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Atsuko Kasajima Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany
Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Marianne Pavel Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Silvia Darb-Esfahani Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Aurelia Noske Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Albrecht Stenzinger Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany
Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Hironobu Sasano Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Manfred Dietel Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Carsten Denkert Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Christoph Röcken Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Bertram Wiedenmann Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Wilko Weichert Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany
Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (P=0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (P=0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.

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Atsuko Kasajima Department of Pathology, Technical University Munich, Munich, Germany
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan

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Yuichi Ishikawa Pathology Department, The Cancer Institute Hospital of JFCR, Tokyo, Japan

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Ayaka Iwata Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan

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Katja Steiger Department of Pathology, Technical University Munich, Munich, Germany

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Naomi Oka Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
National Hospital Organization, Sendai Medical Center, Sendai, Japan

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Hirotaka Ishida Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan

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Akira Sakurada Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University Graduate School of Medicine, Sendai, Japan

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Hiroyoshi Suzuki National Hospital Organization, Sendai Medical Center, Sendai, Japan

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Toru Kameya Division of Pathology, Shizuoka Cancer Center Hospital and Research Institute, Sizuoka, Japan

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Björn Konukiewitz Department of Pathology, Technical University Munich, Munich, Germany

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Günter Klöppel Department of Pathology, Technical University Munich, Munich, Germany

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Yoshinori Okada Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University Graduate School of Medicine, Sendai, Japan

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Hironobu Sasano Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan

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Wilko Weichert Department of Pathology, Technical University Munich, Munich, Germany
Member of the German Cancer Consortium (DKTK)

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In the light of novel cancer immune therapies, the status of antitumor inflammatory response and its regulation has gained much attention in patients with lung cancer. Ample datasets exist for non-small-cell lung cancer, but those for pulmonary neuroendocrine tumors are scarce and controversial. Here, tumor-associated inflammation, CD8+ cell infiltration and PD-L1 status were evaluated in a cohort of 57 resected carcinoids and 185 resected neuroendocrine carcinomas of the lung (58 large cell carcinomas and 127 small cell carcinomas). Data were correlated with clinicopathological factors and survival. Moderate or high tumor-associated inflammation was detected in 4 carcinoids (7%) and in 37 neuroendocrine carcinomas (20%). PD-L1 immunoreactivity was seen in immune cells of 73 (39%) neuroendocrine carcinomas, while tumor cells were labeled in 21 (11%) cases. Inflammatory cells and tumor cells in carcinoids lacked any PD-L1 expression. In neuroendocrine carcinomas, PD-L1 positivity in immune cells, but not in tumor cells, was associated with intratumoral CD8+ cell infiltration (P < 0.001), as well as with the severity of tumor-associated inflammation (P < 0.001). In neuroendocrine carcinomas, tumor-associated inflammation and PD-L1 positivity in immune cells correlated with prolonged survival and the latter factor was also an independent prognosticator (P < 0.01, hazard ratio 0.4 for overall survival, P < 0.001 hazard ratio 0.4 for disease-free survival). Taken together, in neuroendocrine tumors, antitumor inflammatory response and PD-L1 expression are largely restricted to neuroendocrine carcinomas, and in this tumor entity, PD-L1 expression in inflammatory cells is positively correlated to patient survival.

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Silvia Darb-Esfahani
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Ralph M Wirtz Institute of Pathology, Siemens Healthcare Diagnostics, Department of Gynaecology and Obstetrics, Medical Oncology Unit, Obstetrics and Gynaecology Unit, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

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Bruno V Sinn
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Jan Budczies
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Aurelia Noske
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Wilko Weichert
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Areeg Faggad
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Susanne Scharff Institute of Pathology, Siemens Healthcare Diagnostics, Department of Gynaecology and Obstetrics, Medical Oncology Unit, Obstetrics and Gynaecology Unit, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

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Jalid Sehouli Institute of Pathology, Siemens Healthcare Diagnostics, Department of Gynaecology and Obstetrics, Medical Oncology Unit, Obstetrics and Gynaecology Unit, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

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Guelten Oskay-Özcelik Institute of Pathology, Siemens Healthcare Diagnostics, Department of Gynaecology and Obstetrics, Medical Oncology Unit, Obstetrics and Gynaecology Unit, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

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Claudio Zamagni Institute of Pathology, Siemens Healthcare Diagnostics, Department of Gynaecology and Obstetrics, Medical Oncology Unit, Obstetrics and Gynaecology Unit, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

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Pierandrea De Iaco Institute of Pathology, Siemens Healthcare Diagnostics, Department of Gynaecology and Obstetrics, Medical Oncology Unit, Obstetrics and Gynaecology Unit, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

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Andrea Martoni Institute of Pathology, Siemens Healthcare Diagnostics, Department of Gynaecology and Obstetrics, Medical Oncology Unit, Obstetrics and Gynaecology Unit, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

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Manfred Dietel
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Carsten Denkert
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Epidemiological and cell culture studies indicate that ovarian carcinoma growth is dependent on estrogen stimulation. However, possibly due to the lack of a reliable biomarker that helps to select patients according to prognostically relevant estrogen receptor (ER) levels, clinical trials using anti-estrogenic therapeutics in ovarian carcinoma have had inconsistent results. Therefore, we tested if ER expression analysis by a quantitative method might be useful in this regard in formalin-fixed paraffin-embedded (FFPE) tissue. In a study group of 114 primary ovarian carcinomas expression of estrogen receptor 1 (ESR1) mRNA was analyzed using a new method for RNA extraction from FFPE tissue that is based on magnetic beads, followed by kinetic PCR. The prognostic impact of ESR1 mRNA expression was investigated and compared to ERα protein expression as determined by immunohistochemistry. In univariate survival analysis the expression level of ESR1 mRNA was a significant positive prognostic factor for patient survival (hazard ratio (HR) 0.230 (confidence interval (CI) 0.102–0.516), P=0.002). ERα protein expression was correlated to ESR1 mRNA expression (P=0.0001); however, ERα protein expression did not provide statistically significant prognostic information. In multivariate analysis, ESR1 mRNA expression emerged as a prognostic factor, independent of stage, grade, residual tumor mass, age, and ERα protein expression (HR 0.227 (CI 0.078–0.656), P=0.006). Our results indicate that the determination of ESR1 levels by kinetic PCR may be superior to immunohistochemical methods in assessment of biologically relevant levels of ER expression in ovarian carcinoma, and is feasible in routinely used FFPE tissue.

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