RESUMO
Pilocytic astrocytomas (PAs) are benign tumors. However, clinically aggressive PAs despite benign histology have been reported, and histological and molecular risk factors for prognosis have not been elucidated. 38 PAs were studied for clinical, histological, and molecular factors, including tumor location, extent of resection, post-operative treatment, glioma-associated molecules (IDH1/2, ATRX, BRAF, FGFR1, PIK3CA, H3F3A, p53, VEGF, Nestin, PD-1/PD-L1), CDKN2A/B deletion, and chromosomal number aberrations, to see if there is any correlation with patient's progression-free survival (PFS). Brainstem/spinal location, extent of resection and post-operative treatment, and VEGF-A, Nestin and PD-L1 expression, copy number gain of chromosome 7q or 19, TP53 mutation were significantly associated with shorter PFS. None of the histological parameters was associated with PFS. Multivariate analyses demonstrated that high Nestin expression, gain of 7q or 19, and extent of removal were independently predictive for early tumor recurrence. The brainstem/spinal PAs appeared distinct from those in the other sites in terms of molecular characteristics. Clinically aggressive PAs despite benign histology exhibited high Nestin expression. Brainstem/spinal location, extent of resection and some molecular factors including Nestin expression and gains of 7q and 19, rather than histological parameters, may be associated with early tumor recurrence in PAs.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Humanos , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/patologia , Recidiva Local de Neoplasia/genética , Nestina/genética , Nestina/metabolismo , Astrocitoma/patologia , Tronco Encefálico/metabolismo , Tronco Encefálico/patologiaRESUMO
The relevance of oligodendroglial histological features to patient prognoses is controversial. 93 LrGGs resected for about 2 decades were re-assessed based on WHO2007 with special interest to pure oligodendroglial diagnosis (oligodendroglioma or anaplastic oligodendroglioma) and presence of CFO features. Those histological features, patients OS, and tumor chromosomal/genetic characteristics were correlated each other in each of the 3 IDH-1p/19q-based molecular groups. There was significant association between 1p19q status with the oligodendroglial histological diagnosis as well as presence of CFO in the entire cohort. The oligodendroglial diagnosis was associated with longer OS in IDHmut/codel group; however, this association was not significant in the multivariate analyses. In IDHmut/noncodel and IDH-wildtype groups, the oligodendroglial diagnosis was not associated with patient OS. Presence of CFO was not associated with patient OS in any molecular groups. Gain of 8q was associated with the oligodendroglial diagnosis in IDHmut/noncodel group. Neither the oligodendroglial diagnosis nor CFO was predictive for the methylation status of the MGMT gene in any molecular groups. The oligodendroglial histological features are not independently predictive of either patient prognosis or chemotherapeutic response in LrGGs, leaving the possibility of marginal favorable association only in IDHmut/codel tumors.
Assuntos
Neoplasias Encefálicas , Glioma , Oligodendroglioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Glioma/genética , Glioma/patologia , Glioma/terapia , Humanos , Isocitrato Desidrogenase/genética , Mutação , Oligodendroglioma/genética , Oligodendroglioma/patologia , PrognósticoRESUMO
Although promoter methylation status is known to correlate with response to alkylating agents, immunohistochemistry (IHC) is the only available method for MGMT status in many institutions. However, the clinical utility of MGMT IHC is controversial. A hundred and twenty four cases of primary glioblastoma diagnosed by morphology-based criteria over 2 decades were re-appraised based on WHO 2016 classification. Tumor MGMT status was evaluated by IHC and methylation-specific PCR (MSP) to see if any correlation between the results of the 2 methods. The association with patients' prognoses was also investigated. Among 124 cases, 116 were confirmed to be glioblastoma by definition of WHO2016, and median overall survival (OS) of glioblastoma, IDH-wildtype and epithelioid glioblastoma were 18 and 27â¯months, respectively. MGMT promoter methylation status significantly correlated with progression-free survival (PFS) (pâ¯=â¯0.014) but not with OS (pâ¯=â¯0.364) in patients with glioblastoma by the integrated diagnosis. With the cut-off value of 24.5% of positive cell ratio as determined by receiver operating characteristic (ROC) analysis, there was a good correlation between the results of IHC and MSP (pâ¯=â¯0.08â¯×â¯10-24). Accordingly, there was a marginal association between the results of IHC and patients' PFS (pâ¯=â¯0.063), but not OS (pâ¯=â¯0.563). When the patients were divided into pre and post temozolomide era, the association of MGMT promoter methylation status with PFS was only noted in the patients of temozolomide era (pre, pâ¯=â¯0.432; post, pâ¯=â¯0.015).
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Metilação de DNA , Metilases de Modificação do DNA/genética , Glioblastoma/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/metabolismo , Feminino , Glioblastoma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Regiões Promotoras Genéticas , Curva ROCRESUMO
BACKGROUND: The extent of resection has been reported to be associated with overall survival in gliomas. The use of 5-aminolevulinic acid (5-ALA) has been recognized to increase the extent of tumor resection. OBJECTIVE: To evaluate what factors affect the intraoperative fluorescence after administration of 5-ALA in gliomas. METHODS: Correlation of intraoperative fluorescence and several clinical, radiographic, molecular biologic, and histopathologic characters was retrospectively evaluated in 104 patients (53 males and 51 females; mean age 54.2 yr) with gliomas at our institution. To clarify the mechanisms that mutant isocitrate dehydrogenase (IDH) affect the intraoperative fluorescence, in Vitro experiments using genetically engineered glioma cells harboring mutant IDH1 were performed. RESULTS: Intraoperative fluorescence was observed in 82 patients (78.8%). In addition to age, magnetic resonance imaging enhancement, World Health Organization grades, and MIB-1 index, the status of IDH was revealed to be correlated with intraoperative fluorescence. In Vitro assay revealed that mutant IDH indirectly reduced the amount of exogenous 5-ALA-derived protoporphyrinogen IX in glioma cells by increasing activity of ferrochelatase and heme oxygenase 1. CONCLUSION: Mutant IDH1/2-induced metabolite changes of exogenous 5-ALA were suggested to contribute to the lesser intraoperative fluorescence in gliomas with mutant IDH1/2 than in those without.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioma/diagnóstico por imagem , Glioma/cirurgia , Imagem Óptica/métodos , Adulto , Idoso , Ácido Aminolevulínico , Neoplasias Encefálicas/genética , Feminino , Glioma/genética , Humanos , Período Intraoperatório , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Protoporfirinas , Estudos RetrospectivosRESUMO
TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90-100%) were associated with favorable prognosis (p < 0.05). A multivariable Cox regression model revealed that TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio = 0.421, p = 0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio = 0.648, p = 0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.
Assuntos
Neoplasias Encefálicas/genética , Deleção Cromossômica , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 1 , Glioma/genética , Regiões Promotoras Genéticas/genética , Telomerase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Astrocitoma/patologia , Astrocitoma/terapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Glioma/patologia , Glioma/terapia , Humanos , Isocitrato Desidrogenase/genética , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Gradação de Tumores , Procedimentos Neurocirúrgicos , Oligodendroglioma/genética , Oligodendroglioma/patologia , Oligodendroglioma/terapia , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
The genetic features of isocitrate dehydrogenase-wild-type (IDH-wt) lower-grade gliomas (LGGs; World Health Organization grades II and III) are not well defined. This study analyzed the genetic and other features of IDH-wt LGGs to develop a subclassification that can be used to predict their prognosis. Clinical, histopathological, and genetic features of 35 cases of diffuse IDH-wt astrocytoma and IDH-wt anaplastic astrocytoma were analyzed. The following genetic factors were examined: mutations of B-rapidly accelerated fibrosarcoma, telomerase reverse transcriptase promoter (TERTp), histone 3 family 3A, and alpha-thalassemia/mental retardation syndrome, X-linked; and copy number aberrations. In the univariate analysis, the following factors were associated with poor overall survival (OS): the histopathological diagnosis, TERTp mutation, the gain of chromosome 7 (+ 7), and the loss of chromosome 10q (- 10q). In the multivariate analysis, + 7, - 10q, and TERTp mutation were independent prognostic factors associated with poor OS. The median OS was significantly worse for patients who harbored at least one of these factors than for those without any of them (18.5 vs. 54.5 months, P = 0.002). The subclassification of IDH-wt LGGs according to the genetic factors + 7, - 10q, and TERTp mutation is potentially useful for predicting the prognosis.
Assuntos
Glioma/genética , Glioma/patologia , Isocitrato Desidrogenase/genética , Adulto , Idoso , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/genética , Feminino , Glioma/metabolismo , Histonas/genética , Humanos , Isocitrato Desidrogenase/metabolismo , Japão , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Regiões Promotoras Genéticas/genética , Telomerase/genética , Talassemia alfa/genéticaRESUMO
OBJECT: Early-phase clinical studies of glioma vaccines have shown feasibility and encouraging preliminary clinical activity. A vaccine that targets tumor angiogenesis factors in glioma microenvironment has not been reported. Therefore, we performed a pilot study to evaluate the safety and immunogenicity of a novel vaccination targeting tumor angiogenesis with synthetic peptides for vascular endothelial growth factor (VEGF) receptor epitopes in patients with recurrent/progressive high grade gliomas. METHODS: Eight patients received intranodal vaccinations weekly at a dose of 2mg/kg bodyweight 8 times. T-lymphocyte responses against VEGF receptor (VEGFR) epitopes were assessed by enzyme linked immunosorbent spot assays. RESULTS: This treatment was well-tolerated in patients. The first four vaccines induced positive immune responses against at least one of the targeted VEGFR epitopes in the peripheral blood mononuclear cells in 87.5% of patients. The median overall survival time in all patients was 15.9 months. Two achieved progression-free status lasting at least 6 months. Two patients with recurrent GBM demonstrated stable disease. Plasma IL-8 level was negatively correlated with overall survival. CONCLUSION: These data demonstrate the safety and immunogenicity of VEGFR peptide vaccines targeting tumor vasculatures in high grade gliomas.