RESUMO
BACKGROUND AND PURPOSE: Increased cellular density is a hallmark of gliomas, both in the bulk of the tumor and in areas of tumor infiltration into surrounding brain. Altered cellular density causes altered imaging findings, but the degree to which cellular density can be quantitatively estimated from imaging is unknown. The purpose of this study was to discover the best MR imaging and processing techniques to make quantitative and spatially specific estimates of cellular density. MATERIALS AND METHODS: We collected stereotactic biopsies in a prospective imaging clinical trial targeting untreated patients with gliomas at our institution undergoing their first resection. The data included preoperative MR imaging with conventional anatomic, diffusion, perfusion, and permeability sequences and quantitative histopathology on biopsy samples. We then used multiple machine learning methodologies to estimate cellular density using local intensity information from the MR images and quantitative cellular density measurements at the biopsy coordinates as the criterion standard. RESULTS: The random forest methodology estimated cellular density with R 2 = 0.59 between predicted and observed values using 4 input imaging sequences chosen from our full set of imaging data (T2, fractional anisotropy, CBF, and area under the curve from permeability imaging). Limiting input to conventional MR images (T1 pre- and postcontrast, T2, and FLAIR) yielded slightly degraded performance (R2 = 0.52). Outputs were also reported as graphic maps. CONCLUSIONS: Cellular density can be estimated with moderate-to-strong correlations using MR imaging inputs. The random forest machine learning model provided the best estimates. These spatially specific estimates of cellular density will likely be useful in guiding both diagnosis and treatment.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Adulto , Idoso , Neoplasias Encefálicas/patologia , Feminino , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND PURPOSE: Gliomas are highly heterogeneous tumors, and optimal treatment depends on identifying and locating the highest grade disease present. Imaging techniques for doing so are generally not validated against the histopathologic criterion standard. The purpose of this work was to estimate the local glioma grade using a machine learning model trained on preoperative image data and spatially specific tumor samples. The value of imaging in patients with brain tumor can be enhanced if pathologic data can be estimated from imaging input using predictive models. MATERIALS AND METHODS: Patients with gliomas were enrolled in a prospective clinical imaging trial between 2013 and 2016. MR imaging was performed with anatomic, diffusion, permeability, and perfusion sequences, followed by image-guided stereotactic biopsy before resection. An imaging description was developed for each biopsy, and multiclass machine learning models were built to predict the World Health Organization grade. Models were assessed on classification accuracy, Cohen κ, precision, and recall. RESULTS: Twenty-three patients (with 7/9/7 grade II/III/IV gliomas) had analyzable imaging-pathologic pairs, yielding 52 biopsy sites. The random forest method was the best algorithm tested. Tumor grade was predicted at 96% accuracy (κ = 0.93) using 4 inputs (T2, ADC, CBV, and transfer constant from dynamic contrast-enhanced imaging). By means of the conventional imaging only, the overall accuracy decreased (89% overall, κ = 0.79) and 43% of high-grade samples were misclassified as lower-grade disease. CONCLUSIONS: We found that local pathologic grade can be predicted with a high accuracy using clinical imaging data. Advanced imaging data improved this accuracy, adding value to conventional imaging. Confirmatory imaging trials are justified.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Aprendizado de Máquina , Gradação de Tumores/métodos , Neuroimagem/métodos , Adulto , Idoso , Neoplasias Encefálicas/patologia , Feminino , Glioma/patologia , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Biópsia Guiada por Imagem , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the tumor-promoting mechanisms of IGFBP2 are poorly understood. The contributions of intracellular IGFBP2 to tumor development and progression are also unclear. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of epidermal growth factor receptor (EGFR), which subsequently activates signal transducer and activator of transcription factor 3 (STAT3) signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via activation of the nuclear EGFR signaling pathway. Nuclear IGFBP2 directly influences the invasive and migratory capacities of human glioblastoma cells, providing a direct link between intracellular (and particularly nuclear) IGFBP2 and cancer hallmarks. These activities are also consistent with the strong association between IGFBP2 and STAT3-activated genes derived from The Cancer Genome Atlas database for human glioma. A high level of all three proteins (IGFBP2, EGFR and STAT3) was strongly correlated with poorer survival in an independent patient data set. These results identify a novel tumor-promoting function for IGFBP2 of activating EGFR/STAT3 signaling and facilitating EGFR accumulation in the nucleus, thereby deregulating EGFR signaling by two distinct mechanisms. As targeting EGFR in glioma has been relatively unsuccessful, this study suggests that IGFBP2 may be a novel therapeutic target.
Assuntos
Núcleo Celular/metabolismo , Receptores ErbB/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/fisiologia , Fator de Transcrição STAT3/metabolismo , Transporte Ativo do Núcleo Celular/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Núcleo Celular/genética , Transformação Celular Neoplásica/genética , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/mortalidade , Glioma/patologia , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Transporte Proteico/genética , Transdução de Sinais/genética , Ativação Transcricional/genéticaRESUMO
BACKGROUND AND PURPOSE: Dynamic contrast-enhanced perfusion MR imaging has proved useful in determining whether a contrast-enhancing lesion is secondary to recurrent glial tumor or is treatment-related. In this article, we explore the best method for dynamic contrast-enhanced data analysis. MATERIALS AND METHODS: We retrospectively reviewed 24 patients who met the following conditions: 1) had at least an initial treatment of a glioma, 2) underwent a half-dose contrast agent (0.05-mmol/kg) diagnostic-quality dynamic contrast-enhanced perfusion study for an enhancing lesion, and 3) had a diagnosis by pathology within 30 days of imaging. The dynamic contrast-enhanced data were processed by using model-dependent analysis (nordicICE) using a 2-compartment model and model-independent signal intensity with time. Multiple methods of determining the vascular input function and numerous perfusion parameters were tested in comparison with a pathologic diagnosis. RESULTS: The best accuracy (88%) with good correlation compared with pathology (P = .005) was obtained by using a novel, model-independent signal-intensity measurement derived from a brief integration beginning after the initial washout and by using the vascular input function from the superior sagittal sinus for normalization. Modeled parameters, such as mean endothelial transfer constant > 0.05 minutes(-1), correlated (P = .002) but did not reach a diagnostic accuracy equivalent to the model-independent parameter. CONCLUSIONS: A novel model-independent dynamic contrast-enhanced analysis method showed diagnostic equivalency to more complex model-dependent methods. Having a brief integration after the first pass of contrast may diminish the effects of partial volume macroscopic vessels and slow progressive enhancement characteristic of necrosis. The simple modeling is technique- and observer-dependent but is less time-consuming.
Assuntos
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Encéfalo/patologia , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Perfusão , Estudos RetrospectivosRESUMO
BACKGROUND: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue. METHODS: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC). RESULTS: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003). CONCLUSIONS: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.
Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Pirróis/uso terapêutico , Doença de von Hippel-Lindau/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Feminino , Hemangioblastoma/tratamento farmacológico , Hemangioblastoma/metabolismo , Humanos , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Projetos Piloto , Pirróis/efeitos adversos , Radiografia , Sunitinibe , Resultado do Tratamento , Adulto JovemRESUMO
The migration and invasion inhibitor protein (MIIP, also known as IIp45) was discovered as a negative regulator of cell migration and invasion in glioma. Our previous studies have shown that the MIIP protein was reduced or undetectable in some tissue samples obtained from patients with glioblastoma. The significance of MIIP in gliomagenesis is unknown. In this study, we report that MIIP has an important role in the inhibition of gliomagenesis and attenuation of mitotic transition. Increased MIIP expression levels inhibited colony formation and cell growth of glioma cell lines in vitro, whereas decreased expression by specific small interfering RNA for MIIP resulted in increased cell growth. Expression of MIIP in a glial-specific mouse model blocked glioma development and progression, thus showing that MIIP is an inhibitor of gliomagenesis. Furthermore, we show that MIIP attenuates mitotic transition and results in increased mitotic catastrophe. The biochemical mechanism of MIIP in this process is associated with its regulation of anaphase-promoting complex (APC/C) activity. MIIP interacts directly with Cdc20, and the interaction of MIIP with Cdc20 inhibits APC/C-mediated degradation of cyclin B1. Thus, MIIP attenuates mitotic transition and increases mitotic catastrophe, thereby inhibiting glioma development and progression.
Assuntos
Proteínas de Transporte/metabolismo , Glioma/metabolismo , Glioma/patologia , Mitose , Animais , Proteínas de Transporte/genética , Proteínas Cdc20 , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Ciclina B1/química , Ciclina B1/metabolismo , Progressão da Doença , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Transgênicos , Neuroglia/patologia , Especificidade de Órgãos , Estabilidade Proteica , Ubiquitina-Proteína Ligases/metabolismoRESUMO
OBJECTIVE: Epithelioid glioblastoma is a rare morphologic subtype of glioblastoma that closely mimics metastatic carcinoma or metastatic melanoma histologically. All previous case reports of this unusual glioblastoma variant have been solitary lesions. We report here the first case to our knowledge of multifocal epithelioid glioblastoma mimicking cerebral metastasis. CLINICAL PRESENTATION: A 67-year-old man with a prior history of mycosis fungoides, a common form of cutaneous T-cell lymphoma, presented with memory loss and impaired peripheral vision. Two discrete brain lesions highly suspicious for metastases were identified by magnetic resonance imaging (MRI). INTERVENTION: The patient underwent two separate craniotomies; both lesions were successfully resected in toto with an excellent post-surgical outcome. CONCLUSION: Epithelioid glioblastoma is one of the rarest morphologic subtypes of glioblastoma. Here we describe the first case to our knowledge of multifocal epithelioid glioblastoma that convincingly mimicked a secondary metastatic process. Multifocal epithelioid glioblastoma should be included in the differential diagnosis of patients who present with multiple discrete brain lesions. An attempt at gross total resection is recommended when anatomically feasible for definitive histopathological diagnosis and to improve progression free survival of patients who present with similarly ambiguous and potentially misleading multiple lesions.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Idoso , Neoplasias Encefálicas/cirurgia , Diagnóstico Diferencial , Glioblastoma/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Metástase NeoplásicaRESUMO
Objective. Epithelioid glioblastoma is a rare morphologicsubtype of glioblastoma that closely mimicsmetastatic carcinoma or metastatic melanoma histologically.All previous case reports of this unusualglioblastoma variant have been solitary lesions.We report here the first case to our knowledge ofmultifocal epithelioid glioblastoma mimicking cerebralmetastasis.Clinical presentation. A 67-year-old man with aprior history of mycosis fungoides, a common form ofcutaneous T-cell lymphoma, presented with memoryloss and impaired peripheral vision. Two discretebrain lesions highly suspicious for metastases wereidentified by magnetic resonance imaging (MRI).Intervention. The patient underwent two separatecraniotomies; both lesions were successfully resectedin toto with an excellent post-surgical outcome.Conclusion. Epithelioid glioblastoma is one of therarest morphologic subtypes of glioblastoma. Here wedescribe the first case to our knowledge of multifocalepithelioid glioblastoma that convincingly mimicked asecondary metastatic process. Multifocal epithelioidglioblastoma should be included in the differentialdiagnosis of patients who present with multiple discretebrain lesions. An attempt at gross total resectionis recommended when anatomically feasible fordefinitive histopathological diagnosis and to improveprogression free survival of patients who present withsimilarly ambiguous and potentially misleading multiplelesions (AU)
Objetivo. El glioblastoma epiteloide es un subtipomorfológico poco común del glioblastoma que puedeimitar al carcinoma o melanoma metastásico histológicamente.Todos los casos reportados de esta varianteinusual de glioblastoma han sido lesiones solitarias.Presentamos el primer caso de glioblastoma multifocalepiteloide imitando metástasis cerebral.Presentación clínica. Varón de 67 años con historiaprevia de micosis fungoide, una forma común de linfomacutáneo de células T, cuyos síntomas fueron pérdida dememoria y alteraciones del campo visual periférico. Doslesiones sospechosas de metástasis fueron identificadaspor resonancia magnética.Intervención. Mediante dos craneotomías independientes,ambas lesiones se resecaron in toto con buenresultado post-quirúrgico.Conclusión. El glioblastoma epiteloide es uno de lossubtipos morfológicos mas raros de glioblastoma. Losautores describen aquí el primer caso de glioblastomaepiteloide multifocal con apariencia de metástasissecundaria. Este diagnóstico debe ser incluido en eldiferencial de pacientes con lesiones multifocales. Elintento de resección total se recomienda cuando éste seaviable para obtener un diagnóstico definitivo así comopara mejorar la supervivencia libre de enfermedad enpacientes cuya presentación incluya lesiones múltiplesque puedan dirigir a un tratamiento inadecuado (AU)
Assuntos
Humanos , Masculino , Idoso , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Neoplasias Encefálicas/cirurgia , Diagnóstico Diferencial , Glioblastoma/cirurgia , Imageamento por Ressonância Magnética , Metástase NeoplásicaRESUMO
BACKGROUND: Patients can sustain injuries during seizures and the pattern and type of injury (eg, tongue biting) can be a useful silent witness in the diagnosis of seizures. In addition, the seizure type potentially influences the type of injury. METHODS: Patients with dental injury were identified from the Gloucestershire Epilepsy Database (n = 1673). These patients' notes were reviewed and the following data collected: demographic data; seizure types and age of onset; injury; EEG; and MRI. RESULTS: 14 people had dental injuries: 10 incisors (seven had >1 incisor) and five other teeth. Eight had juvenile myoclonic epilepsy (JME), two other primary generalised epilepsy and four focal onset epilepsy. Compared with the rest of the database population (JME; n = 81) there was a highly significant association of dental injury with JME (p<0.0001). CONCLUSIONS: Incisor injury is rare but appears to be associated with JME in patients with epilepsy, presumably reflecting the pattern of seizure onset. This pattern of injury should prompt consideration of this diagnosis. It is hoped that recognition of this can both facilitate earlier diagnosis and help educate patients to protect their teeth.
Assuntos
Incisivo/lesões , Epilepsia Mioclônica Juvenil/complicações , Epilepsia Mioclônica Juvenil/epidemiologia , Traumatismos Dentários/epidemiologia , Traumatismos Dentários/etiologia , Adolescente , Adulto , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
We report the imaging features of 4 cases of patients with papillary tumor of the pineal region, a tumor newly recognized in the 2007 World Health Organization "Classification of Tumors of the Nervous System." In each case, the tumor was intrinsically hyperintense on T1-weighted images with a characteristic location in the posterior commissure or pineal region. The pathologic hallmarks of the tumor are discussed, including a possible explanation for the MR imaging characteristics in our cases.
Assuntos
Neoplasias Encefálicas/patologia , Carcinoma Papilar/patologia , Imageamento por Ressonância Magnética/métodos , Glândula Pineal/patologia , Adulto , Feminino , Humanos , Pessoa de Meia-IdadeAssuntos
Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Doenças do Sistema Nervoso/etiologia , Adulto , Encéfalo/patologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Eletrocardiografia/métodos , Eletroencefalografia/métodos , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Imageamento por Ressonância Magnética/métodos , Masculino , Miocárdio/patologia , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/terapia , Tomografia Computadorizada por Raios XRESUMO
Tumor suppressor in lung cancer-1 (TSLC1) loss is common in many human cancers, including meningioma. In this study, we demonstrate that TSLC1 protein and RNA expression is lost in 60% to 65% of high-grade gliomas, and that TSLC1 reintroduction into glioma cells results in growth suppression. Moreover, Tslc1 loss in mice results in increased astrocyte proliferation in vivo and in vitro. These data indicate that TSLC1 functions as a glioma tumor suppressor.
Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioma/genética , Imunoglobulinas/genética , Proteínas de Membrana/genética , Proteínas Supressoras de Tumor/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/fisiopatologia , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Regulação para Baixo/genética , Glioma/metabolismo , Glioma/fisiopatologia , Humanos , Imunoglobulinas/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/metabolismoRESUMO
The serum of a patient with subacute cerebellar dysfunction was used to probe a cDNA expression library and isolate two genes: Zic1 (zinc-finger of the cerebellum) and Zic4. The patient had intrathecal synthesis of Zic antibodies, suggesting that the Zic proteins were autoantigens of the neurologic disorder. The Zic proteins are involved in cerebellar development and are reported as being preferentially expressed by medulloblastomas. It was found that the expression of Zic proteins is enriched in, but not limited to, medulloblastomas and primitive neuroectodermal tumors.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doenças Cerebelares/patologia , Cerebelo/patologia , Degeneração Neural/patologia , Dedos de Zinco/imunologia , Idoso , Autoanticorpos/análise , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/imunologia , Western Blotting , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , DNA Complementar/genética , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Meduloblastoma/imunologia , Meduloblastoma/patologia , Tumores Neuroectodérmicos/imunologia , Tumores Neuroectodérmicos/patologiaRESUMO
We present evidence that some low-grade oligodendrogliomas may be comprised of proliferating glial progenitor cells that are blocked in their ability to differentiate, whereas malignant gliomas have additionally acquired other mutations such as disruption of cell cycle arrest pathways by loss of Ink4a-Arf. We have modeled these effects in cell culture and in mice by generating autocrine stimulation of glia through the platelet-derived growth factor receptor (PDGFR). In cell culture, PDGF signaling induces proliferation of glial precursors and blocks their differentiation into oligodendrocytes and astrocytes. In addition, coexpression of PDGF and PDGF receptors has been demonstrated in human gliomas, implying that autocrine stimulation may be involved in glioma formation. In this study, using somatic cell type-specific gene transfer we investigated the functions of PDGF autocrine signaling in gliomagenesis by transferring the overexpression of PDGF-B into either nestin-expressing neural progenitors or glial fibrillary acidic protein (GFAP)-expressing astrocytes both in cell culture and in vivo. In cultured astrocytes, overexpression of PDGF-B caused significant increase in proliferation rate of both astrocytes and neural progenitors. Furthermore, PDGF gene transfer converted cultured astrocytes into cells with morphologic and gene expression characteristics of glial precursors. In vivo, gene transfer of PDGF to neural progenitors induced the formation of oligodendrogliomas in about 60% of mice by 12 wk of age; PDGF transfer to astrocytes induced the formation of either oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice in the same time period. Loss of Ink4a-Arf, a mutation frequently found in high-grade human gliomas, resulted in shortened latency and enhanced malignancy of gliomas. The highest percentage of PDGF-induced malignant gliomas arose from of Ink4a-Arf null progenitor cells. These data suggest that chronic autocrine PDGF signaling can promote a proliferating population of glial precursors and is potentially sufficient to induce gliomagenesis. Loss of Ink4a-Arf is not required for PDGF-induced glioma formation but promotes tumor progression toward a more malignant phenotype.