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

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

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

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

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

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

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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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Darren Cowzer Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Ronak H Shah Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Joanne F Chou Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Ritika Kundra Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Sippy Punn Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Laura Fiedler Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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April DeMore Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Marinela Capanu Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Michael F Berger Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Department of Pathology and laboratory medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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

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Nitya Raj Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Weill Medical College of Cornell University, New York, New York, USA

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In advanced pancreatic neuroendocrine neoplasms (PanNEN), there are little data detailing the frequency of genetic alterations identified in cell free DNA (cfDNA), plasma–tissue concordance of detected alterations, and clinical utility of cfDNA. Patients with metastatic PanNENs underwent cfDNA collection in routine practice. Next-generation sequencing (NGS) of cfDNA and matched tissue when available was performed. Clinical actionability of variants was annotated by OncoKB. Thirty-two cfDNA samples were analyzed from 25 patients, the majority who had well-differentiated intermediate grade disease (13/25; 52%). Genomic alterations were detected in 68% of patients and in 66% of all cfDNA samples. The most frequently altered genes were DAXX (28%), TSC2 (24%), MEN1 (24%), ARID1B (20%), ARID1A (12%), and ATRX (12%). Twenty-three out of 25 (92%) patients underwent tumor tissue NGS. Tissue–plasma concordance for select genes was as follows:DAXX (95.7%), ARID1A (91.1%), ATRX (87%), TSC2 (82.6%), MEN1 (69.6%). Potentially actionable alterations were identified in cfDNA of 8 patients, including TSC2 (4; level 3b), ATM (1; level 3b), ARID1A (2; level 4), and KRAS (1; level 4). An ETV6:NTRK fusion detected in tumor tissue was treated with larotrectinib; at progression, sequencing of cfDNA identified an NTRK3 G623R alteration as the acquired mechanism of resistance; the patient enrolled in a clinical trial of a second-generation TRK inhibitor with clinical benefit. In metastatic PanNENs, cfDNA-based NGS identified tumor-associated mutations in 66% of plasma samples with a high level of plasma-tissue agreement in PanNEN-associated genes. Clonal evolution, actionable alterations, and resistance mechanisms were detected through circulating cfDNA genotyping.

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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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Letizia Maria Ippolita Jannello Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada
Department of Urology IEO European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Università degli Studi di Milano, Milan, Italy

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Simone Morra Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada
Department of Neurosciences, Science of Reproduction and Odontostomatology, University of Naples Federico II, Naples, Italy

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Lukas Scheipner Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada
Department of Urology, Medical University of Graz, Graz, Austria

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Andrea Baudo Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada
Università degli Studi di Milano, Milan, Italy
Department of Urology, IRCCS Policlinico San Donato, Milan, Italy

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Carolin Siech Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada
Department of Urology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany

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Mario de Angelis Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada
Division of Experimental Oncology/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy

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Nawar Touma Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada

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Zhe Tian Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada

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Jordan A Goyal Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada

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Stefano Luzzago Department of Urology IEO European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy

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Francesco A Mistretta Department of Urology IEO European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy

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Mattia Luca Piccinelli Department of Urology IEO European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy

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Fred Saad Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada

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Felix K H Chun Department of Urology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany

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Alberto Briganti Division of Experimental Oncology/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy

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Sascha Ahyai Department of Urology, Medical University of Graz, Graz, Austria

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Luca Carmignani Department of Urology, IRCCS Policlinico San Donato, Milan, Italy
Department of Urology, IRCCS Ospedale Galeazzi - Sant'Ambrogio, Milan, Italy

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Nicola Longo Department of Neurosciences, Science of Reproduction and Odontostomatology, University of Naples Federico II, Naples, Italy

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Ottavio de Cobelli Department of Urology IEO European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy

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Gennaro Musi Department of Urology IEO European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy

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Pierre I Karakiewicz Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada

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We developed a novel contemporary population-based model for predicting cancer-specific survival (CSS) in adrenocortical carcinoma (ACC) patients and compared it with the established 8th edition of the American Joint Committee on Cancer staging system (AJCC). Within the Surveillance, Epidemiology, and End Results database (2004–2020), we identified 1056 ACC patients. Univariable Cox regression model addressed CSS. Harrell’s concordance index (C-index) quantified accuracy after 2000 bootstrap resamples for internal validation. The multivariable Cox regression model included the most informative, statistically significant predictors. Calibration and decision curve analyses (DCAs) tested the multivariable model as well as AJCC in head-to-head comparisons. Age at diagnosis (>60 vs ≤60 years), surgery, T, N, and M stages were included in the multivariable model. Multivariable model C-index for 3-year CSS prediction was 0.795 vs 0.757 for AJCC. Multivariable model outperformed AJCC in DCAs for the majority of possible CSS-predicted values. Both models exhibited similar calibration properties. Finally, the range of the multivariable model CSS predicted probabilities raged 0.02–75.3% versus only four single AJCC values, specifically 73.2% for stage I, 69.7% for stage II, 46.6% for stage III, and 15.5% for stage IV. The greatest benefit of the multivariable model-generated CSS probabilities applied to AJCC stage I and II patients. The multivariable model was more accurate than AJCC staging when CSS predictions represented the endpoint. Additionally, the multivariable model outperformed AJCC in DCAs. Finally, the AJCC appeared to lag behind the multivariable model when discrimination addressed AJCC stage I and II patients.

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Igryl S Cordero-Hernandez Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Alicia C Ross Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Arvind Dasari Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Daniel M Halperin Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Beth Chasen Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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James C Yao Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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We observed that some patients with well-differentiated neuroendocrine tumors (NET) who received peptide receptor radionuclide therapy (PRRT) with Lutetium-177 (177Lu) DOTATATE developed rapid disease progression with biopsy-proven histologic transformation to neuroendocrine carcinoma (NEC), an outcome that has not been previously described. Therefore, we conducted a retrospective review of all patients with well-differentiated G1-G2 NET who received at least one cycle of PRRT with (177Lu) DOTATATE at our center from January 2019 to December 2020. Among 152 patients, we identified 7 patients whose NET transformed to NEC. Median time from start of PRRT to transformation was 8.2 months (range: 2.6–14.4 months). All patients whose tumors underwent transformation had pancreatic tail as the primary site and had prior chemotherapy with temozolomide. No differences in the incidence of transformation were observed according to gender, race, original tumor grade, or number of prior therapies. Six patients received treatment with platinum and etoposide after transformation with two patients having partial response as best response. All patients with transformation died from progressive disease with median overall survival (OS) after transformation of 3.3 months (95% CI 2.1–4.4). Molecular testing of transformed NEC identified mutation(s) in TP53 and/or ATM in all cases. Transformation of NET to NEC following PRRT is associated with aggressive course and dismal prognosis. Patients with pancreatic tail as the primary site who had prior therapy with temozolomide may be at a higher risk. Further investigation is necessary to determine the best treatment sequence in this patient population.

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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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