Felipe Andreiuolo - Academia.edu (original) (raw)

Papers by Felipe Andreiuolo

Neuro-Oncology, 2019

NEURO-ONCOLOGY • APRIL 2019 early chromosomal structural alterations followed by point mutations ... more NEURO-ONCOLOGY • APRIL 2019 early chromosomal structural alterations followed by point mutations that distinguish various regions. A novel mutation in SETD2 was discovered in all regions, and overexpression of this novel mutant (SETD2 K2R) led to increased cell proliferation and viability, suggesting that epigenetic misregulation could be a driver of ependymoma heterogeneity. CONCLUSION: Anaplastic ependymoma is associated with a previously unappreciated molecular heterogeneity that may influence tumorigenesis and design of molecular therapeutics.

Additional file 14. Copy number variation profile of case #10.

Additional file 10. Copy number variation profile of case #6.

Additional file 3. Sanger sequencing of RT-PCR products for MN1:ZFTA fusion.

Additional file 3: Figure S3. Variable immunohistochemical findings of HGNET-MN1. (A) Diffuse exp... more Additional file 3: Figure S3. Variable immunohistochemical findings of HGNET-MN1. (A) Diffuse expression of GFAP by glial cells of the pseudorosettes (400x, and insert 400x). (B) Focal expression of GFAP (400x). (C) Diffuse expression of Olig2 in a part of the tumor (400x). (D) Very focal immunoreactivity for Olig2 (400x). (E) Expression of CD56 (400x). (F) Expression of synaptophysin in a part of tumor cells (400x). (G) NeuN immunopositivity (400x). (H) Extra-vascular cellular staining with CD34 in one case (400x). (I) Diffuse expression of cytokeratin 18 (400x).

Additional file 1: Figure S1. Correlation of radiological and morphological features in HGNET-MN1... more Additional file 1: Figure S1. Correlation of radiological and morphological features in HGNET-MN1. (A) Axial T1 weighted image; (B) Axial T1 post contrast weighted image; (C) Axial T2 weighted image; (D) Coronal T1 post contrast weighted image: they showed a large lesion with multinodular appearance and very important edema. It is a well-demarcated non-intraventricular multinodular tumor with a central solid portion (yellow star) surrounded by multiple cystic components (red asterisks). (E) Multilobular tumor with fibrous central scar delimiting tumor nodules (HPS, 60x). (F) Fibrous scar (yellow star) (HPS, 130x). (G) Macro- and microcystic components (red asterisks) (HPS, 100x). (H) Well-delimitation of the tumor from the brain parenchyma (arrows) (HPS, 200x).

Neuro-Oncology, 2021

PURPOSE Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-al... more PURPOSE Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show ...

Neuro-Oncology, 2018

NEURO-ONCOLOGY • JUNE 2018 diagnosis, gender, age, symptom duration, MRI (typical versus atypical... more NEURO-ONCOLOGY • JUNE 2018 diagnosis, gender, age, symptom duration, MRI (typical versus atypical) and association with PFS and OS via the Cox proportional hazard model was performed. Patients treated with radio-labeled antibody delivered via convection enhanced delivery were excluded (n=26). RESULTS: Thirty-nine patients with complete records were analyzed, median age: 6.8 years (range: 2-36.5), gender: 19 girls, atypical MRIs: 18. Six patients had delayed RT (days: 32, 33, 42, 74, 77 and 2793). The patient delayed 2793 days had a biopsy at progression demonstrating K27M staining. Patients had varying treatment courses: concomitant chemotherapy with RT, chemotherapy after RT and re-irradiation. Non-delayed versus delayed RT, PFS (6.7mo versus 10.4mo, p=0.184) and OS (12.7mo versus 12.9mo, p=0.485) were not associated with any significant difference. Univariate analysis found no associations. DISCUSSION: We found no association between delayed initiation of RT and PFS or OS in this retrospective analysis. Our data suggest that in a small subset of patients with DIPG presenting with atypical MRI findings and/or mild symptoms, it may be reasonable to delay initiation of RT.

Neuro-Oncology, 2017

NEURO-ONCOLOGY • JUNE 2017 aggressive surgery (gross total resection x 6) followed by involved fi... more NEURO-ONCOLOGY • JUNE 2017 aggressive surgery (gross total resection x 6) followed by involved field radiation therapy (XRT), with a median event-free survival of 6 months and 4 of 8 patients dead of disease. Frequent and potentially targetable genetic alterations were detected in the MAPK pathway in 4 of 8 cases (BRAF V600E x 3, NTRK2-BEND5) and in PI3K/MTOR pathway genes in 3 of 8 cases (TSC1 x 2, PTEN). Additional aberrations related to the MAPK pathway were identified in 4 patients, including high copy gains in MET and KIT and 2 novel fusions (SOS1-MAP4K3 and MAP3K11-GFAP) which were validated by targeted sequencing and require further functional characterization. Other alterations in known high-grade glioma genes were also detected, including homozygous CDKN2A/B loss (n=3), TP53 mutation (n=2), and amplification events involving MYCN, CDK6, MET, and KIT. CONCLUSION: MEGNT is an aggressive tumor with poor response to conventional therapies. The frequency of potentially-targetable molecular alterations identified in this study indicates an opportunity to test the use of novel targeted agents for children with these tumors.

Brain Pathology, 2017

Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including... more Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As cooccurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty-seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co-occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double-immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow-up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow-up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors.

Journal of Neuropathology & Experimental Neurology, 2016

Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the... more Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the World Health Organization classification version 2016, their histopathological grading criteria are still ill-defined. The aim of the present study was to assess the clinical, imaging, histopathological, and molecular characteristics and outcomes of AGGs in a large consecutive and retrospective adult and pediatric case series. Eighteen patients with AGGs (13 adults and 5 children) were identified (14 de novo and 4 secondary) from a cohort of 222 gangliogliomas (GG) (8%) treated at our institution between 2000 and 2015. AGGs represented a very aggressive disease with poor outcome (median progression-free survival, 10 months; median overall survival, 27 months). They were located in the temporal lobe only in 22% and presented with seizures (44%) or increased intracranial pressure (44%) at diagnosis. Concerning histopathological and molecular data, they shared morphological characteristics and BRAF V600E mutation (39%) with their benign counterparts but also showed hTERT promoter mutation (61%), p53 accumulation (39%), ATRX loss (17%), or p.K27M H3F3A mutation (17%). AGGs are malignant neoplasms requiring aggressive oncological treatment. In the perspective of targeted therapies, AGGs should be screened for BRAF V600E, hTERT, ATRX, and mutations of histone genes.

Posterior Fossa Tumors in Children, 2015

Future Oncology, 2013

Ependymomas are one of the most common pediatric malignant brain tumors. Prognosis, especially in... more Ependymomas are one of the most common pediatric malignant brain tumors. Prognosis, especially in young children, remains poor due to their inherent chemo- and radio-resistance and effective treatment remains one of the more difficult tasks in pediatric oncology: up to half of the patients may die from the disease. The only reproducible prognostic factor is the extent of surgery; neither histological grading nor other biomarkers can be used to reliably make treatment decisions in clinical practice. None of the studies identifying new biomarkers have been conducted prospectively, only few have been undertaken within the context of a clinical trial and most have been conducted with limited samples (often including adults and childhood samples). International collaboration is needed to improve ependymoma prognostication.

Clinical Cancer Research, 2012

Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric ependy... more Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial ependymoma. Experimental Design: Frequency of 1q gain was assessed across 48 ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children's Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 (n = 60) and BBSFOP (n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n = 64). Results were correlated with clinical, histologic, and survival data. Results: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent ependymomas (2/...

Neuro-oncology, Jul 15, 2016

Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the Wo... more Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear. Here, we report a series of 20 ependymomas histologically defined by clear cells and branching capillaries. We observed a strong male predominance. Median age at surgery was 10.4 years (range, 0.8-68.4). All cases were ST, cortical, contrast enhancing, and most often frontal, cystic, an...

PloS one, 2017

Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5... more Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths. This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed. Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic va...

Neuropathology, 2009

Neuropathological analysis of cellular mechanisms underlying gliosis and brain tumors is slowed b... more Neuropathological analysis of cellular mechanisms underlying gliosis and brain tumors is slowed by the lack of markers allowing to distinguish glial subpopulations in normal or pathological human brains. We therefore evaluated GFAPdelta immunostaining in a wide panel of astrogliosis and gliomas, and compared these with GFAP and vimentin. In normal tissue, gliosis and gliomas, GFAPdelta immunostaining was observed in astrocytes with relatively high GFAP levels. GFAPdelta immunostaining was most conspicuous in glia limitans astrocytes. In Chaslin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s gliosis accompanying chronic epilepsy, GFAPdelta immunostaining evidenced the glia limitans reactive astrocytes as the source of the dense fibrillary meshwork typical of Chaslin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s gliosis. Interestingly GFAPdelta and vimentin immunostainings coincided in normal tissues and gliosis, but not in gliomas. Altogether these results show that combined GFAP, GFAPdelta and vimentin labelling reveals fine gliofilament regulation in normal and pathological brain.

Neuro-Oncology Advances

Background Pediatric neuro-oncology was profoundly changed in the wake of the 2016 revision of th... more Background Pediatric neuro-oncology was profoundly changed in the wake of the 2016 revision of the WHO Classification of Tumors of the Central Nervous System. Practitioners were challenged to quickly adapt to a system of tumor classification redefined by molecular diagnostics. Methods We designed a 22-question survey studying the impact of the revised WHO classification on pediatric high-grade glioma. The survey collected basic demographics, general attitudes, issues encountered, and opinions on pediatric subtypes. Participant answers were analyzed along socioeconomic lines utilizing the human development index (HDI) of the United Nations and membership in the group of seven (G7) world economic forum. Results Four hundred and sixty-five participants from 53 countries were included, 187 pediatric neurooncologists (40%), 160 neuropathologists (34%), and 118 other experts (26%). When asked about pediatric high-grade glioma entities, participants from very high development countries pre...

Acta Neuropathologica Communications

The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “... more The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathologi...

Neuro-Oncology

INTRODUCTION Since supratentorial RELA-fusion positive ependymomas are considered a biologically ... more INTRODUCTION Since supratentorial RELA-fusion positive ependymomas are considered a biologically distinct disease, we aimed to identify histological and genetic predictors of outcome in a defined cohort of pediatric patients. MATERIALS AND METHODS We analyzed 54 RELA ependymomas in pediatric patients treated according to HIT2000-E protocols. All cases underwent central neuropathological review. Genome-wide copy number alterations were assessed by molecular inversion probe or SNP array. RELA alterations were detected by RT-PCR, sequencing and assessment of nuclear p65-RelA protein. Copy number alteration of the CDKN2A (cyclin dependent kinase inhibitor 2A) locus and concordant p16 protein expression were analyzed. RESULTS Fifty-two tumors were classified as WHO-grade III (96.3%) with high mitotic activity in 39 cases (72.2%), vascular proliferation in 47 (87.0%), necrosis in 43 (79.6%) and clear cell morphology in 19 (35.2%). All tumors harbored RELA alterations. Homo- or heterozygou...