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1.
J Neurooncol ; 164(3): 683-691, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37812290

RESUMO

PURPOSE: Intraoperative radiotherapy (IORT) has become a viable treatment option for resectable brain metastases (BMs). As data on local control and radiation necrosis rates are maturing, we focus on meaningful secondary endpoints such as time to next treatment (TTNT), duration of postoperative corticosteroid treatment, and in-hospital time. METHODS: Patients prospectively recruited within an IORT study registry between November 2020 and June 2023 were compared with consecutive patients receiving adjuvant stereotactic radiotherapy (SRT) of the resection cavity within the same time frame. TTNT was defined as the number of days between BM resection and start of the next extracranial oncological therapy (systemic treatment, surgery, or radiotherapy) for each of the groups. RESULTS: Of 95 BM patients screened, IORT was feasible in 84 cases (88%) and ultimately performed in 64 (67%). The control collective consisted of 53 SRT patients. There were no relevant differences in clinical baseline features. Mean TTNT (range) was 36 (9 - 94) days for IORT patients versus 52 (11 - 126) days for SRT patients (p = 0.01). Mean duration of postoperative corticosteroid treatment was similar (8 days; p = 0.83), as was mean postoperative in-hospital time (11 versus 12 days; p = 0.97). Mean total in-hospital time for BM treatment (in- and out-patient days) was 11 days for IORT versus 19 days for SRT patients (p < 0.001). CONCLUSION: IORT for BMs results in faster completion of interdisciplinary treatment when compared to adjuvant SRT, without increasing corticosteroid intake or prolonging in-hospital times. A randomised phase III trial will determine the clinical effects of shorter TTNT.


Assuntos
Neoplasias Encefálicas , Radiocirurgia , Humanos , Corticosteroides/uso terapêutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Radiocirurgia/métodos , Radioterapia Adjuvante , Resultado do Tratamento , Estudos Prospectivos
2.
Pediatr Blood Cancer ; 69(9): e29736, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35570402

RESUMO

BACKGROUND: An unexplained regional difference in survival was observed in previous publications on outcome for children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. We aimed now to reevaluate and perform a retrospective molecular-based risk stratification of all embryonal brain tumors (excluding atypical teratoid rhabdoid tumors [ATRT]) in pediatric patients, who underwent surgery and treatment at Oslo University Hospital between 2005 and 2017. PROCEDURE: Specimens from all patients <20 years of age with initial diagnosis of medulloblastoma or CNS-PNET were reviewed. Molecular analyses comprised NanoString gene expression, molecular inversion probe profiling, Sanger sequencing, and 850K-methylation analysis. Whole chromosomal aberration signatures were assessed in standard-risk non-WNT/non-SHH medullobastomas for molecular risk stratification. RESULTS: We identified 53 non-ATRT embryonal tumors among which 33 were medulloblastomas. Molecular genetic parameters including whole chromosomal aberration signatures allowed classification of 17 medulloblastomas as molecular high risk. These patients had a significantly worse 5-year overall survival than the remaining 16 medulloblastoma patients (52.9% vs. 87.1% p = 0.036). Five patients in our cohort had tumors that are considered as new entities in the 2021 classification of tumors of the central nervous system. Five tumors were re-classified as nonembryonal tumors after review. CONCLUSION: Molecular-based risk stratification of standard-risk non-WNT/non-SHH medulloblastoma enabled superior identification of medulloblastomas with dismal prognosis. Our cohort demonstrated a significantly increased fraction of standard-risk non-WNT/non-SHH medulloblastoma with molecular high-risk profile compared to other studies, which might have contributed to previously reported unfavorable outcome data.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Cerebelares , Meduloblastoma , Tumores Neuroectodérmicos Primitivos , Tumor Rabdoide , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/terapia , Criança , Aberrações Cromossômicas , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/terapia , Tumores Neuroectodérmicos Primitivos/patologia , Estudos Retrospectivos , Tumor Rabdoide/genética
3.
Cancer Immunol Immunother ; 70(6): 1781-1788, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33196890

RESUMO

Anti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Antígeno CTLA-4/genética , Metilação de DNA , Ipilimumab/uso terapêutico , Melanoma/mortalidade , Regiões Promotoras Genéticas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
4.
J Transl Med ; 17(1): 96, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894200

RESUMO

BACKGROUND: Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored common drug targets in paired primary vs. recurrent GBM tissue samples. METHODS: Paired surgical tissue samples were derived from a homogeneously treated cohort of 34 GBM patients. All patients received radiotherapy and temozolomide chemotherapy. Verification of common drug targets included immunohistological analysis of PDGFR-ß, FGFR-2, FGFR-3, and mTOR-pathway component (phospho-mTORSer2448) as well as molecular, MLPA-based analysis of specific copy number aberrations at the gene loci of ALK, PDGFRA, VEGFR2/KDR, EGFR, MET, and FGFR1. RESULTS: Paired tumor tissue exhibited significant changes of expression in 9 of the 10 investigated druggable targets (90%). Only one target (FGFR1) was found "unchanged", since dissimilar expression was observed in only one of the 34 paired tumor tissue samples. All other targets were variably expressed with an 18-56% discordance rate between primary and recurrent tissue. CONCLUSIONS: The high incidence of dissimilar target expression status in clinical samples from primary vs. recurrent GBM suggests clinically relevant heterogeneity along the course of disease. Molecular target expression, as determined at primary diagnosis, may not necessarily present rational treatment clues for the clinical care of recurrent GBM. Further studies need to analyze the therapeutic impact of longitudinal heterogeneity in GBM.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/terapia , Heterogeneidade Genética , Glioblastoma/terapia , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia/terapia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Progressão da Doença , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Feminino , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/tendências , Recidiva Local de Neoplasia/genética , Planejamento de Assistência ao Paciente , Estudos Retrospectivos , Adulto Jovem
5.
Am J Med Genet A ; 179(9): 1895-1897, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31291054

RESUMO

Heterozygous activating mutations in platelet-derived growth factor receptor B (PDGFRB) have been recently identified as a cause of autosomal-dominant infantile myofibromatosis. We describe a 36-year-old man with PDGFRB c.1681C>T (p.R561C) mutation. Upon progressive disease, the patient received treatment with imatinib and showed a remarkable response with remission of multiple lesions after 12 months. This is the first report of an adult patient with PDGFRB c.1681C>T mutation treated with imatinib.


Assuntos
Predisposição Genética para Doença , Mesilato de Imatinib/administração & dosagem , Miofibromatose/tratamento farmacológico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Progressão da Doença , Heterozigoto , Humanos , Masculino , Mutação/efeitos dos fármacos , Miofibromatose/genética , Miofibromatose/patologia
6.
Radiology ; 288(1): 226-333, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29514015

RESUMO

Purpose To establish and evaluate a visual score focused on entorhinal cortex atrophy (ERICA), as the entorhinal cortex is one of the first brain structures affected in Alzheimer disease (AD). Materials and Methods In this retrospective study, ERICA was visually evaluated with magnetic resonance imaging (2009-2016). First, a four-point ERICA score was developed by using data in 48 consecutive subjects (20 patients with AD and 28 control subjects). Then, in the main analysis, ERICA and the standard medial temporal lobe atrophy (MTA) scores were determined in an independent cohort of 60 patients suspected of having AD (mean age, 69.4 years; range, 46-86 years) and in 60 age-matched patients with subjective cognitive decline (SCD) (mean age, 72.4 years; range 50-87 years). Score performances were evaluated with κ statistics, receiver operating characteristic analysis, t tests, and analysis of variance according to the Standards for Reporting of Diagnostic Accuracy Studies. Results Patients with AD had higher MTA scores (mean, 2.13) and ERICA scores (mean, 2.05) than patients with SCD (P < .001). An ERICA score of 2 or greater achieved a higher diagnostic accuracy (91%) than the MTA score (74%), with a sensitivity of 83% versus 57% and a specificity of 98% versus 92% in discriminating dementia caused by AD from SCD (P < .001). The ERICA score was correlated with amyloid ß 42/40 ratio (ρ = -0.54, P < .001) and with cerebrospinal fluid tau (ρ = 0.35, P = .001) and p-tau (ρ = 0.31, P = .004). In multivariable linear regression analysis, ERICA was associated with verbal learning and recall (ß = -.40 and -.41), nonverbal recall (ß = -.28), and cued recall (ß = -.41, P ≤ .002 for all). Conclusion An ERICA score of 2 or greater indicates probable AD with high diagnostic accuracy. © RSNA, 2018 Online supplemental material is available for this article.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Córtex Entorrinal/diagnóstico por imagem , Córtex Entorrinal/patologia , Imageamento por Ressonância Magnética/métodos , Idoso , Idoso de 80 Anos ou mais , Atrofia , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos
8.
Strahlenther Onkol ; 194(3): 215-224, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29022050

RESUMO

PURPOSE: As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments. METHODS: Prospectively recorded hematologic and nonhematologic toxicities of children treated with radiochemotherapy in the HIT GBM-C/D and HIT-HGG-2007 trials were compared. Children aged 3-18 years with histologically proven HGG (WHO grade III and IV tumors) or unequivocal radiologic diagnosis of diffuse intrinsic pontine glioma (DIPG) were included in these trials. The HIT-HGG-2007 protocol comprised concomitant radiochemotherapy with temozolomide, while cisplatinum/etoposide (PE) and PE plus ifosfamide (PEI) in combination with weekly vincristine injections were applied during radiochemotherapy in the HIT GBM-C/D protocol. RESULTS: Regular blood counts and information about cellular nadirs were available from 304 patients (leukocytes) and 306 patients (thrombocytes), respectively. Grade 3-4 leukopenia was much more frequent in the HIT GBM-C/D cohort (n = 88, 52%) vs. HIT-HGG-2007 (n = 13, 10%; P <0.001). Grade 3-4 thrombopenia was also more likely in the HIT GBM-C/D cohort (n = 21, 12% vs. n = 3,2%; P <0.001). Grade 3-4 leukopenia appeared more often in children aged 3-7 years (n = 38/85, 45%) than in children aged 8-12 years (n = 39/120, 33%) and 13-18 years (24/100, 24%; P =0.034). In addition, sickness was more frequent in the HIT GBM-C/D cohort (grade 1-2: 44%, grade 3-4: 6% vs. grade 1-2: 28%, grade 3-4: 1%; P <0.001). CONCLUSION: Radiochemotherapy involving cisplatinum-based polychemotherapy is more toxic than radiotherapy in combination with temozolomide. Without evidence of differences in therapeutic efficacy, the treatment with lower toxicity, i. e., radiotherapy with temozolomide should be used.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/terapia , Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Dacarbazina/análogos & derivados , Glioma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/patologia , Quimiorradioterapia/métodos , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Estudos de Coortes , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Glioma/patologia , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Leucopenia/induzido quimicamente , Masculino , Gradação de Tumores , Estudos Prospectivos , Temozolomida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos
9.
Epilepsia ; 59(6): e78-e84, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29417555

RESUMO

In contrast to previous studies, Ljung et al. provide evidence of permanent cognitive consequences of bilateral intrahippocampal depth electrodes for verbal memory in patients who were not operated or operated in the right temporal lobe. Stimulated by this, we provide historical confirmatory and supplementary evidence of the detrimental effect of bilateral depth electrodes implanted along the longitudinal axis of the hippocampus on verbal learning and especially on delayed verbal memory and recognition performance. This is demonstrated in 31 patients with memory assessments before implantation, after explantation, and 3 months later after left/right temporal lobe surgery. After surgery, significant recovery from postimplantation impairment is found in right temporal patients. Left temporal resection patients stay on the level seen after implantation and do not recover. Surgery, however, has its own effects in addition to the implantation. Intracranial electrodes for electroencephalographic monitoring or electrical stimulation are commonly and increasingly used for diagnosis or treatment in pharmacoresistant epilepsies. Thus, the monitoring of invasive stereotactic approaches is recommended to find safe procedures for the patients. In response to the findings, we restricted indications and used different implantation schemes, different trajectories, and targets to minimize the risk of additional damage.


Assuntos
Estimulação Elétrica/métodos , Epilepsia do Lobo Temporal/terapia , Hipocampo/fisiologia , Transtornos da Memória/etiologia , Transtornos da Memória/terapia , Aprendizagem Verbal/fisiologia , Adolescente , Adulto , Eletrodos Implantados , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Feminino , Lateralidade Funcional , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/diagnóstico por imagem , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto Jovem
10.
J Neuroradiol ; 45(4): 242-248, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29410063

RESUMO

BACKGROUND AND PURPOSE: Kinetic parameters of T1-weighted dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are considered to be influenced by microvessel environment. This study was performed to explore the extent of this association for meningiomas. MATERIALS AND METHODS: DCE-MRI kinetic parameters (contrast agent transfer constants Ktrans and kep, volume fractions vp and ve) were determined in pre-operative 3T MRI of meningioma patients for later biopsy sites (19 patients; 15 WHO Io, no previous radiation, and 4 WHO IIIo pre-radiated recurrent tumors). Sixty-three navigated biopsies were consecutively retrieved. Biopsies were immunohistochemically investigated with endothelial marker CD34 and VEGF antibodies, stratified in a total of 4383 analysis units and computationally assessed for VEGF expression and vascular parameters (vessel density, vessel quantity, vascular fraction within tissue [vascular area ratio], vessel wall thickness). Derivability of kinetic parameters from VEGF expression or microvascularization was determined by mixed linear regression analysis. Tissue kinetic and microvascular parameters were tested for their capacity to identify the radiation status in a subanalysis. RESULTS: Kinetic parameters were neither significantly related to the corresponding microvascular parameters nor to tissue VEGF expression. There was no significant association between microvessel density and its presumed correlate vp (P=0.07). The subgroup analysis of high-grade radiated meningiomas showed a significantly reduced microvascular density (AUC 0.91; P<0.0001) and smaller total vascular fraction (AUC 0.73; P=0.01). CONCLUSIONS: In meningioma, DCE-MRI kinetic parameters neither allow for a reliable prediction of tumor microvascularization, nor for a prediction of VEGF expression. Kinetic parameters seem to be determined from different independent factors.


Assuntos
Imageamento por Ressonância Magnética/métodos , Neoplasias Meníngeas , Meningioma , Microvasos/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Feminino , Humanos , Aumento da Imagem , Biópsia Guiada por Imagem , Masculino , Neoplasias Meníngeas/irrigação sanguínea , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/metabolismo , Meninges/irrigação sanguínea , Meninges/patologia , Meningioma/irrigação sanguínea , Meningioma/diagnóstico por imagem , Meningioma/metabolismo , Pessoa de Meia-Idade
11.
J Magn Reson Imaging ; 46(4): 1187-1199, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28152250

RESUMO

PURPOSE: To investigate the effect of the choice of the curve-fitting model on the perfusion fraction (fIVIM ) with regard to tissue type characterization, correlation with microvascular anatomy, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters. Several curve-fitting models coexist in intravoxel incoherent motion (IVIM) MRI to derive the (fIVIM ). MATERIALS AND METHODS: In all, 29 patients with brain lesions (12 gliomas, 11 meningiomas, three metastases, two gliotic scars, one multiple sclerosis) underwent IVIM-MRI (32 b-values, 0 to 2000 s/mm2 ) at 3T. fIVIM was determined by classic monoexponential, biexponential, and a novel nonnegative least squares (NNLS) fitting in 352 regions of interest (lesion-containing and normal-appearing tissue) and tested their correlation with DCE-MRI kinetic parameters and microvascular anatomy derived from 57 region of interest (ROI)-based biopsies and their capacities to differentiate histologically different lesions. RESULTS: fIVIM differed significantly between all three models and all tissue types (monoexponential confidence interval in percent [CI 3.4-3.8]; biexponential [CI 11.21-12.45]; NNLS [CI 2.06-2.60]; all P < 0.001). For all models an increase in fIVIM was associated with a shift to larger vessels and higher vessel area / tissue area ratio (regression coefficient 0.07-0.52; P = 0.04-0.001). Correlation with kinetic parameters derived from DCE-MRI was usually not significant. Only biexponential fitting allowed differentiation of both gliosis from edema and high- from low-grade glioma (both P < 0.001). CONCLUSION: The curve-fitting model has an important impact on fIVIM and its capacity to differentiate tissues. fIVIM may possibly be used to assess microvascular anatomy and is weakly correlated with DCE-MRI kinetic parameters. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1187-1199.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Meios de Contraste , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
J Neurooncol ; 133(1): 155-163, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28425048

RESUMO

Current biopsy planning based on contrast-enhanced T1W (CET1W) or FLAIR sequences frequently delivers biopsy samples that are not in concordance with the gross tumor diagnosis. This study investigates whether the quantitative information of transfer constant Ktrans maps derived from T1W dynamic contrast-enhanced MRI (DCE-MRI) can help enhance the quality of biopsy target selection in glioma. 28 patients with suspected glioma received MRI including DCE-MRI and a standard neuronavigation protocol of 3D FLAIR- and CET1W data sets (0.1 mmol/kg gadobutrol) at 3.0 T. After exclusion of five cases with no Ktrans-elevation, 2-6 biopsy targets were independently selected by a neurosurgeon (samples based on standard imaging) and a neuroradiologist (samples based on kinetic parameter Ktrans) per case and tissue samples corresponding to these targets were collected by a separate independent neurosurgeon. Standard technique and Ktrans-based samples were rated for diagnostic concordance with the gross tumor resection reference diagnosis (67 WHO IV; 24 WHO III and II) by a neuropathologist blinded for selection mode. Ktrans-based sample targets differed from standard technique sample targets in 90/91 cases. More Ktrans-based than standard imaging-based samples could be extracted. Diagnoses from Ktrans-based samples were more frequently concordant with the reference gross tumor diagnoses than those from standard imaging-based samples (WHO IV: 30/39 vs. 11/20; p = 0.08; WHO III/II: 12/13 vs. 6/11; p = 0.06). In 4/5 non-contrast-enhancing gliomas, Ktrans-based selection revealed significantly more accurate samples than standard technique sample-selection (10/12 vs. 2/8 samples; p = 0.02). If Ktrans elevation is present, Ktrans-based biopsy targeting provides significantly more diagnostic tissue samples in non-contrast-enhancing glioma than selection based on CET1W and FLAIR-weighted images alone.


Assuntos
Biópsia/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Meios de Contraste , Glioma/diagnóstico por imagem , Imagem por Ressonância Magnética Intervencionista/métodos , Neuronavegação , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Meios de Contraste/farmacocinética , Método Duplo-Cego , Feminino , Glioma/patologia , Glioma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neuronavegação/métodos , Compostos Organometálicos/farmacocinética , Estudos Prospectivos
13.
J Neurooncol ; 132(2): 255-266, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28110411

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma/diagnóstico por imagem , Serviços de Informação , Cooperação Internacional , Imageamento por Ressonância Magnética , Sistema de Registros , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Ponte/diagnóstico por imagem , Adulto Jovem
14.
Neuroradiology ; 59(12): 1223-1231, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28894890

RESUMO

PURPOSE: Magnetic resonance (MR) imaging biomarkers can assist in the non-invasive assessment of the genetic status in glioblastomas (GBMs). Telomerase reverse transcriptase (TERT) promoter mutations are associated with a negative prognosis. This study was performed to identify MR imaging biomarkers to forecast the TERT mutation status. METHODS: Pre-operative MRIs of 64/67 genetically confirmed primary GBM patients (51/67 TERT-mutated with rs2853669 polymorphism) were analyzed according to Visually AcceSAble Rembrandt Images (VASARI) ( https://wiki.cancerimagingarchive.net/display/Public/VASARI+Research+Project ) imaging criteria by three radiological raters. TERT mutation and O6-methylguanine-DNA methyltransferase (MGMT) hypermethylation data were obtained through direct and pyrosequencing as described in a previous study. Clinical data were derived from a prospectively maintained electronic database. Associations of potential imaging biomarkers and genetic status were assessed by Fisher and Mann-Whitney U tests and stepwise linear regression. RESULTS: No imaging biomarkers could be identified to predict TERT mutational status (alone or in conjunction with TERT promoter polymorphism rs2853669 AA-allele). TERT promoter mutations were more common in patients with tumor-associated seizures as first symptom (26/30 vs. 25/37, p = 0.07); these showed significantly smaller tumors [13.1 (9.0-19.0) vs. 24.0 (16.6-37.5) all cm3; p = 0.007] and prolonged median overall survival [17.0 (11.5-28.0) vs. 9.0 (4.0-12.0) all months; p = 0.02]. TERT-mutated GBMs were underrepresented in the extended angularis region (p = 0.03), whereas MGMT-methylated GBMs were overrepresented in the corpus callosum (p = 0.03) and underrepresented temporomesially (p = 0.01). CONCLUSION: Imaging biomarkers for prediction of TERT mutation status remain weak and cannot be derived from the VASARI protocol. Tumor-associated seizures are less common in TERT mutated glioblastomas.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Imageamento por Ressonância Magnética/métodos , Telomerase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prognóstico , Regiões Promotoras Genéticas
15.
EMBO J ; 31(1): 201-13, 2012 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-22036947

RESUMO

Early during Gram-negative sepsis, excessive release of pro-inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo-responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T-cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T-cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T-cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro-inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well-known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T-cell immunity after sepsis.


Assuntos
Imunidade Adaptativa , Interferon Tipo I/metabolismo , Macrófagos/metabolismo , Sepse/imunologia , Baço/metabolismo , Animais , Células Dendríticas/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , Sepse/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
16.
Acta Neuropathol ; 131(2): 309-319, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26493382

RESUMO

Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification.


Assuntos
Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA , Metilação de DNA , Neoplasias Neuroepiteliomatosas/classificação , Neoplasias Neuroepiteliomatosas/genética , Adulto , Idoso , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Humanos , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Neuroepiteliomatosas/patologia , Neoplasias Neuroepiteliomatosas/terapia , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Adulto Jovem
17.
Acta Neuropathol ; 131(2): 321-322, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26744347

RESUMO

Erratum to: Acta Neuropathol DOI 10.1007/s00401­015­1495­z. The original version of this article contained errors in the alignment of several entries in Tables 4 and 5. The corrected Tables 4 and 5 are given below. The original article has been updated accordingly.

18.
J Neurooncol ; 118(2): 289-296, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24664371

RESUMO

The karyopherin protein family comprises importins and exportins which are nucleocytoplasmic shuttling receptors. Increased levels of karyopherin a2 and chromosome region maintenance protein 1 correlate with a higher WHO grade and a poorer prognosis in patients with infiltrative astrocytomas. The aim of this study was to evaluate representative members of importins and exportins (i.e. karyopherin a2 and chromosome region maintenance protein 1) as novel biomarkers for meningiomas of WHO grades I-III. We semiquantitatively analyzed nuclear expression of karyopherin a2, chromosome region maintenance protein 1 and the MIB1 labeling index using immunohistochemistry in 108 primary (44 meningiomas WHO grade I, 48 meningiomas WHO grade II, 16 meningiomas WHO grade III) and 13 recurrent meningiomas. Statistical analysis was performed using standard techniques. Karyopherin a2 (p < 0.001) and chromosome region maintenance protein 1 (p = 0.002) expression correlated significantly with the histological grade. Karyopherin a2 expression correlated with proliferative activity as assessed by the MIB1 index (p < 0.001). Recurrent tumors expressed significantly higher levels of karyopherin a2 (p = 0.045) when compared to primary growths. Multivariate analysis of the overall series as well as of patients with atypical meningiomas identified higher karyopherin a2 (≥ 5 vs. <5%) and chromosome region maintenance protein 1 (≥ 60 vs. 60%) expression as independent predictors of tumor recurrence. Karyopherin a2 and chromosome region maintenance protein 1 expression may have potential as novel biomarkers for meningiomas.


Assuntos
Carioferinas/metabolismo , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , alfa Carioferinas/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Proliferação de Células , Progressão da Doença , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/terapia , Meningioma/diagnóstico , Meningioma/patologia , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Neoplasias da Base do Crânio/diagnóstico , Neoplasias da Base do Crânio/metabolismo , Neoplasias da Base do Crânio/patologia , Neoplasias da Base do Crânio/terapia , Proteína Exportina 1
19.
Mol Oncol ; 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38899375

RESUMO

Low-grade neuroepithelial tumors (LGNTs), particularly those with glioneuronal histology, are highly associated with pharmacoresistant epilepsy. Increasing research focused on these neoplastic lesions did not translate into drug discovery; and anticonvulsant or antitumor therapies are not available yet. During the last years, animal modeling has improved, thereby leading to the possibility of generating brain tumors in mice mimicking crucial genetic, molecular and immunohistological features. Among them, intraventricular in utero electroporation (IUE) has been proven to be a valuable tool for the generation of animal models for LGNTs allowing endogenous tumor growth within the mouse brain parenchyma. Epileptogenicity is mostly determined by the slow-growing patterns of these tumors, thus mirroring intrinsic interactions between tumor cells and surrounding neurons is crucial to investigate the mechanisms underlying convulsive activity. In this review, we provide an updated classification of the human LGNT and summarize the most recent data from human and animal models, with a focus on the crosstalk between brain tumors and neuronal function.

20.
J Clin Med ; 13(10)2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38792513

RESUMO

Background: Primary spinal cord diffuse gliomas (SpDG) are rare tumors that may harbor, like diffuse intrinsic pontine gliomas (DIPG), H3K27M mutations. According to the WHO (2021), SpDGs are included in diffuse midline H3K27-altered gliomas, which occur more frequently in adults and show unusual clinical presentation, neuroradiological features, and clinical behavior, which differ from H3 G34-mutant diffuse hemispheric glioma. Currently, homogeneous adult-only case series of SpDG, with complete data and adequate follow-up, are still lacking. Methods: We conducted a qualitative systematic review, focusing exclusively on adult and young adult patients, encompassing all studies reporting cases of primitive, non-metastatic SpDG with H3K27 mutation. We analyzed the type of treatment administered, survival, follow-up duration, and outcomes. Results: We identified 30 eligible articles published between 1990 and 2023, which collectively reported on 62 adult and young adult patients with primitive SpDG. Postoperative outcomes were assessed based on the duration of follow-up, with outcomes categorized as either survival or mortality. Patients who underwent surgery were followed up for a mean duration of 17.37 months, while those who underwent biopsy had a mean follow-up period of 14.65 months. Among patients who were still alive, the mean follow-up duration was 18.77 months. The radiological presentation of SpDG varies widely, indicating its lack of uniformity. Conclusion: Therefore, we presented a descriptive scenario where SpDG was initially suspected to be a meningioma, but was later revealed to be a malignant SpDG with H3K27M mutation.

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