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This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term "midline" areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4-78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9-11.9, 95% CI) and 16.6 ± 1.4 (13.9-19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma.
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Glioma , Histonas , Mutación , Humanos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Glioma/genética , Glioma/patología , Glioma/terapia , Anciano , Adolescente , Estudios Retrospectivos , Adulto Joven , Histonas/genética , Niño , Preescolar , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Estudios de Cohortes , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/diagnósticoRESUMEN
OBJECTIVE: While several studies reported epidermal growth factor receptor (EGFR) expression in salivary gland cancer (SGC), results varied due to a lack of unified definition of EGFR positivity. In this study, we assessed the EGFR expression level using both EGFR positive score and cumulative EGFR score in the patients with SGC. METHODS: Between January 2010 and April 2021, 102 patients with SGC who underwent surgical resection were reviewed retrospectively by immunohistochemistry. The membrane staining intensity was scored as follows: no staining (0), weak staining (1+), intermediate staining (2+), and strong staining (3+). The cumulative EGFR score was determined on a continuous scale of 0-300 using the formula:1 × (1+: percentage of weakly stained cells) + 2 × (2+: percentage of moderately stained cells) + 3 × (3+: percentage of strongly stained cells). RESULTS: EGFR expression in SGC varied widely even among the same as well as different histopathological types. The average EGFR positive scores were 46.0 %, 55.7 %, 51.6 %, 1.0 %, 26.8 %, 50 %, and 76.8 % for mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), adenoid cystic carcinoma (AdCC), acinic cell carcinoma (AcCC), adenocarcinoma NOS (ACNOS), carcinoma ex pleomorphic adenoma (CAexPA), and squamous cell carcinoma (SqCC), respectively. The average cumulative EGFR scores were 82, 91, 80, 1, 52, 93, and 185 for MEC, SDC, AdCC, AcCC, ACNOS, CAexPA, and SqCC, respectively. CONCLUSIONS: EGFR positive scores and cumulative EGFR scores in SGCs varied among the various histological types, and even in the same histological type. These scores may predict the clinical outcome of SGC treated with EGFR-targeting therapies, such as head and neck photoimmunotherapy, and need to be evaluated in future studies.
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Adenoma Pleomórfico , Carcinoma Adenoide Quístico , Carcinoma Mucoepidermoide , Receptores ErbB , Neoplasias de las Glándulas Salivales , Humanos , Receptores ErbB/metabolismo , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Carcinoma Mucoepidermoide/patología , Carcinoma Mucoepidermoide/metabolismo , Estudios Retrospectivos , Anciano , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Adenoma Pleomórfico/patología , Adenoma Pleomórfico/metabolismo , Adulto , Inmunohistoquímica , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirugía , Adulto Joven , Carcinoma de Células Acinares/patología , Carcinoma de Células Acinares/metabolismoRESUMEN
Background: The study aims to explore MRI phenotypes that predict glioblastoma's (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images. Methods: A total of 193 histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. From the Cancer Imaging Archive/Cancer Genome Atlas (TCGA) 93 patients were used as validation cohorts. "Thickened structure" was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. "Methylated contrast phenotype" was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status. Results: Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the exploratory and 0.55 for the validation cohort, and for "Methylated contrast phenotype," 0.30 and 0.39, respectively. The imaging feature, the presence of "Thickened structure" and absence of "Methylated contrast phenotype," was significantly predictive of pMGMT unmethylation both for the exploratory (pâ =â .015, odds ratioâ =â 2.44) and for the validation cohort (pâ =â .006, odds ratioâ =â 7.83). The sensitivities and specificities of the imaging feature, the presence of "Thickened structure," and the absence of "Methylated contrast phenotype" for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort. Conclusions: The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM's pMGMT methylation status.
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HL7 FHIR is the standard for healthcare information exchange. In November 2022, our medication subgroup developed 8 profiles and 23 extensions for medication procedures in Japan, as part of the JP Core Implementation Guide 1.1. Our work demonstrates the ability of HL7 FHIR to describe Japanese prescription procedures while also addressing the requirements of other countries.
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Prescripciones , JapónRESUMEN
Despite recent signs of progress in diagnostic radiology, it is quite rare that a glioblastoma (GBM) is detected asymptomatically. We describe two patients with asymptomatic nonenhancing GBMs that were not diagnosed with neoplasia at first. The patients had brain scans as medical checkups, and incidentally lesions were detected. In both cases, surgical specimens histopathologically showed no evidence of neoplasia, whereas molecular genetic findings were isocitrate dehydrogenase (IDH)-wildtype, O6-methylguanine-DNA methyltransferase promoter (pMGMT) unmethylated, and telomerase reverse transcriptase (TERT) promoter mutated, which matched to GBM. One patient was observed without adjuvant therapy and the tumor recurred 7 months later. Reoperation was performed, and histopathologically GBM was confirmed with the same molecular diagnosis as the first surgical specimen. Another patient was carefully observed, and chemoradiotherapy was begun 6 months after the operation following the extension of the lesion. Eventually, because of disease progression, both patients deceased. We postulate that in each case, the tumor was not lower-grade glioma but corresponded to the early growth phase of GBM cells. Thus far, cases of malignant transformation from lower-grade glioma or asymptomatic GBM with typical histologic features are reported. Nevertheless, to the best of our knowledge, no such case of nonenhancing, nonhistologically confirmed GBM was reported. We conjecture these cases shed light on the yet unknown natural history of GBM. GBM can take the form of radiological nonenhancing and histological nonneoplastic fashion before typical morphology. Molecular genetic analysis can diagnose atypical preceding GBM, and we recommend early surgical removal and adjuvant treatment.
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This case report concerns a 72-year-old-female with severe functional tricuspid stenosis due to phosphoglyceride crystal deposition disease and a history of atrial septum closure and tricuspid valvuloplasty. Phosphoglyceride crystal deposition disease is extremely rare, and percutaneous transcatheter biopsy under intracardiac echocardiographic guidance proved to be useful for its diagnosis. (Level of Difficulty: Advanced.).
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BACKGROUND: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. METHODS: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. RESULTS: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. CONCLUSION: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.
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Neoplasias Encefálicas/genética , Genes ras/genética , Glioma/genética , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Astrocitoma/genética , Neoplasias Encefálicas/patología , Niño , Preescolar , Metilación de ADN , Metilasas de Modificación del ADN/metabolismo , Análisis Mutacional de ADN/métodos , Enzimas Reparadoras del ADN/metabolismo , Exones/genética , Femenino , Glioblastoma/genética , Glioma/patología , Histonas/genética , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Oligodendroglioma/genética , Fenotipo , Regiones Promotoras Genéticas , Telomerasa/genética , Proteínas Supresoras de Tumor/metabolismo , Adulto JovenRESUMEN
Medulloblastoma is the second-most common malignant tumor in children. Medulloblastoma has been categorized into four distinct molecular subgroups: WNT, sonic hedgehog (SHH), group 3, and group 4. We report on a male child with medulloblastoma, in whom an enlarged ventricle was diagnosed in utero. Magnetic resonance imaging showed cyst formation in the cerebellar hemisphere initially, with tumor growth being indicated later. Tumor resection was performed when the boy was 12 months old. The histological findings showed extensive nodularity. Further genetic analysis revealed the tumor to be SHH type. This is the first description of a medulloblastoma observed from the fetal stage. Our findings in this case indicate that cyst formation may be the pre-neoplastic lesion of SHH-subtype medulloblastomas.
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Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Cerebelosas/diagnóstico por imagen , Neoplasias Cerebelosas/cirugía , Cerebelo/metabolismo , Niño , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Meduloblastoma/diagnóstico por imagen , Meduloblastoma/cirugíaRESUMEN
Cluster of differentiation (CD) 166 or activated leukocyte cell adhesion molecule (ALCAM) is a transmembrane molecule known to be an intercellular adhesion factor. The expression and function of ALCAM in medulloblastoma (MB), a pediatric brain tumor with highly advanced molecular genetics, remains unclear. Therefore, this study aimed to clarify the significance and functional role of ALCAM expression in MB. ALCAM expression in 45 patients with MB was evaluated by immunohistochemical analysis of formalin-fixed paraffin-embedded clinical specimens and the relationship between ALCAM expression and pathological type/molecular subgroup, such as WNT, SHH, Group 3, and Group 4, was examined. Eight ALCAM positive (18%), seven partially positive (16%), and 30 negative (67%) cases were detected. All seven cases of the WNT molecular subgroup were ALCAM positive and ALCAM expression strongly correlated with this subgroup (P < 0.0001). In addition, functional studies using MB cell lines revealed ALCAM expression affected proliferation and migration as a positive regulator in vitro. However, ALCAM silencing did not affect survival or the formation of leptomeningeal dissemination in an orthotopic mouse model, but did induce a malignant phenotype with increased tumor cell invasion at the dissemination sites (P = 0.0029). In conclusion, our results revealed that ALCAM exhibited highly specific expression in the WNT subgroup of MB. Furthermore, we demonstrated that the cell kinetics of MB cell lines can be altered by the expression of ALCAM.
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Antígenos CD/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas Fetales/metabolismo , Meduloblastoma/metabolismo , Proteínas Wnt/metabolismo , Molécula de Adhesión Celular del Leucocito Activado/genética , Adolescente , Animales , Antígenos CD/fisiología , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Adhesión Celular/genética , Moléculas de Adhesión Celular Neuronal/fisiología , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Cerebelosas/genética , Niño , Preescolar , Femenino , Proteínas Fetales/fisiología , Expresión Génica/genética , Perfilación de la Expresión Génica , Humanos , Lactante , Japón/epidemiología , Masculino , Meduloblastoma/fisiopatología , Ratones , Invasividad Neoplásica , ARN Mensajero/genética , Proteínas Wnt/genética , Adulto JovenAsunto(s)
Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Antígenos Comunes de Leucocito/metabolismo , Linfoma de Células T/metabolismo , Linfoma de Células T/patología , Anciano , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Humanos , Linfoma de Células T/diagnóstico por imagen , MasculinoRESUMEN
Aging is a known negative prognostic factor in glioblastomas (GBM). Whether particular genetic backgrounds are a factor in poor outcomes of elderly patients with GBM warrants investigation. We aim to elucidate any differences between older and younger adult patients with IDH-wildtype GBM regarding both molecular characteristics and clinical outcomes. We collected adult cases diagnosed with IDH-wildtype GBM from the Kansai Network. Clinical and pathological characteristics were analyzed retrospectively and compared between older (≥ 70 years) and younger (≤ 50 years) cases. Included were 92 older vs. 33 younger cases. The older group included more patients with preoperative Karnofsky performance status score < 70 and had a shorter survival time than the younger group. MGMT promoter was methylated more frequently in the older group. TERT promoter mutation was more common in the older group. There were significant differences in DNA copy-number alteration profiles between age groups in PTEN deletion and CDK4 amplification/gain. In the older group, no molecular markers were identified, but surgical resection was an independent prognostic factor. Age-specific survival difference was significant in the MGMT methylated and TERT wildtype subgroup. Elderly patients have several potential factors in poor prognosis of glioblastomas. Varying molecular profiles may explain differing rates of survival between generations.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , Isocitrato Deshidrogenasa/genética , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/mortalidad , Estudios de Cohortes , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Femenino , Glioblastoma/mortalidad , Humanos , Japón , Masculino , Metilación , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
OBJECTIVES: Whether the extent of expression of programmed death-ligand 1 (PD-L1) is clinically significant remains uncertain, although immuno-oncological features have been studied in thymic epithelial cell tumors (TETs). We investigated the histological features of PD-L1 expression in TETs, and assessed PD-L1 expression using digital image analysis. MATERIALS AND METHODS: Participants comprised 66 patients with TET who underwent surgical resection between 2001 and 2016. We calculated tumor cell-positive ratio as total proportion score (TPS) with immunohistochemistry using SP263 anti-PD-L1 monoclonal antibody. PD-L1 expression was also quantified using digital image analysis of whole-slide images. We evaluated the relationship between conventional visual TPS using optical microscopy (TPS-V) and TPS from digital image analysis (TPS-IA). We further classified all TETs into high or low PD-L1 expression groups and assessed the clinical significance of PD-L1 expression level using TPS-V and TPS-IA. RESULTS: WHO histological types were Type A (nâ¯=â¯8), AB (nâ¯=â¯18), B1 (nâ¯=â¯5), B2 (nâ¯=â¯16), B3 (nâ¯=â¯6), metaplastic thymoma (nâ¯=â¯2), and thymic carcinoma (TC) (nâ¯=â¯11). Median TPS-Vs were 2%, 2%, 10 %, 65 %, 90 %, 1%, and 20 %, respectively. TPS-IAs correlated with TPS-Vs in TETs overall and in thymomas, but not in TCs. PD-L1 expression levels in TETs differed significantly among histological types. Whether TPS-V or TPS-IA were used, the PD-L1high group included more cases of the more aggressive histological types. Recurrence-free survival (RFS) was shorter in the PD-L1high group than in the PD-L1low group in thymoma using TPS-IA, whereas RFS of the PD-L1high group was shorter in all TETs using TPS-V. CONCLUSION: PD-L1 expression levels depended on the histological type of TET. Extensive PD-L1 expression in TETs was associated with poor prognosis. Digital image analysis is feasible for evaluating PD-L1 expression in TETs and might offer clinically relevant features of thymomas.
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Neoplasias Pulmonares , Timoma , Neoplasias del Timo , Antígeno B7-H1 , Células Epiteliales , HumanosRESUMEN
Intracranial myxoid mesenchymal tumors harboring EWSR1 fusions with CREB transcriptional factor gene families were recently described in several case reports and a few case series and this tumor closely resembles the myxoid variant of angiomatoid fibrous histiocytoma. We herein present an intracranial mesenchymal myxoid tumor arising in the third ventricle of a middle-aged woman. The tumor displayed prominent myxoid features consisting of mildly atypical oval to round cells, arranged in reticular and cord-like structures, with starburst-like amianthoid fibers, whereas it lacked pseudoangiomatoid spaces, pseudocapsules and lymphoid cuffing. Immunophenotypically, tumor cells were positive for EMA, desmin, and ALK (focal). EWSR1 and CREB1 rearrangements were identified using FISH assay. The proliferation index was low. It is currently uncertain whether these myxoid tumors represent a variant of angiomatoid fibrous histiocytoma or a novel tumor entity.
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Neoplasias Encefálicas/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Fusión Génica , Histiocitoma Fibroso Maligno/genética , Proteína EWS de Unión a ARN/genética , Neoplasias Encefálicas/patología , Femenino , Reordenamiento Génico , Histiocitoma Fibroso Maligno/patología , Humanos , Persona de Mediana EdadRESUMEN
We attempted to establish a magnetic resonance imaging (MRI)-based radiomic model for stratifying prognostic subgroups of newly diagnosed glioblastoma (GBM) patients and predicting O (6)-methylguanine-DNA methyltransferase promotor methylation (pMGMT-met) status of the tumor. Preoperative MRI scans from 201 newly diagnosed GBM patients were included in this study. A total of 489 texture features including the first-order feature, second-order features from 162 datasets, and location data from 182 datasets were collected. Supervised principal component analysis was used for prognostication and predictive modeling for pMGMT-met status was performed based on least absolute shrinkage and selection operator regression. 22 radiomic features that were correlated with prognosis were used to successfully stratify patients into high-risk and low-risk groups (p = 0.004, Log-rank test). The radiomic high- and low-risk stratification and pMGMT status were independent prognostic factors. As a matter of fact, predictive accuracy of the pMGMT methylation status was 67% when modeled by two significant radiomic features. A significant survival difference was observed among the combined high-risk group, combined intermediate-risk group (this group consists of radiomic low risk and pMGMT-unmet or radiomic high risk and pMGMT-met), and combined low-risk group (p = 0.0003, Log-rank test). Radiomics can be used to build a prognostic score for stratifying high- and low-risk GBM, which was an independent prognostic factor from pMGMT methylation status. On the other hand, predictive accuracy of the pMGMT methylation status by radiomic analysis was insufficient for practical use.
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Neoplasias Encefálicas/genética , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Glioblastoma/genética , Regiones Promotoras Genéticas , Proteínas Supresoras de Tumor/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Estudios de Cohortes , Glioblastoma/diagnóstico por imagen , Glioblastoma/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Pronóstico , RadiometríaRESUMEN
The diagnosis and prognostication of glioblastoma (GBM) remain to be solely dependent on histopathological findings and few molecular markers, despite the clinical heterogeneity in this entity. To address this issue, we investigated the prognostic impact of copy number alterations (CNAs) using two population-based IDH-wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). The molecular disproportions between these cohorts were dissected in light of cohort differences in GBM. The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The somatic landscape around CNAs was analyzed for 212 KNBTG cases and 359 TCGA cases. Next, the clinical impacts of CNA profiles were investigated for 140 KNBTG cases and 152 TCGA cases treated by standard adjuvant therapy using temozolomide-based chemoradiation. The comparative profiling indicated unequal distribution of specific CNAs such as EGFR, CDKN2A, and PTEN among the two cohorts. Especially, the triple overlap CNAs in these loci (triple CNA) were much higher in frequency in TCGA (70.5%) than KNBTG (24.3%), and its prognostic impact was independently validated in both cohorts. The KNBTG cohort significantly showed better prognosis than the TCGA cohort (median overall survival 19.3 vs 15.6 months). This survival difference between the two cohorts completely resolved after subclassifying all cases according to the triple CNA status. The prognostic significance of triple CNA was identified in IDH-wild-type GBM. Distribution difference in prognostic CNA profiles potentially could cause survival differences across cohorts in clinical studies.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Variaciones en el Número de Copia de ADN , Glioblastoma/diagnóstico , Glioblastoma/genética , Isocitrato Deshidrogenasa/genética , Pueblo Asiatico/genética , Estudios de Cohortes , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , PronósticoRESUMEN
We focused on histological and immunohistochemical characteristics of ependymoma (EPN) with molecular profiles to develop more reproducible criteria of the diagnosis. Three expert neuropathologists reviewed the pathology of 130 samples from the Japan Pediatric Molecular Neuro-Oncology Group study. Confirmed cases were assessed for histology, surrogate markers, molecular subgrouping, and survival data. We reached a consensus regarding the diagnosis of EPNs in 100% of spinal cord tumors and 93% of posterior fossa (PF) tumors that had been diagnosed as EPNs by local pathologists, whereas we reached a consensus regarding only 77% of the local diagnosis of supratentorial (ST) EPNs. Among the PF-EPNs, most of anaplastic ependymomas (AEPNs) were defined as EPN-A by methylation profiling, which was significantly correlated with the subgroup assignment. Regarding prognosis, the overall survival of patients with PF-EPN was significantly better than that of patients with PF AEPN (p = 0.01). Histologically, all ependymoma, RELA fusion-positive (EPN-RELA) qualified as Grade III. Both L1 cell adhesion molecule and nuclear factor kappaB p65 antibodies showed good sensitivity for detecting EPN-RELA. This study indicated that the expert consensus pathological diagnosis could correlate well with the molecular classifications in EPNs. ST EPNs should be diagnosed more carefully by histological and molecular analyses.
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Ependimoma/genética , Ependimoma/patología , Adulto , Niño , Preescolar , Células Ependimogliales/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Perfil Genético , Humanos , Neoplasias Infratentoriales/patología , Japón , Masculino , FN-kappa B/genética , Molécula L1 de Adhesión de Célula Nerviosa/genética , Pronóstico , Neoplasias de la Médula Espinal/genética , Neoplasias Supratentoriales/patología , Adulto JovenRESUMEN
Identification of genotypes is crucial for treatment of glioma. Here, we developed a method to predict tumor genotypes using a pretrained convolutional neural network (CNN) from magnetic resonance (MR) images and compared the accuracy to that of a diagnosis based on conventional radiomic features and patient age. Multisite preoperative MR images of 164 patients with grade II/III glioma were grouped by IDH and TERT promoter (pTERT) mutations as follows: (1) IDH wild type, (2) IDH and pTERT co-mutations, (3) IDH mutant and pTERT wild type. We applied a CNN (AlexNet) to four types of MR sequence and obtained the CNN texture features to classify the groups with a linear support vector machine. The classification was also performed using conventional radiomic features and/or patient age. Using all features, we succeeded in classifying patients with an accuracy of 63.1%, which was significantly higher than the accuracy obtained from using either the radiomic features or patient age alone. In particular, prediction of the pTERT mutation was significantly improved by the CNN texture features. In conclusion, the pretrained CNN texture features capture the information of IDH and TERT genotypes in grade II/III gliomas better than the conventional radiomic features.
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Glioma/diagnóstico , Glioma/genética , Isocitrato Deshidrogenasa/genética , Imagen por Resonancia Magnética , Mutación , Redes Neurales de la Computación , Regiones Promotoras Genéticas , Telomerasa/genética , Biomarcadores de Tumor , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética/métodos , Masculino , Clasificación del Tumor , Estadificación de Neoplasias , Reproducibilidad de los ResultadosRESUMEN
Molecular biological characterization of tumors has become a pivotal procedure for glioma patient care. The aim of this study is to build conventional MRI-based radiomics model to predict genetic alterations within grade II/III gliomas attempting to implement lesion location information in the model to improve diagnostic accuracy. One-hundred and ninety-nine grade II/III gliomas patients were enrolled. Three molecular subtypes were identified: IDH1/2-mutant, IDH1/2-mutant with TERT promoter mutation, and IDH-wild type. A total of 109 radiomics features from 169 MRI datasets and location information from 199 datasets were extracted. Prediction modeling for genetic alteration was trained via LASSO regression for 111 datasets and validated by the remaining 58 datasets. IDH mutation was detected with an accuracy of 0.82 for the training set and 0.83 for the validation set without lesion location information. Diagnostic accuracy improved to 0.85 for the training set and 0.87 for the validation set when lesion location information was implemented. Diagnostic accuracy for predicting 3 molecular subtypes of grade II/III gliomas was 0.74 for the training set and 0.56 for the validation set with lesion location information implemented. Conventional MRI-based radiomics is one of the most promising strategies that may lead to a non-invasive diagnostic technique for molecular characterization of grade II/III gliomas.
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Glioma/diagnóstico por imagen , Glioma/genética , Isocitrato Deshidrogenasa/genética , Imagen por Resonancia Magnética/métodos , Regiones Promotoras Genéticas/genética , Telomerasa/genética , Adulto , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Femenino , Glioma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Mutación/genética , Adulto JovenRESUMEN
INTRODUCTION: This study investigates the current state of clinical practice and molecular analysis for elderly patients with diffuse gliomas and aims to elucidate treatment outcomes and prognostic factors of patients with glioblastomas. METHODS: We collected elderly cases (≥ 70 years) diagnosed with primary diffuse gliomas and enrolled in Kansai Molecular Diagnosis Network for CNS Tumors. Clinical and pathological characteristics were analyzed retrospectively. Various factors were evaluated in univariate and multivariate models to examine their effects on overall survival. RESULTS: Included in the study were 140 elderly patients (WHO grade II: 7, III: 19, IV: 114), median age was 75 years. Sixty-seven patients (47.9%) had preoperative Karnofsky Performance Status score of ≥ 80. All patients underwent resection (gross-total: 20.0%, subtotal: 14.3%, partial: 39.3%, biopsy: 26.4%). Ninety-six of the patients (68.6%) received adjuvant treatment consisting of radiotherapy (RT) with temozolomide (TMZ). Seventy-eight of the patients (75.0%) received radiation dose of ≥ 50 Gy. MGMT promoter was methylated in 68 tumors (48.6%), IDH1/2 was wild-type in 129 tumors (92.1%), and TERT promoter was mutated in 78 of 128 tumors (60.9%). Median progression-free and overall survival of grade IV cases was 8.2 and 13.6 months, respectively. Higher age (≥ 80 years) and TERT promoter mutated were associated with shorter survival. Resection and adjuvant RT + TMZ were identified as independent factors for good prognosis. CONCLUSIONS: This community-based study reveals characteristics and outcomes of elderly glioma patients in a real-world setting. Elderly patients have several potential factors for poor prognosis, but resection followed by RT + TMZ could lengthen duration of survival.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Glioma/metabolismo , Glioma/terapia , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Metilación de ADN , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Femenino , Glioma/genética , Glioma/mortalidad , Humanos , Isocitrato Deshidrogenasa/genética , Japón , Masculino , Mutación , Clasificación del Tumor , Pronóstico , Estudios Retrospectivos , Telomerasa/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Gliomas are genetically and histopathologically heterogeneous. Intratumoral heterogeneity in the MGMT promoter methylation status is an important clinical biomarker of glioblastoma. A higher uptake of 11C-methionine in positron-emission tomography (PET) reportedly reflects increased MGMT promoter methylation; however, non-stereotactic comparison of MGMT methylation and 11C-methionine PET images may not be accurate. The present study examined the correlation between 11C-methionine uptake and MGMT promoter methylation in non-enhancing gliomas using stereotactic image-based histological analysis. Data were collected from 9 patients with newly diagnosed non-enhancing glioma who underwent magnetic resonance imaging and 11C-methionine PET during pre-surgical examination. Clinical data were also collected from 3 patients during repeat surgery. The correlation between 11C-methionine uptake and MGMT methylation or cell density was analyzed using histological specimens obtained by multiple stereotactic sampling and an exact local comparison of 11C-methionine PET images and histological specimens was made. A total of 31 stereotactic sample sites were identified. In newly diagnosed cases, the tumor to normal uptake (T/N) ratio revealed a significant positive correlation with MGMT methylation (R=0.54, P=0.009) and a marginal correlation with cell density (R=0.42, P=0.05). In recurrent cases, the T/N ratio demonstrated no correlation with MGMT methylation (R=0.01, P=0.97) or cell density (R=0.15, P=0.70). An increased uptake of 11C-methionine in PET may reflect increased MGMT promoter methylation according to stereotactic image-based histological analysis. 11C-methionine PET could therefore be a useful tool for detecting regional MGMT promoter methylation in non-enhancing primary glioma.