{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T12:38:31Z","timestamp":1780922311991,"version":"3.54.1"},"reference-count":54,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 inhibitors, have become the standard of care for many cancer types. However, they induce immune-related adverse events (irAEs), including neurotoxicity and hypophysitis. The incidence and outcomes of neurotoxicity and hypophysitis in patients treated with immune checkpoint inhibitors are not well established. We conducted a retrospective study of 812 patients with solid cancers who received immune checkpoint inhibitors at the University General Hospital of Ioannina between January 2018 and January 2023. We assessed demographic and clinical data, including the severity of symptoms, treatment regimen, other irAEs, resolution type and time, and death. Two patients experienced neurotoxicity and two hypophysitis. All four patients required inpatient administration and received corticosteroids or\/and hormone replacement. Three patients responded to the initial therapy, experiencing full recovery, while one patient was corticosteroid-resistant, and immunoglobin G was administered. Two patients never received immunotherapy after their toxicity due to the severity of symptoms; one patient continued monotherapy with nivolumab, changing from combination therapy with ipilimumab\u2013nivolumab, while the fourth patient continued his initial treatment with nivolumab. Our study suggests that the incidence of neurotoxicity and hypophysitis in patients treated with immune checkpoint inhibitors is low, but careful monitoring and prompt treatment with corticosteroids are necessary for effective management.<\/jats:p>","DOI":"10.3390\/curroncol30120766","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T12:57:56Z","timestamp":1702904276000},"page":"10509-10518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exploring a Rarity: Incidence of and Therapeutic Approaches for Neurological Complications and Hypophysitis in Cancer Patients on Immune Checkpoint Inhibitors\u2014A Single-Center Study"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2791-9255","authenticated-orcid":false,"given":"Anna Lea","family":"Amylidi","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"},{"name":"Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristeidis","family":"Gogadis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"},{"name":"Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melina","family":"Yerolatsite","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"},{"name":"Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5961-2237","authenticated-orcid":false,"given":"George","family":"Zarkavelis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"},{"name":"Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanteznta","family":"Torounidou","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"},{"name":"Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varvara","family":"Keramisanou","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"},{"name":"Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6865-7255","authenticated-orcid":false,"given":"Eleftherios","family":"Kampletsas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"},{"name":"Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Mauri","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"},{"name":"Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece"},{"name":"Faculty of Medicine, School of Health Sciences, University of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1038\/s41467-020-17670-y","article-title":"A decade of immune-checkpoint inhibitors in cancer therapy","volume":"11","author":"Robert","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nature10673","article-title":"Cancer immunotherapy comes of age","volume":"480","author":"Mellman","year":"2011","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ejca.2019.04.035","article-title":"The evolving landscape of \u2018next-generation\u2019 immune checkpoint inhibitors: A review","volume":"117","author":"Mazzarella","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4828","DOI":"10.1200\/JCO.2011.38.0899","article-title":"Cancer immunotherapy comes of age","volume":"29","author":"Topalian","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1038\/s41590-019-0512-0","article-title":"Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: Breakthroughs or backups","volume":"20","author":"Andrews","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13045-021-01056-8","article-title":"Next generation of immune checkpoint inhibitors and beyond","volume":"14","author":"Kimbrough","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa1104621","article-title":"Ipilimumab plus dacarbazine for previously untreated metastatic melanoma","volume":"364","author":"Robert","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1038\/s41590-023-01569-z","article-title":"LAG-3 as the third checkpoint inhibitor","volume":"24","author":"Aggarwal","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"150934","DOI":"10.1016\/j.soncn.2019.08.013","article-title":"The Future of Immunotherapy in the Treatment of Cancer","volume":"35","author":"Kottschade","year":"2019","journal-title":"Semin. Oncol. Nurs."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"594","DOI":"10.6004\/jnccn.2018.0047","article-title":"New NCCN Guidelines: Recognition and Management of Immunotherapy-Related Toxicity","volume":"16","author":"Thompson","year":"2018","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41571-019-0218-0","article-title":"Adverse effects of immune-checkpoint inhibitors: Epidemiology, management and surveillance","volume":"16","author":"Martins","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s11910-020-01038-2","article-title":"Neurologic Toxicities of Cancer Immunotherapies: A Review","volume":"20","author":"Harrison","year":"2020","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13073-019-0652-8","article-title":"Mechanisms of immune-related adverse events associated with immune checkpoint blockade: Using germline genetics to develop a personalized approach","volume":"11","author":"Khan","year":"2019","journal-title":"Genome Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.annonc.2022.10.001","article-title":"Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"33","author":"Haanen","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.currproblcancer.2016.12.001","article-title":"Cutaneous adverse effects of the immune checkpoint inhibitors","volume":"41","author":"Collins","year":"2017","journal-title":"Curr. Probl. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bertrand, A., Kostine, M., Barnetche, T., Truchetet, M.E., and Schaeverbeke, T. (2015). Immune related adverse events associated with anti-CTLA-4 antibodies: Systematic review and meta-analysis. BMC Med., 13.","DOI":"10.1186\/s12916-015-0455-8"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1517\/14712598.2016.1141195","article-title":"Combination immune checkpoint blockade with ipilimumab and nivolumab in the management of advanced melanoma","volume":"16","author":"Spain","year":"2016","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1136\/gutjnl-2018-316948","article-title":"Enterocolitis due to immune checkpoint inhibitors: A systematic review","volume":"67","author":"Soularue","year":"2018","journal-title":"Gut"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1080\/14740338.2020.1738382","article-title":"Neurologic complications of immune checkpoint inhibitors","volume":"19","author":"Haugh","year":"2020","journal-title":"Expert. Opin. Drug Saf."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1056\/NEJMoa1412082","article-title":"Nivolumab in previously untreated melanoma without BRAF mutation","volume":"22","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S1470-2045(15)70076-8","article-title":"Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial","volume":"16","author":"Weber","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/S1470-2045(15)00083-2","article-title":"Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial","volume":"16","author":"Ribas","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/NRL.0000000000000230","article-title":"Risk of Neurological Toxicities Following the Use of Different Immune Checkpoint Inhibitor Regimens in Solid Tumors: A Systematic Review and Meta-analysis","volume":"24","author":"Xu","year":"2019","journal-title":"Neurologist"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1001\/jamaoncol.2019.0393","article-title":"Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis","volume":"5","author":"Wang","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_26","unstructured":"Prete, A., and Salvatori, R. (2023, October 15). Hypophysitis, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK519842\/."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102979","DOI":"10.1016\/j.critrevonc.2020.102979","article-title":"Metabolic consequences of immune checkpoint inhibitors: A new challenge in clinical practice","volume":"151","author":"Parthymos","year":"2020","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1158\/1078-0432.CCR-18-2795","article-title":"Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1-Based Immunotherapy","volume":"25","author":"Lim","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1016\/j.ajpath.2016.08.020","article-title":"Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights into Pathogenesis from an Autopsy Series","volume":"186","author":"Caturegli","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1756286418799864","DOI":"10.1177\/1756286418799864","article-title":"Neurological complications of immune checkpoint inhibitors: What happens when you \u2018take the brakes off\u2019 the immune system","volume":"11","author":"Dalakas","year":"2018","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3348","DOI":"10.4049\/jimmunol.1700643","article-title":"PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8+ T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination","volume":"199","author":"Memarnejadian","year":"2017","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.semcancer.2019.12.026","article-title":"Roles of microbiota in response to cancer immunotherapy","volume":"65","author":"Inamura","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1210\/er.2018-00006","article-title":"Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints","volume":"40","author":"Chang","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1158\/1078-0432.CCR-14-2353","article-title":"Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: A retrospective cohort study","volume":"21","author":"Min","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_35","unstructured":"(2023, October 15). National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Published 2017, Available online: https:\/\/ctep.cancer.gov\/protocoldevelopment\/electronic_applications\/ctc.htm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"150","DOI":"10.5306\/wjco.v12.i3.150","article-title":"Systemic adverse effects and toxicities associated with immunotherapy: A review","volume":"12","author":"Kichloo","year":"2021","journal-title":"World J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nrclinonc.2016.58","article-title":"Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination","volume":"13","author":"Boutros","year":"2016","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1097\/WCO.0000000000000503","article-title":"Neurological toxicities associated with immune-checkpoint inhibitors","volume":"30","author":"Touat","year":"2017","journal-title":"Curr. Opin. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s40425-019-0617-x","article-title":"Neurologic toxicity associated with immune checkpoint inhibitors: A pharmacovigilance study","volume":"7","author":"Johnson","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1093\/annonc\/mdw558","article-title":"Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: A single centre experience and review of the literature","volume":"28","author":"Spain","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1634\/theoncologist.2016-0487","article-title":"Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis","volume":"22","author":"Larkin","year":"2017","journal-title":"Oncologist"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"w20377","DOI":"10.4414\/smw.2020.20377","article-title":"Immune checkpoint inhibitor therapy-associated encephalitis: A case series and review of the literature","volume":"150","author":"Stuby","year":"2020","journal-title":"Swiss Med. Wkly."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1001\/jamaneurol.2021.0249","article-title":"Encephalitis Induced by Immune Checkpoint Inhibitors: A Systematic Review","volume":"78","author":"Velasco","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e604","DOI":"10.1212\/NXI.0000000000000604","article-title":"Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors","volume":"6","author":"Vogrig","year":"2019","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11910-018-0810-1","article-title":"Neurological Adverse Events Associated with Immune Checkpoint Inhibitors: Diagnosis and Management","volume":"18","author":"Astaras","year":"2018","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1007\/s11060-022-03997-7","article-title":"Immune-related aseptic meningitis and strategies to manage immune checkpoint inhibitor therapy: A systematic review","volume":"157","author":"Nannini","year":"2022","journal-title":"J. Neurooncol"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/ajco.13375","article-title":"Neurological immune-related adverse events associated with immune checkpoint inhibitors: A review of the literature","volume":"16","author":"Fan","year":"2020","journal-title":"Asia Pac. J. Clin. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s11060-018-2752-5","article-title":"Neurologic complications of immune checkpoint inhibitors","volume":"137","author":"Fellner","year":"2018","journal-title":"J. Neurooncol"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"20420986211004745","DOI":"10.1177\/20420986211004745","article-title":"Immune checkpoint inhibitor-induced aseptic meningitis and encephalitis: A case-series and narrative review","volume":"12","author":"Thouvenin","year":"2021","journal-title":"Ther. Adv. Drug Saf."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11102-009-0193-z","article-title":"Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: Serious immune related adverse events across a spectrum of cancer subtypes","volume":"13","author":"Dillard","year":"2010","journal-title":"Pituitary"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1097\/01.cji.0000178913.41256.06","article-title":"Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer","volume":"28","author":"Blansfield","year":"2005","journal-title":"J. Immunother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/CJI.0000000000000300","article-title":"Immune-related Adverse Events and Survival in Solid Tumors Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis","volume":"43","author":"Petrelli","year":"2020","journal-title":"J. Immunother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1007\/s00262-020-02803-5","article-title":"Immune-related adverse events: Promising predictors for efficacy of immune checkpoint inhibitors","volume":"70","author":"Zhong","year":"2021","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_54","unstructured":"(2023, September 28). Management of Immune Checkpoint Inhibitor-Related Toxicities; NCCN Guidelines. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/immunotherapy.pdf."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/30\/12\/766\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:40:34Z","timestamp":1760132434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/30\/12\/766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,18]]},"references-count":54,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["curroncol30120766"],"URL":"https:\/\/doi.org\/10.3390\/curroncol30120766","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,18]]}}}