Browsing by Author "Casar-Borota, Olivera (54411899300)"

Purpose: Inactivating mutations of isocitrate dehydrogenase (IDH) 1 and 2, mitochondrial enzymes participating in the Krebs tricarboxylic acid cycle play a role in the tumorigenesis of gliomas and also less frequently in acute myeloid leukemia and other malignancies. Inhibitors of mutant IDH1 and IDH2 may potentially be effective in the treatment of the IDH mutation driven tumors. Mutations in the succinate dehydrogenase, the other enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation occur in the paragangliomas, gastrointestinal stromal tumors, and occasionally in the pituitary adenomas. We aimed to determine whether the IDH1(R132H) mutation, the most frequent IDH mutation in human malignancies, occurs in pituitary adenomas. Methods: We performed immunohistochemical analysis by using a monoclonal anti-IDH1(R132H) antibody on the tissue microarrays containing specimens from the pituitary adenomas of different hormonal types from 246 patients. In positive samples, the status of the IDH1 gene was further examined by molecular genetic analyses. Results: In all but one patient, there was no expression of mutated IDH1(R132H) protein in the tumor cells by immunohistochemistry. Only one patient with a recurring clinically non-functioning gonadotroph adenoma demonstrated IDH1(R132H)-immunostaining in both the primary tumor and the recurrence. However, no mutation in the IDH1 gene was detected using different molecular genetic analyses. Conclusion: IDH1(R132H) mutation occurs only exceptionally in pituitary adenomas and does not play a role in their pathogenesis. Patients with pituitary adenomas do not seem to be candidates for treatment with the inhibitors of mutant IDH1. © 2016, Springer Science+Business Media New York.

Purpose: Inactivating mutations of isocitrate dehydrogenase (IDH) 1 and 2, mitochondrial enzymes participating in the Krebs tricarboxylic acid cycle play a role in the tumorigenesis of gliomas and also less frequently in acute myeloid leukemia and other malignancies. Inhibitors of mutant IDH1 and IDH2 may potentially be effective in the treatment of the IDH mutation driven tumors. Mutations in the succinate dehydrogenase, the other enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation occur in the paragangliomas, gastrointestinal stromal tumors, and occasionally in the pituitary adenomas. We aimed to determine whether the IDH1(R132H) mutation, the most frequent IDH mutation in human malignancies, occurs in pituitary adenomas. Methods: We performed immunohistochemical analysis by using a monoclonal anti-IDH1(R132H) antibody on the tissue microarrays containing specimens from the pituitary adenomas of different hormonal types from 246 patients. In positive samples, the status of the IDH1 gene was further examined by molecular genetic analyses. Results: In all but one patient, there was no expression of mutated IDH1(R132H) protein in the tumor cells by immunohistochemistry. Only one patient with a recurring clinically non-functioning gonadotroph adenoma demonstrated IDH1(R132H)-immunostaining in both the primary tumor and the recurrence. However, no mutation in the IDH1 gene was detected using different molecular genetic analyses. Conclusion: IDH1(R132H) mutation occurs only exceptionally in pituitary adenomas and does not play a role in their pathogenesis. Patients with pituitary adenomas do not seem to be candidates for treatment with the inhibitors of mutant IDH1. © 2016, Springer Science+Business Media New York.

In the original publication of this article, upper and lower part of Table 2 was incorrectly formatted. The incorrect and correct version of Table 2 are shown in this correction article. The original article has been corrected. Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper table) and in the entire cohort (lower table) Hypermethylated and positive enriched in PC pval padj NES size KEGG cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG focal adhesion 7.16E-05 0.0015 1.44 191 KEGG adherens junction 8.97E-05 0.0017 1.64 67 KEGG calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG gap junction 0.0063 0.036 1.40 83 KEGG axon guidance 1.60E-06 0.00028 1.53 122 KEGG calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG leukocyte transendothelial migration 0.011 0.10 1.28 108 Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper part of the table) and in the entire cohort (lower part of the table) Hypermethylated and positive enriched in PC pval padj NES size KEGG Cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG Axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG Pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG Neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG Focal adhesion 7.16E-05 0.0015 1.44 191 KEGG Adherens junction 8.97E-05 0.0017 1.64 67 KEGG Calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG Leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG Gap junction 0.0063 0.036 1.40 83 Hypermethylated and positive enriched in PC pval padj NES size KEGG Axon guidance 1.60E-06 0.00028 1.53 122 KEGG Calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG Neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG Regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG Cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG Leukocyte transendothelial migration 0.011 0.10 1.28 108 © The Author(s) 2024.

In the original publication of this article, upper and lower part of Table 2 was incorrectly formatted. The incorrect and correct version of Table 2 are shown in this correction article. The original article has been corrected. Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper table) and in the entire cohort (lower table) Hypermethylated and positive enriched in PC pval padj NES size KEGG cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG focal adhesion 7.16E-05 0.0015 1.44 191 KEGG adherens junction 8.97E-05 0.0017 1.64 67 KEGG calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG gap junction 0.0063 0.036 1.40 83 KEGG axon guidance 1.60E-06 0.00028 1.53 122 KEGG calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG leukocyte transendothelial migration 0.011 0.10 1.28 108 Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper part of the table) and in the entire cohort (lower part of the table) Hypermethylated and positive enriched in PC pval padj NES size KEGG Cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG Axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG Pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG Neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG Focal adhesion 7.16E-05 0.0015 1.44 191 KEGG Adherens junction 8.97E-05 0.0017 1.64 67 KEGG Calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG Leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG Gap junction 0.0063 0.036 1.40 83 Hypermethylated and positive enriched in PC pval padj NES size KEGG Axon guidance 1.60E-06 0.00028 1.53 122 KEGG Calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG Neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG Regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG Cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG Leukocyte transendothelial migration 0.011 0.10 1.28 108 © The Author(s) 2024.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors. © The Author(s) 2024.

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors. © The Author(s) 2024.

Non-functioning pituitary neuroendocrine tumors do not cause endocrine symptoms related to hypersecretion of adenohypophyseal hormones and are clinically characterized by symptoms due to growing sellar tumor mass. Histopathological classification of this tumor group has always been challenging due to their heterogeneity, limited knowledge on their biology, and diverse methodological problems. We have searched PubMed database for data related to the histopathological classification of non-functioning pituitary tumors and methods for its application. Principles of the classification and grading presented in the recently released 4th edition of the World Health Organization classification of endocrine tumors have been summarized. Based on the expression of anterior pituitary hormones and pituitary specific transcription factors, gonadotroph tumors dominate within the group of clinically non-functioning tumors, followed by corticotroph type; however, other less common types of the non-functioning tumors can be identified. Assessment of tumor cell proliferation is important to identify “high-risk adenomas.” A few subtypes of non-functioning tumors belong to the category of potentially aggressive tumors, independent of the cell proliferation rate. Here, we present up to date criteria for the classification of clinically non-functioning pituitary tumors, offer a diagnostic approach for the routine clinical use, and emphasize a need for inclusion of prognostic and predictive markers in the classification. © 2017, The Author(s).

Non-functioning pituitary neuroendocrine tumors do not cause endocrine symptoms related to hypersecretion of adenohypophyseal hormones and are clinically characterized by symptoms due to growing sellar tumor mass. Histopathological classification of this tumor group has always been challenging due to their heterogeneity, limited knowledge on their biology, and diverse methodological problems. We have searched PubMed database for data related to the histopathological classification of non-functioning pituitary tumors and methods for its application. Principles of the classification and grading presented in the recently released 4th edition of the World Health Organization classification of endocrine tumors have been summarized. Based on the expression of anterior pituitary hormones and pituitary specific transcription factors, gonadotroph tumors dominate within the group of clinically non-functioning tumors, followed by corticotroph type; however, other less common types of the non-functioning tumors can be identified. Assessment of tumor cell proliferation is important to identify “high-risk adenomas.” A few subtypes of non-functioning tumors belong to the category of potentially aggressive tumors, independent of the cell proliferation rate. Here, we present up to date criteria for the classification of clinically non-functioning pituitary tumors, offer a diagnostic approach for the routine clinical use, and emphasize a need for inclusion of prognostic and predictive markers in the classification. © 2017, The Author(s).

The anatomical and histological complexity of the parasellar region as well as the presence of embryonic remnants determine the huge diversity of parasellar neoplasms. Some of them are only located in the parasellar region, whereas others can occur elsewhere, within or outside the central nervous system. Their spectrum ranges from histologically benign and low-grade malignant to high-grade malignant tumours. Although rare, metastases can pose differential diagnostic dilemmas. The severity of the clinical picture, the challenges of surgery and the risk of adverse sequelae related to surgery or radiotherapy make parasellar tumours interesting entities for the clinicians irrespective of their histological malignancy grade. Due to the different cell origins of parasellar tumours, the World Health Organization classification system does not categorise them as a distinct group. Detailed criteria for classification and malignancy grading are presented in the classification systems covering central nervous system tumours, haematological malignancies and tumours of the soft tissue and bone. In the last few years, molecular genetic features have been integrated into the diagnosis of several types of the parasellar tumours enhancing diagnostic accuracy and providing information of the value for targeting therapies. In this review, we will present histopathological and molecular genetic features, updated classification criteria and recent advances in the diagnostics and rationale for novel pharmacological therapies of selected types of parasellar neoplasms. © 2020 S. Karger AG, Basel. All rights reserved.

The anatomical and histological complexity of the parasellar region as well as the presence of embryonic remnants determine the huge diversity of parasellar neoplasms. Some of them are only located in the parasellar region, whereas others can occur elsewhere, within or outside the central nervous system. Their spectrum ranges from histologically benign and low-grade malignant to high-grade malignant tumours. Although rare, metastases can pose differential diagnostic dilemmas. The severity of the clinical picture, the challenges of surgery and the risk of adverse sequelae related to surgery or radiotherapy make parasellar tumours interesting entities for the clinicians irrespective of their histological malignancy grade. Due to the different cell origins of parasellar tumours, the World Health Organization classification system does not categorise them as a distinct group. Detailed criteria for classification and malignancy grading are presented in the classification systems covering central nervous system tumours, haematological malignancies and tumours of the soft tissue and bone. In the last few years, molecular genetic features have been integrated into the diagnosis of several types of the parasellar tumours enhancing diagnostic accuracy and providing information of the value for targeting therapies. In this review, we will present histopathological and molecular genetic features, updated classification criteria and recent advances in the diagnostics and rationale for novel pharmacological therapies of selected types of parasellar neoplasms. © 2020 S. Karger AG, Basel. All rights reserved.