scholarly journals Pituitary tumors: genetic and molecular factors underlying pathogenesis and clinical behavior

2021 ◽  
Author(s):  
Anna Spada ◽  
Giovanna Mantovani ◽  
Donatella Treppiedi ◽  
Federica Mangili ◽  
Rosa Catalano ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Pituitary Tumors ◽  
Clinical Behavior ◽  
Molecular Alterations ◽  
Behavior Understanding ◽  
Pituitary Tumorigenesis ◽  
Stimulatory G Protein ◽  
Specific Protease ◽  
Drug Responsiveness ◽  
Acth Secreting

Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases the presence of germline mutations in specific genes predisposes to PitNETs formation, as part of syndromic diseases or familial isolated pituitary adenomas (FIPA), and associates to more aggressive, invasive and drug resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the  subunit of stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNETs drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNETs clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNETs clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.

scholarly journals Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1302
Author(s):  
Daniela D’Angelo ◽  
Marco De Martino ◽  
Claudio Arra ◽  
Alfredo Fusco
Keyword(s):  
Molecular Mechanisms ◽  
Pituitary Tumors ◽  
Clinical Impact ◽  
Pituitary Tumorigenesis ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Non Coding Rnas

Two novel molecular mechanisms with a driver role in pituitary tumorigenesis have been recently identified. They are (a) mutations in the Ubiquitin-Specific Protease 8 (USP8) gene in corticotroph tumors and (b) overexpression of the HMGA1 and HMGA2 genes in most of the pituitary tumors. Moreover, deregulated expression of the non-coding RNAs has been very frequently observed in this neoplasia. The aim of this review is to better elucidate the role, the mechanisms, and the possible clinical impact of these novel alterations in the development of pituitary neoplasia.

scholarly journals Temozolomide in the Treatment of Aggressive Pituitary Tumors—An Overview of Existing Knowledge and Future Perspectives

2012 ◽  
Vol 08 (02) ◽  
pp. 112
Author(s):  
Ann McCormack ◽  
Keyword(s):  
Dna Methyltransferase ◽  
Treatment Algorithm ◽  
Pituitary Tumors ◽  
Methylguanine Dna Methyltransferase ◽  
Pituitary Tumorigenesis ◽  
Significant Efficacy ◽  
Primary Determinant ◽  
Acth Secreting ◽  
Term Data

The management of aggressive pituitary tumors remains a challenge, however, the recent identification of temozolomide as a chemotherapeutic agent with significant efficacy against these tumors has heralded a new therapeutic era. There has been an exponential growth in the international experience with temozolomide over the past five years, now totaling 50 published cases. Overall, 67 % of cases demonstrated a response to temozolomide. Prolactin- and adrenocorticotrophic hormone (ACTH)-secreting tumors respond more frequently than non-functioning tumors. Response is typically evident in the first three months of treatment. Adverse effects occur in almost half of patients, although the majority are mild. The expression of a DNA repair enzyme, 06-methylguanine-DNA methyltransferase (MGMT), as determined by immunohistochemistry, appears to be the primary determinant of response to temozolomide in pituitary tumors. There is suggestion that MGMT may also play a role in pituitary tumorigenesis. Over the next few years we will see temozolomide used earlier in the treatment algorithm of aggressive pituitary tumors, making it imperative to collect global long-term data on its use.

scholarly journals Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab

2018 ◽  
Vol 103 (10) ◽  
pp. 3925-3930 ◽  
Author(s):  
Andrew L Lin ◽  
Philip Jonsson ◽  
Viviane Tabar ◽  
T Jonathan Yang ◽  
John Cuaron ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Liver Metastasis ◽  
Effective Treatment ◽  
Somatic Hypermutation ◽  
Treatment Options ◽  
Pituitary Tumors ◽  
Pituitary Carcinoma ◽  
Tumor Resistance ◽  
Clinical Sequencing ◽  
Acth Secreting

Abstract Context Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options. Case A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL. Molecular Evaluation Both prospective clinical sequencing with Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation. Conclusion Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.

scholarly journals Endoscopic endonasal transsphenoidal approach for pituitary adenomas: technical aspects and report of casuistic

2010 ◽  
Vol 68 (4) ◽  
pp. 608-612 ◽  
Author(s):  
Américo Rubens Leite dos Santos ◽  
Roberto Monteiro Fonseca Neto ◽  
José Carlos Esteves Veiga ◽  
José Viana Jr ◽  
Nilza Maria Scaliassi ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Pituitary Tumors ◽  
Hormonal Control ◽  
Subtotal Resection ◽  
Endoscopic Endonasal ◽  
Technical Aspects ◽  
Transphenoidal Approach ◽  
Acth Secreting ◽  
Csf Leaks

OBJECTIVE: Analyse technical aspects, effectiveness and morbidity of the endoscopic endonasal transphenoidal approach for pituitary adenomas. METHOD: From January 2005 to September 2008, 30 consecutive patients underwent endoscopic endonasal resection of pituitary adenomas with a follow up from 3 to 36 months. Their medical charts were retrospectively analysed. RESULTS: There were 18 women and 12 men, mean age 44 years (range 17-65 yr). Among the 30 patients, 23 had macroadenomas and 7 microadenomas. Twelve patients had non-functioning tumors, 9 had ACTH-secreting tumors, 8 had GH-secreting tumors and 1 prolactinoma. Complete resection and hormonal control was achieved in all microadenomas. Macroadenomas were completely removed in 6 patients, subtotal resection in 6 and partial resection in 11. Three patients had diabetes insipidus and 5 had CSF leaks treated with lumbar drainage. CONCLUSION: The endonasal endoscopic approach for pituitary tumors is effective and has low morbidity.

scholarly journals Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing

2019 ◽  
Vol 110 (1-2) ◽  
pp. 119-129 ◽  
Author(s):  
Antonella Sesta ◽  
Maria Francesca Cassarino ◽  
Mariarosa Terreni ◽  
Alberto G. Ambrogio ◽  
Laura Libera ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Pituitary Adenomas ◽  
Expression Profiles ◽  
Primary Cultures ◽  
Acth Secretion ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Specific Protease ◽  
Acth Secreting

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

Bevacizumab in Aggressive Pituitary Adenomas – Experience with 3 Patients

2020 ◽  
Author(s):  
Katharina Osterhage ◽  
Roman Rotermund ◽  
Michael Droste ◽  
Judith Dierlamm ◽  
Wolfgang Saeger ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Transsphenoidal Surgery ◽  
Pituitary Tumors ◽  
Considerable Effect ◽  
General Statement ◽  
Patient Deterioration ◽  
Short Period ◽  
Acth Secreting ◽  
Design And Methods ◽  
Current Stage

Abstract Objective To investigate bevacizumab as alternative treatment of aggressive pituitary adenomas after exhaustion of standard therapies. Design and Methods Retrospectively, 3 patients undergoing microscopic transsphenoidal surgery of aggressive pituitary adenomas from 2008 till 2018 that were treated with bevacizumab were identified. Development of disease and treatment were evaluated. Results Two patients suffered from ACTH-secreting adenomas, one from a non-functioning adenoma. All patients underwent multiple surgical, chemo- and radiotherapeutical approaches including temozolomide, showing favorable results in one patient. Deterioration of clinical condition in all patients led to an individual, palliative attempt of bevacizumab. Patients 1 and 2 showed a decrease of ACTH after first administrations, but therapy had to be ended shortly after due to a further deterioration of their condition. Patient 3 showed a stabilization of the disease for 18 months. Patients died 8, 15 and 7 years after initial diagnosis, respectively, and 2, 4, and 24 months after initiation of bevacizumab therapy, respectively. Conclusion The demonstrated results suggest a considerable effect of bevacizumab in aggressive pituitary adenomas. The advanced stage of disease in all three patients, the overall short period of administration and just one patient showing a clinical benefit do not allow a general statement on the effectiveness. At the current stage of clinical experience, an approach with bevacizumab can be considered as an individual palliative attempt of treatment, when standard treatments are exhausted. Our results underline the need for further studies to evaluate this drug as potential player in therapy resistant aggressive pituitary tumors.

MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior

2020 ◽  
Vol 43 (7) ◽  
pp. 947-958 ◽  
Author(s):  
T. M. Vicchio ◽  
F. Aliquò ◽  
R. M. Ruggeri ◽  
M. Ragonese ◽  
G. Giuffrida ◽  
...  
Keyword(s):  
Functional Status ◽  
Pituitary Tumors ◽  
Pathological Features ◽  
Clinical Behavior

Screening for New Markers to Assess Thyroid Hormone Action by OMICs Analysis of Human Samples

2020 ◽  
Vol 128 (06/07) ◽  
pp. 479-487 ◽  
Author(s):  
Nele Friedrich ◽  
Maik Pietzner ◽  
Beatrice Engelmann ◽  
Georg Homuth ◽  
Dagmar Führer ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Function ◽  
Clinical Symptoms ◽  
Pituitary Tumors ◽  
Population Based ◽  
Thyroid Stimulating Hormone ◽  
Central Hypothyroidism ◽  
Free Thyroid Hormones ◽  
Molecular Alterations ◽  
Novel Biomarkers

ABSTRACTDetermination of the levels of thyroid-stimulating hormone (TSH) and free thyroid hormones (fTHs) is crucial for assessing thyroid function. However, as a result of inter-individual genetic variability and different environmental factors individual set points exist for TSH and fTHs and display considerable variation. Furthermore, under specific pathophysiological conditions like central hypothyroidism, TSH secreting pituitary tumors, or thyroid hormone resistance the established markers TSH and fTH fail to reliably predict thyroid function and adequate supply of TH to peripheral organs. Even in case of overt hyper- and hypothyroidism circulating fTH concentrations do not correlate with clinical symptoms. Therefore, there is a clear need for novel, more specific biomarkers to diagnose and monitor thyroid function. OMICs screening approaches allow parallel profiling of hundreds to thousands of molecules and thus comprehensive monitoring of molecular alterations in tissues and body fluids that might be associated with changes in thyroid function. These techniques thus constitute promising tools for the identification of urgently needed novel biomarkers. This mini review summarizes the findings of OMICs studies in thyroid research with a particular focus on population-based and patient studies as well as interventional approaches investigating the effects of thyroid hormone administration.

ACTH Secreting Transplantable Pituitary Tumors.

1953 ◽  
Vol 84 (1) ◽  
pp. 253-254 ◽  
Author(s):  
J. Furth ◽  
E. L. Gadsen ◽  
A. C. Upton
Keyword(s):  
Pituitary Tumors ◽  
Acth Secreting
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