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Mieke E R Henfling Department of Molecular Cell Biology, GROW-School for Oncology & Developmental Biology, Maastricht University, Maastricht, The Netherlands

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Aurel A Perren Institute of Pathology, University of Bern, Bern, Switzerland

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Anja M Schmitt Institute of Pathology, University of Bern, Bern, Switzerland

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Christiane M Saddig Insulinoma and GEP-Tumor Center Neuss-Düsseldorf, Klinik für Endokrine Chirurgie, Lukaskrankenhaus Neuss, Germany

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Achim A Starke Insulinoma and GEP-Tumor Center Neuss-Düsseldorf, Klinik für Endokrine Chirurgie, Lukaskrankenhaus Neuss, Germany

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Robert G Riedl Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands

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Yvonne M H Versleijen-Jonkers Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands

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Diana M Sprij-Mooij Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

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Frans C S Ramaekers Department of Molecular Cell Biology, GROW-School for Oncology & Developmental Biology, Maastricht University, Maastricht, The Netherlands

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Leo J Hofland Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

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Ernst-Jan M Speel Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands

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Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n = 48) and immunohistochemistry (n = 86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2- to 4-folds higher than those in islets. High protein expression of IGF2, IGF1R and INSR (in 51–92% of the tumors) and low-to-moderate expression of mTORC1 pathway proteins p-S6k and p-4EBP1 (7–28% of the tumors) were observed. Correlations were found between (1) ERK1 mRNA expression and that of numerous IGF pathway genes, (2) p-ERK and IGF1R protein expression and (3) decrease of IGF pathway components and both metastatic disease and shorter 10-year disease-free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.

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Peter M van Koetsveld Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Giovanni Vitale Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Richard A Feelders Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Marlijn Waaijers Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Diana M Sprij-Mooij Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Ronald R de Krijger Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Ernst-Jan M Speel Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Johannes Hofland Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Steven W J Lamberts Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Wouter W de Herder Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Leo J Hofland Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Adrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-β (IFN-β), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13 human ACCs, three adrenal hyperplasias, three adrenal adenomas, and in two ACC cell lines. Moreover, the interrelationship between the effects of IGF2 and IFN-β was evaluated. Mitotane inhibited cell total DNA content/well (representing cell number) in 7/11 (IC50: 38±9.2 μM) and cortisol secretion in 5/5 ACC cultures (IC50: 4.5±0.1 μM). IFN-β reduced cell number in 10/11 (IC50: 83±18 IU/ml) and cortisol secretion in 5/5 ACC cultures (IC50: 7.3±1.5 IU/ml). The effect of IFN-β on cell number included the induction of apoptosis. IFN-β strongly inhibited mRNA expression of STAR, CYP11A1, CYP17A1, and CYP11B1. Mitotane and IFN-β induced an additive inhibitory effect on cell number and cortisol secretion. IGF2 (10 nM) inhibited apoptosis and increased cell number and cortisol secretion. These effects were counteracted by IFN-β treatment. Finally, IFN-β inhibited IGF2 secretion and mRNA expression. In conclusion, IFN-β is a potent inhibitor of ACC cell growth in human primary ACC cultures, partially mediated by an inhibition of the effects of IGF2, as well as its production. The increased sensitivity of ACC cells to mitotane induced by treatment with IFN-β may open the opportunity for combined treatment regimens with lower mitotane doses. The inhibition of the expression of steroidogenic enzymes by IFN-β is a novel mechanism that may explain its inhibitory effect on cortisol production.

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Laura Moonen Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands

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Jules L Derks Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands

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Lisa M Hillen Department of Pulmonary Diseases, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands

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Robert Jan van Suylen Pathology-DNA, Jeroen Bosch Hospital, s’Hertogenbosch, The Netherlands

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Michael A den Bakker Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

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Jan H von der Thüsen Department of Pathology, Maasstad Hospital, Rotterdam, The Netherlands

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Ronald A Damhuis Department of Research, Comprehensive Cancer Association, Utrecht, The Netherlands

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Wieneke A Buikhuisen Department of Thoracic Oncology, Netherlands Cancer Institute Amsterdam, The Netherlands

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Esther C van den Broek PALGA (Dutch Nationwide Pathology Databank), Houten, The Netherlands

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Jos Maessen Department of Cardiothoracic Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands

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Alexander P W M Maat Department of Cardiothoracic Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

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Paul van Schil Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Antwerp, Belgium

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Ernst J M Speel Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pathology, Maasstad Hospital, Rotterdam, The Netherlands

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A-M C Dingemans Department of Pulmonary Diseases, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands

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The predictive value of the extent of peri-operative lymph node (LN) sampling in relation to disease relapse in patients with pulmonary carcinoid (PC) is unknown. Furthermore, post-surgery follow-up recommendations rely on institutional retrospective studies with short follow-ups. We aimed to address these shortcomings by examining the relation between LN sampling and relapse in a population-based cohort with long-term follow-up. By combining the Dutch nationwide pathology and cancer registries, all patients with surgically resected PC (2003–2012) were included in this analysis (last update 2020). The extent of surgical LN dissection was scored for the number of LN samples, location (hilar/mediastinal), and completeness of resection according to European Society of Thoracic Surgeons (ESTS) guidelines. Relapse-free interval (RFI) was evaluated using Kaplan Meier and multivariate regression analysis. 662 patients were included. The median follow-up was 87.5 months. Relapse occurred in 10% of patients, mostly liver (51.8%) and locoregional sites (45%). The median RFI was 48.1 months (95% CI 36.8–59.4). Poor prognostic factors were atypical carcinoid, pN1/2, and R1/R2 resection. In 546 patients LN dissection data could be retrieved; at least one N2 LN was examined in 44% and completeness according to ESTS in merely 7%. In 477 cN0 patients, 5.9% had pN1 and 2.5% had pN2 disease. In conclusion, relapse occurred in 10% of PC patients with a median RFI of 48.1 months thereby underscoring the necessity of long-term follow-up. Extended mediastinal LN sampling was rarely performed but systematic nodal evaluation is recommended as it provides prognostic information on distant relapse.

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