{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:20:09Z","timestamp":1788967209596,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,17]],"date-time":"2024-08-17T00:00:00Z","timestamp":1723852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lung neuroendocrine neoplasms (L-NEN) are heterogeneous tumors. While bone metastases (BM) have been associated with worse prognosis in other NEN, their role in L-NEN deserves in-depth analysis. This study analyzes the clinical presentation, treatment and survival outcomes of L-NEN, focusing on patients with BM compared with patients without metastases or with metastases in other sites (OtherMtx). The clinicopathological and survival data of L-NEN admitted to the Federico II University were retrospectively evaluated. Fifty L-NEN were included. Among 27 metastatic patients (54%), 13 (26%) had BM, more commonly occurring in males than females and in primary bilateral L-NEN or L-NEN &gt; 26 mm, with higher Ki67. Atypical carcinoid and hypovitaminosis D were associated with BM. The number of metastatic sites was higher in patients with BM than OtherMtx. Synchronous metastases were associated with shorter overall survival (OS). The median progression-free survival (PFS) and OS in patients with BM were similar to OtherMtx, but a two-times increased risk of shorter OS was detected. BM do not impact PFS or OS more than OtherMtx, but the increased risk of shorter OS in patients with BM should be considered. Periodic bone evaluation in L-NEN should be recommended.<\/jats:p>","DOI":"10.3390\/ijms25168957","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T07:37:21Z","timestamp":1724053041000},"page":"8957","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Role of Bone Metastases in Lung Neuroendocrine Neoplasms: Clinical Presentation, Treatment and Impact on Prognosis"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3768-5803","authenticated-orcid":false,"given":"Roberta","family":"Modica","sequence":"first","affiliation":[{"name":"Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4489-3651","authenticated-orcid":false,"given":"Elio","family":"Benevento","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2616-3249","authenticated-orcid":false,"given":"Barbara","family":"Altieri","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8823-0702","authenticated-orcid":false,"given":"Roberto","family":"Minotta","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1784-5491","authenticated-orcid":false,"given":"Alessia","family":"Liccardi","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-1131","authenticated-orcid":false,"given":"Giuseppe","family":"Cannavale","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9737-9912","authenticated-orcid":false,"given":"Gianfranco","family":"Di Iasi","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Colao","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy"},{"name":"UNESCO Chair \u201cEducation for Health and Sustainable Development\u201d, Federico II University, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s40618-022-01905-4","article-title":"Neuroendocrine Neoplasms in the Context of Inherited Tumor Syndromes: A Reappraisal Focused on Targeted Therapies","volume":"46","author":"Ruggeri","year":"2023","journal-title":"J. Endocrinol. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1080\/17446651.2023.2279540","article-title":"Current Understanding of Pathogenetic Mechanisms in Neuroendocrine Neoplasms","volume":"19","author":"Modica","year":"2024","journal-title":"Expert. Rev. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s11912-021-01029-7","article-title":"Epidemiology, Incidence, and Prevalence of Neuroendocrine Neoplasms: Are There Global Differences?","volume":"23","author":"Das","year":"2021","journal-title":"Curr. Oncol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e49","DOI":"10.1016\/j.canep.2011.05.011","article-title":"Neuroendocrine Tumors: A Population-Based Study of Incidence and Survival in Girona Province, 1994\u20132004","volume":"35","author":"Alsina","year":"2011","journal-title":"Cancer Epidemiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1001\/jamaoncol.2017.0589","article-title":"Trends in the Incidence, Prevalence, and Survival Outcomes in Patients with Neuroendocrine Tumors in the United States","volume":"3","author":"Dasari","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-11276-9","article-title":"Integrative and Comparative Genomic Analyses Identify Clinically Relevant Pulmonary Carcinoid Groups and Unveil the Supra-Carcinoids","volume":"10","author":"Alcala","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.jtho.2021.11.003","article-title":"The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015","volume":"17","author":"Nicholson","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41379-021-00943-2","article-title":"Lung Neuroendocrine Neoplasms: Recent Progress and Persistent Challenges","volume":"35","author":"Rekhtman","year":"2022","journal-title":"Mod. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Altieri, B., Di Dato, C., Martini, C., Sciammarella, C., Di Sarno, A., Colao, A., Faggiano, A., Albertelli, M., Ambrosetti, E., and Bianchi, A. (2019). Bone Metastases in Neuroendocrine Neoplasms: From Pathogenesis to Clinical Management. Cancers, 11.","DOI":"10.3390\/cancers11091332"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1159\/000287255","article-title":"ENETS Consensus Guidelines for the Management of Bone and Lung Metastases from Neuroendocrine Tumors","volume":"91","author":"Falconi","year":"2010","journal-title":"Neuroendocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.jtho.2019.02.002","article-title":"Characterization, Prognosis, and Treatment of Patients With Metastatic Lung Carcinoid Tumors","volume":"14","author":"Robelin","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1159\/000197899","article-title":"Survival and Prognostic Factor Analysis of 146 Metastatic Neuroendocrine Tumors of the Mid-Gut","volume":"89","author":"Strosberg","year":"2009","journal-title":"Neuroendocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.21037\/jtd.2018.06.78","article-title":"A Single-Institution Retrospective Analysis of Metachronous and Synchronous Metastatic Bronchial Neuroendocrine Tumors","volume":"10","author":"Peri","year":"2018","journal-title":"J. Thorac. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1080\/17446651.2022.2099840","article-title":"Therapeutic Strategies for Patients with Neuroendocrine Neoplasms: Current Perspectives","volume":"17","author":"Modica","year":"2022","journal-title":"Expert. Rev. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/978-3-319-40389-2_3","article-title":"Lung Cancer Staging and Prognosis","volume":"170","author":"Woodard","year":"2016","journal-title":"Cancer Treat. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ejca.2016.03.081","article-title":"RECIST 1.1\u2014Update and Clarification: From the RECIST Committee","volume":"62","author":"Schwartz","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s12020-023-03542-0","article-title":"Thyroid Transcription Factor-1 Expression in Lung Neuroendocrine Tumours: A Gender-Related Biomarker?","volume":"83","author":"Siciliani","year":"2023","journal-title":"Endocrine"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Altieri, B., Di Dato, C., Modica, R., Bottiglieri, F., Di Sarno, A., Pittaway, J.F.H., Martini, C., Faggiano, A., and Colao, A. (2020). Bone Metabolism and Vitamin D Implication in Gastroenteropancreatic Neuroendocrine Tumors. Nutrients, 12.","DOI":"10.3390\/nu12041021"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102168","DOI":"10.1016\/j.ctrv.2021.102168","article-title":"Knowns and Unknowns of Bone Metastases in Patients with Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis","volume":"94","author":"Spada","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1002\/ijc.30400","article-title":"The Epidemiology of Metastases in Neuroendocrine Tumors","volume":"139","author":"Hemminki","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00432-021-03672-w","article-title":"Survival Predictors of 177Lu-Dotatate Peptide Receptor Radionuclide Therapy (PRRT) in Patients with Progressive Well-Differentiated Neuroendocrine Tumors (NETS)","volume":"148","author":"Swiha","year":"2021","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/s12020-022-03160-2","article-title":"Bone Metastases in Midgut Neuroendocrine Tumors: Imaging Characteristics, Distribution, and Risk Factors","volume":"78","author":"Triumbari","year":"2022","journal-title":"Endocrine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e210568","DOI":"10.1530\/EC-21-0568","article-title":"Bone Metastases from Neuroendocrine Tumors: Clinical and Biological Considerations","volume":"11","author":"Scopel","year":"2022","journal-title":"Endocr. Connect."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1016\/j.jtho.2019.05.003","article-title":"Gene Expression Profiling of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Transcriptomic Subtypes with Specific Genomic Alterations","volume":"14","author":"Simbolo","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1210\/jc.2011-0385","article-title":"Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline","volume":"96","author":"Holick","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Capobianco, E., McGaughey, V., Seraphin, G., Heckel, J., Rieger, S., and Lisse, T.S. (2023). Vitamin D Inhibits Osteosarcoma by Reprogramming Nonsense-Mediated RNA Decay and SNAI2-Mediated Epithelial-to-Mesenchymal Transition. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1188641"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s12020-022-03015-w","article-title":"Prognostic Significance of Laterality in Lung Neuroendocrine Tumors","volume":"76","author":"Persano","year":"2022","journal-title":"Endocrine"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Liccardi, A., Colao, A., and Modica, R. (2024). Gender Differences in Lung Neuroendocrine Tumors: A Single-Center Experience. Neuroendocrinology, 1\u201310.","DOI":"10.1159\/000539412"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"513","DOI":"10.21037\/tlcr.2017.09.04","article-title":"Classification of Pulmonary Neuroendocrine Tumors: New Insights","volume":"6","author":"Pelosi","year":"2017","journal-title":"Transl. Lung Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/16\/8957\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:38:06Z","timestamp":1760110686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/16\/8957"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,17]]},"references-count":29,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ijms25168957"],"URL":"https:\/\/doi.org\/10.3390\/ijms25168957","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,17]]}}}