors; in pulmonary carcinoids, the mitotic count delineates typical carcinoid (TC) from atypical carcinoid (AC). Data on the reproducibility of manual mitotic counting and other methods of proliferation index evaluation in this tumor entity are sparse. Nine experienced pulmonary pathologists evaluated 20 carcinoid tumors for mitotic count (hematoxylin and eosin) and Ki-67 index. In addition, Ki-67 index was automatically evaluated with a software-based algorithm. Results were compared with respect to correlation coefficients (CC) and kappa values for clinically relevant grouping algorithms. Evaluation of mitotic activity resulted in a low interobserver agreement with a median CC of 0.196 and a median kappa of 0.213 for the delineation of TC from AC. The median CC for hotspot (0.658) and overall (0.746) Ki-67 evaluation was considerably higher. However, kappa values for grouped comparisons of overall Ki-67 were only fair (median 0.323). The agreement of manual and automated Ki-67 evaluation was good (median CC 0.851, median kappa 0.805) and was further increased when more than one participant evaluated a given case. Ki-67 staining clearly outperforms mitotic count with respect to interobserver agreement in pulmonary carcinoids, with the latter having an unacceptable low performance status. Manual evaluation of Ki-67 is reliable, and consistency further increases with more than one evaluator per case. Although the prognostic value needs further validation, Ki-67 might perspectively be considered a helpful diagnostic parameter to optimize the separation of TC from AC. © 2013 Springer-Verlag Berlin Heidelberg.


Loibl S.,German Breast Group | Muller B.M.,Charite University Hospital | Von Minckwitz G.,German Breast Group | Schwabe M.,Charite University Hospital | And 10 more authors.
Breast Cancer Research and Treatment | Year: 2011

The androgen receptor (AR) has been shown to be of potential prognostic importance in retrospective cohorts. We evaluated immunohistochemical AR expression on a tissue microarray of 673 core biopsies from primary breast cancer patients treated with neoadjuvant docetaxel/doxorubicin/cyclophosphamide (TAC) chemotherapy in the prospective GeparTrio phase-III trial. AR was detected in 53.2% of tumours. Lowest AR expression was detected in triple-negative breast cancers (TNBC) with 21.2%. Highest AR expression was observed in Luminal A-like tumours with 67%. In AR-positive tumours, pathological complete response (pCR) rate was 12.8% compared to 25.4% in AR-negative tumours (P<0.0001). In multivariate analysis, AR independently predicted pCR (OR 1.86; 95% CI [1.16-2.79] P = 0.0086). Overall patients with an AR-positive tumour had a significant better disease-free (DFS) (AR-positive 78.9% vs. AR-negative 72.5%; log-rank P = 0.0329) and overall survival (OS) (88.8% vs. 82.7%; log-rank P = 0.0234) than those with AR-negative tumours. Stratified analysis revealed that in the TNBC subgroup, but not in the other subgroups defined by ER, PgR and HER2, AR expression predicted a better DFS (AR-positive 85.7% vs. AR-negative 65.5% log-rank P = 0.0544) and OS (95.2% vs. 76.2%; log-rank P = 0.0355). Within the non-pCR subgroup, AR positivity selected a group with a significant better DFS (P = 0.045) and OS (0.021) but not within the pCR group. Patients with an AR-negative tumour have a higher chance of achieving a pCR than those with an AR-positive one. But, patients with AR-positive tumours have a better survival especially if they did not achieve a pCR. © Springer Science+Business Media, LLC. 2011.


Eminaga O.,University of Cologne | Hinkelammert R.,University Hospital Muenster | Abbas M.,Hannover Medical School | Titze U.,University Hospital Muenster | And 3 more authors.
Prostate | Year: 2013

Purpose: High-grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor of prostate cancer (PCa). This study evaluated whether HGPIN was located close to PCa in whole radical prostatectomy specimens (RPSs). materials And Methods: We evaluated 1,374 prostate specimens from 1999 to 2010 using a cMDX-based map model of the prostate. The distribution of 10,439 PCa foci was analyzed and visualized on a heat map. The color gradient of the heat map was reduced to six colors representing the frequency classification of the relative frequency of PCa using an image posterization effect. We defined 22 regions in the prostate according to the frequency of PCa occurrence. Seven hundred ninety RPSs containing 6,374 PCa foci and 4,502 HGPIN foci were evaluated. The topographical association between PCa and HGPIN in the RPSs was analyzed by estimating the frequencies of PCa and HGPIN in 22 regions. A logistic regression analysis was performed to assess the odds ratios of HGPIN for the presence of PCa in 22 regions. RESULTS Fifty-eight percent of PCa specimens included HGPIN and had significantly more favorable Gleason scores, lower PSA levels and smaller relative tumor volumes than isolated PCa specimens. HGPIN (68%) and PCa (69%) were predominantly localized to the apical half of the prostate. HGPIN was mainly concentrated in the peripheral zone medial to regions with high PCa frequencies. Upon logistic regression analysis, HGPIN was a significant predictor of PCa co-existence in 11 regions. Conclusions: HGPIN was located adjacent to PCa in whole RPSs. PCa concomitant with HGPIN had more favorable pathologic features than isolated PCa. Copyright © 2013 Wiley Periodicals, Inc.


Fisseler-Eckhoff A.,Institute of Pathology and Cytology
Frontiers of Radiation Therapy and Oncology | Year: 2010

Carcinoma of the lung is the most common cause of cancer-related death in men and women. Prognosis correlates strongly with stage of disease at presentation and to some degree with the histological subtype of the tumor. Histological classifications of lung cancer were some what arbitrary and a matter of convenience. However, multiple lines of differentiation are often found within a single tumor, if it is sufficiently sampled. The new therapeutic approaches especially of non-small cell lung cancer place high demands on pathologists: a clear histological diagnosis with information on the predominant histological subtype is required, obtained by using additional immunohistochemical methods. Using molecular methods, predictive and prognostic factors for adjuvant and neoadjuvant therapies can be identified in tumor cells of small cell lung cancer and non-small cell lung cancer. Biological and molecular factors known in this regard include the epidermal growth factor family and its receptors, K-RAS mutations, neuroendocrine tumor differentiation, and nucleotide-excision-repair proteins (ERCC1 and RRM1). Thymidilate synthase is an interesting target for anticancer agents such as the antifolate pemetrexed. Given the aspect of individualized lung cancer therapy, the collective term small cell/non-small cell lung cancer introduced by the groups of Chuang in1984 and Thomas in 1993 can be regarded as no longer sufficient. © 2010 S. Karger AG.


Kubler K.,University of Bonn | Ayub T.H.,University of Bonn | Weber S.K.,University of Bonn | Zivanovic O.,University of Bonn | And 9 more authors.
Gynecologic Oncology | Year: 2014

Objective Endometrial adenocarcinoma is one of the most common gynecologic malignancies worldwide and in stages confined to the uterus considered to have an excellent prognosis. However, in advanced or recurrent cases when surgery fails to achieve disease control other treatment options are less effective. Thus, new therapeutic avenues are needed.Methods To provide the rationale for the use of novel agents that target immune checkpoints 163 type I endometrial cancer samples were immunohistochemically screened for the presence of CD163+ tumor-associated macrophages and Foxp3+ regulatory T cells. Further, a D2-40-based evaluation of lymph vessel density and lymphovascular space invasion was carried out. Correlation analysis with clinicopathological parameters was performed; Kaplan-Meier curves were generated; multivariate analysis was undertaken as appropriate.Results A substantial amount of tumor-associated macrophages and regulatory T cells was detected in all specimens characterizing endometrial cancer as an immunogenic tumor. However, only the increased infiltration of tumor-associated macrophages was proportionally associated with advanced FIGO stages, high tumor grade, increased lymph vessel density, lymphovascular space invasion and lymph node metastasis. Thus, the presence of tumor-associated macrophages indicates aggressive tumor behavior and appeared to be an independent prognostic factor for recurrence-free survival.Conclusions Our results make future therapeutic approaches that target tumor-associated macrophages reasonable to improve the outcome of women with advanced or recurrent endometrial adenocarcinoma. © 2014 Elsevier Inc. All rights reserved.


Knappe U.J.,Johannes Wesling Klinikum | Fink T.,Institute of Pathology and Cytology | Fisseler-Eckhoff A.,Institute of Pathology and Cytology | Schoenmayr R.,Dr. Horst Schmidt Klinik
Acta Neurochirurgica | Year: 2010

Purpose: To describe the pattern of expression of extracellular matrix (ECM) proteins in perisellar connective tissue. Methods: Dural and perisellar specimens from ten individuals were investigated immunohistochemically for collagens I to IV, tenascin, fibronectin, elastin, laminin, and vitronectin. Findings: Collagen I and III and fibronectin were strongly expressed and collagen IV, tenascin, and vitronectin were moderately expressed in the boundaries of the sella and around the CS. In six of nine specimens from the anterior boundary of the sella, and in 11 of 19 samples from the lateral boundary of the sella (medial wall of CS), two different layers could be detected by the expression of different ECM proteins. None of the antigens generally allowed differentiation between two layers of the pituitary envelope. Conclusions: The pituitary boundary may consist of a single or a double layer, infrequently differentiated from each other by the expression of different ECM proteins. © 2009 Springer-Verlag.


Wolff J.-C.,Max Planck Institute for Heart and Lung Research | Wolff J.-C.,Justus Liebig University | Wilhelm J.,Justus Liebig University | Fink L.,Justus Liebig University | And 5 more authors.
European Respiratory Journal | Year: 2010

Although increasing numbers of patients suffer from chronic destructive lung diseases, there are no effective therapeutic options apart from transplantation. Understanding the mechanisms of physiological and regenerative alveolar septation is prerequisite for the development of regenerative therapies for the lung. We compared lung gene expression in the phase of induction of post-natal and post-pneumonectomy alveolarisation to identify regulatory genes involved in both processes. We performed genome-wide microarray screenings of newborn and pneumonectomised mouse lungs 1 and 3 days after birth or surgery. Selected candidates were validated by real-time PCR, Western blot and in situ hybridisation. We found 58 genes to be regulated in both models with 40 candidates being changed likewise. Many of these genes participated in growth and differentiation processes. Additionally, immune system, structural molecules, respiratory chain, signal transduction and metabolism were involved. Some candidates were not yet linked to specific functions. The highest regulatory concordance was observed for various isoforms of (pro-)collagen molecules, elastin and the elastin-associated protein fibrillin1 being corporately upregulated. Our findings do not definitively support a common regulating mechanism for induction of postnatal and adult alveolarisation, but some candidates in the intersection of both models are promising for further investigations. Copyright©ERS Journals Ltd 2010.


PubMed | Hannover Medical School, University of Bonn, University of Cologne, University of Munster and 2 more.
Type: | Journal: The Prostate | Year: 2016

Fresh tissue is mandatory to perform high-quality translation studies. Several models for tissue extraction from prostatectomy specimens without guidance by frozen sections are already introduced. However, little is known about the sampling efficacy of these models, which should provide representative tissue in adequate volumes, account for multifocality and heterogeneity of tumor, not violate the routine final pathological examination, and perform quickly without frozen section-based histological control. The aim of the study was to evaluate the sampling efficacy of the existing tissue extraction models without guidance by frozen sections (blind) and to develop an optimized model for tissue extraction.Five hundred thirty-three electronic maps of the tumor distribution in prostates from a single-center cohort of the patients subjected to radical prostatectomy were used for analysis. Six available models were evaluated in silico for their sampling efficacy. Additionally, a novel model achieving the best sampling efficacy was developed.The available models showed high efficacies for sampling any part from the tumor (up to 100%), but were uniformly low in efficacy to sample all tumor foci from the specimens (with the best technique sampling only 51.6% of the all tumor foci). The novel 4-level extraction model achieved a sampling efficacy of 93.1% for all tumor foci.The existing blind tissue extraction models from prostatectomy specimens without frozen sections control are suitable to target tumor tissues but these tissues do not represent the whole tumor. The novel 4-level model provides the highest sampling efficacy and a promising potential for integration into routine. Prostate 2016 Wiley Periodicals, Inc.


PubMed | Institute for Pathology Saarbrucken Rastpfuhl, Institute of Pathology and Cytology, University of Cologne and University Hospital Muenster
Type: | Journal: Journal of biomedical informatics | Year: 2016

Understanding the topographical distribution of prostate cancer (PCa) foci is necessary to optimize the biopsy strategy. This study was done to develop a technical approach that facilitates the analysis of the topographical distribution of PCa foci and related pathological findings (i.e., Gleason score and foci dimensions) in prostatectomy specimens.The topographical distribution of PCa foci and related pathologic evaluations were documented using the cMDX documentation system. The project was performed in three steps. First, we analyzed the document architecture of cMDX, including textual and graphical information. Second, we developed a data model supporting the topographic analysis of PCa foci and related pathologic parameters. Finally, we retrospectively evaluated the analysis model in 168 consecutive prostatectomy specimens of men diagnosed with PCa who underwent total prostate removal. The distribution of PCa foci were analyzed and visualized in a heat map. The color depth of the heat map was reduced to 6 colors representing the PCa foci frequencies, using an image posterization effect. We randomly defined 9 regions in which the frequency of PCa foci and related pathologic findings were estimated.Evaluation of the spatial distribution of tumor foci according to Gleason score was enabled by using a filter function for the score, as defined by the user. PCa foci with Gleason score (Gls) 6 were identified in 67.3% of the patients, of which 55 (48.2%) also had PCa foci with Gls between 7 and 10. Of 1173 PCa foci, 557 had Gls 6, whereas 616 PCa foci had Gls>6. PCa foci with Gls 6 were mostly concentrated in the posterior part of the peripheral zone of the prostate, whereas PCa foci with Gls>6 extended toward the basal and anterior parts of the prostate. The mean size of PCa foci with Gls 6 was significantly lower than that of PCa with Gls>6 (P<0.0001).The cMDX-based technical approach facilitates analysis of the topographical distribution of PCa foci and related pathologic findings in prostatectomy specimens.

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