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1.
Am J Surg Pathol ; 44(1): 11-20, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31567202

RESUMO

The pineal parenchymal tumors of intermediate differentiation (PPTIDs) are extremely rare tumor entities. They exhibit low-risk (grade II) and high-risk (grade III) malignancies, which may lead to different therapies and prognosis. However, the histological grading criteria remains elusive, and novel biomarkers may be helpful to differentiate the grade of PPTIDs. Immunohistochemical staining for CD24, PRAME, POU4F2, and HOXD13, and their clinicopathologic analyses were performed in pineal parenchymal tumors and other tumors in the pineal region. CD24 and PRAME were expressed in 9/11 (81.8%) and 8/11(72.7%) cases of PPTIDs grade III, compared with 6/18 (33.3%) and 5/18(27.8%) cases of PPTIDs grade II. The levels of CD24 and PRAME were significantly higher in PPTIDs grade III than grade II. However, there were no differences of HOXD13 and POU4F2 expression levels in PPTIDs grade II and grade III. Interestingly, high expression of CD24 and PRAME were prevalently found in high-grade tumors of the central nervous system. In addition, PPTIDs patients with high expression levels of CD24 and PRAME exhibited a significant shorter survival time. The results of PPTIDs grading by CD24 and PRAME were mostly consistent with WHO criteria, except for two cases. According to the prognostic information of patients, we found that the combination of CD24 and PRAME expression for grading PPTIDs might be more valuable than WHO criteria only. CD24 and PRAME are novel markers for grading and prognostic evaluation of PPTIDs that may be helpful to determine the therapeutic decision for PPTIDs patients.


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Neoplasias Encefálicas/patologia , Antígeno CD24/análise , Glândula Pineal , Pinealoma/química , Pinealoma/patologia , Adolescente , Adulto , Diferenciação Celular , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Estudos Retrospectivos , Adulto Jovem
2.
Analyst ; 144(22): 6517-6532, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31647061

RESUMO

Raman spectroscopy is a promising tool for neurosurgical guidance and cancer research. Quantitative analysis of the Raman signal from living tissues is, however, limited. Their molecular composition is convoluted and influenced by clinical factors, and access to data is limited. To ensure acceptance of this technology by clinicians and cancer scientists, we need to adapt the analytical methods to more closely model the Raman-generating process. Our objective is to use feature engineering to develop a new representation for spectral data specifically tailored for brain diagnosis that improves interpretability of the Raman signal while retaining enough information to accurately predict tissue content. The method consists of band fitting of Raman bands which consistently appear in the brain Raman literature, and the generation of new features representing the pairwise interaction between bands and the interaction between bands and patient age. Our technique was applied to a dataset of 547 in situ Raman spectra from 65 patients undergoing glioma resection. It showed superior predictive capacities to a principal component analysis dimensionality reduction. After analysis through a Bayesian framework, we were able to identify the oncogenic processes that characterize glioma: increased nucleic acid content, overexpression of type IV collagen and shift in the primary metabolic engine. Our results demonstrate how this mathematical transformation of the Raman signal allows the first biological, statistically robust analysis of in vivo Raman spectra from brain tissue.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Análise Espectral Raman/métodos , Teorema de Bayes , Neoplasias Encefálicas/química , Colágeno Tipo IV/metabolismo , Conjuntos de Dados como Assunto , Feminino , Glioma/química , Humanos , Cuidados Intraoperatórios , Luz , Masculino , Pessoa de Meia-Idade , Ácidos Nucleicos/metabolismo , Análise de Componente Principal , Estudos Retrospectivos
3.
Br J Radiol ; 92(1104): 20190216, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556332

RESUMO

OBJECTIVE: Magnetic resonance spectroscopy (MRS) has been useful in radiotherapy treatment planning (RTP) especially in tumor delineation. Routinely, 2D/3D MRSI data are used for this application. However, not all centers have access to 2D/3D MRSI. The objective of this study was to introduce a method of using single-voxel spectroscopy (SVS) data in target delineation and assess its reliability. METHODS: A gel-based phantom containing Creatine (Cr), N-acetyl-l-aspartic-acid (NAA), and Choline (Cho) was designed and built. The metabolite ratios simulate the normal and tumoral part of the brain. The jMRUI software (v. 6.0) was used to simulate a 1.5 T GE MRI scanner. The metabolite spectra provided by different time of echos (TE)s of the Point-RESolved Spectroscopy pulse-sequence (PRESS), different data-points, and post-processings were quantized by jMRUI. PseudoMRSI maps of Cho/Cr, NAA/Cr, and Cho + Cr/NAA were created. A conformity index (CI) was used to determine which metabolite-ratio isolines are more appropriate for tumor delineation. RESULTS: The simulation accuracy was verified. There were no differences > 4% between the measured and simulated spectra in peak regions. The pseudoMRSI map of Cho + Cr/NAA smoothly followed the complicated geometry of the tumor inside the gel-based phantom. The results showed that the single-voxel spectra produced by the PRESS pulse sequence with the TE of 144 ms, 512 data-points, and minimum post-processings of water suppression, eddy current correction, and baseline correction can be used for target delineation. CONCLUSION: This study suggests that SVS data can be used to aid target delineation by using a mathematical approach. This can enable a wider use of MR-derived information in radiotherapy. ADVANCES IN KNOWLEDGE: To the best of our knowledge, until now, 2D or 3D MRSI data provided from 3T MRI scanners have been used for MRS-based radiotherapy treatment planning. However, there are a lot of centers that are equipped to 1.5 T MRI scanners and some of them just equipped to SVS. This study introduces a mathematical approach to help these centers to take the benefits of MRS-based treatment planning.


Assuntos
Química Encefálica , Neoplasias Encefálicas/química , Neoplasias Encefálicas/diagnóstico , Espectroscopia de Ressonância Magnética/métodos , Imagens de Fantasmas , Ácido Aspártico/análogos & derivados , Colina , Creatina , Humanos , Reprodutibilidade dos Testes , Software
4.
Anticancer Res ; 39(6): 3067-3070, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177150

RESUMO

We report a rare case of primary intracranial alveolar rhabdomyosarcoma (ARMS) in the right temporal lobe of a 51-year-old male. ARMS is one of 3 histological subtypes of rhabdomyosarcoma that most commonly presents in older children and younger adults. To our knowledge, there have been no prior published reports of primary intracranial ARMS in adults. Known cases of intracranial ARMS in adults are due to central nervous system (CNS) metastases from the head and neck and extremities. Diagnostic workup did not reveal any primary source outside the CNS. Given that risk factors for ARMS have not been studied in adults, it is difficult to ascertain what aspects of this patient's clinical history may have contributed to his diagnosis. Interestingly, he had prior history of traumatic brain injury requiring evacuation of a right fronto-temporal intraparenchymal hematoma.


Assuntos
Neoplasias Encefálicas/patologia , Rabdomiossarcoma Alveolar/patologia , Lobo Temporal/patologia , Biomarcadores Tumorais/análise , Lesões Encefálicas Traumáticas/complicações , Neoplasias Encefálicas/química , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/etiologia , Progressão da Doença , Evolução Fatal , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rabdomiossarcoma Alveolar/química , Rabdomiossarcoma Alveolar/diagnóstico por imagem , Rabdomiossarcoma Alveolar/etiologia , Fatores de Risco , Lobo Temporal/química , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/efeitos da radiação , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
5.
AJNR Am J Neuroradiol ; 40(6): 979-986, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31097430

RESUMO

BACKGROUND AND PURPOSE: Acidification of the tumor microenvironment from abnormal metabolism along with angiogenesis to meet metabolic demands are both hallmarks of malignant brain tumors; however, the interdependency of tumor acidity and vascularity has not been explored. Therefore, our aim was to investigate the association between pH-sensitive amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) and relative cerebral blood volume (CBV) measurements obtained from dynamic susceptibility contrast (DSC) perfusion MRI in patients with gliomas. MATERIALS AND METHODS: In this retrospective study, 90 patients with histologically confirmed gliomas were scanned between 2015 and 2018 (median age, 50.3 years; male/female ratio = 59:31). pH-weighting was obtained using chemical exchange saturation transfer echo-planar imaging estimation of the magnetization transfer ratio asymmetry at 3 ppm, and CBV was estimated using DSC-MR imaging. The voxelwise correlation and patient-wise median value correlation between the magnetization transfer ratio asymmetry at 3 ppm and CBV within T2-hyperintense lesions and contrast-enhancing lesions were evaluated using the Pearson correlation analysis. RESULTS: General colocalization of elevated perfusion and high acidity was observed in tumors, with local intratumor heterogeneity. For patient-wise analysis, median CBV and magnetization transfer ratio asymmetry at 3 ppm within T2-hyperintense lesions were significantly correlated (R = 0.3180, P = .002), but not in areas of contrast enhancement (P = .52). The positive correlation in T2-hyperintense lesions remained within high-grade gliomas (R = 0.4128, P = .001) and in isocitrate dehydrogenase wild-type gliomas (R = 0.4300, P = .002), but not in World Health Organization II or in isocitrate dehydrogenase mutant tumors. Both magnetization transfer ratio asymmetry at 3 ppm and the voxelwise correlation between magnetization transfer ratio asymmetry and CBV were higher in high-grade gliomas compared with low-grade gliomas in T2-hyperintense tumors (magnetization transfer ratio asymmetry, P = .02; Pearson correlation, P = .01). The same trend held when comparing isocitrate dehydrogenase wild-type gliomas and isocitrate dehydrogenase mutant gliomas (magnetization transfer ratio asymmetry, P = .04; Pearson correlation, P = .01). CONCLUSIONS: A positive linear correlation between CBV and acidity in areas of T2-hyperintense, nonenhancing tumor, but not enhancing tumor, was observed across patients. Local heterogeneity was observed within individual tumors.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Glioma/diagnóstico por imagem , Glioma/patologia , Adulto , Idoso , Neoplasias Encefálicas/química , Imagem Ecoplanar/métodos , Feminino , Glioma/química , Humanos , Concentração de Íons de Hidrogênio , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Estudos Retrospectivos
6.
Clin Transl Oncol ; 21(10): 1413-1423, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30877636

RESUMO

BACKGROUND: Some phase 2 trials had reported encouraging progression-free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma. METHODS: We used Immunochemical analysis on tumor samples and pretreatment and post-treatment perfusion-MRI to try to identify possible predictive angiogenesis-related biomarkers of response and survival in patients with glioblastoma treated with bevacizumab in the first recurrence. We analyzed histological parameters: vascular proliferation, mitotic number and Ki-67 index; molecular factors: MGMT promoter methylation, EGFR amplification and EGFR variant III; immunohistochemical: MET, Midkine, HIF1, VEGFA, VEGF-R2, CD44, Olig2, microvascular area and microvascular density; and radiological: rCBV. RESULTS: In the statistical analysis, no significant correlation of any histological, molecular, microvascular or radiological parameters could be demonstrated with the response rate, PFS or OS with bevacizumab treatment. CONCLUSION: Unfortunately, in this histopathological, molecular, immunohistochemical and neuroradiological study we did not find any predictive biomarker of response or survival benefit for Bevacizumab in glioblastoma.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/química , Neoplasias Encefálicas/diagnóstico por imagem , Circulação Cerebrovascular , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Amplificação de Genes , Genes erbB-1 , Glioblastoma/irrigação sanguínea , Glioblastoma/química , Glioblastoma/diagnóstico por imagem , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Masculino , Metilação , Microvasos/patologia , Pessoa de Meia-Idade , Índice Mitótico , Recidiva Local de Neoplasia/irrigação sanguínea , Recidiva Local de Neoplasia/química , Recidiva Local de Neoplasia/diagnóstico por imagem , Estudos Retrospectivos , Análise Serial de Tecidos , Proteínas Supressoras de Tumor/metabolismo
7.
Zhonghua Bing Li Xue Za Zhi ; 48(3): 192-198, 2019 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-30831644

RESUMO

Objective: To analyze the clinicopathological characteristics and prognosis of diffuse midline glioma (DMG) with H3K27M mutation. Methods: Thirty cases of DMG were collected in Guangdong Sanjiu Brain Hospital from October 2016 to May 2018. The patients' clinicopathological data including age, tumor site and histological grade, treatment and follow-up data were collected and analyzed. Results: There were 21 males and 9 females, with a mean age of 26 years (range 5-53 years). Fourteen tumors were located in thalamus, 12 in brainstem (one involved both thalamus and brainstem), and one each in hypothalamus, fourth ventricle, and sellar region, respectively. Two cases presented as diffuse intracranial lesions. Three cases (10.0%) were of WHO grade Ⅰ, 10 cases (33.3%) were grade Ⅱ, eight cases (26.7%) were grade Ⅲ, and nine cases (30.0%) were grade Ⅳ.All patients with gradeⅠ tumors were older than 20 years. Histologically, all were pilocytic astrocytoma-like. Immunohistochemical staining demonstrated that all tumors were IDH1 negative. Twenty-eight tumors showed diffuse expression of H3K27M, and two showed focal expression. Twenty-one tumors(100.0%, 21/21) showed absent expression of H3K27me3. Sixteen tumors (57.1%, 16/28) showed strongly positive expression of p53, and ATRX was negative in eight tumors (38.1%, 8/21). The Ki-67 proliferation index ranged from 5% to 40%. Eight cases (including two cases of H3K27M expression of individual cells) showed K27M mutation in H3F3A gene. Intracranial and spinal cord dissemination occurred in six cases (20.0%, 6/30). Median progression-free survival (PFS) was 9.5 months and median overall survival (OS) was 34 months. Mean PFS was 11.2 months and mean OS was 24.3 months. Compared with adults (>20 years old), children/adolescents (no more than 20 years old) had significantly shorter median OS (8 months vs. 34 months, P=0.013). There was no significant difference in PFS and OS between DMGs located in the brain stem/thalamus and other sites within midline (P>0.05). There was no significant difference in PFS and OS between WHO grade ⅠDMGs and WHO grade Ⅱ-Ⅳ DMGs (P>0.05). Conclusions: DMGs occur more commonly in children and adolescents with male predominance. DMGs present with WHO Ⅰ-Ⅳ tumors morphologically, and pilocytic astrocytoma-like lesions with WHO Ⅰ are more common in adults. Expression of H3K27M but not H3K27me3 is helpful for diagnosis of DMG. The prognosis of children/adolescents is significantly worse than that of adults, whereas histological grade and tumor location do not affect prognosis.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Histona Desmetilases com o Domínio Jumonji/genética , Mutação , Adolescente , Adulto , Fatores Etários , Astrocitoma/química , Astrocitoma/enzimologia , Astrocitoma/mortalidade , Astrocitoma/patologia , Neoplasias Encefálicas/química , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias do Tronco Encefálico/química , Neoplasias do Tronco Encefálico/enzimologia , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Feminino , Glioma/química , Glioma/mortalidade , Glioma/patologia , Histonas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Tálamo , Adulto Jovem
8.
J Clin Endocrinol Metab ; 104(6): 2395-2402, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30722009

RESUMO

CONTEXT: Neurocytoma (NC) is a rare, low-grade tumor of the central nervous system, with a 10-year survival rate of 90% and local control rate of 74%. However, 25% of NCs will be atypical, with an elevated Ki-67 labeling index >2%, and will exhibit a more aggressive course, with a high propensity for local recurrence and/or craniospinal dissemination. Although no standard treatment regimen exists for these atypical cases, adjuvant stereotactic or conventional radiotherapy and/or chemotherapy have been typically offered but have yielded inconsistent results. CASE DESCRIPTION: We have described the case of a patient with a vasopressin-secreting atypical NC of the sellar and cavernous sinus region. After subtotal resection via endoscopic transsphenoidal surgery, the residual tumor showed increased fluorodeoxyglucose uptake and high somatostatin receptor (SSTR) expression on a 68Ga-DOTA-TATE positron emission tomography/CT scan. Somatostatin receptor ligand (SRL) therapy with lanreotide (120 mg every 28 days) was initiated. Four years later, the residual tumor was stable with decreased fluorodeoxyglucose tumor uptake. Immunocytochemical SSTR2 and SSTR5 expression >80% was further confirmed in a series of NC tissues. CONCLUSIONS: To the best of our knowledge, we have described the first use of SRL therapy for an atypical NC. Our results support consideration of adjuvant SRL therapy for NC refractory to surgical removal. Our findings further raise the possibility of SSTR-directed peptide receptor radionuclide therapy as NC therapy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neurocitoma/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Adolescente , Neoplasias Encefálicas/química , Neoplasias Encefálicas/diagnóstico por imagem , Seio Cavernoso/patologia , Fluordesoxiglucose F18 , Humanos , Masculino , Neurocitoma/química , Neurocitoma/diagnóstico por imagem , Receptores de Somatostatina/análise , Sela Túrcica/patologia , Somatostatina/uso terapêutico , Vasopressinas/metabolismo
9.
J Neurosurg ; 132(1): 168-179, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30641835

RESUMO

OBJECTIVE: Despite intensive medical treatment, patients with glioblastoma (grade IV glioma [GBM]) have a low 5-year survival rate of 5.5%. In this study, the authors tried to improve currently used therapies by identification of a therapeutic target, IGFBP3, for glioma treatment. METHODS: IGFBP3 RNA expression in 135 patients newly diagnosed with glioma was correlated with clinicopathological factors. Immunohistochemical analysis was performed to determine IGFBP3 protein expression in glioma specimens. The effect of IGFBP3 depletion on cell proliferation was examined using IGFBP3 knockdown glioma cells. Intracranial infusion of IGFBP3 siRNAs was performed to evaluate the effect of IGFBP3 depletion in mouse intracranial xenograft models. RESULTS: We demonstrated higher IGFBP3 expression in GBM than in tumor margin and grade II glioma. IGFBP3 expression was not only positively correlated with tumor grades but also associated with tumor histology and IDH1/2 mutation status. Additionally, higher IGFBP3 expression predicted shorter overall survival in glioma and GBM proneural subgroup patients. In vitro cell culture studies suggested IGFBP3 knockdown suppressed cell proliferation and induced cell cycle G2/M arrest as well as apoptosis in glioma cells. Also, accumulation of DNA double-strand breaks and γH2AX was observed in IGFBP3 knockdown cells. IGFBP3 knockdown delayed in vivo tumor growth in mouse subcutaneous xenograft models. Furthermore, convection-enhanced delivery of IGFBP3 siRNA to mouse brain suppressed intracranial tumor growth and prolonged survival of tumor-bearing mice. CONCLUSIONS: Our findings suggest IGFBP3 predicts poor outcome of glioma patients and is a potential therapeutic target for which depletion of its expression suppresses tumor growth through inducing apoptosis and accumulation of DNA damage in glioma cells.


Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/antagonistas & inibidores , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/uso terapêutico , Animais , Apoptose , Neoplasias Encefálicas/química , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Quebras de DNA de Cadeia Dupla , Feminino , Glioblastoma/química , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Glioma/química , Glioma/genética , Glioma/patologia , Histonas/análise , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/biossíntese , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Isocitrato Desidrogenase/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Invest New Drugs ; 37(4): 595-601, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30101388

RESUMO

The response of tumor intracellular pH to a pharmacological challenge could help identify aggressive cancer. Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that is dependent on intracellular pH (pHi). pHi is important in the maintenance of normal cell function and is normally maintained within a narrow range by the activity of transporters located at the plasma membrane. In cancer, changes in pHi have been correlated with both cell proliferation and cell death. Quercetin is a bioflavonoid and monocarboxylate transporter (MCT) inhibitor. Since MCTs plays a significant role in maintaining pH balance in the tumor microenvironment, we hypothesized that systemically administered quercetin could selectively acidify brain tumors. The goals of the current study were to determine whether CEST MRI measurements sensitive to tumor pH could detect acidification after quercetin injection and to measure the magnitude of the pH change (ΔpH). Using a 9.4 T MRI, amine and amide concentration independent detection (AACID) CEST spectra were acquired in six mice approximately 15 ± 1 days after implanting 105 U87 human glioblastoma multiforme cells in the brain, before and after administration of quercetin (dose: 200 mg/kg) by intraperitoneal injection. Three additional mice were studied as controls and received only vehicle dimethyl sulfoxide (DMSO) injection. Repeated measures t-test was used to compare AACID changes in tumor and contralateral tissue regions of interest. Two hours after quercetin injection there was a significant increase in tumor AACID by 0.07 ± 0.03 corresponding to a 0.27 decrease in pHi, and no change in AACID in contralateral tissue. There was also a small average increase in AACID in tumors within the three mice injected with DMSO only. The use of the natural compound quercetin in combination with pH weighted MRI represents a unique approach to cancer detection that does not require injection of an imaging contrast agent.


Assuntos
Neoplasias Encefálicas/química , Glioblastoma/química , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Quercetina/farmacologia , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Glioblastoma/diagnóstico por imagem , Humanos , Concentração de Íons de Hidrogênio , Imagem por Ressonância Magnética , Camundongos
11.
Neurocirugia (Astur) ; 30(1): 11-18, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30143443

RESUMO

BACKGROUND AND PURPOSE: Our objectives were: (1) compare dynamic susceptibility-weighted (DSC) and dynamic contrast-enhanced (DCE) permeability parameters, (2) evaluate diagnostic accuracy of DSC and DCE discriminating high- and low-grade tumors, (3) analyze relationship of permeability parameters with overall (OS) and progression-free survival (PFS) and (4) assess differences in high-grade tumors classified according to molecular biomarkers. MATERIALS AND METHODS: 49 patients with histologically proved diffuse gliomas underwent DSC and DCE imaging. Parametric maps of cerebral blood volume (CBV), CBV-leakage corrected, volume transfer coefficient (Ktrans), fractional volume of the extravascular extracellular space (EES) (Ve), fractional blood plasma volume (Vp) and rate constant between EES and blood plasma (Kep) were calculated. High-grade gliomas were also classified according to isocitrate dehydrogenase (IDH), alpha-thalassemia/mental retardation syndrome X-linked (ATRX) and O6-methylguanine-dna-methyltransferase promoter methylation (MGMT) status. RESULTS: There is correlation between parameters leakage, Ktrans and Vp. ROC curve analysis showed significance in both Ktrans and Ve for glioma grading. Threshold value of 0.075 for Ve generated the best combination of sensitivity (80%) and specificity (75%) in tumor gradation. Leakage was the only permeability parameter related to OS (P=0.006) and PFS (0.012); with prolonged survival for leakage values lower than 1.2. IDH-mutated high-grade tumors showed lower leakage and Ktrans values. High-grade tumors with loss of ATRX presented lower leakage and Vp values. CONCLUSIONS: Both DSC and DCE permeability parameters serve as non-invasive method for glioma grading. Leakage was the unique permeability parameter related to survival and the best discriminating high-grade gliomas classified according to IDH and ATRX status.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Permeabilidade Capilar , Glioma/diagnóstico por imagem , Angiografia por Ressonância Magnética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/análise , Enzimas Reparadoras do DNA/análise , Feminino , Glioma/química , Glioma/mortalidade , Glioma/patologia , Humanos , Isocitrato Desidrogenase/análise , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Retrospectivos , Taxa de Sobrevida , Proteínas Supressoras de Tumor/análise , Proteína Nuclear Ligada ao X/análise , Adulto Jovem
12.
Lab Invest ; 99(4): 588-598, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30573870

RESUMO

The metabolic genes encoding isocitrate dehydrogenase (IDH1, 2) are frequently mutated in gliomas. Mutation of IDH defines a distinct subtype of glioma and predicts therapeutic response. IDH mutation has a remarkable neomorphic activity of converting α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which is now commonly referred to as an oncometabolite and biomarker for gliomas. PCR-sequencing (n = 220), immunohistochemistry staining (IHC, n = 220), and gas chromatography mass spectrometry (GC-MS, n = 87) were applied to identify IDH mutation in gliomas, and the sensitivity and specificity of these strategies were compared. PCR-sequencing and IHC staining are reliable for retrospective assessment of IDH1 mutation in gliomas, but both methods usually take 1-2 days, which hinders their application for rapid diagnosis. GC-MS-based methods can detect 2-HG qualitatively and quantitatively, offering information on the IDH1 mutation status in gliomas with the sensitivity and specificity being 100%. Further optimization of the GC-MS based methodology (so called as the mini-column method) enabled us to determine 2-HG within 40 min in glioma samples without complex or time-consuming preparation. Most importantly, the ratio of 2-HG/glutamic acid was shown to be a reliable parameter for determination of mutation status. The mini-column method enables rapid identification of 2-HG, providing a promising strategy for intraoperative diagnosis of IDH1-mutated gliomas in the future.


Assuntos
Neoplasias Encefálicas , Cromatografia Gasosa-Espectrometria de Massas/métodos , Glioma , Glutaratos/análise , Isocitrato Desidrogenase/genética , Adulto , Neoplasias Encefálicas/química , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Glioma/química , Glioma/diagnóstico , Glioma/genética , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação/genética
13.
Eur J Cancer ; 102: 1-9, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30099223

RESUMO

BACKGROUND: Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited. METHODS: We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions. RESULTS: Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p < 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p < 0.0001). CONCLUSIONS: Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Feminino , Alemanha , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/química , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia , Adulto Jovem
14.
Hum Pathol ; 82: 149-157, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30067950

RESUMO

Epithelial-to-mesenchymal transition (EMT) plays an important role in invasion and metastasis of various cancers including gliomas. EMT has also been linked to cancer stem cells and resistance to chemotherapy. An initial in-silico data mining in a published ependymoma (EPN) patient series (GSE21687) revealed up-regulation of EMT transcription factors in tumor samples. Furthermore, quantitative real-time polymerase chain reaction-based gene expression analysis of EMT transcription factors in 96 EPNs showed significant up-regulation of SNAI1, SNAI2, ZEB1, and TWIST1 as compared with normal brain, associated with up-regulation of CDH2/N-cadherin and down-regulation of CDH1/E-cadherin. Although this was observed in varying degrees in all clinicopathological-molecular subgroups of EPNs, it was most evident in supratentorial EPNs harboring fusions of RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A) gene and in posterior fossa EPNs. Immunohistochemistry performed in 60 of the above cases corroborated with gene expression patterns, and immunopositivity for Snail, Slug, Zeb1, and Twist1 was observed in 80%, 80%, 81%, and 63% of all EPNs. Immunopositivity for N-cadherin and E-cadherin was observed in 76.6% and 2% of the cases, respectively. Univariate Cox regression analysis showed that low expression of CDH1/E-cadherin (P = .002) and high expression levels of CDH2/N-cadherin (P < .001), SNAI1/Snail (P = .023), SNAI2/Slug (P < .001), and ZEB1 (P < .001) were associated with shorter progression-free survival. Here, we report for the first time the existence of EMT-like phenotype in EPNs. These factors could represent new prognostic and therapeutic targets in EPN.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Ependimoma/genética , Transição Epitelial-Mesenquimal/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Estudos de Casos e Controles , Criança , Pré-Escolar , Mineração de Dados , Bases de Dados Genéticas , Ependimoma/química , Ependimoma/patologia , Ependimoma/terapia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Fatores de Tempo , Fatores de Transcrição/análise , Regulação para Cima , Adulto Jovem
15.
Sci Rep ; 8(1): 12543, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135440

RESUMO

Protoporphyrin IX (PpIX) induced by 5-aminolevulinic acid (5-ALA) is increasingly used as a fluorescent marker for fluorescence-guided resection of malignant gliomas. Understanding how the properties of the excitation light source and PpIX fluorescence interact with the surgical microscope is critical for effective use of the fluorescence-guided tumor resection technique. In this study, we performed a detailed assessment of the intensity of the emitted blue light and white light and the light beam profile of clinical grade operating microscopes used for PpIX visualization. These measurements revealed both recognized fluorescence photobleaching limitations and unrecognized limitations that may alter quantitative observations of PpIX fluorescence obtained with the operating microscope with potential impact on research and clinical uses. We also evaluated the optical properties of a photostable fluorescent standard with an excitation-emission profile similar to PpIX. In addition, we measured the time-dependent dynamics of 5-ALA-induced PpIX fluorescence in an animal glioma model. Finally, we developed a ratiometric method for quantification of the PpIX fluorescence that uses the photostable fluorescent standard to normalize PpIX fluorescence intensity. This method increases accuracy and allows reproducible and direct comparability of the measurements from multiple samples.


Assuntos
Microscopia de Fluorescência/instrumentação , Procedimentos Neurocirúrgicos/instrumentação , Fotodegradação , Protoporfirinas/análise , Ácido Aminolevulínico/química , Animais , Neoplasias Encefálicas/química , Neoplasias Encefálicas/cirurgia , Desenho de Equipamento , Feminino , Fluorescência , Corantes Fluorescentes , Glioma/química , Glioma/cirurgia , Camundongos Mutantes , Neoplasias Experimentais/cirurgia , Neuronavegação , Protoporfirinas/química
16.
Medicine (Baltimore) ; 97(22): e10859, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29851800

RESUMO

RATIONALE: Despite the approval of antiangiogenic therapy for high grade glioma (HGG) patients, survival benefits are still limited. New treatment plans have always been developed to improve the survival. PATIENT CONCERNS: A 26-year-old woman was admitted to our hospital for distending pain of head and eye. DIAGNOSES: Resonance imaging (MRI) revealed a large spherical heterogeneously enhancing, mixed cystic and solid mass in the right frontal region, and the midline shifted. INTERVENTION: The patient received apatinib therapy for positive vascular endothelial growth factor. OUTCOMES: A partial response was observed after 4 weeks and remains sustained until now. LESSONS: It suggests that apatinib might be a feasible option for the treatment in advanced HGG patients or patients with poor physical condition.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Neoplasias Encefálicas/química , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Lobo Frontal/diagnóstico por imagem , Glioma/química , Glioma/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Gradação de Tumores , Recidiva Local de Neoplasia/química , Recidiva Local de Neoplasia/diagnóstico por imagem , Fator A de Crescimento do Endotélio Vascular/análise
17.
Radiology ; 289(1): 204-209, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29944079

RESUMO

Purpose To determine whether multiple doses of gadobutrol increase the T1 signal intensity in the brains of children. Materials and Methods This retrospective imaging study evaluated 91 children (median age, 5.4 years; age range, 0-17 years) with brain tumors who underwent five or more MR brain examinations at a single institution. A subgroup of 46 patients received five or more administrations of gadobutrol (0.1 mmol/kg) and underwent follow-up MRI. T1 signal intensity in the globus pallidus and dentate nucleus was measured at the first to sixth unenhanced MR brain examination in these children. Globus pallidus-to-corpus callosum and dentate nucleus-to-corpus callosum signal intensity ratios were analyzed by linear mixed-effect analysis. Subgroup analysis was performed for six children who underwent 14 or more administrations of gadobutrol. Results The globus pallidus-to-corpus callosum ratio increased with patient age (absolute change, 0.0052 per year; 95% confidence interval: 0.0033, 0.0071; P < .0001). There was no change in the dentate nucleus-to-corpus callosum ratio with age (P = .30). Among 46 children who received five or more doses of gadobutrol (median dose, 11 mL; range, 3.9-31 mL), there was no change in signal intensity ratio of the globus pallidus (P = .17) or dentate nucleus (P = .44). Among six children who underwent more than 14 administrations of gadobutrol (median dose, 64 mL; range, 40-91 mL) there was no change in signal intensity ratio of the globus pallidus (P = .15) or dentate nucleus (P = .50). Conclusion No increase in T1-weighted signal intensity ratio was observed in the globus pallidus or dentate nucleus after the administration of at least five doses of gadobutrol. © RSNA, 2018 Online supplemental material is available for this article.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Imagem por Ressonância Magnética/métodos , Compostos Organometálicos/administração & dosagem , Adolescente , Neoplasias Encefálicas/química , Núcleos Cerebelares/química , Núcleos Cerebelares/diagnóstico por imagem , Criança , Pré-Escolar , Meios de Contraste/efeitos adversos , Meios de Contraste/farmacocinética , Globo Pálido/química , Globo Pálido/diagnóstico por imagem , Humanos , Interpretação de Imagem Assistida por Computador , Lactente , Recém-Nascido , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/farmacocinética , Estudos Retrospectivos
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 43(4): 403-409, 2018 Apr 28.
Artigo em Chinês | MEDLINE | ID: mdl-29774877

RESUMO

OBJECTIVE: To analyze the prognostic factors for survival in elderly patients with glioma.
 Methods: We performed a retrospective analysis of prognostic factors for elderly patients with glioma, who were treated by the same attending doctor during June 2014 and June 2016, to investigate the correlations of the age, dimension of pathology, histological grade, extent of resection, adjuvant therapy, preoperative Karnofsky Performance Scale (KPS) score, postoperative KPS score, molecular markers [isocitrate dehydrogenase-1 (IDH-1), O6-methylguanine DNA-transferase (MGMT), epidermal growth factor receptor (EGFR), Ki-67] with the prognosis.
 Results: A total of 45 patients were included in the study. The median overall survival (OS) was 11 months. The median progression-free survival (PFS) was 6 months. Univariate analysis revealed that the age, gender, dimension of pathology, histological grade and preoperative KPS score had no significant correlation with survival (P>0.05). The gross total resection, higher postoperative KPS score, adjuvant therapy, lower Ki-67 index were significantly correlated with survival. The expressions of MGMT and EGFR were significant factors for survival. High postoperative KPS score (P=0.019), adjuvant therapy (P=0.024), and the expression of MGMT (P=0.026) were independent predictors for increased median OS in a multivariate regression model.
 Conclusion: The extent of resection, adjuvant therapy, postoperative KPS score and molecular markers are the influential factors for survival. Larger prospective studies are needed to confirm these findings.


Assuntos
Neoplasias Encefálicas/mortalidade , Glioma/mortalidade , Idoso , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Neoplasias Encefálicas/terapia , Metilases de Modificação do DNA/análise , Enzimas Reparadoras do DNA/análise , Intervalo Livre de Doença , Receptores ErbB/análise , Glioma/química , Glioma/terapia , Humanos , Isocitrato Desidrogenase/análise , Avaliação de Estado de Karnofsky , Antígeno Ki-67/análise , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Proteínas Supressoras de Tumor/análise
19.
J Clin Lab Anal ; 32(7): e22454, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29687495

RESUMO

BACKGROUND: Recent studies have found circular RNAs (circRNAs) involved in the biological process of cancers. However, little is known about their functional roles in glioblastoma. METHODS: Human circRNA microarray analysis was performed to screen the expression profile of circRNAs in IDH1 wild-type glioblastoma tissue. The expression of hsa_circ_0008344 in glioblastoma and normal brain samples was quantified by qRT-PCR. Functional experiments were performed to investigate the biological functions of hsa_circ_0008344, including MTT assay, colony formation assay, transwell assay, and cell apoptosis assay. RESULTS: CircRNA microarray revealed a total of 417 abnormally expressed circRNAs (>1.5-fold, P < .05) in glioblastoma tissue compared with the adjacent normal brain. Hsa_circ_0008344, among the top differentially expressed circRNAs, was significantly upregulated in IDH1 wild-type glioblastoma. Further in vitro studies showed that knockdown of hsa_circ_0008344 suppressed glioblastoma cell proliferation, colony formation, migration, and invasion, but increased cell apoptotic rate. CONCLUSIONS: Hsa_circ_0008344 is upregulated in glioblastoma and may contribute to the progression of this malignancy.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Glioblastoma/genética , Invasividade Neoplásica/genética , RNA , Neoplasias Encefálicas/química , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioblastoma/metabolismo , Humanos , RNA/genética , RNA/metabolismo , RNA Circular
20.
J Thromb Haemost ; 16(6): 1121-1127, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29676036

RESUMO

Essentials Risk stratification for venous thromboembolism (VTE) in patients with brain tumors is challenging. Patients with IDH1 wildtype and high podoplanin expression have a 6-month VTE risk of 18.2%. Patients with IDH1 mutation and no podoplanin expression have a 6-month VTE risk of 0%. IDH1 mutation and podoplanin overexpression in primary brain tumors appear to be exclusive. SUMMARY: Background Venous thromboembolism (VTE) is a frequent complication in primary brain tumor patients. Independent studies revealed that podoplanin expression in brain tumors is associated with increased VTE risk, whereas the isocitrate dehydrogenase 1 (IDH1) mutation is associated with very low VTE risk. Objectives To investigate the interrelation between intratumoral podoplanin expression and IDH1 mutation, and their mutual impact on VTE development. Patients/Methods In a prospective cohort study, intratumoral IDH1 R132H mutation and podoplanin were determined in brain tumor specimens (mainly glioma) by immunohistochemistry. The primary endpoint of the study was symptomatic VTE during a 2-year follow-up. Results All brain tumors that expressed podoplanin to a medium-high extent showed also an IDH1 wild-type status. A score based on IDH1 status and podoplanin expression levels allowed prediction of the risk of VTE. Patients with wild-type IDH1 brain tumors and high podoplanin expression had a significantly increased VTE risk compared with those with mutant IDH1 tumors and no podoplanin expression (6-month risk 18.2% vs. 0%). Conclusions IDH1 mutation and podoplanin overexpression seem to be exclusive. Although brain tumor patients with IDH1 mutation are at very low risk of VTE, the risk of VTE in patients with IDH1 wild-type tumors is strongly linked to podoplanin expression levels.


Assuntos
Biomarcadores Tumorais , Neoplasias Encefálicas/química , Neoplasias Encefálicas/genética , Isocitrato Desidrogenase/genética , Glicoproteínas de Membrana/análise , Tromboembolia Venosa/etiologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Regulação para Cima , Tromboembolia Venosa/diagnóstico
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