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Xi Zhang Shenzhen Bay Laboratory, Shenzhen, P R China

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Vijay Pandey Tsinghua Berkeley Shenzhen Institute and Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, P R China

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Vipul Bhardwaj Tsinghua Berkeley Shenzhen Institute and Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, P R China

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Tao Zhu Shenzhen Bay Laboratory, Shenzhen, P R China
Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P R China
The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P R China

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Peter E Lobie Shenzhen Bay Laboratory, Shenzhen, P R China
Tsinghua Berkeley Shenzhen Institute and Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, P R China

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Abstract

It is now apparent that growth hormone (GH), an anterior pituitary hormone predominantly regulating postnatal somatic growth and metabolism, is also expressed in extrapituitary tissues. An extrapituitary synthetic site of GH that has garnered interest is the de novo or enhanced expression of GH in carcinoma or other cancers. In a number of cancers, including carcinoma of the mammary gland, endometrium, liver, prostate, and colon, the expression of GH is independently associated with more advanced clinicopathologic parameters of the cancer. In some of these cancers, tumor human growth hormone (hGH) expression portends worse survival outcomes for patients. Functionally, tumor-derived hGH exerts both autocrine and paracrine functions on carcinoma cells and cancer-associated stroma. Expression of autocrine/paracrine hGH in cancer drives tumor growth, angiogenesis, metastasis, and resistance to therapy by promotion of cancer cell proliferation, survival, epithelial-to-mesenchymal transition, motility, invasion, cancer stem cell-like behavior, and metastasis. Autocrine/paracrine hGH activates oncogenic signaling pathways and specific transcriptome signatures and enhances the expression of an oncogenic secretome to promote these functions. Hence, extrapituitary expression of GH in cancer promotes cancer progression independent of endocrine hGH, and may be considered as a validated target in oncology.

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Gergely Huszty Department of Surgery, Transplantation and Gastroenterology, Faculty of Medicine, Semmelweis University, Budapest, Hungary

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Peter Igaz Department of Endocrinology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary

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Robin Schürfeld Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Leipzig, Germany

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Christina Pamporaki TU Dresden, Medical Clinic III, University Hospital Carl Gustav Carus, Dresden, Germany

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Mirko Peitzsch TU Dresden, Institute of Clinical Chemistry and Laboratory Medicine, Dresden, Germany

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Nada Rayes Center of Surgery, Division of Endocrine Surgery, Department for Visceral, Transplant, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany

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Osama Sabri Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany

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Silvio Rohm Center of Surgery, Department for Visceral, Transplant, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany
Center of Surgery, Department for Vascular Surgery, Diakonissen Hospital of Leipzig, Leipzig, Germany

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Ronald Biemann Institute of Clinical Chemistry and Laboratory Medicine, University of Leipzig, Leipzig, Germany

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Benjamin Sandner Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Leipzig, Germany

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Anke Tönjes Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Leipzig, Germany

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Graeme Eisenhofer TU Dresden, Medical Clinic III, University Hospital Carl Gustav Carus, Dresden, Germany

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Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, in this retrospective observational study, we measured plasma metanephrines and methoxytyramine in 61 patients taking norepinephrine reuptake blockers (tricyclic antidepressants or serotonin–norepinephrine reuptake inhibitors) and 17 others taking selective serotonin reuptake inhibitors, all without pheochromocytoma/paraganglioma. We highlight a singular case with strongly elevated plasma normetanephrine and methoxytyramine concentrations associated with norepinephrine reuptake blockade. Data were compared to results from 252 and 1804 respective patients with and without tumors. Plasma normetanephrine was 40% higher (P < 0.0001) in patients on norepinephrine reuptake blockers and methoxytyramine was 127% higher (P = 0.0062) in patients taking tricyclic antidepressants compared to patients not taking uptake blockers and without tumors. The corresponding false-positive rates rose (P < 0.0001) from 4.8% to 23.0% for normetanephrine and from 0.9% to 28.6% for methoxytyramine. Selective serotonin reuptake inhibitors did not increase plasma concentrations of metabolites. In the highlighted case, plasma normetanephrine and methoxytyramine were elevated more than six times above upper reference limits. A pheochromocytoma/paraganglioma, however, was excluded by functional imaging. All biochemical test results normalized after discontinuation of norepinephrine reuptake blockers. These findings clarify that norepinephrine reuptake blockers usually result in mild elevations of normetanephrine and methoxytyramine that, nevertheless, significantly increase the number of false-positive results. There can, however, be exceptions where increases in normetanephrine and methoxytyramine reach pathological levels. Such exceptions may reflect failure of centrally mediated sympathoinhibition that normally occurs with the norepinephrine reuptake blockade.

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Ajay-Mohan Mohan Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany

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Sonal Prasad Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany

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Fabian Schmitz-Peiffer Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany

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Catharina Lange Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Mathias Lukas Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Eva J Koziolek Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany

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Jakob Albrecht Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany

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Daniel Messroghli Department of Internal Medicine - Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany
Preclinical MRI Center, Charité - Universitätsmedizin Berlin, Berlin, Germany

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Ulrike Stein German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany
Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Translational Oncology of Solid Tumours, Berlin, Germany

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Matthias Ilmer German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany
Department of General, Visceral, and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany

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Katharina Wang Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

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Laura Schober Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

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Astrid Reul Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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Julian Maurer Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

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Juliane Friemel Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zürich, Zurich, Switzerland

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Achim Weber Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zürich, Zurich, Switzerland

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Richard A Zuellig Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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Constanze Hantel Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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Ralph Fritsch Department of Medical Oncology and Hematology, University Zurich and University Hospital Zürich, Zurich, Switzerland

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Martin Reincke Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

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Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health (NIH), Bethesda, Maryland, USA

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Ashley B Grossman Green Templeton College, University of Oxford, London, United Kingdom
Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
ENETS Centre of Excellence, Royal Free Hospital, London, United Kingdom

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Christoph J Auernhammer Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany
ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich, Munich, Germany

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Felix Beuschlein Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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Winfried Brenner Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany

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Nicola Beindorff Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany

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Svenja Nölting Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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The mechanistic target of rapamycin complex 1 (mTORC1) inhibitor everolimus is one of the few approved therapies for locally advanced and metastatic neuroendocrine tumours (NETs). However, after initial disease stabilisation, most patients develop resistance within 1 year. Our aim was to overcome resistance to everolimus by additional treatment with the PI3K-alpha inhibitor alpelisib in an everolimus-resistant orthotopic pancreatic neuroendocrine carcinoma xenograft mouse model. Female SCID mice underwent laparoscopic pancreatic transplantation of everolimus-sensitive (BON1KDMSO) or everolimus-resistant (BON1RR2) NET cells. Both groups were further divided into four treatment groups: placebo, everolimus, alpelisib, and everolimus + alpelisib (combination). Oral treatment was started at a tumour volume of approximately 140 mm3 and continued until 1900–2000 mm3, validated by weekly MRI. Somatostatin receptor expression and tumour viability were analysed by 68Ga-DOTATOC and 18F-FDG PET/CT. Everolimus resistance of the BON1RR2 tumours was confirmed. In the everolimus-sensitive group, everolimus alone, alpelisib alone, and combination treatment significantly prolonged survival, compared to placebo, while in the BON1RR2 group, only combination treatment significantly prolonged survival compared to placebo, but neither everolimus nor alpelisib alone. Placebo-treated everolimus-sensitive tumours grew more rapidly (median survival 45 days), compared to placebo-treated everolimus-resistant tumours (60 days). Within the everolimus-sensitive group, the combination-treated mice showed the longest median survival (52 days). Of all groups, the everolimus-resistant combination-treated group survived longest (69 days). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.

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Liang Zhang Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Tobias Åkerström Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

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Kazhan Mollazadegan Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Felix Beuschlein Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich (USZ) and Univeristät Zürich (UZH), Zurich, Switzerland
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany

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Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Britt Skogseid Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Joakim Crona Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Claire K Mulvey Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA

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Alan Paciorek Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA

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Farhana Moon Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA

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Paige Steiding Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA

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Brandon Shih Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA

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Matthew A Gubens Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA

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Li Zhang Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA

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Emily K Bergsland Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA

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Iona Cheng Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA

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Lung neuroendocrine tumors (NETs) have few known predictors of survival. We investigated associations of sociodemographic, clinicopathologic, and treatment factors with overall survival (OS) and lung cancer-specific survival (LCSS) for incident lung NET cases (typical or atypical histology) in the California Cancer Registry (CCR) from 1992 to 2019. OS was estimated with the Kaplan–Meier method and compared by sociodemographic and disease factors univariately with the log-rank test. We used sequential Cox proportional hazards regression for multivariable OS analysis. LCSS was estimated using Fine-Gray competing risks regression. There were 6038 lung NET diagnoses (5569 typical, 469 atypical carcinoid); most were women (70%) and non-Hispanic White (73%). In our multivariable model, sociodemographic factors were independently associated with OS, with better survival for women (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.57–0.68, P < 0.001), married (HR 0.76, 95% CI 0.70–0.84, P < 0.001), and residents of high socioeconomic status (SES) neighborhoods (HRQ5vsQ1 0.73, 95% CI 0.62–0.85, P < 0.001). Compared to cases with private insurance, OS was worse for cases with Medicare (HR 1.24, 95% CI 1.10–1.40, P < 0.001) or Medicaid/other public insurance (HR 1.45, 95% CI 1.24–1.68, P < 0.001). In our univariate model, non-Hispanic Black Californians had worse OS than other racial/ethnic groups, but differences attenuated after adjusting for stage at diagnosis. In our LCSS models, we found similar associations between sex and marital status on survival, but no differences in outcomes by SES or insurance. By race/ethnicity, American Indian cases had worse LCSS. In summary, beyond disease-related and treatment variables, sociodemographic factors were independently associated with survival in lung NETs.

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Elena Sabini Department of Pathology, Johns Hopkins Hospital, School of Medicine, Baltimore, Maryland, USA
Department of Pathology, Johns Hopkins Hospital, School of Medicine, Baltimore, Maryland, USA

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Amna Khan Department of Pathology, Johns Hopkins Hospital, School of Medicine, Baltimore, Maryland, USA
Department of Pathology, Johns Hopkins Hospital, School of Medicine, Baltimore, Maryland, USA

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Patrizio Caturegli Department of Pathology, Johns Hopkins Hospital, School of Medicine, Baltimore, Maryland, USA
Department of Pathology, Johns Hopkins Hospital, School of Medicine, Baltimore, Maryland, USA

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Cytotoxic T lymphocyte-associated protein 4 (CTLA4), a negative regulator typically expressed on the surface of T lymphocytes, is targeted by immunotherapy in patients with an ever-expanding spectrum of cancers. Characterizing the expression of CTLA4 in the pituitary gland could provide additional rationale for using immune checkpoint inhibitors in pituitary adenoma patients who do not respond to conventional treatments. We assessed the expression of CTLA4 mRNA and protein in a panel of 157 human pituitary glands, 45 collected at autopsy and 112 at surgery. These specimens included 50 normal glands and 107 adenomas: 41 nonsecreting, 25 PRL-, 24 ACTH-, 11 GH-, 2 TSH-, 1 FSH-secreting, and 3 atypical. Specimens were stained for CTLA4 and adenohypophyseal hormones using RNAscope in situ hybridization, immunohistochemistry, and RNAscope Multiplex Fluorescent Assay. CTLA4 mRNA was detectable in most normal pituitary glands (48 of 50, 96%) but varied in expression, with a histological score (H-score) ranging from 0.6 to 20. The variation did not depend upon the patient’s gender and age and was not significantly affected by the archival storage time. CTLA4 expression was higher (P = 0.022) in pituitary adenomas than normal glands, with the greatest levels seen in PRL- and GH-secreting adenomas (P = 0.009 and 0.023 versus normal, respectively). Eight of 25 (32%) prolactinomas and 3 of 11 (27%) GH-adenomas had an H-score greater than 20, while no differences were seen for the other types. These novel data highlight the expression of an immune checkpoint such as CTLA4 on pituitary endocrine cells, a finding that could be exploited for therapeutical applications.

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Chiara Alessandra Cella Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy

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Riccardo Cazzoli Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy
Metal Targeted Therapy & Immunology lab, Childrens’ cancer institute, Sydney, NSW, Australia

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Nicola Fazio Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy

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Giuseppina De Petro Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy

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Germano Gaudenzi Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy

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Silvia Carra Laboratory of Endocrine and Metabolic Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy

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Mauro Romanenghi Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy

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Francesca Spada Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy

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Ilaria Grossi Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy

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Isabella Pallavicini Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy

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Saverio Minucci Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

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Giovanni Vitale Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Neuroendocrine tumors (NETs) are highly vascularized malignancies in which angiogenesis may entail cell proliferation and survival. Among the emerging compounds with antivascular properties, cabozantinib (CAB) appeared promising. We analyzed the antitumor activity of CAB against NETs utilizing in vitro and in vivo models. For cell cultures, we used BON-1, NCI-H727 and NCI-H720 cell lines. Cell viability was assessed by manual count coupled with quantification of cell death, performed through fluorescence-activated cell sorting analysis as propidium iodide exclusion assay. In addition, we investigated the modulation of the antiapoptotic myeloid cell leukemia 1 protein under CAB exposure, as a putative adaptive pro-survival mechanism, and compared the responses with sunitinib. The activity of CAB was also tested in mouse and zebrafish xenograft tumor models. Cabozantinib showed a dose-dependent and time-dependent effect on cell viability and proliferation in human NET cultures, besides a halting of cell cycle progression for endoduplication, never reported for other tyrosine kinase inhibitors. In a transplantable zebrafish model, CAB drastically inhibited NET-induced angiogenesis and migration of implanted cells through the embryo body. CAB showed encouraging activity in NETs, both in vitro and in vivo models. On this basis, we envisage future research to further investigate along these promising lines.

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Paola De Marco Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Enrica Romeo Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Adele Vivacqua Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Roberta Malaguarnera Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

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Sergio Abonante Regional Hospital, Cosenza, Italy

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Francesco Romeo Regional Hospital, Cosenza, Italy

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Vincenzo Pezzi Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Antonino Belfiore Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

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Marcello Maggiolini Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Walid Zeyghami Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Marie-Louise Uhre Hansen Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Kathrine Kronberg Jakobsen Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Christian Groenhøj Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Endocrinology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Clinical Sciences, University of Copenhagen, Copenhagen, Denmark

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Christian von Buchwald Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Clinical Sciences, University of Copenhagen, Copenhagen, Denmark

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Christoffer Holst Hahn Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Thyroid cancer (TC) represents the most common endocrine malignant tumor. Liquid biopsy has been suggested as a new and accurate biomarker in cancer. This systematic review analyzes the existing literature on circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA integrity index (cfDI), and their potential as biomarkers for TC, including the subtypes: differentiated (papillary and follicular), medullary, and anaplastic. A systematic search was performed in PubMed, Embase, and Cochrane databases for published articles in English between 1 January 1970 and 6 September 2022 (PROSPERO: CRD42022358592). The literature search generated a total of 635 articles. In total, 36 articles were included (patients = 2566). Four studies reported that higher levels of CTCs were associated with metastases and worse prognosis. Nineteen studies found the presence of mutated ctDNA in TC patients. The diagnostic accuracy in detecting BRAFV600E as ctDNA was determined in 11 studies regarding papillary TC. The pooled sensitivity, specificity, and diagnostic odds ratio were estimated at 56% (95% CI 36–74), 91% (95% CI 84–95) and 12 (95% CI 4.09–33.11), respectively. Four studies concluded that the cfDI was higher in patients with TC compared to benign thyroid lesions and healthy controls. The detection of CTCs, ctDNA, and cfDI may have a potential prognostic value in TC in relation to diagnosis, disease progression, and treatment efficacy. Despite the promising potential of CTCs, ctDNA, and cfDI in TC management, limitations hinder direct comparison and generalization of findings. Standardized methodologies, larger patient cohorts, and a consensus on relevant markers are needed to validate their clinical applicability and enhance TC management.

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