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Aleksander Skardal Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, USA
The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA
Center for Cancer Engineering, The Ohio State University, Columbus, Ohio, USA

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Hemamylammal Sivakumar Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, USA

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Marco A Rodriguez Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, USA

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Liudmila V Popova Division of Surgical Oncology, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Priya H Dedhia The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA
Center for Cancer Engineering, The Ohio State University, Columbus, Ohio, USA
Division of Surgical Oncology, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Graphical abstract

Abstract

Endocrine tumors are a heterogeneous cluster of malignancies that originate from cells that can secrete hormones. Examples include, but are not limited to, thyroid cancer, adrenocortical carcinoma, and neuroendocrine tumors. Many endocrine tumors are relatively slow to proliferate, and as such, they often do not respond well to common antiproliferative chemotherapies. Therefore, increasing attention has been given to targeted therapies and immunotherapies in these diseases. However, in contrast to other cancers, many endocrine tumors are relatively rare, and as a result, less is understood about their biology, including specific targets for intervention. Our limited understanding of such tumors is in part due to a limitation in model systems that accurately recapitulate and enable mechanistic exploration of these tumors. While mouse models and 2D cell cultures exist for some endocrine tumors, these models often may not accurately model nuances of human endocrine tumors. Mice differ from human endocrine physiology and 2D cell cultures fail to recapitulate the heterogeneity and 3D architectures of in vivo tumors. To complement these traditional cancer models, bioengineered 3D tumor models, such as organoids and tumor-on-a-chip systems, have advanced rapidly in the past decade. However, these technologies have only recently been applied to most endocrine tumors. In this review we provide descriptions of these platforms, focusing on thyroid, adrenal, and neuroendocrine tumors and how they have been and are being applied in the context of endocrine tumors.

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Xiangqian Zheng Thyroid Neck Oncology Department, Tianjin Medical University Cancer Institute & Hospital, Tianjin, Tianjin, China

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Meiyu Fang Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

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Yun Fan Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

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Yuping Sun Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China

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Meili Sun Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China

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Ankui Yang Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

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Bin Zhang Head and Neck Surgery Department, Beijing Cancer Hospital, Beijing, Beijing, China

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Qinjiang Liu Head and Neck Surgery, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China

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Hui Liu Head and Neck Oncology Surgical Department, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, China

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Xiaohong Zhou Head and Neck Surgery, Chongqing Cancer Hospital, Chongqing, Chongqing, China

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Tao Huang Breast and Thyroid Surgery, Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China

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Jianwu Qin Head and Neck Surgery, Henan Cancer Hospital, Zhengzhou, Henan, China

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Zhaohui Wang Head and Neck Surgery Department, Sichuan Cancer Hospital & Institute, Chengdu, Sichuan, China

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Mengmeng Qin Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, Jiangsu, China

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Zhenwei Shen Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, Jiangsu, China

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Sheng Yao Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, Jiangsu, China

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Jason Yang Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, Jiangsu, China

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Yu Wang Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China

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Ming Gao Thyroid Neck Oncology Department, Tianjin Medical University Cancer Institute & Hospital, Tianjin, Tianjin, China
Department of Breast and Thyroid Surgery, Tianjin Union Medical Center, Tianjin, Tianjin, China

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Pralsetinib has demonstrated efficacious activity in various solid tumors, including medullary thyroid cancer (MTC), as observed in the phase 1/2 global ARROW study (BLU-667-1101; NCT03037385). We evaluated the safety and efficacy of pralsetinib in Chinese patients with advanced RET-mutant MTC. In the extension cohort of ARROW, adult patients with advanced MTC, who had not received systemic therapy (except for cytotoxic chemotherapy), were treated with pralsetinib (400 mg once daily, orally). The primary endpoints were blinded independent central-reviewed (BICR) objective response rate (ORR) and safety. Between October 9, 2019, and April 29, 2020, 34 patients were enrolled at 12 centers across China. Among them, 28 patients tested positive for RET mutations in the central laboratory, and 26 of these, with measurable disease at baseline per BICR, were included in the analysis set for tumor response. As of April 12, 2021 (data cutoff), the ORR was 73.1% (95% CI: 52.2–88.4), and the median duration of response was not reached. The most common (≥15%) grade ≥3 treatment-related adverse events (TRAEs) in the 28 patients with RET-mutant MTC were neutrophil count decreased (8/28, 28.6%), blood creatine phosphokinase increased (6/28, 21.4%), and lymphocyte count decreased (5/28, 17.9%). Serious TRAEs were reported by six patients (21.4%), with the most common event being pneumonia (3/28, 10.7%). No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, as well as a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.

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Anna Angelousi 1st Department of Internal Medicine, Unit of Endocrinology, Laikon Hospital, Athens, Greece

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Ploutarchos Tzoulis Department of Metabolism & Experimental Therapeutics, Division of Medicine, University College London, London, UK

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Marina Tsoli 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Eleftherios Chatzellis 251 HAF and VA Hospital, Athens, Greece

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Anna Koumarianou Fourth Department of Internal Medicine, Hematology Oncology Unit, Attikon University Hospital, National and Kapodistrian University of Athens, Greece

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Gregory Kaltsas 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.

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Philipp Melhorn Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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Peter Mazal Department of Pathology, Medical University of Vienna, Vienna, Austria

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Ladislaia Wolff Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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Petar Popov Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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Elisabeth Kretschmer-Chott Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Alexander Haug Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Marius E Mayerhoefer Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Weill Cornell Medical College, Cornell University, New York, New York, USA

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

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Barbara Kiesewetter Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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The chemotherapy regimen capecitabine/temozolomide (CAPTEM) is routinely used in neuroendocrine tumors (NET), with antitumor activity particularly demonstrated in pancreatic or high-grade neuroendocrine neoplasms (NEN). However, different dosing regimens are used, and the optimal schedule remains to be defined. This single-center retrospective analysis assessed the efficacy and safety of CAPTEM in patients with NEN using a schedule starting both compounds simultaneously (temozolomide on days 1–5 and capecitabine on days 1–14 of a 28-day cycle) rather than sequentially. The primary parameters of interest were response rates, progression-free survival (PFS), and toxicities following this treatment regimen, hereinafter referred to as TEMCAP. The study population comprised 40 patients, half of whom (n = 20) had pancreatic NEN, and 9 patients (22.5%) had pulmonary or thymic NETs. The most common histology was NET G3 (n = 15, 37.5%), and 8 patients (20.0%) had a neuroendocrine carcinoma (NEC). Most patients (77.5%) had at least one prior systemic therapy, and 16 patients (40.0%) prior chemotherapy. The median number of TEMCAP cycles was 6 (range 1–16). Median PFS for the highly heterogeneous population was 13.3 months, while the median overall survival was 31.9 months. In total, 14/36 patients (38.9%) exhibited a partial response, and the disease control rate was 75.0%. The safety profile of TEMCAP (at a below-target mean temozolomide dose of 118.85 mg/m2) in our cohort was remarkably good with no toxicities of grade 3 or 4. Taken together, the results of this analysis further support the use of temozolomide/capecitabine in NEN and prompt further assessment of our modified TEMCAP schedule.

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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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Verónica A Bahamondes Lorca Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago, Chile

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Shiyong Wu Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA

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Radiotherapy is one of the major options currently for cancer treatment. Radiotherapy causes cellular damage inducing cell death, which is expected to be selective for tumor cells. However, side effects that alter the surrounding normal tissue are often hard to be avoided. When radiation involves the hypothalamic–pituitary axis, growth hormone deficiency (GHD) is frequently induced, causing developmental and metabolic-related diseases in childhood cancer survivors. Growth hormone (GH) replacement therapy has been used for these patients and has been shown to be safe in general. However, there are some debating for its long-term safety due to the known roles of GH in inducing cell growth, which could be related to cancer recurrence. In addition, studies have shown that GH is involved in the development of resistance to chemotherapy and radiotherapy through various mechanisms. In this review, we will first discuss the effects of GHD induced after radiotherapy and the safety of the GH replacement treatment. Then, we will discuss the role of the GH–IGF-1 axis in radioresistance via a mechanism of improving DNA repair.

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Sijin Li Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China

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Zhen Chen Department of Thyroid Surgery, Guangzhou First People’s Hospital, Guangzhou, China

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Mengchu Liu School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, China

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Liang Li Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Wensong Cai Department of Thyroid Surgery, Guangzhou First People’s Hospital, Guangzhou, China

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Zhe-Xiong Lian Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Haixia Guan Department of Endocrinology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Bo Xu Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China

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The activation of Treg cell subsets is critical for the prognosis of tumor patients; however, their heterogeneity and disease association in papillary thyroid carcinoma (PTC) need further investigation. We performed high-dimensional flow cytometry for immunophenotyping on thyroid tissues and matched peripheral blood samples from patients with multinodular goiters or PTC. We analyzed CD4+ T cell and Treg cell phenotypes and compared the recurrence-free survival of PTC patients with different Treg cell subset characteristics using TCGA. Furthermore, PTC recurrent and non-recurrent group were compared by multiplex immunohistochemistry. High-dimensional flow cytometry and bioinformatics analysis revealed an enrichment of Tregs in tumors compared with multinodular goiters and peripheral blood specimens. Moreover, effector Tregs (e-Tregs) as well as FOXP3+ non-Tregs were enriched in tumor samples, and the expression of CD39, PD-1, and CD103 increased on tumor Tregs. TCGA data analysis showed that individuals with CD39hi PD-1loCD103loe-Treghi and CD39loPD-1loCD103hie-Treghi expression patterns had a high recurrence rate. According to the multiplex immunohistochemistry and analysis, compared with non-recurrent group, the proportion of high recurrence rate effector Treg clusters (CD39+PD-1CD103 plus CD39PD-1CD103+) was increased in recurrent patients. Overall, our results highlight the potential of e-Treg subsets as future immunotherapy targets for PTC recurrence.

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Julia Beck ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
Department of Clinical Research, University of Basel, Basel, Switzerland

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Alexander Siebenhüner Hirslanden Zurich AG, Clinic for Hematology and Oncology, Zurich, Switzerland

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Damian Wild ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland

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Emanuel Christ ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
Department of Clinical Research, University of Basel, Basel, Switzerland

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Julie Refardt ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
Department of Clinical Research, University of Basel, Basel, Switzerland

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Sex differences affect the management of several diseases in both male and female patients. However, the influence of sex on neuroendocrine neoplasms (NENs) has been scarcely investigated. Thus, this study aimed to compare tumor characteristics, treatment decisions, and overall survival in patients with NENs, stratified by sex. The retrospective analysis of the SwissNET cohort covered NENs of gastroenteropancreatic, pulmonary, or unknown origin from July 2014 to September 2022. The analysis included 1985 patients (46% female and 54% male). No significant difference in tumor grading was found between male and female patients. However, male patients presented with higher staging at time of diagnosis and with more lymph node and bone metastases. Surgery was performed more often in female compared to male patients (73.4% vs 68.7%, P = 0.023). Male patients received peptide receptor nuclide therapy (PRRT) earlier than female patients (7.8 months vs 13.1 months from time of diagnosis, P = 0.003). The median overall survival was significantly shorter for male compared to female patients (male: 18 years, female: not reached, P < 0.001, hazard ratio (HR) 1.55 (1.19–2.01), P = 0.001). Multivariable analyses revealed advanced age (HR 1.02 (1.01–1.04)), cancer of unknown origin (HR 2.01 (1.09–3.70)), higher grading (G3: HR 6.74 (4.22–10.76)), having metastases at the time of diagnosis (HR 2.11 (1.47–3.02)), and surgical treatment (HR 0.67 (0.48–0.93)) as independent predictors for overall survival. In conclusion, male sex was associated with worse outcome in NEN patients, likely due to more advanced tumor stage at the time of diagnosis. Further investigations are required to understand the underlying mechanisms of these sex differences.

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Yihao Chen Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Jiahong Chen Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Yongcheng Shi Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Xiaohui Ling Reproductive Medicine Center, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Shumin Fang Science Research Center, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Chuanfan Zhong Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

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Fengping Liu State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China

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Weide Zhong State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China
Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, Guangdong

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Xuecheng Bi Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Zhong Dong Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Jianming Lu Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China

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Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis and high mortality rate. A high tumor mutational burden (TMB) has been found to be associated with poor prognosis in ACC. Thus, exploring ACC biomarkers based on TMB holds significant importance for patient risk stratification. In our research, we utilized weighted gene coexpression network analysis and an assay for transposase-accessible chromatin with high-throughput sequencing to identify genes associated with TMB. Through the comprehensive analysis of various public datasets, Lamin B1 (LMNB1) was identified as a biomarker associated with a high TMB and low chromatin accessibility. Immunohistochemical staining demonstrated high expression of LMNB1 in ACC compared to noncancerous tissues. Functional enrichment analyses revealed that the function of LMNB1 is associated with cell proliferation and division. Furthermore, cell assays suggested that LMNB1 promotes tumor proliferation and invasion. In addition, mutation analysis suggested that the high expression of LMNB1 is associated with TP53 mutations. Additionally, LMNB1 was highly expressed in the vast majority of solid tumors across cancers. In our immune analysis, we discovered that the high expression of LMNB1 might suppress the infiltration of CD8+ T cells in the ACC microenvironment. In summary, LMNB1 is a predictive factor for the poor prognosis of adult and pediatric ACC. Its high expression in ACC is positively associated with high TMB and lower chromatin accessibility, and it promotes ACC cell proliferation and invasion. Therefore, LMNB1 holds promise as a novel biomarker and potential therapeutic target for ACC.

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Andreas Machens Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Kerstin Lorenz Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Frank Weber Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Henning Dralle Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1–40 mm (node metastasis and biochemical cure) and 10.1–40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27–41% (overall 24.0%) point difference, followed by biochemical cure with a −15–35% (overall −20.3%) point difference and extrathyroid extension with a 17–24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

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