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Andrew McDonald Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Vaidehi Avadhani Grady Memorial Hospital, Atlanta, Georgia, USA

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Gabriela Oprea-Ilies Grady Memorial Hospital, Atlanta, Georgia, USA

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Katerina Zakka Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Gregory B Lesinski Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Olumide B Gbolahan Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Olatunji Alese Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Gastroenteropancreatic high-grade (HG) neuroendocrine carcinoma (GEP-NEC) is an aggressive malignancy with limited treatment options and increasing incidence in the United States. Due to the rarity of the cancer and heterogeneity of the primary tumor location, data on GEP-NEC oncogenesis and its interaction with the host immune system are limited. A greater understanding of GEP-NEC and its tumor microenvironment (TME) would benefit efforts to develop more effective targeted therapies and rationally adapt immunotherapy to this disease. In this study, we profiled the expression of 770 unique genes using 21 biopsy samples from patients with GEP-NEC using the NanoString nCounter PanCancer IO 360 platform. Our results show several trends evident within the GEP-NEC TME. Greater expression of genes indicative of immune cell infiltration was present within the TME of patients <60 years of age and in patients with greater overall survival (OS). Tumors from patients with non-pancreatic NEC had diminished MHCII expression compared to pancreatic NEC, suggesting more prominent adaptive immune responses in the pancreatic GEP-NEC subtype. Patients with a >6 months OS had tumors with elevated NK cell gene signatures compared to patients with poor survival. Further, the analysis revealed numerous differentially expressed genes based on patient age, tumor location, response to treatment, and OS, which warrant future validation for assessing the relationship with clinical outcomes in patients.

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Marta García-Goñi Department of Endocrinology and Nutrition, University of Navarra, Pamplona, Spain

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Beatriz Vázquez Gutiérrez Department of Endocrinology and Nutrition, University of Navarra, Pamplona, Spain

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Miguel F Sanmamed Department of Oncology, University of Navarra, Pamplona, Spain

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Salvador Martín-Algarra Department of Oncology, University of Navarra, Pamplona, Spain
IdiSNA (Instituto de investigación en la Salud de Navarra), Pamplona, Spain

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José Luis Pérez-Gracia Department of Oncology, University of Navarra, Pamplona, Spain
IdiSNA (Instituto de investigación en la Salud de Navarra), Pamplona, Spain

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María Olmedo Department of Oncology, University of Navarra, Pamplona, Spain

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Estefanía Chumbiauca Department of Endocrinology and Nutrition, University of Navarra, Pamplona, Spain

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Nerea Martín-Calvo IdiSNA (Instituto de investigación en la Salud de Navarra), Pamplona, Spain
Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
CIBER de Fisiopatología de la Obesidad y la Nutrición, Pamplona, Spain

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Juan C Galofré Department of Endocrinology and Nutrition, University of Navarra, Pamplona, Spain
Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain

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A common immune-related adverse event (irAE) with immune checkpoint inhibitors (ICIs) is thyroid dysfunction (TD-irAEs). The clinical presentation can be varied, and its association with prognosis remains unclear. We investigated the characteristics of TD-irAEs and their association with clinical outcomes among cancer patients treated with ICIs in a real-life setting. Response to treatment was assessed using RECIST v1.1. We calculated the probability of recurrence and survival associated with TD-irAEs using multivariable-adjusted regression and Cox proportional hazards models. In this single-center retrospective analysis, we included 238 patients (72% male) with a median age of 69.5 years. Primary tumors were melanoma (23.1%), lung (60.5%), or urothelial cancer (16.4%), treated with atezolizumab (23.1%), pembrolizumab (44.5%), ipilimumab (0.4%), and/or nivolumab (25.6%). Seventy (29%) patients developed TD-irAEs in a median time of 69 days (41–181). The incidence of TD-irAEs with combination therapy was higher than with monotherapy (67% vs 6.3%, P = 0.011). TD-irAE patients showed a higher objective response rate (ORR) than those without TD-irAEs (60% vs 42.3%, P = 0.013) and longer overall survival (OS) 45 vs 16 months, P < 0.006. Patients who developed TD-irAEs had a relative reduction of 77% (OR 0.23, 95% CI 0.11–0.47) in the risk of progression and of 47% in the risk of mortality (HR 0.53, 95% CI 0.36–0.80), independent of age, sex, primary tumor, or ICI regimen. TD-irAEs occur in nearly 30% of our patients receiving ICIs. In our analysis, TD-irAEs appeared to be associated with higher ORR and longer OS and showed a reduction in the risk of progression and mortality.

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Liyan Zhou Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Guiying Bai Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yue Song Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Xiaohui Liu Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Xiaoqing Li Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yilin Deng Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yiran Si Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yehui Shi Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Hongli Li Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Scientific evidence has linked diabetes to a higher incidence and increased aggressiveness of breast cancer; however, mechanistic studies of the numerous regulators involved in this process are insufficiently thorough. Advanced glycation end products (AGEs) play an important role in the chronic complications of diabetes, but the mechanisms of AGEs in breast cancer are largely unexplored. In this study, we first demonstrate that high AGE levels in breast cancer tissues are associated with the diabetic state and poor patient outcomes. Furthermore, AGEs interact with the receptor for AGEs (RAGE) to promote breast cancer cell migration and invasion. Mechanistically, based on RNA sequencing (RNA-seq) analysis, we reveal that growth arrest and DNA damage gene 45α (GADD45α) is a vital protein upregulated by AGEs through a P53-dependent pathway. Next, GADD45α recruits thymine DNA glycosylase for base excision repair to form the demethylation complex at the promoter region of MMP-9 and enhance MMP-9 transactivation through DNA demethylation. Overall, our results indicate a critical regulatory role of AGEs in patients with breast cancer and diabetes and reveal a novel mechanism of epigenetic modification in promoting breast cancer metastasis.

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Marta Villanova M Villanova, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, United States

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Sara M. Tolaney S Tolaney, Medical Oncology, Dana-Farber Cancer Institute, Boston, United States

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Le Min L Min, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, United States

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Pembrolizumab-related thyroid dysfunction has been associated with better outcomes in metastatic cancer patients. This study aims to examine the outcomes [pathological Complete Response (pCR) and event-free survival (EFS)] in early-stage triple negative breast cancer (TNBC) patients receiving preoperative therapy who developed pembrolizumab-related thyroid dysfunction. Patients were divided into four groups based on the occurrence or not of pembrolizumab-related thyroid dysfunction (group A and D, respectively) and, in case of pre-existing thyroid disorder, based on the need of levothyroxine start/adjustment or not (group B and C, respectively). pCR and EFS in groups ABC were compared to the ones in group D. Sixty-four early-stage TNBC patients were included and the median follow-up was 16.5 months (IQR 12.0-23.8). Multiple patterns of thyroid irAEs were observed (overt hypothyroidism in 56.3%, subclinical thyrotoxicosis in 28.1%, overt thyrotoxicosis and subclinical hypothyroidism in 21.9%, and 21.9% of patients). No statistical difference was found in pCR (chi-square test, p=0.611) comparing groups ABC to group D. The median EFS in groups ABC and in group D were 16.5 (IQR 12.0-24.0) and 16.0 (IQR 12.0–22.3) months, respectively (log-rank test, p=0.671). The percentage of patients obtaining pCR was 85.7% in patients developing pembrolizumab–related overt thyrotoxicosis and 42.1% in remaining patients (Chi-square test, p=0.036). The EFS was 16.0 months (IQR 12.0-25.0) in patients developing pembrolizumab–related overt thyrotoxicosis and 16.0 months (IQR 12.0-23.5) in the remaining patients (log-rank test, p=0.494). In conclusion, multiple patterns of pembrolizumab-related thyroid dysfunction occurs in early-stage TNBC. Patients developing pembrolizumab-related overt thyrotoxicosis are more likely to achieve pCR.

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David Kishlyansky D Kishlyansky, Medicine , McMaster University, Hamilton, Canada

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Alexander A Leung A Leung, Medicine, University of Calgary Cumming School of Medicine, Calgary, Canada

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Janice Pasieka J Pasieka, Department of Surgery, Cumming School of Medicine, Calgary, T2N 2T9, Canada

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Amita Mahajan A Mahajan, Department of Medicine, University of Calgary, Calgary, Canada

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Gregory Kline G Kline, Department of Medicine, University of Calgary, Calgary, Canada

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Adrenocorticotropic hormone-producing pheochromocytoma/paraganglioma are rare neuroendocrine tumours that co-secrete excess catecholamines and adrenocorticotropic hormone, resulting in Cushing syndrome. This review aims to summarize important patient characteristics, investigations, and outcomes in all cases reported in the English literature. A literature search was conducted to identify all English-language case reports and case-series describing adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas. Relevant characteristics were systematically recorded. Cases that did not provide definitive evidence of an ACTH-producing pheochromocytoma/paraganglioma were excluded. Our search strategy identified 93 published cases that met the inclusion criteria. We additionally reported one patient for a total of 94 cases. Details related to patient characteristics, laboratory data, and outcomes were commonly underreported. The median age was 47 years and females accounted for 72% of cases. A cushingoid appearance was reported in 82% and hypertension in 86%. Infections were reported in 23% of patients. Urinary metanephrines were elevated at least 3-fold above normal in 74%. ACTH levels were high in 88% and inappropriately normal in 12%. The median 24-hour urinary cortisol was 21-fold the upper limit of normal. Adrenalectomy was performed in nearly all patients with 88% achieving cure of both catecholamine and glucocorticoid excess. A total of 11 patients died. Metastases were uncommon (6%). Adrenocorticotropic hormone-producing pheochromocytoma/paraganglioma is associated with considerable morbidity and mortality. It should be considered in the diagnostic workup of all patients with ectopic Cushing Syndrome. Surgical cure is achieved in most patients and infections are the leading cause of peri-operative mortality.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Vicente Rodrigues Marczyk Thyroid Unit, Endocrine division, Hospital de Clínicas de Porto Alegre (HCPA), Brazil
Medical School, Universidade Federal do Rio Grande do Sul (UFRGS), Brazil

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Ana Luiza Maia Thyroid Unit, Endocrine division, Hospital de Clínicas de Porto Alegre (HCPA), Brazil
Medical School, Universidade Federal do Rio Grande do Sul (UFRGS), Brazil

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Iuri Martin Goemann Thyroid Unit, Endocrine division, Hospital de Clínicas de Porto Alegre (HCPA), Brazil
Medical School, Universidade Federal do Rio Grande do Sul (UFRGS), Brazil
Medical School, Universidade do Vale do Rio dos Sinos (UNISINOS), Brazil

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TERT promoter mutations C228T and C250T are associated with disease aggressiveness and poor clinical outcomes in patients with papillary thyroid carcinomas. However, very little is known about the transcriptional consequences of these mutations and whether they both carry similar oncogenic potential. Here we characterized the transcriptional disturbances and clinical outcomes associated with the presence of each of these two mutations using data derived from The Cancer Genome Atlas. We observed that tumors harboring the C228T mutation (n = 27) exhibited a 16-fold increase in TERT mRNA levels (P = 5.3 × 10−42), whereas C250T tumors (n = 8) showed only a two-fold increase in expression (P = 0.034). The C228T mutation was associated with the activation of signaling pathways controlling the cell cycle, cellular division, and extracellular matrix degradation. Univariate analysis demonstrated that the C228T mutation was associated with older age at diagnosis, large tumor size, lymph node invasion, and distant metastases at diagnosis. The C228T mutation was also associated with worse progression-free interval (PFI) in comparison to WT tumors (HR = 5,04; P < 0.001). This association remained significant in a multivariate analysis (HR = 3.74, P = 0.003) adjusting for BRAF-V600E status and ATA risk group. Our data indicate that TERT promoter mutations C228T and C250T have distinct transcriptional consequences in papillary thyroid carcinoma (PTC), suggesting a greater oncogenic potential for the C228T mutation. TERT promoter mutation C228T may be a useful prognostic marker to identify patients at high risk of distant recurrence. Clinical data for the C250T mutation is still limited, with no evidence up to date to confirm its prognostic significance.

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Takuya Mikoshiba Department of Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

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Mariko Sekimizu Department of Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

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Shin Saito Department of Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

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Shintaro Nakamura Department of Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

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Ryoto Nagai Department of Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

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Miho Kawaida Division of Diagnostic Pathology, Keio University Hospital, Shinanomachi, Shinjuku-ku, Tokyo, Japan

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Isao Kurihara Division of Medical Education Improvement and Planning, Medical Education and Clinical Training Center, National Defense Medical College, Namiki, Tokorozawa, Saitama, Japan
Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

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Sakiko Kobayashi Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
Department of Endocrinology, Metabolism and Nephrology, NHO Tokyo Medical Center, Higashigaoka, Meguro-ku, Tokyo, Japan

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Hiroyuki Ozawa Department of Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

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Olfactory neuroblastomas rarely secrete adrenocorticotropic hormone, leading to ectopic adrenocorticotropic hormone syndrome. However, the prevalence, timing, and triggers of ectopic adrenocorticotropic hormone syndrome in patients with olfactory neuroblastomas remain unclear. This study aimed to investigate these factors and conduct a literature review. Fifteen patients with olfactory neuroblastomas who underwent surgery at our institution were included. The prevalence of ectopic adrenocorticotropic hormone syndrome development was assessed by evaluating adrenocorticotropic hormone expression using immunohistochemistry. Furthermore, 26 patients with olfactory neuroblastomas who developed ectopic adrenocorticotropic hormone syndrome from previous reports were reviewed. Among the 15 patients, three (20%) showed adrenocorticotropic hormone-positive tumor cells at the time of initial surgery, and two (13%) developed ectopic adrenocorticotropic hormone syndrome. The timing of developing ectopic adrenocorticotropic hormone syndrome was 2.5 and 10 years following the initial treatment of olfactory neuroblastoma. Based on the literature review, nine patients with recurrent and metastatic olfactory neuroblastoma developed ectopic adrenocorticotropic hormone syndrome after the initial surgery, of whom, three had confirmed disease after developing ectopic adrenocorticotropic hormone syndrome, three developed during disease progression, two developed after receiving chemotherapy, and one developed after undergoing a biopsy. The timing of ectopic adrenocorticotropic hormone syndrome was 2.5–15 years after initial treatment. Our study revealed that acknowledging olfactory neuroblastomas can manifest as ectopic adrenocorticotropic hormone syndrome with a certain low prevalence is crucial. Moreover, our study speculated that tumor stimulation, such as biopsy or chemotherapy, as well as disease progression, could trigger ectopic adrenocorticotropic hormone syndrome onset. Thus, olfactory neuroblastomas can develop into ectopic adrenocorticotropic hormone syndrome, even long after the initial treatment.

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Marta Araujo-Castro Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain & Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Madrid, Spain

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Betina Biagetti Department of Endocrinology and Nutrition, Hospital Universitario Vall de Hebrón, CIBERER U747 (ISCIII), ENDO-ERN, Barcelona, Spain

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Edelmiro Menéndez Torre Department of Endocrinology and Nutrition, Hospital Universitario Central de Asturias & Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain

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Iría Novoa-Testa Department of Endocrinology and Nutrition, Hospital Universitario de A Coruña, A Coruña, Spain

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Fernando Cordido Department of Endocrinology and Nutrition, Hospital Universitario de A Coruña, A Coruña, Spain

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Eider Pascual-Corrales Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain & Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Madrid, Spain

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Víctor Rodríguez Berrocal Department of Neurosurgery, Hospital Universitario Ramón y Cajal, Madrid, Spain

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Fernando Guerrero-Pérez Department of Endocrinology and Nutrition, Hospital Universitario de Bellvitge, Cataluña L’Hospitalet de Llobregat, Spain

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Almudena Vicente Department of Endocrinology and Nutrition, Hospital Universitario de Toledo, Toledo, Spain

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Juan Carlos Percovich Hualpa Department of Endocrinology and Nutrition, Hospital Universitario Gregorio Marañón, Madrid, Spain

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Rogelio García-Centeno Department of Endocrinology and Nutrition, Hospital Universitario Gregorio Marañón, Madrid, Spain

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Laura González-Fernández Department of Endocrinology and Nutrition, Hospital Universitario Gregorio Marañón, Madrid, Spain

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María Dolores Ollero García Department of Endocrinology and Nutrition, Hospital Universitario Navarra, Pamplona, Spain

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Ana Irigaray Echarri Department of Endocrinology and Nutrition, Hospital Universitario Navarra, Pamplona, Spain

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María Dolores Moure Rodríguez Department Endocrinology and Nutrition, Hospital Universitario de Cruces, Bilbao, Spain

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Cristina Novo-Rodríguez Department of Endocrinology and Nutrition, Hospital Universitario Virgen de las Nieves, Granada, Spain

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María Calatayud Department of Endocrinology and Nutrition, Hospital Universitario Doce de Octubre, Madrid, Spain

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Rocío Villar-Taibo Department of Endocrinology and Nutrition, Hospital Universitario de Santiago de Compostela, Madrid, Spain

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Ignacio Bernabéu Department of Endocrinology and Nutrition, Hospital Universitario de Santiago de Compostela, Madrid, Spain

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Cristina Alvarez-Escola Department of Endocrinology and Nutrition, Hospital Universitario La Paz, Madrid, Spain

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Pamela Benítez Valderrama Department of Endocrinology and Nutrition, Hospital Universitario La Paz, Madrid, Spain

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Carmen Tenorio-Jiménez Department of Endocrinology and Nutrition, Hospital Universitario Virgen de las Nieves, Granada, Spain

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Pablo Abellán Galiana Department of Endocrinology and Nutrition, Hospital General Universitario de Castellón, Castellón, Spain
Department of Medicine and Surgery, Universidad Cardenal Herrera-CEU, CEU Universities, Castellón, Spain

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Eva Venegas Department of Endocrinology and Nutrition, Hospital Universitario Virgen del Rocío, Sevilla, Spain

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Inmaculada González-Molero Endocrinology and Nutrition Department, Hospital Regional Universitario de Málaga, IBIMA Plataforma Bionand, Málaga, Spain

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Pedro Iglesias Department of Endocrinology and Nutrition, Hospital Universitario Puerta de Hierro, Madrid, Spain

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Concepción Blanco-Carrera Department of Endocrinology and Nutrition, Hospital Universitario Príncipe de Asturias, Madrid, Spain

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Fernando Vidal-Ostos De Lara Department of Endocrinology and Nutrition, Hospital Universitario Príncipe de Asturias, Madrid, Spain

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Paz de Miguel Novoa Department of Endocrinology and Nutrition, Hospital Clínico San Carlos, Madrid, Spain

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Elena López Mezquita Department of Endocrinology and Nutrition, Hospital Universitario Clínico San Cecilio, Granada, Spain

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Felicia Alexandra Hanzu Department of Endocrinology and Nutrition, Hospital Clinic de Barcelona, Barcelona, Spain

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Iban Aldecoa Biomedical Diagnostic Center, Department of Pathology, Hospital Clinic - University of Barcelona, Barcelona, Spain
Neurological Tissue Bank of the Biobank, FCRB-IDIBAPS-Hospital Clinic Barcelona, Barcelona, Spain

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Silvia Aznar Department of Endocrinology and Nutrition, Hospital Universitario De Albacete, Albacete, Spain

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Cristina Lamas Department of Endocrinology and Nutrition, Hospital Universitario De Albacete, Albacete, Spain

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Anna Aulinas Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, IR-SANT PAU, CIBERER U747 (ISCIII), Barcelona, Spain
Department of Medicine, Universitat de Vic-Universitat Central de Catalunya, Vic, Spain

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Queralt Asla Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, IR-SANT PAU, CIBERER U747 (ISCIII), Barcelona, Spain
Department of Medicine, Universitat de Vic-Universitat Central de Catalunya, Vic, Spain

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Paola Gracia Gimeno Department of Endocrinology and Nutrition, Hospital Royo Villanova, Zaragoza, Spain

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José María Recio-Córdova Department of Endocrinology and Nutrition, Hospital Universitario de Salamanca, Salamanca, Spain

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María Dolores Avilés-Pérez Department of Endocrinology and Nutrition, Hospital Universitario Clínico San Cecilio, Granada, Spain

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Diego Asensio-Wandosell Department of Endocrinology and Nutrition, Hospital Universitario Germans Trias i Pujol, Cataluña, Spain

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Miguel Sampedro-Núñez Department of Endocrinology and Nutrition, Hospital Universitario La Princesa Madrid, Spain

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Rosa Cámara Department of Endocrinology and Nutrition, Hospital Universitario y Politécnico La Fe, Valencia, Spain

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Miguel Paja Fano Department of Endocrinology and Nutrition, OSI Bilbao-Basurto, Hospital Universitario de Basurto & University of the Basque Country UPV/EHU, Bilbao, Spain

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Ignacio Ruz-Caracuel Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS & CIBER Cáncer (CIBERONC), Madrid, Spain

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Carmen Fajardo Department of Endocrinology and Nutrition, Hospital Universitario La Ribera, Valencia, Spain

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Mónica Marazuela Department of Endocrinology and Nutrition, Hospital Universitario La Princesa Madrid, Spain

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Manel Puig-Domingo Department of Endocrinology and Nutrition, Hospital Universitario Germans Trias i Pujol, Cataluña, Spain

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Fredrika Svahn Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Karolina Solhusløkk Höse Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Adam Stenman Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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Yaxuan Liu Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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Jan Calissendorff Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Emma Tham Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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Ákos Végvári Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

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Roman A Zubarev Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

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Na Wang Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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Reju Korah Yale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA

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Tobias Carling Yale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
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Jan Zedenius Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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Robert Bränström Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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C Christofer Juhlin Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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Catharina Larsson Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here, we re-analyzed whole-exome sequencing data for PCC patients and identified two patients with rare missense variants in the calcium voltage-gated channel subunit 1H gene (CACNA1H). CACNA1H variants were also found in the clinical setting in PCC patients using targeted sequencing and from analysis of The Cancer Genome Atlas database. In total, CACNA1H variants were found in six PCC cases. Three of these were constitutional, and two are known to have functional consequences on hormone production and gene expression in primary aldosteronism and aldosterone-producing adrenocortical adenoma. In general, PPGL exhibited reduced CACNA1H mRNA expression as compared to normal adrenal. Immunohistochemistry showed strong CACNA1H (CaV3.2) staining in adrenal medulla while PPGL typically had weak or negative staining. Reduced CACNA1H gene expression was especially pronounced in PCC compared to aPGL and in PPGL with cluster 2 kinase signaling phenotype. Furthermore, CACNA1H levels correlated with HIF1A and HIF2A. Moreover, TCGA data revealed a correlation between CACNA1H methylation density and gene expression. Expression of rCacna1h in PC12 cells induced differential protein expression profiles, determined by mass spectrometry, as well as a shift in the membrane potential where maximum calcium currents were observed, as determined by electrophysiology. The findings suggest the involvement of CACNA1H/CaV3.2 in pheochromocytoma development and establish a potential link between the etiology of adrenomedullary and adrenocortical tumor development.

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