{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:14:30Z","timestamp":1783487670999,"version":"3.55.0"},"reference-count":121,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T00:00:00Z","timestamp":1703462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Pituitary neuroendocrine tumors (PitNETs) are the most common pituitary tumors and the second most common brain tumors. Although the vast majority (&gt;90%) are benign, a small percentage (&lt;2%) are aggressive. These aggressive PitNETs (AgPitNETs) are defined by the presence of radiological invasion, a high rate of cell proliferation, resistance to conventional treatments, and\/or a high propensity for recurrence. Lastly, there are the rare pituitary carcinomas, also known as metastatic PitNETs (MetPitNETs), which account for only 0.2% of cases and are defined by the presence of craniospinal or distant metastases. At present, there are no definitive factors that allow us to predict with certainty the aggressive behavior of PitNETs, making the therapeutic management of AgPitNETs a real challenge. Surgery is considered the first-line treatment for AgPitNETs and MetPitNETs. Radiation therapy can be effective in controlling tumor growth and regulating hormone hypersecretion. Currently, there are no approved non-endocrine medical therapies for the management of AgPitNETs\/MetPitNETs, mainly due to the lack of randomized controlled clinical trials. As a result, many of the medical therapies used are off-label drugs, and several are under investigation. Temozolomide (TMZ) is now recognized as the primary medical treatment following the failure of standard therapy (medical treatment, surgery, and radiotherapy) in AgPitNETs\/MetPitNETs due to its ability to improve overall and progression-free survival rates in responding patients over 5 years. Other therapeutic options include pituitary-targeted therapies (dopamine agonists and somatostatin analogs), hormonal antisecretory drugs, non-hormonal targeted therapies, radionuclide treatments, and immunotherapy. However, the number of patients who have undergone these treatments is limited, and the results obtained to date have been inconsistent. As a result, it is imperative to expand the cohort of patients undergoing treatment to better determine the therapeutic efficacy and safety of these drugs for individuals with AgPitNETs\/MetPitNETs.<\/jats:p>","DOI":"10.3390\/jcm13010116","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T22:59:09Z","timestamp":1703545149000},"page":"116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Aggressive and Metastatic Pituitary Neuroendocrine Tumors: Therapeutic Management and Off-Label Drug Use"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0126-1985","authenticated-orcid":false,"given":"Pedro","family":"Iglesias","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de Investigaci\u00f3n Sanitaria Puerta de Hierro Segovia de Arana (IDIPHISA), 28222 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1056\/NEJMra1810772","article-title":"Pituitary-Tumor Endocrinopathies","volume":"382","author":"Melmed","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.1210\/jc.2011-2031","article-title":"Clinical Review: Pituitary Carcinoma: Difficult Diagnosis and Treatment","volume":"96","author":"Heaney","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1530\/EJE-17-0796","article-title":"European Society of Endocrinology Clinical Practice Guidelines for the Management of Aggressive Pituitary Tumours and Carcinomas","volume":"178","author":"Raverot","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_4","first-page":"469","article-title":"Multimodal Therapy in Aggressive Pituitary Tumors","volume":"67","author":"Iglesias","year":"2020","journal-title":"Endocrinol. Diabetes Nutr. (Engl. Ed.)"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1530\/EJE-17-0933","article-title":"Treatment of Aggressive Pituitary Tumours and Carcinomas: Results of a European Society of Endocrinology (ESE) Survey 2016","volume":"178","author":"McCormack","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s12022-022-09703-7","article-title":"Overview of the 2022 WHO Classification of Pituitary Tumors","volume":"33","author":"Asa","year":"2022","journal-title":"Endocr. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e230021","DOI":"10.1530\/ERC-23-0021","article-title":"The World Health Organization Classifications of Pituitary Neuroendocrine Tumours: A Clinico-Pathological Appraisal","volume":"30","author":"Villa","year":"2023","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s11154-020-09556-7","article-title":"The Epidemiology of Aggressive Pituitary Tumors (and Its Challenges)","volume":"21","author":"Dekkers","year":"2020","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1530\/EJE-22-0440","article-title":"Aggressive Pituitary Tumours and Carcinomas, Characteristics and Management of 171 Patients","volume":"187","author":"Burman","year":"2022","journal-title":"Eur. J. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1210\/clinem\/dgad098","article-title":"Aggressive Pituitary Tumors and Pituitary Carcinomas: From Pathology to Treatment","volume":"108","author":"Burman","year":"2023","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"773905","DOI":"10.3389\/fonc.2021.773905","article-title":"Anti-VEGF Therapy in Refractory Pituitary Adenomas and Pituitary Carcinomas: A Review","volume":"11","author":"Dai","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11102-011-0341-0","article-title":"New Targeted Therapies in Pituitary Carcinoma Resistant to Temozolomide","volume":"15","author":"Jouanneau","year":"2012","journal-title":"Pituitary"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1007\/s11102-023-01298-4","article-title":"Refractory Nonfunctioning Pituitary Adenomas","volume":"26","author":"Kolitz","year":"2023","journal-title":"Pituitary"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1204206","DOI":"10.3389\/fendo.2023.1204206","article-title":"Efficacy and Safety of Temozolomide in the Treatment of Aggressive Pituitary Neuroendocrine Tumours in Spain","volume":"14","author":"Lamas","year":"2023","journal-title":"Front. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/s41574-021-00550-w","article-title":"Aggressive Pituitary Tumours and Pituitary Carcinomas","volume":"17","author":"Raverot","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.36401\/JIPO-22-25","article-title":"Recent Therapeutic Advances in Pituitary Carcinoma","volume":"6","author":"Robertson","year":"2023","journal-title":"J. Immunother. Precis Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.clineuro.2012.01.033","article-title":"Successful Treatment for Giant Pituitary Adenomas through Diverse Transcranial Approaches in a Series of 15 Consecutive Patients","volume":"114","author":"Guo","year":"2012","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1007\/s00701-021-04953-6","article-title":"Aggressive Pituitary Neuroendocrine Tumors: Current Practices, Controversies, and Perspectives, on Behalf of the EANS Skull Base Section","volume":"163","author":"Ng","year":"2021","journal-title":"Acta Neurochir."},{"key":"ref_19","first-page":"228","article-title":"Comparison of transcranial and transsphenoidal approaches in intra and suprasellar pituitary adenomas\u2014Systematic review","volume":"19","author":"Toader","year":"2023","journal-title":"Acta Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.wneu.2018.07.245","article-title":"Combined Endoscopic Endonasal and Video-Microscopic Transcranial Approach with Preoperative Embolization for a Posterior Pituitary Tumor","volume":"119","author":"Yoshida","year":"2018","journal-title":"World Neurosurg."},{"key":"ref_21","first-page":"292","article-title":"Executive Summary of the Expert Consensus Document from the Spanish Society of Neurosurgery and the Spanish Society of Endocrinology and Nutrition: Clinical Recommendations on the Perioperative Management of Pituitary Tumors","volume":"34","author":"Berrocal","year":"2023","journal-title":"Neurocirugia (Astur. Engl. Ed.)"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s11102-023-01345-0","article-title":"Pilot Study to Define Criteria for Pituitary Tumors Centers of Excellence (PTCOE): Results of an Audit of Leading International Centers","volume":"26","author":"Giustina","year":"2023","journal-title":"Pituitary"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1007\/s11102-023-01348-x","article-title":"Pituitary Tumor Centers of Excellence (PTCOE) Should Now Include Neuro-Oncologic Input","volume":"26","author":"Jouanneau","year":"2023","journal-title":"Pituitary"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101269","DOI":"10.1016\/j.beem.2019.04.003","article-title":"The Risk\/Benefit Ratio of Radiotherapy in Pituitary Tumors","volume":"33","author":"Minniti","year":"2019","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1016\/j.ijrobp.2011.02.053","article-title":"Tumor Shrinkage Assessed by Volumetric MRI in Long-Term Follow-up after Fractionated Stereotactic Radiotherapy of Nonfunctioning Pituitary Adenoma","volume":"82","author":"Kopp","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1530\/EJE-14-0872","article-title":"Fractionated Stereotactic Radiotherapy for Large and Invasive Non-Functioning Pituitary Adenomas: Long-Term Clinical Outcomes and Volumetric MRI Assessment of Tumor Response","volume":"172","author":"Minniti","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1007\/s11102-018-0868-4","article-title":"Management of Nonfunctioning Pituitary Tumors: Radiotherapy","volume":"21","author":"Minniti","year":"2018","journal-title":"Pituitary"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E539","DOI":"10.1227\/NEU.0000000000001385","article-title":"Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline for the Management of Patients With Residual or Recurrent Nonfunctioning Pituitary Adenomas","volume":"79","author":"Sheehan","year":"2016","journal-title":"Neurosurgery"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3171\/2013.3.JNS12766","article-title":"Gamma Knife Radiosurgery for the Management of Nonfunctioning Pituitary Adenomas: A Multicenter Study","volume":"119","author":"Sheehan","year":"2013","journal-title":"J. Neurosurg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s11154-020-09551-y","article-title":"Temozolomide Therapy for Aggressive Pituitary Tumours\u2014Current Understanding and Future Perspectives","volume":"21","author":"Burman","year":"2020","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101713","DOI":"10.1016\/j.beem.2022.101713","article-title":"Temozolomide in Aggressive Pituitary Tumours and Pituitary Carcinomas","volume":"36","author":"McCormack","year":"2022","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"700007","DOI":"10.3389\/fneur.2021.700007","article-title":"Clinical Efficacy of Temozolomide and Its Predictors in Aggressive Pituitary Tumors and Pituitary Carcinomas: A Systematic Review and Meta-Analysis","volume":"12","author":"Luo","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101712","DOI":"10.1016\/j.beem.2022.101712","article-title":"Immunotherapy in Pituitary Carcinomas and Aggressive Pituitary Tumors","volume":"36","author":"Raverot","year":"2022","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1158\/0008-5472.CAN-16-2983","article-title":"Temozolomide in the Era of Precision Medicine","volume":"77","author":"Thomas","year":"2017","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"774686","DOI":"10.3389\/fendo.2021.774686","article-title":"Early Initiation of Temozolomide Therapy May Improve Response in Aggressive Pituitary Adenomas","volume":"12","author":"Das","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"bvab190","DOI":"10.1210\/jendso\/bvab190","article-title":"Temozolomide Nonresponsiveness in Aggressive Prolactinomas and Carcinomas: Management and Outcomes","volume":"6","author":"Das","year":"2022","journal-title":"J. Endocr. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1080\/17446651.2023.2185221","article-title":"Knowing When to Discontinue Temozolomide Therapy in Responding Aggressive Pituitary Tumors and Carcinomas: A Systematic Review and Padua (Italy) Case Series","volume":"18","author":"Padovan","year":"2023","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_39","unstructured":"Peking Union Medical College Hospital (2020). Radiotherapy Plus Concomitant Temozolomide for Refractory Pituitary Adenomas, a Randomized, Double-Blind, Placebo-Controlled Phase II Trial, Peking Union Medical College Hospital."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1007\/s12022-020-09647-w","article-title":"Effects of CAPTEM (Capecitabine and Temozolomide) on a Corticotroph Carcinoma and an Aggressive Corticotroph Tumor","volume":"32","author":"Satou","year":"2021","journal-title":"Endocr. Pathol."},{"key":"ref_41","unstructured":"Weill Medical College of Cornell University (2022). Capecitabine and Temozolomide for Treatment of Recurrent Pituitary Adenomas, Weill Medical College of Cornell University."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4233","DOI":"10.1210\/jcem.83.12.5300","article-title":"The Role of Cytotoxic Chemotherapy in the Management of Aggressive and Malignant Pituitary Tumors","volume":"83","author":"Kaltsas","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1210\/jc.2003-030837","article-title":"Dopamine Receptor Expression and Function in Corticotroph Pituitary Tumors","volume":"89","author":"Pivonello","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1530\/EJE-16-0662","article-title":"Cabergoline for Cushing\u2019s Disease: A Large Retrospective Multicenter Study","volume":"176","author":"Ferriere","year":"2017","journal-title":"Eur. J. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1007\/s40618-021-01661-x","article-title":"The Dopaminergic Control of Cushing\u2019s Syndrome","volume":"45","author":"Pivonello","year":"2022","journal-title":"J. Endocrinol. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1227\/NEU.0000000000000657","article-title":"Crooke\u2019s Cell Tumors of the Pituitary","volume":"76","author":"Davidson","year":"2015","journal-title":"Neurosurgery"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"650791","DOI":"10.3389\/fendo.2021.650791","article-title":"Aggressive Cushing\u2019s Disease: Molecular Pathology and Its Therapeutic Approach","volume":"12","author":"Yamamoto","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"dgz200","DOI":"10.1210\/clinem\/dgz200","article-title":"Outcomes of Patients with Nelson\u2019s Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers","volume":"105","author":"Fountas","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_49","first-page":"300","article-title":"Nelson\u2019s Syndrome: Complete Remission with Cabergoline but Not with Bromocriptine or Cyproheptadine Treatment","volume":"62","author":"Casulari","year":"2004","journal-title":"Horm. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1007\/BF03343660","article-title":"Complete Remission of Nelson\u2019s Syndrome after 1-Year Treatment with Cabergoline","volume":"22","author":"Pivonello","year":"1999","journal-title":"J. Endocrinol. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s11102-006-9290-4","article-title":"Clinical and Biochemical Stabilization of Nelson\u2019s Syndrome with Long-Term Low-Dose Cabergoline Treatment","volume":"9","author":"Shimon","year":"2006","journal-title":"Pituitary"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1530\/eje.0.1440051","article-title":"ACTH Silent Adenoma Shrinking under Cabergoline","volume":"144","author":"Petrossians","year":"2001","journal-title":"Eur. J. Endocrinol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s11102-016-0737-y","article-title":"The Role of Combination Medical Therapy in the Treatment of Acromegaly","volume":"20","author":"Lim","year":"2017","journal-title":"Pituitary"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1210\/clinem\/dgac037","article-title":"Approach to the Patient with Treatment-Resistant Acromegaly","volume":"107","author":"Coopmans","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1507\/endocrj.EJ12-0272","article-title":"Efficacy of Combined Octreotide and Cabergoline Treatment in Patients with Acromegaly: A Retrospective Clinical Study and Review of the Literature","volume":"60","author":"Suda","year":"2013","journal-title":"Endocr. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/s11102-010-0272-1","article-title":"Role of the Addition of Cabergoline to the Management of Acromegalic Patients Resistant to Longterm Treatment with Octreotide LAR","volume":"14","author":"Vilar","year":"2011","journal-title":"Pituitary"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1210\/jc.2003-030859","article-title":"Dopamine Receptor Expression and Function in Clinically Nonfunctioning Pituitary Tumors: Comparison with the Effectiveness of Cabergoline Treatment","volume":"89","author":"Pivonello","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/COC.0000000000000505","article-title":"Cabergoline in the Management of Residual Nonfunctioning Pituitary Adenoma: A Single-Center, Open-Label, 2-Year Randomized Clinical Trial","volume":"42","author":"Batista","year":"2019","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1530\/EJE-16-0206","article-title":"Treatment of Clinically Nonfunctioning Pituitary Adenomas with Dopamine Agonists","volume":"175","author":"Greenman","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s11060-022-04149-7","article-title":"Effect of Cabergoline on Tumor Remnant after Surgery in Nonfunctioning Pituitary Adenoma","volume":"160","author":"Iglesias","year":"2022","journal-title":"J. Neurooncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s11102-023-01305-8","article-title":"Refractory Lactotroph Adenomas","volume":"26","author":"Urwyler","year":"2023","journal-title":"Pituitary"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1530\/EJE-07-0806","article-title":"Somatostatinergic Ligands in Dopamine-Sensitive and -Resistant Prolactinomas","volume":"158","author":"Fusco","year":"2008","journal-title":"Eur. J. Endocrinol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1136\/jcp.2005.026914","article-title":"Mapping of Somatostatin Receptor Types in GH or\/and PRL Producing Pituitary Adenomas","volume":"59","author":"Thodou","year":"2006","journal-title":"J. Clin. Pathol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s11102-008-0162-y","article-title":"Efficacy of the Combined Cabergoline and Octreotide Treatment in a Case of a Dopamine-Agonist Resistant Macroprolactinoma","volume":"14","author":"Fusco","year":"2011","journal-title":"Pituitary"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s12020-018-1638-9","article-title":"Treatment of Multiresistant Prolactinomas with a Combination of Cabergoline and Octreotide LAR","volume":"61","author":"Espinosa","year":"2018","journal-title":"Endocrine"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1530\/eje.1.02313","article-title":"Quantitative Analysis of Somatostatin Receptor Subtype (SSTR1-5) Gene Expression Levels in Somatotropinomas and Non-Functioning Pituitary Adenomas","volume":"156","author":"Taboada","year":"2007","journal-title":"Eur. J. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s11102-011-0370-8","article-title":"Treatment with Octreotide LAR in Clinically Non-Functioning Pituitary Adenoma: Results from a Case-Control Study","volume":"15","author":"Fusco","year":"2012","journal-title":"Pituitary"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"K21","DOI":"10.1530\/EJE-19-0279","article-title":"Excellent Response to Pasireotide Therapy in an Aggressive and Dopamine-Resistant Prolactinoma","volume":"181","author":"Coopmans","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ando.2018.07.013","article-title":"Pasireotide: A Potential Therapeutic Alternative for Resistant Prolactinoma","volume":"80","author":"Lasolle","year":"2019","journal-title":"Ann. Endocrinol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"C1","DOI":"10.1530\/EJE-19-0359","article-title":"Confirmation of a New Therapeutic Option for Aggressive or Dopamine Agonist-Resistant Prolactin Pituitary Neuroendocrine Tumors","volume":"181","author":"Raverot","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s11102-017-0853-3","article-title":"A Prospective Longitudinal Study of Pasireotide in Nelson\u2019s Syndrome","volume":"21","author":"Daniel","year":"2018","journal-title":"Pituitary"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40842-020-00110-7","article-title":"Rapid Response of Nelson\u2019s Syndrome to Pasireotide in Radiotherapy-Naive Patient","volume":"6","author":"He","year":"2020","journal-title":"Clin. Diabetes Endocrinol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1210\/jc.2013-1497","article-title":"Sustained Improvements in Plasma ACTH and Clinical Status in a Patient with Nelson\u2019s Syndrome Treated with Pasireotide LAR, a Multireceptor Somatostatin Analog","volume":"98","author":"Katznelson","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/BF02738884","article-title":"Vascular Endothelial Growth Factor (VEGF) Expression in Human Pituitary Adenomas and Carcinomas","volume":"10","author":"Lloyd","year":"1999","journal-title":"Endocr. Pathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/s004280000373","article-title":"Microvessel Density in Pituitary Adenomas and Carcinomas","volume":"438","author":"Vidal","year":"2001","journal-title":"Virchows Arch."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"102017","DOI":"10.1016\/j.ctrv.2020.102017","article-title":"Bevacizumab (Avastin\u00ae) in Cancer Treatment: A Review of 15 Years of Clinical Experience and Future Outlook","volume":"86","author":"Garcia","year":"2020","journal-title":"Cancer Treat Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s13045-020-00977-0","article-title":"Tyrosine Kinase Inhibitors for Solid Tumors in the Past 20 Years (2001\u20132020)","volume":"13","author":"Huang","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"470","DOI":"10.2174\/138920009788897975","article-title":"Tyrosine Kinase Inhibitors\u2014A Review on Pharmacology, Metabolism and Side Effects","volume":"10","author":"Hartmann","year":"2009","journal-title":"Curr. Drug Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2015.07.010","article-title":"A Historical Overview of Protein Kinases and Their Targeted Small Molecule Inhibitors","volume":"100","author":"Roskoski","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.3892\/ijo.2017.4120","article-title":"Trophic and Neurotrophic Factors in Human Pituitary Adenomas (Review)","volume":"51","author":"Spoletini","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1210\/endo.135.5.7956924","article-title":"Expression of Epidermal Growth Factor (EGF), Its Receptor, and Related Oncoprotein (erbB-2) in Human Pituitary Tumors and Response to EGF in Vitro","volume":"135","author":"Chaidarun","year":"1994","journal-title":"Endocrinology"},{"key":"ref_82","first-page":"656","article-title":"Epidermal Growth Factor and Its Receptor (EGF-R) in Human Pituitary Adenomas: EGF-R Correlates with Tumor Aggressiveness","volume":"81","author":"LeRiche","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/modpathol.3800118","article-title":"Analysis of Epidermal Growth Factor Receptor and Activated Epidermal Growth Factor Receptor Expression in Pituitary Adenomas and Carcinomas","volume":"17","author":"Onguru","year":"2004","journal-title":"Mod. Pathol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Wang, C., Zhang, Y., Zhang, T., Xu, J., Yan, S., Liang, B., and Xing, D. (2023). Epidermal Growth Factor Receptor Dual-Target Inhibitors as a Novel Therapy for Cancer: A Review. Int. J. Biol. Macromol., 253.","DOI":"10.1016\/j.ijbiomac.2023.127440"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.3390\/ijms13021886","article-title":"The mTOR Signalling Pathway in Human Cancer","volume":"13","author":"Lopes","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1677\/ERC-09-0101","article-title":"Activation of RAF\/MEK\/ERK and PI3K\/AKT\/mTOR Pathways in Pituitary Adenomas and Their Effects on Downstream Effectors","volume":"16","author":"Dworakowska","year":"2009","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_87","first-page":"3123","article-title":"Expression of the mTOR Pathway Regulators in Human Pituitary Adenomas Indicates the Clinical Course","volume":"33","author":"Jia","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Derwich, A., Sykutera, M., Bromi\u0144ska, B., Rubi\u015b, B., Rucha\u0142a, M., and Sawicka-Gutaj, N. (2023). The Role of Activation of PI3K\/AKT\/mTOR and RAF\/MEK\/ERK Pathways in Aggressive Pituitary Adenomas-New Potential Therapeutic Approach-A Systematic Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310952"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1210\/jc.2009-1641","article-title":"Effect of Everolimus on Cell Viability in Nonfunctioning Pituitary Adenomas","volume":"95","author":"Zatelli","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s12022-019-9568-5","article-title":"An Institutional Experience of Tumor Progression to Pituitary Carcinoma in a 15-Year Cohort of 1055 Consecutive Pituitary Neuroendocrine Tumors","volume":"30","author":"Alshaikh","year":"2019","journal-title":"Endocr. Pathol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Lamb, L.S., Sim, H.-W., and McCormack, A.I. (2020). Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature-\u201cAre We There Yet?\u201d. Cancers, 12.","DOI":"10.3390\/cancers12020308"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1210\/jc.2018-02461","article-title":"Effect of Everolimus in Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas","volume":"104","author":"Zhang","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/S2213-8587(21)00235-7","article-title":"Consensus on Diagnosis and Management of Cushing\u2019s Disease: A Guideline Update","volume":"9","author":"Fleseriu","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/S2213-8587(22)00244-3","article-title":"Acromegaly: Pathogenesis, Diagnosis, and Management","volume":"10","author":"Fleseriu","year":"2022","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1530\/EJE-08-0910","article-title":"Investigators of German Pegvisomant Observational Study Pituitary Tumor Size in Acromegaly during Pegvisomant Treatment: Experience from MR Re-Evaluations of the German Pegvisomant Observational Study","volume":"161","author":"Buchfelder","year":"2009","journal-title":"Eur. J. Endocrinol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Farkona, S., Diamandis, E.P., and Blasutig, I.M. (2016). Cancer Immunotherapy: The Beginning of the End of Cancer?. BMC Med., 14.","DOI":"10.1186\/s12916-016-0623-5"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.4110\/in.2022.22.e9","article-title":"Targeted Immunotherapy for Autoimmune Disease","volume":"22","author":"Jung","year":"2022","journal-title":"Immune Netw."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"961805","DOI":"10.3389\/fimmu.2022.961805","article-title":"Clinical Cancer Immunotherapy: Current Progress and Prospects","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"111ra120","DOI":"10.1126\/scitranslmed.3003130","article-title":"The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells","volume":"3","author":"Amarnath","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/nri3108","article-title":"The Emerging Role of CTLA4 as a Cell-Extrinsic Regulator of T Cell Responses","volume":"11","author":"Walker","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"S87","DOI":"10.3747\/co.27.5223","article-title":"A Review of Cancer Immunotherapy: From the Past, to the Present, to the Future","volume":"27","author":"Esfahani","year":"2020","journal-title":"Curr. Oncol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"76565","DOI":"10.18632\/oncotarget.12088","article-title":"Increased Expression of Programmed Death Ligand 1 (PD-L1) in Human Pituitary Tumors","volume":"7","author":"Mei","year":"2016","journal-title":"Oncotarget"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s11060-018-2844-2","article-title":"The Expression Profile of PD-L1 and CD8+ Lymphocyte in Pituitary Adenomas Indicating for Immunotherapy","volume":"139","author":"Wang","year":"2018","journal-title":"J. Neurooncol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Cossu, G., La Rosa, S., Brouland, J.P., Pitteloud, N., Harel, E., Santoni, F., Brunner, M., Daniel, R.T., and Messerer, M. (2023). PD-L1 Expression in Pituitary Neuroendocrine Tumors\/Pituitary Adenomas. Cancers, 15.","DOI":"10.3390\/cancers15184471"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1158\/1078-0432.CCR-18-3486","article-title":"Targeting PD-L1 Initiates Effective Antitumor Immunity in a Murine Model of Cushing Disease","volume":"26","author":"Kemeny","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1158\/1078-0432.CCR-06-2149","article-title":"Loss of the Mismatch Repair Protein MSH6 in Human Glioblastomas Is Associated with Tumor Progression during Temozolomide Treatment","volume":"13","author":"Cahill","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1210\/jc.2018-01347","article-title":"Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab","volume":"103","author":"Lin","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/cen.14645","article-title":"Should Pituitary Carcinoma Be Treated Using a NET-like Approach? A Case of Complete Remission of a Metastatic Malignant Prolactinoma with Multimodal Therapy Including Immunotherapy","volume":"98","author":"Goichot","year":"2023","journal-title":"Clin. Endocrinol."},{"key":"ref_109","unstructured":"Memorial Sloan Kettering Cancer Center (2023). Phase II Trial of Nivolumab Plus Ipilimumab in Patients with Aggressive Pituitary Tumors, Memorial Sloan Kettering Cancer Center."},{"key":"ref_110","unstructured":"(2023). National Cancer Institute (NCI) DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1097\/RLU.0000000000001629","article-title":"Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years\u2019 Assessment","volume":"42","author":"Hamiditabar","year":"2017","journal-title":"Clin. Nucl. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1007\/s00259-019-04578-z","article-title":"An Aggressive Functioning Pituitary Adenoma Treated with Peptide Receptor Radionuclide Therapy","volume":"47","author":"Assadi","year":"2020","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"S57","DOI":"10.1007\/s11102-011-0373-5","article-title":"First Demonstration of the Effectiveness of Peptide Receptor Radionuclide Therapy (PRRT) with 111In-DTPA-Octreotide in a Giant PRL-Secreting Pituitary Adenoma Resistant to Conventional Treatment","volume":"15","author":"Baldari","year":"2012","journal-title":"Pituitary"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s11102-013-0494-0","article-title":"Peptide Receptor Radionuclide Therapy in a Patient with Disabling Non-Functioning Pituitary Adenoma","volume":"17","author":"Komor","year":"2014","journal-title":"Pituitary"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1007\/s11102-013-0540-y","article-title":"Peptide Receptor Radionuclide Therapy for Aggressive Atypical Pituitary Adenoma\/Carcinoma: Variable Clinical Response in Preliminary Evaluation","volume":"17","author":"Maclean","year":"2014","journal-title":"Pituitary"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/RLU.0000000000000589","article-title":"The Use of (68)Ga DOTATATE PET\/CT for Diagnostic Assessment and Monitoring of (177)Lu DOTATATE Therapy in Pituitary Carcinoma","volume":"40","author":"Novruzov","year":"2015","journal-title":"Clin. Nucl. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"346","DOI":"10.3171\/2015.6.JNS15363","article-title":"Growth Hormone-Secreting Macroadenoma of the Pituitary Gland Successfully Treated with the Radiolabeled Somatostatin Analog (90)Y-DOTATATE: Case Report","volume":"125","author":"Gut","year":"2016","journal-title":"J. Neurosurg."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e129","DOI":"10.1097\/RLU.0000000000000462","article-title":"Improvement in Diagnosis of Metastatic Pituitary Carcinoma by 68Ga DOTATATE PET\/CT","volume":"40","author":"Xiao","year":"2015","journal-title":"Clin. Nucl. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"C7","DOI":"10.1530\/ERC-19-0186","article-title":"The next Generation of Peptide Receptor Radionuclide Therapy","volume":"26","author":"Brabander","year":"2019","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s002590050034","article-title":"Affinity Profiles for Human Somatostatin Receptor Subtypes SST1-SST5 of Somatostatin Radiotracers Selected for Scintigraphic and Radiotherapeutic Use","volume":"27","author":"Reubi","year":"2000","journal-title":"Eur. J. Nucl. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1111\/cen.14425","article-title":"Pre- and Postoperative 68 Ga-DOTATOC Positron Emission Tomography for Hormone-Secreting Pituitary Neuroendocrine Tumours","volume":"94","author":"Heurling","year":"2021","journal-title":"Clin. Endocrinol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/1\/116\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:41:38Z","timestamp":1760132498000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/1\/116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,25]]},"references-count":121,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["jcm13010116"],"URL":"https:\/\/doi.org\/10.3390\/jcm13010116","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,25]]}}}