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Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.
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MicroRNAs/genética , Neoplasias Embrionárias de Células Germinativas/genética , RNA Helicases DEAD-box/genética , DNA Topoisomerases Tipo I/genética , Humanos , Mutação , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante , Recidiva , Ribonuclease III/genéticaRESUMO
The neuroepithelial tumor with PATZ1 fusion is a recently described tumor type, at the border between central nervous system and mesenchymal tumors. The histopathological diagnosis of this neoplasm, not recognized by the 2021 WHO classification, is challenging due to its varied and non-specific morphologic features. Most cases are densely cellular with monomorphous nuclei. Perivascular pseudo-rosettes of the ependymal type and astroblastic features are frequent. Blood vessels may be hyalinized. The tumor may display low- or high-grade features. OLIG2 and GFAP are variably expressed. Guided by DNA methylation profiling, a pathologist aware of this tumor type will search for a fusion involving PATZ1 and EWSR1 or MN1. The physiopathology of neuroepithelial tumor with PATZ1 fusion is not fully understood. The prognosis appears to align with that of intermediate-grade tumors but follow-up data are scarce. The therapeutic management is often similar to that of high-grade neoplasms. Nonetheless, PATZ1 fusion is a potential therapeutic avenue that may lead to personalized and less aggressive treatments.
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Salivary gland tumors represent a diagnostic challenge for pathologists due to their rarity, their very wide histopathological and immuno-phenotypic spectrum, and the recent identification of new entities. This article presents the main molecular characteristics of these tumors in order to allow any pathologist to perceive the diagnostic tracks of these ENT tumors and to better guide the molecular approach to establish the diagnosis and guide therapy.
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BACKGROUND: Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB. METHODS: Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected. RESULTS: Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only. CONCLUSION: Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747).
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Neoplasias Encefálicas , Glioblastoma , Radiocirurgia , Reirradiação , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Resultado do Tratamento , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Radiocirurgia/efeitos adversos , CitocinasRESUMO
Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8-5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location.
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Astrocitoma , Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Humanos , Criança , Pré-Escolar , Estudos Retrospectivos , Astrocitoma/patologia , Neoplasias do Sistema Nervoso Central/genética , Glioma/genética , Epigênese Genética , Neoplasias Encefálicas/genéticaRESUMO
AIMS: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low-grade epilepsy-associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma-like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours. METHODS: Centralised pathological examination was performed as well as targeted molecular analysis of v-Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done. RESULTS: We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/paediatric-type low-grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 [NTRK2] in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG-DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG-GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low-grade neuroepithelial tumour of the young belonged to Cluster 2, whereas diffuse LGG mitogen-activated protein kinase (MAPK) pathway-altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma-like component. CONCLUSIONS: Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma-like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinicopathological relevance of the four types recognised by the WHO CNS5 within this spectrum of tumours is questionable.
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Neoplasias Encefálicas/patologia , Encéfalo/patologia , Epilepsia/patologia , Neoplasias Neuroepiteliomatosas/patologia , Oligodendroglia/patologia , Adolescente , Adulto , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Metilação de DNA , Epilepsia/etiologia , Epilepsia/genética , Feminino , Humanos , Lactente , Masculino , Neoplasias Neuroepiteliomatosas/complicações , Neoplasias Neuroepiteliomatosas/genética , Estudos Retrospectivos , Adulto JovemRESUMO
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 do Sistema Nervoso Central , Glioma , Neoplasias Neuroepiteliomatosas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Glioma/genética , Glioma/patologia , Humanos , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
BACKGROUND: Congenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres. METHODS: Using next-generation sequencing, we identified three patients with pathogenic variants in the Troponin T type 1 (TNNT1) gene, coding for the troponin T (TNT) skeletal muscle isoform. RESULTS: The clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of TNNT1 revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3.Western blot analyses confirmed the absence of the TNT protein resulting from these mutations. DISCUSSION: The clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive TNNT1 mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.
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Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Miopatias da Nemalina/diagnóstico , Miopatias da Nemalina/genética , Fenótipo , Troponina T/genética , Biópsia , Pré-Escolar , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Imuno-Histoquímica , Lactente , Análise de Sequência de DNA , Deleção de Sequência , Troponina T/metabolismoRESUMO
BACKGROUND: IDH-mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear. METHODS: In a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression-free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity. RESULTS: The 4-year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38-0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41-0.97; p = .0348) in multivariable analysis. The 4-year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30-1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001). CONCLUSION: RT + PCV significantly improved PFS compared with RT + TMZ for IDH-mutant AA. However, RT + TMZ was better tolerated. IMPLICATIONS FOR PRACTICE: In the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH-mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH-mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression-free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH-mutant AA.
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Astrocitoma , Neoplasias Encefálicas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Astrocitoma/radioterapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Humanos , Lomustina/uso terapêutico , Procarbazina/uso terapêutico , Estudos Retrospectivos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Vincristina/uso terapêuticoRESUMO
Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Proteínas Repressoras/genética , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genéticaRESUMO
PURPOSE: The aim of this study was to assess the performance of Narrow Band Imaging (NBI) added to White Light (WL) in the delineation of laryngopharyngeal superficial cancer spread during office-based transnasal flexible endoscopy. METHODS: This bi-centric prospective study was conducted between October 2014 and December 2017. We included consecutive patients with laryngopharyngeal malignant tumors. Transnasal flexible endoscopy was performed by two endoscopists who were blinded to each other's assessments and who examined each patient independently. The first endoscopist only performed a WL examination, while the second endoscopist carried out both WL and NBI. The extent of tumor involvement was reported based on predefined anatomical sub-units. Biopsies in NBI + /WL- sub-units were subsequently performed during panendoscopy. RESULTS: Eighty-four patients were included in the study. A total of 72 NBI + /WL- sub-units were sampled in 38 patients, and 37 of the biopsies were positive (51.4%): 16 for invasive carcinoma, 17 for high-grade dysplasia/carcinoma in situ and 4 for low-grade dysplasia. Ultimately, 26.2% of patients had at least one positive biopsy in an NBI + /WL- sub-unit and, therefore, a better tumor delineation. The clinical T stage was upgraded in 4.8% of cases examined. CONCLUSION: Adding NBI to WL imaging during transnasal flexible endoscopy in patients presenting with laryngopharyngeal pre-malignant or malignant lesions improves the delineation of superficial cancer spread, thereby leading to better adapted treatments. Clinicaltrials.gov registration number: NCT02035735.
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Carcinoma in Situ , Imagem de Banda Estreita , Biópsia , Endoscopia , Humanos , Estudos Prospectivos , Sensibilidade e EspecificidadeAssuntos
Neoplasias Encefálicas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagem , Masculino , Feminino , AdultoRESUMO
BACKGROUND: The decision between definitive radio(chemo)therapy (RCT) or a surgical strategy, i.â¯e. surgery⯱ adjuvant radio(chemo)therapy for optimal treatment of oropharyngeal cancer is highly debated. Human papillomavirus(HPV)-related tumours are a distinct entity associated with p16 overexpression. While this represents a major prognostic factor, its predictive significance remains unknown. RESULTS: Among 183 consecutive unselected patients treated between 2009 and 2013 with a state-of-the-art surgical procedure ± adjuvant radio(chemo)therapy or definitive RCT including intensity-modulated radiotherapy, 3year disease-free survival (DFS) was 74 vs. 57%, respectively (pâ¯= 0.007). When focusing on p16+ patients (49%), there was no significant difference in tumour control rate between surgery⯱ radio(chemo)therapy and the definitive RCT group (3-year DFS 83 vs. 82%, respectively; pâ¯= 0.48). However, delayed severe dysphagia was significantly lower in favour of definitive RCT: 35 vs. 4%, respectively; pâ¯= 0.0002. CONCLUSION: Our results highlight distinct outcomes after definitive RCT or initial surgical treatment according to p16 status, which should thus be considered during the decision process.
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Quimiorradioterapia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Técnicas de Apoio para a Decisão , Expressão Gênica/genética , Neoplasias Orofaríngeas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/cirurgiaRESUMO
BACKGROUND: Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival. METHODS/DESIGN: In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status. DISCUSSION: This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging. TRIAL REGISTRATION: NCT01507506 , registration date December 20, 2011.
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Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Glioblastoma/terapia , Radioterapia de Intensidade Modulada/métodos , Temozolomida/uso terapêutico , Adulto , Neoplasias Encefálicas/mortalidade , Diagnóstico por Imagem , Glioblastoma/mortalidade , Humanos , Espectroscopia de Ressonância Magnética , Recidiva Local de Neoplasia , Estudos Prospectivos , Dosagem Radioterapêutica , Análise de SobrevidaRESUMO
An increasing number of sarcomas displaying a primitive, monomorphic spindle cell phenotype have been shown to harbor recurrent gene fusions, including biphenotypic sinonasal sarcoma (SNS). Occurring in the sinonasal area of middle-aged patients, SNS is a locally aggressive tumor harboring in 90% of cases recurrent gene fusions involving the PAX3 gene, in which the chimeric transcription factor induces an aberrant dual myogenic and neural phenotype. Here, we report an unusual oropharyngeal monomorphic spindle cell sarcoma in a 53-year-old man that revealed a novel RREB1-MKL2 gene fusion by RNA sequencing with the Illumina TruSight RNA Fusion Panel. The gene fusion was validated by RT-PCR. Although the tumor location is unusual (but head and neck seated), most of the other clinical, morphologic, immunophenotypic (focal combined expression of S100 protein, SMA, desmin, and myogenin) and oncogenic data suggest that this biphenotypic "oropharyngeal" sarcoma is closely related to the biphenotypic SNS spectrum. Notably, the RREB1-MKL2 chimeric transcription factor encoded by this fusion gene produced an increase in MKL2 expression, which regulates both neural and myogenic differentiation, mimicking the crucial role of PAX3 reported in SNS oncogenesis. NGS and especially RNA sequencing may be used to identify new candidate fusion oncogenes in soft tissue tumors, which would help in updating the existing classification. In turn, this would lead to better therapeutic management of patients.
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Proteínas de Ligação a DNA/genética , Neoplasias dos Seios Paranasais/genética , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/metabolismo , Fusão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Neoplasias Orofaríngeas/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição/metabolismoRESUMO
Salivary gland-like tumours are described in the breast but remain very rare and difficult to diagnose in this location. Only 37 cases of mucoepidermoid carcinoma have been described in the literature. We report the challenging diagnosis of a mucoepidermoid carcinoma sampled by core biopsy in a 51-year-old woman.
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Neoplasias da Mama/patologia , Carcinoma Mucoepidermoide/patologia , Neoplasias de Mama Triplo Negativas/patologia , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Mucoepidermoide/química , Carcinoma Mucoepidermoide/diagnóstico , Carcinoma Mucoepidermoide/diagnóstico por imagem , Hibridização Genômica Comparativa , Diagnóstico Diferencial , Feminino , Humanos , Mamografia , Mastectomia Segmentar , Pessoa de Meia-Idade , Especificidade de Órgãos , Neoplasias das Glândulas Salivares/patologia , Biópsia de Linfonodo Sentinela , Transativadores/genética , Neoplasias de Mama Triplo Negativas/química , Neoplasias de Mama Triplo Negativas/diagnósticoRESUMO
Medical education is currently facing great changes that affect all medical specialties, including anatomical pathology. Due to rapidly increasing medical knowledge and diagnostic complexity, we are living an era of teaching resources mutualization. We present different tools that allow large numbers of students to access courses, self-evaluations, and competencies assessments. MOOC platforms and e-learning platforms are central to these new online tools, which include the French National Platform of Medical Specialties, dedicated to the teaching of 50,000 medical residents in France. We also discuss "serious games" and the use of images and virtual slides in anatomical pathology teaching. These new modalities can deliver essential knowledge to large student populations, but they must be used in conjunction with adapted teacher-led courses focusing on competencies and professional skills in order to be fully effective.