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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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Barbora Bulanova Pekova Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Vlasta Sykorova Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Karolina Mastnikova Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Eliska Vaclavikova Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Jitka Moravcova Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Petr Vlcek Department of Nuclear Medicine and Endocrinology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

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Lucie Lancova Department of Nuclear Medicine and Endocrinology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

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Petr Lastuvka Departments of Otorhinolaryngology and Head and Neck Surgery, 1st Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

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Rami Katra Department of Ear, Nose and Throat, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

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Petr Bavor Department of Surgery, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

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Daniela Kodetova Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

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Martin Chovanec Department of Otorhinolaryngology, 3rd Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic

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Jana Drozenova Department of Pathology, 3rd Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic

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Radoslav Matej Department of Pathology, 3rd Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic

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Jaromir Astl Department of Otorhinolaryngology and Maxillofacial Surgery, 3rd Faculty of Medicine and Military University Hospital, Prague, Czech Republic

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Jiri Hlozek Department of Otorhinolaryngology and Maxillofacial Surgery, 3rd Faculty of Medicine and Military University Hospital, Prague, Czech Republic

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Petr Hrabal Department of Pathology, Military University Hospital, Prague, Czech Republic

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Josef Vcelak Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Bela Bendlova Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Thyroid cancer is associated with a broad range of different mutations, including RET (rearranged during transfection) fusion genes. The importance of characterizing RET fusion-positive tumors has recently increased due to the possibility of targeted treatment. The aim of this study was to identify RET fusion-positive thyroid tumors, correlate them with clinicopathological features, compare them with other mutated carcinomas, and evaluate long-term follow-up of patients. The cohort consisted of 1564 different thyroid tissue samples (including 1164 thyroid carcinoma samples) from pediatric and adult patients. Samples were analyzed for known driver mutations occurring in thyroid cancer. Negative samples were subjected to extensive RET fusion gene analyses using next-generation sequencing and real-time PCR. RET fusion genes were not detected in any low-risk neoplasm or benign thyroid tissue and were detected only in papillary thyroid carcinomas (PTCs), in 113/993 (11.4%) patients, three times more frequently in pediatric and adolescent patients (29.8%) than in adult patients (8.7%). A total of 20 types of RET fusions were identified. RET fusion-positive carcinomas were associated with aggressive tumor behavior, including high rates of lymph node (75.2%) and distant metastases (18.6%), significantly higher than in NTRK fusion, BRAF V600E and RAS-positive carcinomas. Local and distant metastases were also frequently found in patients with microcarcinomas positive for the RET fusions. ’True recurrences’ occurred rarely (2.4%) and only in adult patients. The 2-, 5-, 10-year disease-specific survival rates were 99%, 96%, and 95%, respectively. RET fusion-positive carcinomas were associated with high invasiveness and metastatic activity, but probably due to intensive treatment with low patient mortality.

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Parvin Yenki The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

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Satyam Bhasin The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Liang Liu The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Noushin Nabavi The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Chi Wing Cheng The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Kevin J Tam The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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James W Peacock The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Hans H Adomat The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Tabitha Tombe The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Ladan Fazli The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Larissa Ivanova The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Christopher Dusek The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

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Shahram Khosravi The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Emma S Tomlinson Guns The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Yuzhuo Wang The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

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Ralph Buttyan The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

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Martin E Gleave The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

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Christopher J Ong The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

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Intratumoral androgen biosynthesis contributes to castration-resistant prostate cancer progression in patients treated with androgen deprivation therapy. The molecular mechanisms by which castration-resistant prostate cancer acquires the capacity for androgen biosynthesis to bypass androgen deprivation therapy are not entirely known. Here, we show that semaphorin 3C, a secreted signaling protein that is highly expressed in castration-resistant prostate cancer, can promote steroidogenesis by altering the expression profile of key steroidogenic enzymes. Semaphorin 3C not only upregulates enzymes required for androgen synthesis from dehydroepiandrosterone or de novo from cholesterol but also simultaneously downregulates enzymes involved in the androgen inactivation pathway. These changes in gene expression correlate with increased production of androgens induced by semaphorin 3C in prostate cancer model cells. Moreover, semaphorin 3C upregulates androgen synthesis in LNCaP cell-derived xenograft tumors, likely contributing to the enhanced in vivo tumor growth rate post castration. Furthermore, semaphorin 3C activates sterol regulatory element-binding protein, a transcription factor that upregulates enzymes involved in the synthesis of cholesterol, a sole precursor for de novo steroidogenesis. The ability of semaphorin 3C to promote intratumoral androgen synthesis may be a key mechanism contributing to the reactivation of the androgen receptor pathway in castration-resistant prostate cancer, conferring continued growth under androgen deprivation therapy. These findings identify semaphorin 3C as a potential therapeutic target for suppressing intratumoral steroidogenesis.

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Roberto Olmos Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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José Miguel Domínguez Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Sergio Vargas-Salas Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Lorena Mosso Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Carlos E Fardella Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Gilberto González Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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René Baudrand Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Francisco Guarda Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Felipe Valenzuela Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Eugenio Arteaga Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Pablo Forenzano Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Flavia Nilo Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Nicole Lustig Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Alejandra Martínez Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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José M López Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile

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Francisco Cruz Department of Radiology, School of Medicine Pontificia Universidad Católica de Chile

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Soledad Loyola Department of Radiology, School of Medicine Pontificia Universidad Católica de Chile

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Augusto Leon Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Nicolás Droppelmann Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Pablo Montero Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Francisco Domínguez Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Mauricio Camus Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Antonieta Solar Department of Anatomic Pathology, School of Medicine Pontificia Universidad Católica de Chile

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Pablo Zoroquiain Department of Anatomic Pathology, School of Medicine Pontificia Universidad Católica de Chile

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Juan Carlos Roa Department of Anatomic Pathology, School of Medicine Pontificia Universidad Católica de Chile

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Estefanía Muñoz Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Elsa Bruce Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Rossio Gajardo Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Giovanna Miranda Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Francisco Riquelme Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Natalia Mena Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Hernán E González Department of Surgical Oncology, School of Medicine Pontificia Universidad Católica de Chile

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Molecular testing contributes to improving the diagnosis of indeterminate thyroid nodules (ITNs). ThyroidPrint® is a ten-gene classifier aimed to rule out malignancy in ITN. Post-validation studies are necessary to determine the real-world clinical benefit of ThyroidPrint® in patients with ITN. A single-center, prospective, noninterventional clinical utility study was performed, analyzing the impact of ThyroidPrint® in the physicians’ clinical decisions for ITN. Demographics, nodule characteristics, benign call rates (BCRs), and surgical outcomes were measured. Histopathological data were collected from surgical biopsies of resected nodules. Of 1272 fine-needle aspirations, 109 (8.6%) were Bethesda III and 135 (10.6%) were Bethesda IV. Molecular testing was performed in 155 of 244 ITN (63.5%), of which 104 were classified as benign (BCR of 67.1%). After a median follow-up of 15 months, 103 of 104 (99.0%) patients with a benign ThyroidPrint® remained under surveillance and one patient underwent surgery which was a follicular adenoma. Surgery was performed in all 51 patients with a suspicious for malignancy as per ThyroidPrint® result and in 56 patients who did not undergo testing, with a rate of malignancy of 70.6% and 32.1%, respectively. A higher BCR was observed in follicular lesion of undetermined significance (87%) compared to atypia of undetermined significance (58%) (P < 0.05). False-positive cases included four benign follicular nodules and six follicular and four oncocytic adenomas. Our results show that, physicians chose active surveillance instead of diagnostic surgery in all patients with a benign ThyroidPrint® result, reducing the need for diagnostic surgery in 67% of patients with preoperative diagnosis of ITN.

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Jaime Guevara-Aguirre Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador
Instituto de Endocrinología IEMYR, Quito, Ecuador
Maastricht University, Maastricht, The Netherlands

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Gabriela Peña Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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William Acosta Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Gabriel Pazmiño Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Jannette Saavedra Instituto de Endocrinología IEMYR, Quito, Ecuador

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Lina Soto Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Daniela Lescano Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador

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Alexandra Guevara Instituto de Endocrinología IEMYR, Quito, Ecuador

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Antonio W D Gavilanes Maastricht University, Maastricht, The Netherlands

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The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and thyroid neoplasms. However, recent studies found increased risks in gastric, breast, and urinary tract cancer also. Concordantly, clinical situations where GH and insulin-like growth facto-I deficits exist are indeed associated with diminished malignancy incidence. In line with these observations, gain-of-function mutations of various enzymes belonging to the GH and IGF-I signaling pathways have been associated with increased carcinogenesis; similarly, loss-of-function mutations of other enzymes that usually work as tumor repressors are also associated with augmented cancer risk. In a study performed in Ecuador, it was demonstrated that subjects in the Ecuadorian cohort with Laron syndrome (ELS), who have a mutant GH receptor and greatly diminished GH and IGF-I signaling, display diminished incidence of cancer. Along with absent action of GH and IGF-I, ELS individuals also have low serum insulin levels and decreased insulin resistance. Furthermore, hyperglycemia and hyperinsulinemia are indispensable for fast cell mitosis, including that of those cells present in the benign and malignant neoplasms. Notably, and despite their obesity, subjects with the ELS display normoglycemia and hypo-insulinemia, along with diminished incidence of malignancies. We believe that the dual low-IGF-I/low insulin serum levels are responsible for the cancer protection, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic as well as pathologic events.

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Bilal F Samhouri Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
Division of Pulmonary and Critical Care Medicine, Asante Health System, Medford, Oregon, USA

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Thorvardur R Halfdanarson Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA

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Chi Wan Koo Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA

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Cormac McCarthy School of Medicine, University College Dublin, Dublin, Ireland
Department of Respiratory Medicine, St Vincent’s University Hospital, Elm Park, Dublin, Ireland

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Eunhee S Yi Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

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Charles F Thomas Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA

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Jay H Ryu Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA

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Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms ‘diffuse’ and ‘idiopathic.’ We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

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Andreas Venizelos K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

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Halfdan Sorbye Department of Oncology, Haukeland University Hospital, Bergen, Norway
Department of Clinical Science, University of Bergen, Bergen, Norway

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Hege Elvebakken Department of Oncology, Ålesund Hospital, Møre og Romsdal Hospital Trust, Ålesund, Norway
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

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Aurel Perren Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland

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Inger Marie B Lothe Department of Pathology, Oslo University Hospital, Oslo, Norway

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Anne Couvelard Department of Pathology, Université Paris Cité and AP-HP, Bichat Hospital, Paris, France

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Geir Olav Hjortland Department of Oncology, Oslo University Hospital, Oslo, Norway

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Anna Sundlöv Departmentt of Oncology, Skåne University Hospital, Lund, Sweden
Department of Medical Radiation Physics, Lund University, Lund, Sweden

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Johanna Svensson Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

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Harrish Garresori Department of Oncology, Stavanger University Hospital, Stavanger, Norway

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Christian Kersten Department of Research, Hospital of Southern Norway, Kristiansand, Norway

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Eva Hofsli Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
Department of Oncology, St. Olavs Hospital, Trondheim, Norway

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Sönke Detlefsen Department of Pathology, Odense University Hospital, Odense, Denmark
Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

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Lene W Vestermark Department of Oncology, Odense University Hospital, Odense, Denmark

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Morten Ladekarl Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
Department of Oncology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark

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Elizaveta Mitkina Tabaksblat Department of Oncology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark

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Stian Knappskog K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

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High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0–17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.

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Christopher A Galifi Department of Pharmacology, Physiology, & Neuroscience, Center for Cell Signaling and Cancer Institute of New Jersey, Rutgers Biomedical and Health Sciences, Newark, New Jersey, United States

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Teresa L Wood Department of Pharmacology, Physiology, & Neuroscience, Center for Cell Signaling and Cancer Institute of New Jersey, Rutgers Biomedical and Health Sciences, Newark, New Jersey, United States

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Despite decades of research presenting insulin-like growth factor-1 receptor (IGF1R) as an attractive target for cancer therapy, IGF1R inhibitors ultimately failed in clinical trials. This was surprising due to the known cancer-promoting functions of IGF1R, including stimulation of cell invasion, proliferation, and survival. Discourse in the literature has acknowledged that a lack of patient stratification may have impacted the success of IGF1R-inhibitor trials. This argument alludes to the possibility that IGF1R function may be contingent on tumor type and cellular composition. Looking into the known roles of IGF1R, it becomes clear that this receptor interacts with a multitude of different proteins and even has tumor-suppressing functions. IGF1R is implicated in both cell–cell and cell–surface adhesion dynamics, and the effects of either IGF1R downregulation or pharmacological inhibition on cellular adhesion remain poorly understood. In turn, adhesion receptors modulate IGF1R signaling. In addition, our understanding of IGF1R function in tumor-associated immune and stromal cells is lacking, which could contribute to the overwhelming failure of IGF1R inhibitors in the clinic. In this review, we re-investigate clinical trial data to make connections between the failure of these drugs in human cancer patients and the understudied facets of IGF1R function. We describe lesser-known and potentially tumor-suppressive functions of IGF1R that include promoting cell–cell adhesion through E-cadherin, augmenting a pro-inflammatory macrophage phenotype, and stimulating B cells to produce immunoglobulins. We also highlight the important role of adhesion receptors in regulating IGF1R function, and we use this information to infer stratification criteria for selecting patients that might benefit from IGF1R inhibitors.

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Giulia Cantini Department of Experimental and Clinical Biomedical Sciences, Endocrinology Section, University of Florence, Florence, Italy
European Network for the Study of Adrenal Tumors (ENS@T) Center of Excellence, Florence, Italy
Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy
Istituto Nazionale Biostrutture e Biosistemi (I.N.B.B.), via delle Medaglie D’Oro, Rome, Italy

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Elena Niccolai Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Letizia Canu Department of Experimental and Clinical Biomedical Sciences, Endocrinology Section, University of Florence, Florence, Italy
European Network for the Study of Adrenal Tumors (ENS@T) Center of Excellence, Florence, Italy
Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy

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Leandro Di Gloria Department of Experimental and Clinical Biomedical Sciences, Biochemical Sciences Section, University of Florence, Florence, Italy

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Simone Baldi Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Arianna Pia Propato Department of Experimental and Clinical Biomedical Sciences, Endocrinology Section, University of Florence, Florence, Italy
European Network for the Study of Adrenal Tumors (ENS@T) Center of Excellence, Florence, Italy

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Laura Fei Department of Experimental and Clinical Biomedical Sciences, Endocrinology Section, University of Florence, Florence, Italy
European Network for the Study of Adrenal Tumors (ENS@T) Center of Excellence, Florence, Italy

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Giulia Nannini Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Soraya Puglisi Department of Clinical and Biological Sciences, Internal Medicine, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy

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Gabriella Nesi Department of Health Sciences, Pathology Section, University of Florence, Florence, Italy

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Matteo Ramazzotti Department of Experimental and Clinical Biomedical Sciences, Biochemical Sciences Section, University of Florence, Florence, Italy

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Amedeo Amedei Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Michaela Luconi Department of Experimental and Clinical Biomedical Sciences, Endocrinology Section, University of Florence, Florence, Italy
European Network for the Study of Adrenal Tumors (ENS@T) Center of Excellence, Florence, Italy
Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy
Istituto Nazionale Biostrutture e Biosistemi (I.N.B.B.), via delle Medaglie D’Oro, Rome, Italy

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The infiltrating microbiota represents a novel cellular component of the solid tumour microenvironment that can influence tumour progression and response to therapy. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy for which mitotane (MTT) treatment represents the first-line therapy, though its efficacy is limited to a therapeutic window level (14–20 mg/L). Novel markers able to predict those patients who would benefit from MTT therapy are urgently needed to improve patient’s management. The aim of our study was to evaluate the presence of intratumoural bacterial microbiota DNA in 26 human ACC tissues vs 9 healthy adrenals; moreover, the association between the relative bacterial composition profile, the tumour mass characteristics and MTT ability to reach high circulating levels in the early phase of treatment, were explored. We found the presence of bacterial DNA in all adrenal samples from both tumours and healthy cortex specimens, documenting significant differences in the microbial composition between malignancy and normal adrenals: in detail, the ACC tissues were characterised by a higher abundance of the Proteobacteria phylum (especially the Pseudomonas and Serratia genera). In addition, the Proteobacteria’s low abundance was negatively associated with tumour size, Ki67 and cortisol secretion. MTT levels reached higher levels at 9 months in ACC patients with high abundance of Proteobacteria, Pseudomonas and Serratia and with low abundance of Bacteroidota, Firmicutes and Streptococcus. These findings are the first indication that human ACCs are characterised by infiltrating bacteria and their specific abundance profile seems to influence the increase in circulating MTT levels at 9 months.

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Jared S Rosenblum Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States

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Herui Wang Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States

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Matthew A Nazari Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, Maryland, United States

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Zhengping Zhuang Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States

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Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, Maryland, United States

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This article is a summary of the plenary lecture presented by Jared Rosenblum that was awarded the Manger Prize at the Sixth International Symposium on Pheochromocytoma/Paraganglioma held on 19–22 October 2022 in Prague, Czech Republic. Herein, we review our initial identification of a new syndrome of multiple paragangliomas, somatostatinomas, and polycythemia caused by early postzygotic mosaic mutations in EPAS1, encoding hypoxia-inducible factor 2 alpha (HIF-2α), and our continued exploration of new disease phenotypes in this syndrome, including vascular malformations and neural tube defects. Continued recruitment and close monitoring of patients with this syndrome as well as the generation and study of a corresponding disease mouse model as afforded by the pheochromocytoma/paraganglioma translational program at the National Institutes of Health has provided new insights into the natural history of these developmental anomalies and the pathophysiologic role of HIF-2α. Further, these studies have highlighted the importance of the timing of genetic defects in the development of related disease phenotypes. The recent discovery and continued study of this syndrome has not only rapidly evolved our understanding of pheochromocytoma and paraganglioma but also deepened our understanding of other developmental tumor syndromes, heritable syndromes, and sporadic diseases.

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