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E Baudin Endocrine Oncology Unit, Imaging Department, Gustave Roussy, Villejuif, France

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J Capdevila Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), IOB Quirón-Teknon, Barcelona, Spain

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D Hörsch ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany

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S Singh Division of Medical Oncology, University of Toronto, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, Ontario, Canada

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M E Caplin Neuroendocrine Tumour Unit, Royal Free Hospital School of Medicine, London, UK

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E M Wolin Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

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W Buikhuisen Department of Thorax Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands

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M Raderer Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria

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E Dansin Thoracic Oncology Unit, Centre Oscar Lambret, Lille, France

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C Grohe Department of Respiratory Diseases, Evangelische Lungenklinik, Berlin, Germany

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D Ferone Neuroendocrine Tumour Unit, Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy

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A Houchard Data and Insights Generation and Strategy, Ipsen, Boulogne-Billancourt, France

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X-M Truong-Thanh Medical Affairs, Ipsen, Boulogne-Billancourt, France

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D Reidy-Lagunes Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, New York, New York, USA

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the SPINET Study Group
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the SPINET Study Group

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients’ quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

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Marcia S Brose Department of Medical Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania, USA

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Jaume Capdevila Gastrointestinal and Endocrine Tumor Unit, Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Rossella Elisei Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Lars Bastholt Department of Clinical Oncology, Odense University Hospital, Odense, Denmark

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Dagmar Führer-Sakel Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry, University Hospital Essen, Essen, Germany

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Sophie Leboulleux Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France
Department of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Hôpitaux Universitaires de Genève, Geneve, Switzerland

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Iwao Sugitani Department of Endocrine Surgery, Nippon Medical School Graduate School of Medicine, Tokyo, Japan

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Matthew H Taylor Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA

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Zhuoying Wang Department of Head Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
Department of Head Neck Surgery, Renji Hospital Affiliated to Jiaotong University School of Medicine, Shanghai, China

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Lori J Wirth Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Francis P Worden Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA

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John Bernard Sanofi, Cambridge, Massachusetts, USA

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Paolo Caferra Sanofi, Amsterdam, The Netherlands
Department of Pharmacy, University of Pisa, Pisa, Italy

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Raffaella M Colzani Sanofi, Cambridge, Massachusetts, USA

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Shiguang Liu Sanofi, Cambridge, Massachusetts, USA

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Martin Schlumberger Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France

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The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55–1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

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Lei Qiao Department of Breast and Thyroid Surgery, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China

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Chao Dong Department of Breast and Thyroid Surgery, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China

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Wenlei Jia Department of Breast and Thyroid Surgery, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China

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Gang Sun Department of Breast and Thyroid Surgery, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China

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Breast cancer is the leading cause of cancer-related deaths in females, and triple-negative breast cancer (TNBC) is characterized as one of the main subtypes of breast cancer, with poor prognosis and limited treatments. Investigating the molecular basis or discovering relevant oncogenes will greatly help in developing effective targeted therapies. In this study, we ascertained that RAB5A depletion in TNBC cells suppresses the secretion of exosomes and blocks the polarization of macrophages toward an M2 phenotype. By scanning miRNAs associated with macrophage polarization, we identified that miR-21 was the pivotal component in tumor cell-derived exosomes and played a key role in RAB5A-mediated macrophage polarization. The enhanced expression of miR-21 in macrophages is able to potentiate the M2 polarization of macrophages in the presence of tumor cells. Pellino-1 (PELI1) was subsequently identified as the target of miR-21, and forced PELI1 expression partially abrogated the M2 polarization of macrophages induced by miR-21 overexpression. Macrophages stimulated with RAB5A-depleted TNBC cells (coculture, conditioned medium or exosomes) impaired their capability to promote the proliferation, migration, and invasion of tumor cells. In vivo xenograft experiments further confirmed that RAB5A knockdown TNBC cells exhibited reduced tumor formation and impaired tumor-associated macrophage recruitment. These studies shed light on the potential underlying mechanism of RAB5A-mediated macrophage polarization in an exosomal miR-21-dependent manner and provide an experimental basis for the development of RAB5A- or exosome-based tumor therapeutic strategies.

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Zixia Tao Department of General Surgery, Thyroid and Parathyroid Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Xianzhao Deng Department of General Surgery, Thyroid and Parathyroid Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Bomin Guo Department of General Surgery, Thyroid and Parathyroid Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Zheng Ding Department of General Surgery, Thyroid and Parathyroid Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Youben Fan Department of General Surgery, Thyroid and Parathyroid Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

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The incidence rate of medullary thyroid carcinoma (MTC) continues to grow, along with its mortality rate in the USA. However, the subgroup trends in MTC have not yet been established. This population-based retrospective cohort study was based on the Surveillance, Epidemiology, and End Results (SEER) 17/12 registry database. Subgroup analysis was performed through clinicopathological and treatment-related characteristics. Annual average percentage change (AAPC) was calculated using joinpoint regression analysis. A total of 3833 MTC patients and 536 death cases were diagnosed in the SEER database. Between 2000 and 2019, the incidence (AAPC = 1.64) and mortality (AAPC = 3.46) rates of MTC continued to rise. Subgroup analysis showed the proportion of elderly patients (65–84 years) gradually increased in incidence between 2000 and 2020. Patients with early-stage tumors, such as tumors ≤20 mm, showed the same trends. Aspects of treatment, the implementation rate of total thyroidectomy (AAPC = 0.38) and lymph node dissection (AAPC = 1.06) also increased persistently in almost all of the age subgroups. The incidence and mortality of MTC consistently increased from 2000 to 2019. Subgroup analysis indicated a significant increase in elderly patients and early-stage patients, and more attention should be paid to the management of these increased subgroups.

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Luming Wu Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Jing Xie Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yan Qi Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Tingwei Su Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Lei Jiang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Weiwei Zhou Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yiran Jiang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Cui Zhang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Xu Zhong Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yanan Cao Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Weiqing Wang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China

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Andres Elía Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Leo Saldain Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Silvia Lovisi Hospital de Agudos “Magdalena V de Martínez”, General Pacheco, Argentina

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Paula Martínez Vazquez Hospital de Agudos “Magdalena V de Martínez”, General Pacheco, Argentina

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Javier Burruchaga Hospital de Agudos “Magdalena V de Martínez”, General Pacheco, Argentina

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Caroline A Lamb Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Isabel Alicia Lüthy Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Federico Diez University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK

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Natalie Z M Homer University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK

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Ruth Andrew University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK

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Paola Rojas Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Claudia Lanari Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography–tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.

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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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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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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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