RESUMEN
High-grade endometrial stromal sarcomas (HGESSs) are aggressive uterine tumors harboring oncogenic fusion proteins. We performed a molecular study of 36 HGESSs with YWHAE::NUTM2 gene fusion, assessing co-occurring genetic events, and showed that these tumors frequently harbor recurrent events involving the CDKN2A locus on chromosome 9p. Using array-based copy number profiling and CDKN2A fluorescence in situ hybridization, we identified homozygous and hemizygous deletions of CDKN2A in 18% and 14% of tumors (n = 22 analyzed), respectively. While all YWHAE-rearranged HGESSs with retained disomy for CDKN2A were immunohistochemically positive for p16INK4 (p16), all tumors with homozygous deletion of CDKN2A showed complete absence of p16 staining. Of the 2 tumors with a hemizygous deletion of CDKN2A, 1 showed diffuse and strong p16 positivity, whereas the other showed complete absence of staining. In the p16-negative case, we did not find intragenic mutations or DNA promoter methylation to explain the p16 protein loss, implicating other mechanisms in the regulation of protein expression. In our cohort, subclonal or complete absence of p16 staining was associated with worse overall survival compared with positive p16 staining (1-year overall survival: 28.6% vs 90.7%, respectively; n = 32; P < .001), with all 7 patients in the p16-negative group having succumbed to their disease within 2 years of diagnosis. Our results suggested CDKN2A alterations as a cooperative driver of tumorigenesis in a subset of HGESSs with the YWHAE::NUTM2 gene fusion and showed p16 to be a potential prognostic marker.
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Neoplasias Endometriales , Sarcoma Estromático Endometrial , Sarcoma , Femenino , Humanos , Neoplasias Endometriales/patología , Pronóstico , Hibridación Fluorescente in Situ , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/patología , Homocigoto , Eliminación de Secuencia , Sarcoma/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Fusión Génica , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismoRESUMEN
Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent the cardiac analog of ISA due to morphological overlap and high prevalence of MDM2 amplifications in both neoplasms. However, little is known about ISAs and cardiac UPS without MDM2 amplifications and molecular data supporting their common classification is sparse. Here, we report a series of 35 cases comprising 25 ISAs of the pulmonary artery, one ISA of the renal artery and 9 UPS of the left atrium. Tumors were analyzed utilizing the Illumina Infinium MethylationEPIC BeadChip array, enabling copy number profile generation and unsupervised DNA methylation analysis. DNA methylation patterns were investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis. Histologically, all ISAs and UPS of the left atrium resembled extra-cardiac UPS. All cases exhibited highly complex karyotypes with overlapping patterns between ISA and UPS. 29/35 cases showed mutually exclusive amplifications in the cell-cycle associated oncogenes MDM2 (25/35), MDM4 (2/35), and CDK6 (2/35). We further observed recurrent co-amplifications in PDGFRA (21/35), CDK4 (15/35), TERT (11/35), HDAC9 (9/35), and CCND1 (4/35). Sporadic co-amplifications occurred in MYC, MYCN, and MET (each 1/35). The tumor suppressor CDKN2A/B was frequently deleted (10/35). Interestingly, DNA methylation profiling (t-SNE) revealed an overlap of ISA and cardiac UPS. This "ISA" methylation signature was distinct from potential histologic and molecular mimics. In conclusion, our data reveal MDM4 and CDK6 amplifications in ISAs and UPS of the left atrium, lacking MDM2 amplification. We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epigenetic concordance of ISAs and UPS of the left atrium further supports a shared pathogenesis and common classification.
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Proteínas de Ciclo Celular/genética , Quinasa 6 Dependiente de la Ciclina/genética , Metilación de ADN/genética , ADN de Neoplasias/genética , Neoplasias Cardíacas/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas/genética , Sarcoma/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Diferenciación Celular , Variaciones en el Número de Copia de ADN , Femenino , Amplificación de Genes , Estudio de Asociación del Genoma Completo , Neoplasias Cardíacas/patología , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Sarcoma/patología , Túnica Íntima/patología , Adulto JovenRESUMEN
Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.
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Adenoma Oxifílico/genética , Tumor de Células Granulares/genética , Neoplasias Hipofisarias/genética , Epigénesis Genética , HumanosRESUMEN
PURPOSE: Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (null cell PA) or the pituitary hormone(s) of the cell lineage of origin. In 0.5-1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown. METHODS: Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA). RESULTS: In accordance with the literature, combinations of GH/prolactin/TSH-FSH/LH adenoma (4/12), GH/prolactin/TSH-ACTH adenoma (3/12), and ACTH-FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern. CONCLUSION: Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct cell types.
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Adenoma , Neoplasias Hipofisarias , Adenoma/genética , Variaciones en el Número de Copia de ADN , Epigénesis Genética/genética , Humanos , Hipófisis , Neoplasias Hipofisarias/genéticaRESUMEN
To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated Pseudomonas exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.
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Antígenos de Neoplasias/inmunología , Autoantígenos/inmunología , Neoplasias del Sistema Nervioso Central/inmunología , Linfoma de Células B Grandes Difuso/inmunología , Proteínas de Microfilamentos/inmunología , Proteínas de Neoplasias/inmunología , Proteínas del Tejido Nervioso/inmunología , Proteínas Represoras/inmunología , Antígenos de Neoplasias/genética , Autoantígenos/genética , Línea Celular Tumoral , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/terapia , Glicosilación , Células HEK293 , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Proteínas de Microfilamentos/genética , Proteínas de Neoplasias/genética , Proteínas del Tejido Nervioso/genética , Proteínas Represoras/genéticaRESUMEN
Diffuse IDH-mutant astrocytic tumors are rarely diagnosed in the cerebellum or brainstem. In this multi-institutional study, we characterized a series of primary infratentorial IDH-mutant astrocytic tumors with respect to clinical and molecular parameters. We report that about 80% of IDH mutations in these tumors are of non-IDH1-R132H variants which are rare in supratentorial astrocytomas. Most frequently, IDH1-R132C/G and IDH2-R172S/G mutations were present. Moreover, the frequencies of ATRX-loss and MGMT promoter methylation, which are typically associated with IDH mutations in supratentorial astrocytic tumors, were significantly lower in the infratentorial compartment. Gene panel sequencing revealed two samples with IDH1-R132C/H3F3A-K27M co-mutations. Genome-wide DNA methylation as well as chromosomal copy number profiling provided further evidence for a molecular distinctiveness of infratentorial IDH-mutant astrocytomas. Clinical outcome of patients with infratentorial IDH-mutant astrocytomas is significantly better than that of patients with diffuse midline gliomas, H3K27M-mutant (p < 0.005) and significantly worse than that of patients with supratentorial IDH-mutant astrocytomas (p = 0.028). The presented data highlight the very existence and distinctiveness of infratentorial IDH-mutant astrocytomas that have important implications for diagnostics and prognostication. They imply that molecular testing is critical for detection of these tumors, since many of these tumors cannot be identified by immunohistochemistry applied for the mutated IDH1-R132H protein or loss of ATRX.
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Astrocitoma/genética , Astrocitoma/patología , Neoplasias Infratentoriales/genética , Neoplasias Infratentoriales/patología , Isocitrato Deshidrogenasa/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
In the original publication, the second name of the twentieth author was incorrect. It should read as 'Miguel Sáinz-Jaspeado'. The original publication of the article has been updated to reflect the change. This correction was authored by Ulrich Schüller on behalf of all authors of the original publication.
RESUMEN
Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.
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Metilación de ADN , Neuroblastoma/clasificación , Neuroblastoma/genética , Trastornos del Olfato/clasificación , Trastornos del Olfato/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Niño , Diagnóstico Diferencial , Femenino , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Mutación , Transcriptoma , Adulto JovenRESUMEN
Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. ß-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.
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Craneofaringioma/metabolismo , Sistema de Señalización de MAP Quinasas , Neoplasias Hipofisarias/metabolismo , Transcriptoma , Microambiente Tumoral/fisiología , Animales , Biología Computacional , Craneofaringioma/patología , Craneofaringioma/terapia , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/metabolismo , Inflamación/terapia , Captura por Microdisección con Láser , Ratones , Neuroglía/metabolismo , Odontogénesis/fisiología , Hipófisis/embriología , Hipófisis/patología , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapia , Análisis de Secuencia de ARN , Técnicas de Cultivo de TejidosRESUMEN
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Isocitrato Deshidrogenasa/genética , Transducción de Señal/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Femenino , Histonas/genética , Histonas/metabolismo , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mutación/genética , Estudios Retrospectivos , Proteínas Supresoras de Tumor/metabolismo , Proteína Nuclear Ligada al Cromosoma X/genética , Adulto JovenRESUMEN
PURPOSE: To analyse the antigen expression profiles of 27 cases of pituicytoma, spindle cell oncocytoma, and granular cell tumour of the sellar region concerning a common pituicytic origin of neoplastic cells. METHODS: Material from 12 female and 15 male patients (13 granular cell tumours of the sellar region, 10 pituicytomas, four spindle cell oncocytomas) collected in the German Registry of Pituitary Tumours between 1993 and 2015 was re-evaluated according to the current WHO classification of tumours of the central nervous system and supplementary immunohistochemistry including S100-protein, CD56, CD68, thyroid transcription factor-1 (TTF-1), and Ki-67 was performed. RESULTS: S100-protein was detected in all 27 tumours and TTF-1 in all 16 tumours that were assessed. Vimentin was expressed in all 13 cases investigated whereas broad spectrum cytokeratin was not detected in any of 14 evaluated cases. GFAP was observed in nine out of 21 cases. 15 out of 17 investigated lesions showed some CD68 expression and five out of 14 cases were labelled with CD56 antibodies. Proliferative activity did not differ significantly between the three tumour subgroups although one primary and one recurrent pituicytoma showed exceptionally high Ki-67-proliferation indices of 15.3 and 12.7 %, respectively (means: granular cell tumour of the sellar region 2.0 %, pituicytoma 2.8 %, spindle cell oncocytoma 2.7 %). CONCLUSIONS: The study confirms and expands earlier data and is in line with the notion that the three tumour types are variants of pituicytoma.
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Biomarcadores de Tumor/metabolismo , Neurohipófisis/inmunología , Neurohipófisis/metabolismo , Neoplasias Hipofisarias/inmunología , Neoplasias Hipofisarias/metabolismo , Adulto , Anciano , Femenino , Tumor de Células Granulares/inmunología , Tumor de Células Granulares/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Proteínas S100/metabolismo , Sarcoma/inmunología , Sarcoma/metabolismo , Factor Nuclear Tiroideo 1 , Factores de Transcripción/metabolismo , Vimentina/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: Even if treated, acromegaly has a considerable impact on patient quality of life (QoL); despite this, the exact clinical determinants of QoL in acromegaly are unknown. This study retrospectively examines a cohort of treated patients with acromegaly, with the aim of identifying these determinants. METHODS: Retrospective survey analysis, with 165 patients included in the study. All patients completed a survey, which included demographic data and the clinical details of their disease, the Short Form-36 Health Survey (SF-36), the revised Beck Depression Inventory (BDI-II), and the Bern Embitterment Inventory (BEI). Stepwise regression was used to identify predictors of QoL. RESULTS: The strongest predictors of the physical component score of the SF-36 were (in order of declining strength of association): Delay between first presentation of the disease and diagnosis, body mass index (BMI), number of doctors visited before the diagnosis of acromegaly, and age at diagnosis. For the mental component score, the strongest predictors were: number of doctors visited, previous radiotherapy, and age at study entry; and, for the BDI-II score: number of doctors visited, previous radiotherapy, age at study entry, and employment status at the time of diagnosis. The following were predictors of the BEI score: number of doctors visited, and age at study entry. CONCLUSION: Diagnostic delay and lack of diagnostic acumen in medical care provision are strong predictors of poor QoL in patients with acromegaly. Other identified parameters are radiotherapy, age, BMI, and employment status. An efficient acromegaly service should address these aspects when devising disease management plans. ABBREVIATIONS: BDI-II = Beck Depression Inventory II BEI = Bern Embitterment Inventory BMI = body mass index IGF-1 = insulin-like growth factor 1 MCS = mental component summary (score) PCS = physical component summary (score) QoL = quality of life SDS = standard deviation score SF-36 = Short Form-36 Health Survey.
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Acromegalia/fisiopatología , Adenoma/fisiopatología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/fisiopatología , Calidad de Vida , Acromegalia/diagnóstico , Acromegalia/psicología , Acromegalia/terapia , Adenoma/diagnóstico , Adenoma/psicología , Adenoma/terapia , Adolescente , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , Niño , Irradiación Craneana , Diagnóstico Tardío , Depresión/psicología , Agonistas de Dopamina/uso terapéutico , Empleo , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/psicología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/terapia , Hormona de Crecimiento Humana/análogos & derivados , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Pesimismo/psicología , Análisis de Regresión , Estudios Retrospectivos , Somatostatina/análogos & derivados , Encuestas y Cuestionarios , Adulto JovenRESUMEN
PURPOSE: Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor. Despite improved multimodal therapies, the tumor recurs in most cases. Diverging patient survival suggests great tumor heterogeneity and different therapy responses. Danger signals such as high-mobility group box protein 1 (HMGB1), heat shock protein 70 (HSP70), and calreticulin (CRT) are biomarker candidates, due to their association with tumor progression versus induction of antitumor immune responses. Overexpression of these danger signals has been reported for various types of tumors; however, their role in GBM is still elusive. A direct comparison of their expression in the primary tumor versus the corresponding relapse is still lacking for most tumor entities. PATIENTS AND METHODS: We therefore performed an expression analysis by immunohistochemistry of the danger signals HMGB1, HSP70, and CRT in primary tumors and the corresponding relapses of 9 patients with de novo GBM. RESULTS: HMGB1 was highly expressed in primary tumors with a significant reduction in the respective relapse. The extracellular HSP70 expression was significantly increased in the relapse compared to the primary tumor. CRT was generally highly expressed in the primary tumor, with a slight increase in the relapse. CONCLUSION: The combination of a decreased expression of HMGB1, an increased expression of extracellular HSP70, and an increased expression of CRT in the relapse seems to be beneficial for patient survival. HMGB1, extracellular HSP70, and CRT could be taken into concerted consideration as potential biomarkers for the prognosis of patients with GBM.
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Calreticulina/metabolismo , Glioblastoma/metabolismo , Glioblastoma/terapia , Proteína HMGB1/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & controlRESUMEN
PURPOSE: Early diagnosis is a success factor for the prevention of long-term comorbidity and premature death in patients with acromegaly, but large-scale data on the diagnostic process and disease management are scarce. Therefore, we aimed to evaluate the diagnostic process, implementation of treatment and changes in life situation in patients with acromegaly, focusing on sex-specific differences. METHODS: Non-interventional patient-reported outcome study. 165 patients with clinically and biochemically proven acromegaly were questioned about the diagnostic process and utilization of health care by means of a self-developed standardized postal survey including questions on acromegaly symptoms experienced before diagnosis, number and specialty of consulted doctors, time to diagnosis and aftercare. RESULTS: The diagnostic process took 2.9 (SD 4.53) years, during which 3.4 (SD 2.99) physicians were consulted. Women waited longer [4.1 (SD 5.53) years] than men [1.6 (SD 2.69) years; p = 0.001] for the correct diagnosis, and consulted more doctors in the process [4.0 (SD 2.99) vs. 2.7 (SD 2.84) doctors, p < 0.001, respectively]. In 48.5 % of patients, acromegaly was diagnosed by an endocrinologist (men: 45.1 %; women: 52.4 %). Overall disease duration from symptom onset until last surgery was 5.5 (SD 6.85) years, with no sex differences. A change in employment status was the most commonly reported event after diagnosis and a quarter of the patients stated that the illness had changed their lives. CONCLUSIONS: Our findings confirm the urgent need to increase awareness of the clinical manifestation of acromegaly to facilitate an earlier diagnosis of the disease and to provide diagnostic equality across the sexes.
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Adenoma/diagnóstico , Adenoma/terapia , Diagnóstico Tardío/estadística & datos numéricos , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/terapia , Derivación y Consulta/estadística & datos numéricos , Adenoma/metabolismo , Adulto , Cuidados Posteriores , Antineoplásicos/uso terapéutico , Irradiación Craneana , Femenino , Prueba de Tolerancia a la Glucosa , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Hormona de Crecimiento Humana/metabolismo , Humanos , Hipofisectomía , Factor I del Crecimiento Similar a la Insulina/metabolismo , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Factores Sexuales , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
OBJECTIVE In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated. METHODS The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures. RESULTS In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA. CONCLUSIONS These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.
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Craneofaringioma/metabolismo , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Inhibidoras de la Apoptosis/metabolismo , Neoplasias Hipofisarias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Adolescente , Adulto , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Supervivencia Celular/efectos de la radiación , Niño , Craneofaringioma/patología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Regulación hacia Abajo/efectos de la radiación , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/efectos de la radiación , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/patología , Tolerancia a Radiación/fisiología , Survivin , Células Tumorales CultivadasRESUMEN
AIMS: Adenohypophysis (AH) hormone-producing cells represent the origin of diverse groups of pituitary adenomas (PA). Deregulation of hypothalamic hormone receptors, growth factors and cAMP signalling have been implicated in the aetiology of PA. Endogenous retroviruses (ERVs) are derived from past exogenous retroviral infections and represent more than 8% of the human genome. Some ERV genes encode open reading frames and produce functional proteins, for example, the ERVW-1 envelope gene Syncytin-1, essential for placentogenesis, but also deregulated in human tumours. Data concerning ERV expression in the AH and related endocrine tumours are missing. METHODS: Syncytin-1 protein was analysed in normal AH (n = 15) and compared with five PA subtypes (n = 117) by immunohistochemistry. Absolute gene expression of 20 ERV functional envelope genes and ERVW-5 gag was measured. PA tissues were examined for Syncytin-1 and the cAMP signalling marker phospho-CREB-Ser133 using immunohistochemistry. Isolated primary human PA cells were treated with different hormones. Murine embryonic and adult pituitary gland ERV expressions were compared with human AH. RESULTS: Syncytin-1 protein colocalized with corticotropic cells of AH. In contrast, all PA demonstrated significant Syncytin-1 protein overexpression, supporting deregulation. All other ERV genes showed significant up-regulations in different PA subtypes. Phospho-CREB-Ser133 and Syncytin-1 colocalized in PA cells. Cultivated primary PA cells with ACTH or CRH induced their respective receptors and ERV genes. Syncytin-A/-B, murine orthologues to human Syncytin-1/-2, localized to embryonic and adult pituitary glands demonstrating functional mammalian conservation. CONCLUSIONS: Deregulated ERV genes may contribute to PA development via cAMP signalling.
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Adenoma/virología , Retrovirus Endógenos , Genes Virales , Hipófisis/virología , Neoplasias Hipofisarias/virología , Adulto , Animales , Femenino , Técnica del Anticuerpo Fluorescente , Productos del Gen env/biosíntesis , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Microscopía Confocal , Proteínas Gestacionales/biosíntesis , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
AIMS: The differential diagnosis of cystic epithelial masses of the sellar region, especially the histopathological differentiation of craniopharyngiomas and Rathke's cleft cysts, poses a challenge even to experienced diagnosticians. Recently, BRAF V600E mutations have been described as a genetic hallmark of papillary craniopharyngiomas. We investigated a series of 33 Rathke's cleft cysts to determine the frequency of BRAF V600E mutations and its suitability as an additional diagnostic marker for the differentiation of cystic lesions of the sellar region. METHODS: Thirty-three Rathke's cleft cysts and 18 papillary craniopharyngiomas were analysed for BRAF mutational status by immunohistochemistry using a monoclonal antibody (VE1) that selectively recognizes the BRAF V600E mutant epitope and additional BRAF pyrosequencing in a subset of samples. RESULTS: Thirty of 33 specimens diagnosed as Rathke's cleft cysts were negative by VE1 immunohistochemistry and pyrosequencing, whereas in three cysts and in all the 18 papillary craniopharyngiomas, a BRAF V600E mutation was detected. Clinical and histological re-evaluation of the three BRAF V600E mutated cases formerly diagnosed as Rathke's cleft cysts revealed unusual presentations. Two of them were rediagnosed as papillary craniopharyngiomas. The patient of the third case had a history of craniopharyngioma operated 14 years before, and reoperation showed a cystic epithelial lesion with unclear histology. CONCLUSIONS: The determination of BRAF mutational status is recommended in any cystic sellar lesion and can in most cases be provided by VE1 immunohistochemistry even in specimens of low cellularity. Confirmation by (pyro-)sequencing should be attempted whenever sufficient epithelium is available due to variable staining results.
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Quistes del Sistema Nervioso Central/genética , Craneofaringioma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Anciano , Anticuerpos Monoclonales , Quistes del Sistema Nervioso Central/patología , Craneofaringioma/patología , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas B-raf/inmunología , Adulto JovenAsunto(s)
Adenoma Hipofisario Secretor de ACTH/genética , Adenoma/genética , Metilación de ADN/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Adenoma Hipofisario Secretor de ACTH/diagnóstico , Adenoma/diagnóstico , Estudio de Asociación del Genoma Completo/métodos , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnósticoRESUMEN
AIMS: Owing to their close embryological relationship, soft tissue perineurioma and meningioma may closely mimic each other, not only histologically but also by immunohistochemistry. We aimed to compare the frequency of perineurial marker expression in these two entities, and to determine whether somatostatin receptor 2 (SSTR2) and progesterone receptor (PR), both expressed frequently in meningiomas, are also expressed in perineuriomas. METHODS AND RESULTS: We analysed and compared the immunohistochemical findings in 58 WHO grade I meningiomas (29 meningothelial, 16 fibrous, 10 transitional, and three others), 10 WHO grade II (atypical) meningiomas, and 20 soft tissue perineuriomas. All tumours were stained using five antibodies against antigens that are known to be expressed in perineuriomas or meningiomas: epithelial membrane antigen (EMA), claudin-1, GLUT-1 (glucose transporter-1), SSTR2, and PR. Of the meningiomas, EMA was expressed in 59 of 61, claudin-1 in five of 63, GLUT-1 in 19 of 62, SSTR2 in 59 of 68, and PR in 44 of 62. Of the perineuriomas, EMA was expressed in 20 of 20, claudin-1 in 17 of 18, GLUT-1 in 14 of 16, SSTR2 in one of 20, and PR in one of 20. The SSTR2-positive/PR-positive phenotype was detected in 42 of 60 meningiomas, but in none of 20 perineuriomas. On the other hand, the claudin-1-positive/GLUT-1-positive phenotype was detected in only four of 62 meningiomas, and in 14 of 16 perineuriomas. CONCLUSIONS: Epithelial membrane antigen expression is ubiquitous in both entities, and does not distinguish between them. SSTR2 and PR are highly sensitive and, in this context, specific meningioma markers. They may be helpful in distinguishing between the two entities, particularly in cases of meningioma occurring at unusual (extracranial) sites.
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Biomarcadores de Tumor/análisis , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Neoplasias de la Vaina del Nervio/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Adulto , Anciano , Niño , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Masculino , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Persona de Mediana Edad , Neoplasias de la Vaina del Nervio/metabolismo , Fenotipo , Neoplasias de los Tejidos Blandos/metabolismo , Adulto JovenRESUMEN
INTRODUCTION: Early disease onset, clinical manifestation, histomorphology, and increased tendency to relapse distinguish the adamantinomatous craniopharyngioma (adaCP) from the more favorable papillary variant (papCP). A molecular hallmark of adaCP is the activated Wnt signaling pathway indicated by nuclear ß-catenin accumulation in a subset of tumor cells. A mouse model recently illustrated that these cells are the driving force in tumorigenesis of adaCP. This observation and the peculiar growth pattern points to the existence of a specific tumor stem cell (TSC) population in human CP. MATERIALS AND METHODS: To prove this hypothesis, the TSC markers CD133 (Prominin1) and CD44 were examined in papCP (n = 8) and adaCP (n = 25) on mRNA level using quantitative real time PCR of total tumor RNA. Furthermore, we investigated protein expression performing immunohistochemical analyses of formalin-fixed paraffin embedded tumor samples. RESULTS: PapCP revealed a homogenous CD44 expression pattern predominantly at the cell membrane, whereas CD133 labeling was hardly detectable. In adaCP, on the other hand all markers were consistently and predominantly co-expressed in nuclear ß-catenin accumulating cell clusters, which was confirmed by double immunofluorescence staining. Overall expression of CD44 was significantly decreased in adaCP versus papCP, whereas CD133 showed significantly higher protein and mRNA levels in adaCP. CONCLUSIONS: Our results indicate tumor stem cell-like characteristics of ß-catenin accumulating cell clusters in adaCP, which may represent a tumor stem cell niche and might contribute to tumor recurrence. The potential impact of these special cell groups in regard to future CP management, including postoperative follow-up and additional treatment remains to be explored.