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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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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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