RESUMEN
A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Mutación , Animales , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/inmunología , Reparación de la Incompatibilidad de ADN/genética , Frecuencia de los Genes , Genoma Humano/efectos de los fármacos , Genoma Humano/genética , Glioma/inmunología , Humanos , Masculino , Ratones , Repeticiones de Microsatélite/efectos de los fármacos , Repeticiones de Microsatélite/genética , Mutagénesis/efectos de los fármacos , Mutación/efectos de los fármacos , Fenotipo , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Análisis de Secuencia de ADN , Temozolomida/farmacología , Temozolomida/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies. We have previously described gene fusions of FGFR3-TACC3 (F3-T3) in 3% of human glioblastoma cases. Subsequent studies have reported similar frequencies of F3-T3 in many other cancers, indicating that F3-T3 is a commonly occuring fusion across all tumour types. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown. Here we show that human tumours with F3-T3 fusions cluster within transcriptional subgroups that are characterized by the activation of mitochondrial functions. F3-T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. Phosphorylation of the phosphopeptide PIN4 is an intermediate step in the signalling pathway of the activation of mitochondrial metabolism. The F3-T3-PIN4 axis triggers the biogenesis of peroxisomes and the synthesis of new proteins. The anabolic response converges on the PGC1α coactivator through the production of intracellular reactive oxygen species, which enables mitochondrial respiration and tumour growth. These data illustrate the oncogenic circuit engaged by F3-T3 and show that F3-T3-positive tumours rely on mitochondrial respiration, highlighting this pathway as a therapeutic opportunity for the treatment of tumours with F3-T3 fusions. We also provide insights into the genetic alterations that initiate the chain of metabolic responses that drive mitochondrial metabolism in cancer.
Asunto(s)
Respiración de la Célula , Proteínas Asociadas a Microtúbulos/genética , Mitocondrias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas de Fusión Oncogénica/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Respiración de la Célula/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Peptidilprolil Isomerasa de Interacción con NIMA/química , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Biogénesis de Organelos , Fosforilación Oxidativa/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Peroxisomas/efectos de los fármacos , Peroxisomas/metabolismo , Fosforilación , Biosíntesis de Proteínas , Especies Reactivas de Oxígeno/metabolismo , Receptores de Estrógenos/metabolismo , Transcripción Genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Diagnosis of primary central nervous system lymphoma (PCNSL) is challenging, and although brain biopsy remains the gold standard, cerebrospinal fluid (CSF) constitutes a less invasive source of lymphomatous biomarkers. In a retrospective cohort of 54 PCNSL cases tested at diagnosis or relapse, we evaluated the contribution of immunoglobulin heavy chain (IGH) gene clonality and MYD88 L265P detection on both CSF cell pellets and supernatants, in comparison with cytology, flow cytometry, interleukin (IL)-10 and IL-6 quantification. Clonality assessment included a new assay to detect partial IGH-DJ rearrangements. Clonal IGH rearrangements and/or MYD88 L265P mutation were detected in 27 (50%) cell pellets and 24 (44%) supernatant cell-free (cf) DNA. Combining analyses on both compartments, 36 (66%) cases had at least one detectable molecular marker, present only in cfDNA for 9 (16%) of them. While cytology and flow cytometry were positive in only 7 (13.0%) and 9 (17.3%) cases respectively, high IL-10 levels were observed in 36 (66.7%) cases. Overall, taking into account molecular and cytokine results, 46/54 (85%) cases had at least one lymphomatous biomarker detectable in the CSF. These results show that this combination of biomarkers evaluated on both cell pellet and supernatant CSF fractions improves significantly the biological diagnosis of PCNSL.
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Ácidos Nucleicos Libres de Células , Factor 88 de Diferenciación Mieloide , Humanos , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Estudios Retrospectivos , Reordenamiento Génico , MutaciónRESUMEN
AIMS: The distinction between CNS WHO grade 2 and grade 3 is instrumental in choosing between observational follow-up and adjuvant treatment for resected astrocytomas IDH-mutant. However, the criteria of CNS WHO grade 2 vs 3 have not been updated since the pre-IDH era. METHODS: Maximal mitotic activity in consecutive high-power fields corresponding to 3 mm2 was examined for 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumour volume, multilobar involvement, post-surgical residual tumour volume and midline involvement) was assessed for tumours with ATRX loss and the absence of CDKN2A homozygous deletion or CDK4 amplification, contrast enhancement, histological necrosis and microvascular proliferation. RESULTS: Seventy-one per cent of the samples had <6 mitoses per 3 mm2 . Mitotic activity, residual volume and multilobar involvement were independent prognostic factors of TTT. The threshold of ≥6 mitoses per 3 mm2 identified patients with a shorter TTT (median 18.5 months). A residual volume ≥1 cm3 also identified patients with a shorter TTT (median 24.5 months). The group defined by <6 mitoses per 3 mm2 and a residual volume <1 cm3 had the longest TTT (median 73 months) and OS (100% survival at 7 years). These findings were confirmed in a validation cohort of 52 tumours. CONCLUSIONS: Mitotic activity and post-surgical residual volume can be combined to evaluate the prognosis for patients with resected astrocytomas IDH-mutant. Patients with <6 mitoses per 3 mm2 and a residual volume <1 cm3 were the best candidates for observational follow-up.
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Astrocitoma , Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/patología , Pronóstico , Homocigoto , Volumen Residual , Eliminación de Secuencia , Mutación , Astrocitoma/genética , Astrocitoma/patología , Isocitrato Deshidrogenasa/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: Spinal cord metastasis arising from an intracranial glioblastoma is a rare and late event during the natural course of the disease. These pathological entities remain poorly characterized. This study aimed to identify and investigate the timeline, clinical and imaging findings, and prognostic factors of spinal cord metastasis from a glioblastoma. METHODS: Consecutive histopathological cases of spinal cord metastasis from glioblastomas in adults entered in the French nationwide database between January 2004 and 2016 were screened. RESULTS: Overall, 14 adult patients with a brain glioblastoma (median age 55.2 years) and harboring a spinal cord metastasis were included. The median overall survival as 16.0 months (range, 9.8-22.2). The median spinal cord Metastasis Free Survival (time interval between the glioblastoma diagnosis and the spinal cord metastasis diagnosis) was 13.6 months (range, 0.0-27.9). The occurrence of a spinal cord metastasis diagnosis greatly impacted neurological status: 57.2% of patients were not ambulatory, which contributed to dramatically decreased Karnofsky Performance Status (KPS) scores (12/14, 85.7% with a KPS score ≤ 70). The median overall survival following spinal cord metastasis was 3.3 months (range, 1.3-5.3). Patients with a cerebral ventricle effraction during the initial brain surgery had a shorter spinal cord Metastasis Free Survival (6.6 vs 18.3 months, p = 0.023). Out of the 14 patients, eleven (78.6%) had a brain IDH-wildtype glioblastoma. CONCLUSIONS: Spinal cord metastasis from a brain IDH-wildtype glioblastoma has a poor prognosis. Spinal MRI can be proposed during the follow-up of glioblastoma patients especially those who have benefited from cerebral surgical resection with opening of the cerebral ventricles.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias de la Médula Espinal , Adulto , Humanos , Persona de Mediana Edad , Glioblastoma/patología , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/cirugía , Encéfalo/patología , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVES: Brain biopsy is a useful surgical procedure in the management of patients with suspected neoplastic lesions. Its role in neurologic diseases of unknown etiology remains controversial, especially in ICU patients. This study was undertaken to determine the feasibility, safety, and the diagnostic yield of brain biopsy in critically ill patients with neurologic diseases of unknown etiology. We also aimed to compare these endpoints to those of non-ICU patients who underwent a brain biopsy in the same clinical context. DESIGN: Monocenter, retrospective, observational cohort study. SETTING: A French tertiary center. PATIENTS: All adult patients with neurologic diseases of unknown etiology under mechanical ventilation undergoing in-ICU brain biopsy between January 2008 and October 2020 were compared with a cohort of non-ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 2,207 brain-biopsied patients during the study period, 234 biopsies were performed for neurologic diseases of unknown etiology, including 29 who were mechanically ventilated and 205 who were not ICU patients. Specific histological diagnosis and final diagnosis rates were 62.1% and 75.9%, respectively, leading to therapeutic management modification in 62.1% of cases. Meningitis on prebiopsy cerebrospinal fluid analysis was the sole predictor of obtaining a final diagnosis (2.3 [1.4-3.8]; p = 0.02). ICU patients who experienced therapeutic management modification after the biopsy had longer survival (p = 0.03). The grade 1 to 4 (mild to severe) complication rates were: 24.1%, 3.5%, 0%, and 6.9%, respectively. Biopsy-related mortality was significantly higher in ICU patients compared with non-ICU patients (6.9% vs 0%; p = 0.02). Hematological malignancy was associated with biopsy-related mortality (1.5 [1.01-2.6]; p = 0.04). CONCLUSIONS: Brain biopsy in critically ill patients with neurologic disease of unknown etiology is associated with high diagnostic yield, therapeutic modifications and postbiopsy survival advantage. Safety profile seems acceptable in most patients. The benefit/risk ratio of brain biopsy in this population should be carefully weighted.
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Enfermedad Crítica , Enfermedades del Sistema Nervioso , Adulto , Biopsia/efectos adversos , Biopsia/métodos , Encéfalo , Enfermedad Crítica/terapia , Estudios de Factibilidad , Humanos , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/etiología , Respiración Artificial , Estudios RetrospectivosRESUMEN
AIM: Rosette-forming glioneuronal tumour (RGNT) is a rare central nervous system (CNS) World Health Organization (WHO) grade 1 brain neoplasm. According to the WHO 2021, essential diagnostic criteria are a 'biphasic histomorphology with neurocytic and a glial component, and uniform neurocytes forming rosettes and/or perivascular pseudorosettes associated with synaptophysin expression' and/or DNA methylation profile of RGNT whereas 'FGFR1 mutation with co-occurring PIK3CA and/or NF1 mutation' are desirable criteria. MATERIAL AND METHODS: We report a series of 46 cases fulfilling the essential pathological diagnostic criteria for RGNT. FGFR1 and PIK3CA hotspot mutations were searched for by multiplexed digital PCR in all cases, whereas DNA methylation profiling and/or PIK3R1 and NF1 alterations were analysed in a subset of cases. RESULTS: Three groups were observed. The first one included 21 intracranial midline tumours demonstrating FGFR1 mutation associated with PIK3CA or PIK3R1 (n = 19) or NF1 (n = 1) or PIK3CA and NF1 (n = 1) mutation. By DNA methylation profiling, eight cases were classified as RGNT (they demonstrated FGFR1 and PIK3CA or PIK3R1 mutations). Group 2 comprised 11 cases associated with one single FGFR1 mutation. Group 3 included six cases classified as low-grade glioma (LGG) other than RGNT (one-sixth showed FGFR1 mutation and one a FGFR1 and NF1 mutation) and eight cases without FGFR1 mutation. Groups 2 and 3 were enriched in lateral and spinal cases. CONCLUSIONS: We suggest adding FGFR1 mutation and intracranial midline location as essential diagnostic criteria. When DNA methylation profiling is not available, a RGNT diagnosis remains certain in cases demonstrating characteristic pathological features and FGFR1 mutation associated with either PIK3CA or PIK3R1 mutation.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Glioma , Neoplasias Neuroepiteliales , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Glioma/genética , Glioma/patología , Humanos , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/patología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
BACKGROUND: Mucosae-associated lymphoid tissue (MALT) lymphomas are a rare and poorly understood form of primary central nervous system lymphoma (PCNSL). The aim of this study was to better describe these tumors, their management and their long-term prognosis. METHODS: Patients with primary CNS MALT lymphoma (PCNSML) were retrospectively selected from the database on PCNSL of the Pitié-Salpêtrière Hospital. RESULTS: Of 662 PCNSL, 11 (1.7%) PCNSML (9 females and 2 males, median age: 56 years) were selected. The median time from first symptoms to diagnosis was 13 months. Location was dural in 8 cases and parenchymal in 3 cases. The disease was multifocal/diffuse in 7 cases. In first line, all patients received chemotherapy (high-dose methotrexate (HD-MTX) based chemotherapy (n = 4) and non-HD-MTX-based chemotherapy (n = 7)), preceded by surgery in 4 cases. None received radiotherapy. According to the IPCG (International PCNSL Collaborative Group) criteria, the overall response rate was 7/11 (64%). At latest news, 5 patients had persistent contrast enhancement, stable with no treatment since a median of 57 months, raising the question of complete response despite persisting contrast enhancement. No patient developed neurotoxicity except for one patient who subsequently received radiotherapy. The median follow-up was 109 months. The median progression-free survival was 78.0 months and the 10-year overall survival rate was 90%. CONCLUSION: This is the largest series demonstrating that chemotherapy is an efficient treatment in PCNSML, with an excellent long-term outcome and the absence of neurotoxicity, and calling into question the relevance of the IPCG criteria for the evaluation of response.
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Neoplasias del Sistema Nervioso Central , Linfoma de Células B de la Zona Marginal , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/etiología , Masculino , Metotrexato , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
INTRODUCTION: The corpus callosum (CC) is frequently involved in primary central nervous system lymphomas (PCNSLs). In this cohort study, we described the neurocognition of patients with PCNSL-CC and its posttherapeutic evolution. METHODS: Immunocompetent patients with PCNSL-CC were identified retrospectively at the Pitié-Salpêtrière Hospital. We described their clinical presentation. Neuropsychological test scores (MMSE; digit spans; Free and Cued Selective Reminding Test; Image Oral Naming Test; Frontal Assessment Battery; Trail Making Test; Stroop and verbal fluency tests; Rey's Complex Figure test) and factors impacting them were analyzed. RESULTS: Twenty-seven patients were included (median age: 67 years, median Karnofsky Performance Status: 70); cognitive impairment and balance disorders were present in 74% and 59%, respectively. At diagnosis, neuropsychological test results were abnormal for global cognitive efficiency (63% of patients), memory (33-80% depending on the test) and executive functions (44-100%). Results for visuospatial and language tests were normal. All patients received high-dose methotrexate-based polychemotherapy, followed in one patient by whole-brain radiotherapy; 67% of patients achieved complete response (CR). With a median follow-up of 48 months (range 6-156), patients in CR had persistent abnormal test results for global cognitive efficiency in 17%, executive function in 18-60%, depending on the test, and memory in 40-60%. Splenium location and age ≥ 60 years were significantly associated with worse episodic memory scores throughout the follow-up. CONCLUSIONS: PCNSL-CC is associated with frequent cognitive dysfunctions, especially memory impairment, which may recover only partially despite CR and warrant specific rehabilitation. Older age (≥ 60) and splenium location are associated with worse neurocognitive outcomes.
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Cuerpo Calloso , Linfoma , Anciano , Estudios de Cohortes , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Humanos , Linfoma/tratamiento farmacológico , Linfoma/terapia , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios RetrospectivosRESUMEN
PURPOSE: This study aimed to assess the benefit-risk ratio by determining diagnostic yield and safety of brainstem biopsies in adult patients. The secondary objectives were (i) to compare brainstem biopsy safety and postbiopsy patients' outcomes and survival with those of patients biopsied for a brain or cerebellar lesion, and (ii) to assess the impact of brainstem biopsy on final diagnosis and further therapeutic management. METHODS: Among 1784 stereotactic biopsies performed in adult patients at a tertiary center between April 2009 and October 2020, we retrospectively examined 50 consecutive brainstem biopsies. We compared variables regarding diagnostic yield, safety and post-biopsy outcomes between brainstem biopsy patients and brain/cerebellum biopsy patients. RESULTS: Brainstem biopsy led to a diagnosis in 86% of patients (94.6% in patients with suspected tumor). Lesion contrast enhancement on imaging was the sole predictor of obtaining a diagnosis. Rates of symptomatic complications and mortality were significantly higher in brainstem biopsy patients compared to brain/cerebellum biopsy patients (20% vs 0%; p < 0.001 and 6% vs 0%; p = 0.01, respectively). Transfrontal trajectory and prebiopsy swallowing disorders were predictors of brainstem biopsy-related symptomatic complications. Brainstem biopsy findings led to diagnostic change in 22% of patients. CONCLUSIONS: Stereotactic biopsy in adult patients with brainstem lesion has a high diagnostic yield. Although stereotactic brainstem biopsy is associated with more functional and fatal complications than biopsies targeting the brain/cerebellum, its safety profile appears acceptable. Thus, the benefit-risk ratio of stereotactic biopsy in patients with brainstem lesion is favorable but should nevertheless be carefully weighted on a case-by-case basis.
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Biopsia , Neoplasias del Tronco Encefálico , Técnicas Estereotáxicas , Adulto , Humanos , Biopsia/efectos adversos , Biopsia/métodos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Neoplasias del Tronco Encefálico/diagnóstico , Neoplasias del Tronco Encefálico/patología , Estudios Retrospectivos , Técnicas Estereotáxicas/efectos adversos , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/etiología , Enfermedades del Sistema Nervioso Central/patología , Medición de Riesgo , Resultado del TratamientoRESUMEN
Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm characterized by proliferation of tumor histiocytes that involves multiple organs including central nervous system. The physiopathologic process underlying degenerative neuro-LCH (i.e., DN-LCH) remains imperfectly settled. Since the main clinical features of DN-LCH are cerebellar ataxia and dysexecutive syndrome, eye movements might be disrupted and may help in disease diagnosis and monitoring. We retrospectively analyzed the medical records of twenty DN-LCH patients investigated using eye movement recording (EMR) in our hospital between 2015 and 2018. DN-LCH patients exhibited (i) abnormal gain in visually guided saccades including hypermetric saccades and excessive gain variability -45.0%-, (ii) increased mean antisaccade error rates -66.7%-, (iii) altered smooth pursuit -50.0%-, and (iv) excessive number of square wave jerks-25%- and gaze-evoked nystagmus. Our study suggests that DN-LCH patients present a peculiar pattern of eye movement impairments supporting cerebellar and prefrontal dysfunctions. As a non-invasive method, EMR could therefore be a useful tool for quantitative monitoring of DN-LCH patients. Further studies are warranted to support our findings.
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Ataxia Cerebelosa , Histiocitosis de Células de Langerhans , Humanos , Movimientos Oculares , Estudios Retrospectivos , Histiocitosis de Células de Langerhans/diagnósticoRESUMEN
BACKGROUND: Human encephalitis represents a medical challenge from a diagnostic and therapeutic point of view. We investigated the cause of 2 fatal cases of encephalitis of unknown origin in immunocompromised patients. METHODS: Untargeted metatranscriptomics was applied on the brain tissue of 2 patients to search for pathogens (viruses, bacteria, fungi, or protozoans) without a prior hypothesis. RESULTS: Umbre arbovirus, an orthobunyavirus never previously identified in humans, was found in 2 patients. In situ hybridization and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) showed that Umbre virus infected neurons and replicated at high titers. The virus was not detected in cerebrospinal fluid by RT-qPCR. Viral sequences related to Koongol virus, another orthobunyavirus close to Umbre virus, were found in Culex pipiens mosquitoes captured in the south of France where the patients had spent some time before the onset of symptoms, demonstrating the presence of the same clade of arboviruses in Europe and their potential public health impact. A serological survey conducted in the same area did not identify individuals positive for Umbre virus. The absence of seropositivity in the population may not reflect the actual risk of disease transmission in immunocompromised individuals. CONCLUSIONS: Umbre arbovirus can cause encephalitis in immunocompromised humans and is present in Europe.
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Agammaglobulinemia , Encefalitis , Orthobunyavirus , Virus , Animales , Europa (Continente) , Francia/epidemiología , Humanos , Orthobunyavirus/genéticaRESUMEN
LESSONS LEARNED: Treatment with temozolomide and BCNU was associated with substantial response and survival rates for patients with unresectable anaplastic glioma, suggesting potential therapeutic alternative for these patients. The optimal treatment for unresectable large anaplastic gliomas remains debated. BACKGROUND: The optimal treatment for unresectable large anaplastic gliomas remains debated. METHODS: Adult patients with histologically proven unresectable anaplastic oligodendroglioma or mixed gliomas (World Health Organization [WHO] 2007) were eligible. Treatment consisted of BCNU (150 mg/m2 ) and temozolomide (110 mg/m2 for 5 days) every 6 weeks for six cycles before radiotherapy. RESULTS: Between December 2005 and December 2009, 55 patients (median age of 53.1 years; range, 20.5-70.2) were included. Forty percent of patients presented with wild-type IDH1 gliomas, and 30% presented with methylated MGMT promoter. Median progression-free survival (PFS), centralized PFS, and overall survival (OS) were 16.6 (95% confidence interval [CI], 12.8-20.3), 15.4 (95% CI, 10.0-20.8), and 25.4 (95% CI, 17.5-33.2) months, respectively. Complete and partial responses under chemotherapy were observed for 28.3% and 17% of patients, respectively. Radiotherapy completion was achieved for 75% of patients. Preservation of functional status and self-care capability (Karnofsky performance status [KPS] ≥70) were preserved until disease progression for 69% of patients. Grade ≥ 3 toxicities were reported for 52% of patients, and three deaths were related to treatment. By multivariate analyses including age and KPS, IDH mutation was associated with better prognostic for both PFS and OS, whereas MGMT promoter methylation was associated with better OS. CONCLUSION: The association of BCNU and temozolomide upfront is active for patients with unresectable anaplastic gliomas, but toxicity limits its use.
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Neoplasias Encefálicas , Glioma , Adulto , Anciano , Antineoplásicos Alquilantes/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/radioterapia , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Adulto JovenRESUMEN
INTRODUCTION: Meningeal solitary fibrous tumors (SFT), like all SFT, are defined by NAB2-STAT6 fusion and share clinicopathologic similarities with meningiomas, the most frequent meningeal tumors. Our aim is to establish the molecular identity of meningeal SFT and seek molecular prognostic factors. METHODS: RNA sequencing and whole exome sequencing were performed in STAT6-positive SFT and grade 2-3 meningiomas, and data concerning other soft tissues tumors was obtained from the local database. Uniform manifold approximation and projection, individual gene expression and Gene Set Enrichment Analysis were performed. RESULTS: RNA clustering shows that SFT share a common molecular signature, different from any other type of tumoral tissue. Meningeal SFT aggregate with other SFT, with no clinical or histological subgroup. Comparison of genes expressions suggests significant over-expressions of ZIC2, ZIC3, ZIC5, GABBR2, TP53 in CNS-SFT. The pathogenic TP53 c.743G>T variant, previously undescribed in SFT, was found in one sample of meningeal SFT during malignant progression. CONCLUSIONS: Meningeal SFT are molecular counterparts of extra-meningeal SFT, completely separate from meningiomas. They might develop from the same tissues and benefit from the same treatments as SFT.
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Hemangiopericitoma , Neoplasias Meníngeas , Neoplasias de los Tejidos Blandos , Tumores Fibrosos Solitarios , Proteínas de Unión al ADN , Hemangiopericitoma/diagnóstico , Hemangiopericitoma/genética , Humanos , Neoplasias Meníngeas/genética , Meningioma/genética , Tumores Fibrosos Solitarios/genética , Factores de TranscripciónRESUMEN
We report a fatal case of measles inclusion-body encephalitis occurring in a woman from Romania with AIDS. After an extensive but unsuccessful diagnostic evaluation, a pan-pathogen shotgun metagenomic approach revealed a measles virus infection. We identified no mutations previously associated with neurovirulence.
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Síndrome de Inmunodeficiencia Adquirida , Sarampión , Panencefalitis Esclerosante Subaguda , Adulto , Encéfalo/diagnóstico por imagen , Femenino , Francia , Humanos , Sarampión/diagnóstico , Virus del Sarampión/genética , RumaníaRESUMEN
In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS (7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS: the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti-proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans.
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Enfermedades de los Perros/genética , Histiocitos/patología , Sarcoma Histiocítico/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biopsia , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Niño , Preescolar , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Enfermedades de los Perros/sangre , Enfermedades de los Perros/patología , Perros , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Sarcoma Histiocítico/tratamiento farmacológico , Sarcoma Histiocítico/patología , Sarcoma Histiocítico/veterinaria , Humanos , Lactante , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Masculino , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Ribonucleasas , Proteínas Supresoras de Tumor , Adulto JovenRESUMEN
BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Leptomeningeal spread (LMS) is a severe complication of GBM, raising diagnostic and therapeutic challenges in clinical routine. METHODS: We performed a review of the literature focused on LMS in GBM. MEDLINE and EMBASE databases were queried from 1989 to 2019 for articles describing diagnosis and therapeutic options in GBM LMS, as well as risk factors and pathogenic mechanisms. RESULTS: We retrieved 155 articles, including retrospective series, case reports, and early phase clinical trials, as well as preclinical studies. These articles confirmed that LMS in GBM remains (a) a diagnostic challenge with cytological proof of LMS obtained in only 35% of cases and (b) a therapeutic challenge with a median overall survival below 2 months with best supportive care alone. For patients faced with suggestive clinical symptoms, whole neuroaxis magnetic resonance imaging and cerebrospinal fluid analysis are both recommended. Liquid biopsies are under investigation and may help prompt a reliable diagnosis. Based on the literature, a multimodal and personalized therapeutic approach of LMS, including surgery, radiotherapy, systemic cytotoxic chemotherapy, and intrathecal chemotherapies, may provide benefits to selected patients. Interestingly, molecular targeted therapies appear promising in case of actionable molecular target and should be considered. CONCLUSION: As the prognosis of glioblastoma is improving over time, LMS becomes a more common complication. Our review highlights the need for translational studies and clinical trials dedicated to this challenging condition in order to improve diagnostic and therapeutic strategies. IMPLICATIONS FOR PRACTICE: This review summarizes the diagnostic tools and applied treatments for leptomeningeal spread, a complication of glioblastoma, as well as their outcomes. The importance of exhaustive molecular testing for molecular targeted therapies is discussed. New diagnostic and therapeutic strategies are outlined, and the need for translational studies and clinical trials dedicated to this challenging condition is highlighted.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Glioblastoma/diagnóstico , Glioblastoma/terapia , Humanos , Imagen por Resonancia Magnética , Pronóstico , Estudios RetrospectivosRESUMEN
Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glándula Pineal , Pinealoma/genética , Pinealoma/patología , Adolescente , Adulto , Factores de Edad , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , MicroARNs/metabolismo , Mutación/genética , Pinealoma/mortalidad , Sistema de Registros , Tasa de Supervivencia , Adulto JovenRESUMEN
INTRODUCTION: Primary Central Nervous System Lymphoma (PCNSL) is a rare disease with different therapeutic implications than systemic lymphoma. In this study, we evaluated whole-body 18FDG-PET/CT for pre-chemotherapy imaging of suspected PCNSL. METHODS: One hundred and thirty consecutive immunocompetent patients were retrospectively included. The results of initial 18FDG-PET/CT, contrast-enhanced CT (CeCT) and bone marrow biopsy (BMB) when available were compared to a gold standard based on pathological diagnosis or follow-up. RESULTS: CNS lesion pathology showed large B-cell lymphoma in 95% of patients, including 11 patients with primary vitro-retinal lymphoma. Ten patients (8%) where ultimately diagnosed with systemic lymphoma involvement, including five pathologically confirmed cases, all of which were detected by 18FDG-PET/CT. 18FDG-PET/CT showed incidental systemic findings unrelated to lymphoma in 14% of patients. An SUVmax threshold of nine enabled good discrimination between systemic lymphoma and other lesions (sensitivity 92% and specificity 89%). CeCT and BMB performed in 108 and 77 patients respectively revealed systemic lesions in only three patients. CONCLUSION: 18FDG-PET/CT detected concomitant occult systemic involvement in a non-negligible proportion of suspected PCNSL cases (8%). In this setting its sensitivity is higher than that of CeCT. All of our patients ultimately diagnosed with concomitant systemic involvement had positive 18FDG-PET/CT. We believe it constitutes a safe one-stop shop evaluation for the systemic pre-treatment imaging of suspected PCNSL.
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Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Linfoma/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Neoplasias del Sistema Nervioso Central/patología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Aumento de la Imagen , Linfoma/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
B-cell non-Hodgkin's lymphoma (NHL) risk associations had been mainly attributed to family history of the disease, inflammation, and immune components including human leukocyte antigen (HLA) genetic variations. Nevertheless, a broad range of genome-wide association studies (GWAS) have shed light into the identification of several genetic variants presumptively associated with B-cell NHL etiologies, survival or shared genetic risk with other diseases. The present review aims to overview HLA structure and diversity and summarize the evidence of genetic variations, by GWAS, on five NHL subtypes (diffuse large B-cell lymphoma DLBCL, follicular lymphoma FL, chronic lymphocytic leukemia CLL, marginal zone lymphoma MZL, and primary central nervous system lymphoma PCNSL). Evidence indicates that the HLA zygosity status in B-cell NHL might promote immune escape and that genome-wide significance variants can give biological insight but also potential therapeutic markers such as WEE1 in DLBCL. However, additional studies are needed, especially for non-DLBCL, to replicate the associations found to date.