RESUMEN
Pediatric central nervous system tumors remain challenging to diagnose. Imaging approaches do not provide sufficient detail to discriminate between different tumor types, while the histopathological examination of tumor tissue shows high inter-observer variability. Recent studies have demonstrated the accurate classification of central nervous system tumors based on the DNA methylation profile of a tumor biopsy. However, a brain biopsy holds significant risk of bleeding and damaging the surrounding tissues. Liquid biopsy approaches analyzing circulating tumor DNA show high potential as an alternative and less invasive tool to study the DNA methylation pattern of tumors. Here, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected cerebrospinal fluid samples from 19 pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. Analyses on the cfDNA showed high variability of cfDNA quantities across patients ranging from levels below the limit of quantification to 40 ng cfDNA per milliliter of CSF. Classification based on methylation profiling of cfDNA from CSF was correct for 7 out of 20 samples in our cohort. Accurate results were mostly observed in samples of high quality, more specifically those with limited high molecular weight DNA contamination. Interestingly, we show that centrifugation of the CSF prior to processing increases the fraction of fragmented cfDNA to high molecular weight DNA. In addition, classification was mostly correct for samples with high tumoral cfDNA fraction as estimated by computational deconvolution (> 40%). In summary, analysis of cfDNA in the CSF shows potential as a tool for diagnosing pediatric nervous system tumors especially in patients with high levels of tumoral cfDNA in the CSF. Further optimization of the collection procedure, experimental workflow and bioinformatic approach is required to also allow classification for patients with low tumoral fractions in the CSF.
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Ácidos Nucleicos Libres de Células , Neoplasias del Sistema Nervioso Central , ADN Tumoral Circulante , Metilación de ADN , Humanos , Metilación de ADN/genética , Niño , Masculino , Femenino , Preescolar , Biopsia Líquida/métodos , ADN Tumoral Circulante/líquido cefalorraquídeo , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Ácidos Nucleicos Libres de Células/líquido cefalorraquídeo , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/diagnóstico , Adolescente , Lactante , Biomarcadores de Tumor/líquido cefalorraquídeo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/líquido cefalorraquídeo , Prueba de Estudio ConceptualRESUMEN
BACKGROUND: The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. METHODS: Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. RESULTS: A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01). CONCLUSIONS: Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future.
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Astrocitoma , Imagen por Resonancia Magnética , Mutación , Clasificación del Tumor , Organización Mundial de la Salud , Humanos , Astrocitoma/genética , Astrocitoma/clasificación , Astrocitoma/patología , Astrocitoma/diagnóstico por imagen , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Imagen por Resonancia Magnética/métodos , Pronóstico , Isocitrato Deshidrogenasa/genética , Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Anciano , Adulto Joven , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/mortalidad , AdolescenteRESUMEN
BACKGROUND/AIM: Central nervous system (CNS) involvement in aggressive B-cell lymphoma, either as a primary or secondary event to systemic disease, portends a poor prognosis. This study sought to identify patients at high risk for CNS relapse by analyzing their human leukocyte antigen (HLA) genotypes. PATIENTS AND METHODS: We retrospectively examined the HLA genotypes of 164 patients with systemic lymphoma, primary CNS lymphoma, and CNS relapse of systemic lymphoma. Patient records were analyzed, and HLA typing was performed by the Finnish Red Cross Blood Service. After excluding patients who received CNS prophylaxis, 131 patients were included in the final analysis. RESULTS: A strong association was found between the HLA-A*31 genotype and CNS disease (p=0.001). Additionally, various HLA genotypes were linked to lactate dehydrogenase levels, extranodal disease, International Prognostic Index score, and disease stage. CONCLUSION: The patient's genetic constitution, rather than solely disease-related factors, plays a role in the tropism of lymphoma for the CNS. If confirmed in a larger study, defining the HLA genotype of a lymphoma patient could provide valuable information for predicting CNS relapse.
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Neoplasias del Sistema Nervioso Central , Genotipo , Antígenos HLA , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Femenino , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Masculino , Persona de Mediana Edad , Anciano , Adulto , Estudios Retrospectivos , Antígenos HLA/genética , Anciano de 80 o más Años , Adulto Joven , Pronóstico , Factores de Riesgo , Predisposición Genética a la EnfermedadRESUMEN
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
Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.
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Inhibidores de Proteínas Quinasas , Pirazoles , Receptor trkB , Humanos , Masculino , Femenino , Niño , Preescolar , Adulto , Adolescente , Persona de Mediana Edad , Anciano , Lactante , Receptor trkB/genética , Receptor trkB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/uso terapéutico , Receptor trkA/genética , Receptor trkA/antagonistas & inhibidores , Glioma/genética , Glioma/patología , Glioma/tratamiento farmacológico , Pirimidinas/uso terapéutico , Proteínas de Fusión Oncogénica/genética , Benzamidas/uso terapéutico , Glicoproteínas de Membrana/genética , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , IndazolesRESUMEN
Aim: Glioneuronal and neuronal tumors are rare primary central nervous system malignancies with heterogeneous features. Due to the rarity of these malignancies diagnosis and treatment remains a clinical challenge. Methods: Here we performed a narrative review aimed to investigate the principal issues concerning the diagnosis, pathology, and clinical management of glioneuronal tumors. Results: Diagnostic criteria have been recently overturned thanks to a better characterization on a histological and molecular biology level. The study of genomic alterations occurring within these tumors has allowed us to identify potential therapeutic targets including BRAF, FGFR, and PDGFRA. Conclusion: Techniques allowing molecular sequencing DNA methylation assessment of the disease are essential diagnostic tools. Targeting agents should be included in the therapeutic armamentarium after loco-regional treatment failure.
[Box: see text].
Asunto(s)
Neoplasias Encefálicas , Humanos , Adulto Joven , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Glioma/terapia , Glioma/genética , Glioma/diagnóstico , Glioma/patologíaAsunto(s)
Neoplasias del Sistema Nervioso Central , Humanos , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Masculino , Niño , Femenino , Proteínas de Fusión Oncogénica/genética , Proteínas RepresorasRESUMEN
This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.
[Box: see text].
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Carbamatos , Cetuximab , Neoplasias Colorrectales , Mutación , Proteínas Proto-Oncogénicas B-raf , Sulfonamidas , Humanos , Cetuximab/uso terapéutico , Cetuximab/administración & dosificación , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas B-raf/genética , Carbamatos/uso terapéutico , Sulfonamidas/uso terapéutico , Bencimidazoles/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/secundario , Neoplasias del Sistema Nervioso Central/patologíaRESUMEN
Early diagnosis is crucial for the successful treatment of primary CNS lymphoma (PCNSL), a rapidly progressing tumour. Suspicion raised on brain MRI must be confirmed by a histopathological diagnosis of a tumour specimen collected by stereotactic biopsy. In rare cases, cerebrospinal fluid (CSF) or vitreous humour might aid in providing a cytological diagnosis. Several disease-related, patient-related, and treatment-related factors affect the timing and accuracy of diagnosis and patient outcome. Some molecules detected in CSF, aqueous and vitreous humour, and peripheral blood were proposed as diagnostic biomarkers for PCNSL; however, detection methods for most of these molecules are not yet standardised, have a long turnaround time, are expensive, and have little reproducibility among labs. By contrast, the MYD88Leu265Pro somatic hotspot mutation, revealed by PCR-based assay, is currently and reliably used during the diagnosis of some lymphomas, and IL-10, measured by enzyme-linked immunosorbent assay, is routinely used to diagnose and monitor different common metabolic and immunological diseases. Several independent studies have shown that MYD88Leu265Pro and IL-10 can be easily assessed in peripheral blood, plasma, aqueous and vitreous humour, and CSF of patients with PCNSL with substantial sensitivity and specificity, especially when evaluated in combination. In this Viewpoint, evidence supporting the routine use of MYD88Leu265Pro and IL-10 in diagnosing PCNSL is considered, and some examples of the frequent difficulties found in the diagnosis of PCNSL are provided, highlighting the role and indications of these two biomarkers to improve the timely recognition of this aggressive tumour.
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Neoplasias del Sistema Nervioso Central , Interleucina-10 , Linfoma , Factor 88 de Diferenciación Mieloide , Humanos , Factor 88 de Diferenciación Mieloide/genética , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Interleucina-10/genética , Interleucina-10/líquido cefalorraquídeo , Linfoma/diagnóstico , Linfoma/genética , Biomarcadores de Tumor/genética , MutaciónRESUMEN
BACKGROUND/AIM: Diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive B-cell lymphoma with clinical and molecular heterogeneity. Primary CNS-DLBCL (PCNSL) affects the brain, eyes, leptomeninges, or spinal cord without systemic involvement. Secondary CNS-DLBCL (SCNSL) manifests concurrently with systemic lymphoma or as an isolated CNS relapse with poor prognosis. MATERIALS AND METHODS: Next-generation sequencing (NGS) was used to identify genomic alterations in 32 PCNSL and 9 SCNSL cases. Single nucleotide variants and copy number variations in addition to the clinicopathologic data and proposed risk predictive values were compared to aid in diagnostic differentiation between the two types of lymphomas. RESULTS: The MCD genotype, characterized by mutations in MYD88 and CD79B, is the most common alteration in PCNSL and is associated with lower survival rates. The frequency of MYD88 mutation was significantly higher in PCNSL compared to SCNSL (75.0% vs. 33.3%; p=0.042). Recurrent copy number loss of 6p21 occurred in 56.1% of cases, more often in PCNSL (65.6%) than in SCNSL (22.2%) (p=0.028). Diagnostic positive predictive values (PPV) of MYD88 mutation and 6p21 loss for PCNSL were 89% and 91%, respectively. PPV of both alterations was 93% for the diagnosis of PCNSL. CONCLUSION: MYD88 mutation and 6p21 loss were significantly higher in PCNSL than in SCNSL, and novel risk prediction models based on these distinct genomic profiles can aid in the clinical differentiation of PCNSL and SCNSL.
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Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Mutación , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/mortalidad , Anciano , Adulto , Factor 88 de Diferenciación Mieloide/genética , Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Anciano de 80 o más Años , Pronóstico , Adulto Joven , Antígenos CD79/genéticaRESUMEN
OBJECTIVE: To investigate gene mutation characteristics of primary central nervous system lymphoma (PCNSL) through whole exome sequencing (WES) to 18 patients with PCNSL. METHODS: Tumor tissues from 18 patients with diffuse large B-cell lymphoma who were diagnosed with PCNSL in Department of Hematology, Lanzhou University Second Hospital from September 2018 to December 2020 and had normal immune function, no history of HIV or immunosuppressant therapy were collected. High-throughput-based WES was performed on the tumor tissues, with an average sequencing depth of >100×. After data processing and bioinformatics analysis of sequencing results, the mutation maps and mutation characteristics of 18 PCNSL patients were obtained. RESULTS: Obvious somatic mutations were detected in all 18 patients. The median number of somatic mutations was 321. Missense mutations were most prominent (accounting for about 90%), and the mutation type was dominated by C>T (50.2%), reflecting the age-related mutation pattern. Among the top 15 frequently mutated genes, PSD3, DUSP5, MAGEB16, TELO2, FMO2, TRMT13, AOC1, PIGZ, SVEP1, IP6K3, and TIAM1 were the driver genes. The enrichment results of driver gene pathways showed that RTK-RAS, Wnt, NOTCH, Hippo and Cell-Cycle pathways were significantly enriched. The tumor mutation burden was between 3.558 48/Mb and 8.780 89/Mb, and the average was 4.953 32/Mb, which was significantly higher than other cancer research cohorts in the TCGA database. CONCLUSIONS: PCNSL occurs somatic missense mutations frequently, mainly point mutations, and the mutation type is mainly C>T. The driver genes are mainly involved in RTK-RAS, Wnt, NOTCH and Hippo pathways, indicating that the above pathways may be related to the pathogenesis of PCNSL. PCNSL has a significantly high tumor mutation burden, which may explain the efficacy of PD-1 inhibitors in PCNSL.
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Neoplasias del Sistema Nervioso Central , Secuenciación del Exoma , Linfoma de Células B Grandes Difuso , Mutación , Humanos , Neoplasias del Sistema Nervioso Central/genética , Linfoma de Células B Grandes Difuso/genética , Mutación MissenseRESUMEN
Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.
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Glioblastoma , Glicoproteínas de Membrana , Receptores Inmunológicos , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Humanos , Animales , Ratones , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/metabolismo , Células Mieloides/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Línea Celular Tumoral , Ratones Endogámicos C57BL , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismoRESUMEN
Central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR-ITD) constitutes a molecularly distinct entity, characterized by internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene (BCOR-ITD). The current study aimed to elucidate the clinical, pathological, and molecular attributes of CNS tumors with BCOR-ITD and explore their putative cellular origin. This study cohort comprised four pediatric cases, aged 23 months to 13 years at initial presentation. Magnetic resonance imaging revealed large, well-circumscribed intra-CNS masses localized heterogeneously throughout the CNS. Microscopically, tumors were composed of spindle to ovoid cells, exhibiting perivascular pseudorosettes and palisading necrosis, but lacking microvascular proliferation. Immunohistochemical staining showed diffuse tumor cell expression of BCOR, CD56, CD99, vimentin, and the stem cell markers PAX6, SOX2, CD133 and Nestin, alongside focal positivity for Olig-2, S100, SOX10, Syn and NeuN. Molecularly, all cases harbored BCOR-ITDs ranging from 87 to 119 base pairs in length, including one case with two distinct ITDs. Notably, the ITDs were interrupted by unique 1-3â¯bp insertions in all cases. In summary, CNS tumors with BCOR-ITD exhibit characteristic clinical, pathological, and molecular features detectable through BCOR immunohistochemistry and confirmatory molecular analyses. Their expression of stem cell markers raises the possibility of an origin from neuroepithelial stem cells rather than representing true embryonal neoplasms.
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Neoplasias del Sistema Nervioso Central , Proteínas Proto-Oncogénicas , Proteínas Represoras , Humanos , Proteínas Represoras/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/metabolismo , Niño , Adolescente , Masculino , Femenino , Lactante , Preescolar , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Secuencias Repetidas en Tándem , Duplicación de GenRESUMEN
Precision in the diagnosis of diverse central nervous system (CNS) tumor types is crucial for optimal treatment. DNA methylation profiles, which capture the methylation status of thousands of individual CpG sites, are state-of-the-art data-driven means to enhance diagnostic accuracy but are also time consuming and not widely available. Here, to address these limitations, we developed Deep lEarning from histoPathoLOgy and methYlation (DEPLOY), a deep learning model that classifies CNS tumors to ten major categories from histopathology. DEPLOY integrates three distinct components: the first classifies CNS tumors directly from slide images ('direct model'), the second initially generates predictions for DNA methylation beta values, which are subsequently used for tumor classification ('indirect model'), and the third classifies tumor types directly from routinely available patient demographics. First, we find that DEPLOY accurately predicts beta values from histopathology images. Second, using a ten-class model trained on an internal dataset of 1,796 patients, we predict the tumor categories in three independent external test datasets including 2,156 patients, achieving an overall accuracy of 95% and balanced accuracy of 91% on samples that are predicted with high confidence. These results showcase the potential future use of DEPLOY to assist pathologists in diagnosing CNS tumors within a clinically relevant short time frame.
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Neoplasias del Sistema Nervioso Central , Metilación de ADN , Aprendizaje Profundo , Humanos , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Islas de CpG/genética , Femenino , MasculinoRESUMEN
PURPOSE: Small cell lung cancer (SCLC) often metastasizes to the brain and has poor prognosis. SCLC subtypes distinguished by expressing transcriptional factors ASCL1 or NEUROD1 have been identified. This study investigates the impact of transcription factor-defined SCLC subtype on incidence and outcomes of brain metastases (BMs). METHODS: Patients with SCLC with ASCL1 (A) and NEUROD1 (N) immunohistochemical expression status were identified and classified: (1) A+/N-, (2) A+/N+, (3) A-/N+, and (4) A-/N-. Cumulative incidence competing risk analyses were used to assess incidence of CNS progression. Cox proportional hazards models were used for multivariable analyses of overall survival (OS) and CNS progression-free survival (CNS-PFS). RESULTS: Of 164 patients, most were either A+/N- or A+/N+ (n = 62, n = 63, respectively). BMs were present at diagnosis in 24 patients (15%). Among them, the 12-month cumulative incidence of subsequent CNS progression was numerically highest for A+/N- (50% [95% CI, 10.5 to 74.7]; P = .47). Among those BM-free at diagnosis, the 12-month cumulative incidence of CNS progression was numerically the highest for A+/N- (16% [95% CI, 7.5 to 27.9]) and A-/N+ (9.1% [95% CI, 0.0 to 34.8]; P = .20). Both subtypes, A+/N- and A-/N+, had worse OS compared with A+/N+ (A+/N-: hazard ratio [HR], 1.62 [95% CI, 1.01 to 2.51]; P < .05; A-/N+: HR, 3.02 [95% CI, 1.35 to 6.76]; P = .007). Excellent response rates (28, 65% CR/PR) across subtypes were seen in patients who had CNS-directed radiotherapy versus systemic therapy alone (9, 36% CR/PR). CONCLUSION: To our knowledge, this report is the first to investigate CNS-specific outcomes based on transcription factor subtypes in patients with SCLC. BM-free patients at diagnosis with A+/N- or A-/N+ subtypes had worse outcomes compared with those with transcriptional factor coexpression. Further investigation into the mechanisms and implications of SCLC subtyping on CNS-specific outcomes is warranted to ultimately guide personalized care.
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Neoplasias Encefálicas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/secundario , Masculino , Femenino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Persona de Mediana Edad , Pronóstico , Anciano , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Adulto , Anciano de 80 o más Años , Neoplasias del Sistema Nervioso Central/secundario , Neoplasias del Sistema Nervioso Central/genética , Estudios RetrospectivosRESUMEN
Methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" was recently defined based on methylation profiling and tSNE analysis of a series of 21 neuroepithelial tumors with predominant presence of a BCOR fusion and/or characteristic CNV breakpoints at chromosome 22q12.31 and chromosome Xp11.4. Clear diagnostic criteria are still missing for this tumor type, specially that BCOR/BCOR(L1)-fusion is not a consistent finding in these tumors despite being frequent and that none of the Heidelberger classifier versions is able to clearly identify these cases, in particular tumors with alternative fusions other than those involving BCOR, BCORL1, EP300 and CREBBP. In this study, we introduce a BCOR::CREBBP fusion in an adult patient with a right temporomediobasal tumor, for the first time in association with methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" in addition to 35 cases of CNS neuroepithelial tumors with molecular and histopathological characteristics compatible with "CNS tumor with BCOR/BCOR(L1)-fusion" based on a comprehensive literature review and data mining in the repository of 23 published studies on neuroepithelial brain Tumors including 7207 samples of 6761 patients. Based on our index case and the 35 cases found in the literature, we suggest the archetypical histological and molecular features of "CNS tumor with BCOR/BCOR(L1)-fusion". We also present four adult diffuse glioma cases including GBM, IDH-Wildtype and Astrocytoma, IDH-Mutant with CREBBP fusions and describe the necessity of complementary molecular analysis in "CNS tumor with BCOR/BCOR(L1)-alterations for securing a final diagnosis.
Asunto(s)
Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Glioma , Neoplasias Neuroepiteliales , Adulto , Humanos , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/genética , Neoplasias Neuroepiteliales/diagnóstico por imagen , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/genética , Metilación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/genética , Proteína de Unión a CREB/genéticaRESUMEN
PURPOSE: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome. One of the most common tumors are central nervous system (CNS) hemangioblastomas. Recommendations on the initiation and continuation of the screening and surveillance program for CNS tumors in pediatric VHL patients are based on small case series and thus low evidence level. To derive more robust screening recommendations, we report on the largest monocentric pediatric cohort of VHL patients. METHODS: We performed a retrospective analysis on a pediatric cohort of 99 VHL patients consulted at our VHL center from 1992 to 2023. Clinical, surgical, genetic, and imaging data were collected and statistically analyzed. RESULTS: 42 patients (50% male) developed CNS hemangioblastomas, of whom 18 patients (56% male) underwent hemangioblastoma surgery (mean age at first surgery: 14.9 ± 1.9 years; range 10.2-17). The first asymptomatic patient was operated on at the age of 13.2 years due to tumor progress. Truncating VHL mutation carriers had a significantly higher manifestation rate (HR = 3.7, 95% CI: 1.9-7.4, p < 0.0001) and surgery rate (HR = 3.3, 95% CI: 1.2-8.9, p = 0.02) compared with missense mutation carriers. CONCLUSION: We recommend starting MRI imaging at the age of 12 years with examination intervals every (1-) 2 years depending on CNS involvement. Special attention should be paid to patients with truncating variants. Affected families should be educated regularly on potential tumor-associated symptoms to enable timely MRI imaging and eventually intervention, as CNS hemangioblastoma may develop before screening begins. GERMAN CLINICAL TRIALS REGISTER REGISTRATION NUMBER: DRKS00029553, date of registration 08/16/2022, retrospectively registered.
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Hemangioblastoma , Enfermedad de von Hippel-Lindau , Humanos , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/complicaciones , Hemangioblastoma/cirugía , Hemangioblastoma/genética , Hemangioblastoma/patología , Masculino , Femenino , Adolescente , Niño , Estudios Retrospectivos , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/cirugía , Neoplasias Cerebelosas/patología , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/cirugía , Neoplasias del Sistema Nervioso Central/patología , Estudios de Seguimiento , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
Advanced molecular testing has increasingly become an integral component for accurate diagnosis of central nervous system (CNS) tumors. We sought to establish the current state of molecular testing availability and approaches for the diagnosis of CNS tumors in US hospitals that conduct high volumes of CNS tumor resections. We distributed a 16-item survey inquiring about molecular testing approaches for CNS tumors to 115 neuropathologists at US hospitals with neurosurgery residency programs. Thirty-five neuropathologists (30.4%) responded to the survey, all of whom indicated their institutions perform molecular testing on CNS tumor tissue. The most commonly offered tests were MGMT methylation profiling and next-generation sequencing. Fourteen respondents (40%) indicated that their institution is able to test for and report all of the molecular alterations included in our survey. Nine (25.7%) respondents indicated that molecular testing is performed as standard of care for all patients with resected CNS tumors. Our results suggest that even in academic hospitals with a high volume of CNS tumor resections, molecular testing for these tumors is limited. Continued initiatives are necessary to expand the availability of molecular testing for CNS tumors to ensure diagnostic accuracy and guide targeted therapy.
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Neoplasias del Sistema Nervioso Central , Humanos , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/diagnóstico , Estados Unidos , Hospitales , Encuestas y CuestionariosRESUMEN
PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is thought to increase the risk of meningioma and ependymoma. Thus, we aimed to describe the frequency, incidence, and specific clinical and histological features of central nervous system (CNS) tumors in the MEN1 population (except pituitary tumors). EXPERIMENTAL DESIGN: The study population included patients harboring CNS tumors diagnosed with MEN1 syndrome after 1990 and followed up in the French MEN1 national cohort. The standardized incidence ratio (SIR) was calculated based on the French Gironde CNS Tumor Registry. Genomic analyses were performed on somatic DNA from seven CNS tumors, including meningiomas and ependymomas from patients with MEN1, and then on 50 sporadic meningiomas and ependymomas. RESULTS: A total of 29 CNS tumors were found among the 1,498 symptomatic patients (2%; incidence = 47.4/100,000 person-years; SIR = 4.5), including 12 meningiomas (0.8%; incidence = 16.2/100,000; SIR = 2.5), 8 ependymomas (0.5%; incidence = 10.8/100,000; SIR = 17.6), 5 astrocytomas (0.3%; incidence = 6.7/100,000; SIR = 5.8), and 4 schwannomas (0.3%; incidence = 5.4/100,000; SIR = 12.7). Meningiomas in patients with MEN1 were benign, mostly meningothelial, with 11 years earlier onset compared with the sporadic population and an F/M ratio of 1/1. Spinal and cranial ependymomas were mostly classified as World Health Organization grade 2. A biallelic MEN1 inactivation was observed in 4/5 ependymomas and 1/2 meningiomas from patients with MEN1, whereas MEN1 deletion in one allele was present in 3/41 and 0/9 sporadic meningiomas and ependymomas, respectively. CONCLUSIONS: The incidence of each CNS tumor was higher in the MEN1 population than in the French general population. Meningiomas and ependymomas should be considered part of the MEN1 syndrome, but somatic molecular data are missing to conclude for astrocytomas and schwannomas.