RESUMO
Tethered cord syndrome is a condition in which the spinal cord is tethered by pathological structures such as a tight filum terminale, intradural lipomas with or without a connecting extradural component, intradural fibrous adhesions, diastematomyelia, and neural placode adhesions following closure of a myelomeningocele.It usually occurs in childhood and adolescence as the spine grows in length, but it can also develop in adulthood. Symptoms of tethered cord syndrome are slowly progressive and varied. Incorrect diagnosis and inappropriate treatment may be provided if the physician lacks knowledge and understanding of this disease.This chapter aims to describe the pathophysiology, syndromes, diagnostic imaging, surgical treatment, and prognosis of tethered cord syndrome to enhance the understanding of this condition.
Assuntos
Defeitos do Tubo Neural , Humanos , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/terapia , Defeitos do Tubo Neural/cirurgia , Procedimentos Neurocirúrgicos/métodosRESUMO
Histological and molecular characterization is essential for the diagnosis of pediatric brain tumors. In the pineal region tumors, it is necessary to remove a sufficient tumor volume to make a diagnosis. However, surgery in this region is challenging due to its deep anatomical location and surrounded by critical structures and complex venous system. Knowledge of the anatomy and function of the pineal region and tumor histological types is imperative for the successful management of pineal region tumors. This article describes surgical approaches to pineal tumors, focusing on the occipital transtentorial approach and adding the author's experience to what has been known in the literature. Recent innovations have made this approach more popular and can be applied to occipital fossa lesions.
Assuntos
Neoplasias Encefálicas , Glândula Pineal , Pinealoma , Criança , Humanos , Pinealoma/diagnóstico por imagem , Pinealoma/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Glândula Pineal/diagnóstico por imagem , Glândula Pineal/cirurgia , Procedimentos NeurocirúrgicosRESUMO
The effectiveness and safety of intraoperative magnetic resonance imaging (iMRI) are evident from many reports over the past decade. However, these reports have mainly concerned surgeries for glioma and other intra-axial tumours, and applications of this approach for extra-axial tumours are poorly documented. We retrospectively examined three cases in which iMRI was used to assist in the removal of epidermoid cysts. T2-weighted images and diffusion-weighted images were acquired during the surgeries. The value to surgeons of images generated by iMRI, the length of interruption of surgery, and the safety of the patients were assessed. In this study, the images obtained through iMRI provided were clear representations of remnant tumours, even with a low-field system (0.4 Tesla). These images generated enough information to help surgeons decide whether to use an assistance device, such as an endoscope, to remove remnant tumours and whether further retraction of the brain was safe for patients and useful in tumour removal. Intraoperative MRI has long been thought unnecessary for surgery for tumours that are well demarcated and clearly visible under a surgical microscope; in this study, however, intraoperative MRI proved to be useful and safe for patients undergoing epidermoid cyst resection.
Assuntos
Neoplasias Encefálicas , Cisto Epidérmico , Glioma , Humanos , Cisto Epidérmico/diagnóstico por imagem , Cisto Epidérmico/cirurgia , Estudos Retrospectivos , Glioma/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
The frequency of split cord malformation (SCM) is approximately 1 in 5000 births; however, patients are rarely diagnosed with SCM in the neonatal period. Moreover, there have been no reports of SCM with hypoplasia of the lower extremities at birth. A 3-day-old girl was transferred to our hospital for a thorough examination of hypoplasia of the left lower extremity and lumbosacral abnormalities detected after birth. The spinal magnetic resonance imaging (MRI) revealed a split spinal cord in a single dural tube. Based on the MRI findings, the patient was diagnosed with SCM type II. Following discussions with the parents, pediatricians, neurosurgeons, psychologists, and social workers, we decided to perform untethering to prevent further neurological impairment after achieving a sufficient body weight. The patient was discharged on day 25 of life. Early diagnosis and intervention may improve the neurological prognosis in terms of motor function, bladder and bowel function, and superficial sensation; thus, clinicians should report infrequent findings that may lead to SCM diagnosis. SCM should be differentiated in patients with left-right differences in the appearance of the lower extremity, particularly in those with lumbosacral abnormalities.
Assuntos
Defeitos do Tubo Neural , Medula Espinal , Recém-Nascido , Feminino , Humanos , Medula Espinal/anormalidades , Defeitos do Tubo Neural/complicações , Defeitos do Tubo Neural/diagnóstico , Coluna Vertebral , Imageamento por Ressonância Magnética , Extremidade InferiorRESUMO
Meningioma is the most common intracranial tumor, with generally favorable patient prognosis. However, patients with malignant meningioma typically experience recurrence, undergo multiple surgical resections, and ultimately have a poor prognosis. Thus far, effective chemotherapy for malignant meningiomas has not been established. We recently reported the efficacy of eribulin (Halaven) for glioblastoma with a telomerase reverse transcriptase (TERT) promoter mutation. This study investigated the anti-tumor effect of eribulin against TERT promoter mutation-harboring human malignant meningioma cell lines in vitro and in vivo. Two meningioma cell lines, IOMM-Lee and HKBMM, were used in this study. The strong inhibition of cell proliferation by eribulin via cell cycle arrest was demonstrated through viability assay and flow cytometry. Apoptotic cell death in malignant meningioma cell lines was determined through vital dye assay and immunoblotting. Moreover, a wound healing assay revealed the suppression of tumor cell migration after eribulin exposure. Intraperitoneal administration of eribulin significantly prolonged the survival of orthotopic xenograft mouse models of both malignant meningioma cell lines implanted in the subdural space (P < .0001). Immunohistochemistry confirmed apoptosis in brain tumor tissue treated with eribulin. Overall, these results suggest that eribulin is a potential therapeutic agent for malignant meningiomas.
Assuntos
Antineoplásicos/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Furanos/farmacologia , Humanos , Estimativa de Kaplan-Meier , Cetonas/farmacologia , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/patologia , Meningioma/genética , Meningioma/mortalidade , Meningioma/patologia , Camundongos , Mutação , Regiões Promotoras Genéticas , Telomerase/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hydrocephalus surgery is one of the most frequently performed procedures in pediatric neurosurgery. The incidence of surgical site infections during this surgery is high. This complication has not improved with the evolution of neurosurgical procedures. This may be due to immature immune system and skin barrier function of children compared to adults and the fact that hydrocephalus surgery involves placement of an alien surgical device in the body. To overcome this issue, it is important to follow procedures that have been validated as beneficial for the prevention of infection in literature. Therefore, in this article, we present our current understanding of infectious complications of hydrocephalus surgery, including shunt device surgery in adults and non-hydrocephalus pediatric neurosurgery, and provide recommendations for minimizing infectious complications and strategies to prevent infections in these surgeries.
Assuntos
Hidrocefalia , Neurocirurgia , Adulto , Criança , Humanos , Hidrocefalia/cirurgia , Incidência , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Infecção da Ferida Cirúrgica/cirurgiaRESUMO
The current standard of diagnosing central nervous system (CNS) lymphoma is stereotactic biopsy, however the procedure has a risk of surgical complication. Liquid biopsy of the CSF is a less invasive, non-surgical method that can be used for diagnosing CNS lymphoma. In this study, we established a clinically applicable protocol for determining mutations in MYD88 in the CSF of patients with CNS lymphoma. CSF was collected prior to the start of chemotherapy from 42 patients with CNS lymphoma and matched tumor specimens. Mutations in MYD88 in 33 tumor samples were identified using pyrosequencing. Using 10 ng each of cellular DNA and cell-free DNA (cfDNA) extracted from the CSF, the MYD88 L265P mutation was detected using digital PCR. The conditions to judge mutation were rigorously determined. The median Target/Total value of cases with MYD88 mutations in the tumors was 5.1% in cellular DNA and 22.0% in cfDNA. The criteria to judge mutation were then determined, with a Target/Total value of 0.25% as the cutoff. When MYD88 mutations were determined based on these criteria, the sensitivity and specificity were 92.2% and 100%, respectively, with cellular DNA; and the sensitivity and specificity were 100% with cfDNA. Therefore, the DNA yield, mutated allele fraction, and accuracy were significantly higher in cfDNA compared with that in cellular DNA. Taken together, this study highlights the importance of detecting the MYD88 L265P mutation in cfDNA of the CSF for diagnosing CNS lymphoma using digital PCR, a highly accurate and clinically applicable method.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Biópsia Líquida/métodos , Linfoma/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Nucleicos Livres/líquido cefalorraquidiano , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/isolamento & purificação , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/diagnóstico , DNA de Neoplasias/líquido cefalorraquidiano , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Linfoma/líquido cefalorraquidiano , Linfoma/diagnóstico , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/líquido cefalorraquidiano , Reação em Cadeia da Polimerase/métodos , Sensibilidade e EspecificidadeRESUMO
Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBM.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Lomustina/uso terapêutico , Nimustina/uso terapêutico , Temozolomida/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/metabolismo , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Glioblastoma/metabolismo , Histonas/metabolismo , Humanos , Injeções Intraperitoneais , Lomustina/administração & dosagem , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Nimustina/administração & dosagem , Terapia de Salvação/métodos , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Since a case of hydrocephalus in humans considered to be caused by ciliary dysfunction was first reported by Greenstone et al. in 1984, numerous papers on the correlation between ciliary function and hydrocephalus have been published. METHODS: We reviewed the published literature on primary ciliary dyskinesia in humans causing hydrocephalus, focusing on articles specifically examining the relation between ciliary function and hydrocephalus and its treatment. In addition, the authors' experience is briefly discussed. RESULTS: Full texts of 16 articles reporting cases of human hydrocephalus (including ventriculomegaly) due to defects in ependymal ciliary function or primary ciliary dyskinesia observed in clinical practice were extracted. In recent years, studies on animal models, especially employing knockout mice, have revealed genetic mutations that cause hydrocephalus via ciliary dysfunction. However, a few reports on the onset of hydrocephalus in human patients with primary ciliary dyskinesia have confirmed that the incidence of this condition was extremely low compared to that in animal models. CONCLUSION: In humans, it is rare for hydrocephalus to develop solely because of abnormalities in the cilia, and it is highly likely that other factors are also involved along with ciliary dysfunction.
Assuntos
Epêndima , Hidrocefalia , Animais , Cílios , Humanos , Hidrocefalia/etiologia , Camundongos , MutaçãoRESUMO
We report a case of subependymal giant cell astrocytoma (SEGA) with anaplastic histological features in a 3-year-old girl. She had no clinical manifestations of tuberous sclerosis complex (TSC) and no relevant family history. A few cases have been reported in which patients with SEGA had no other clinical manifestations of TSC (solitary SEGA). Genetic analysis using a blood sample from the patient showed no germline alterations in TSC1 or TSC2 genes, while the tumor tissue exhibited loss of heterozygosity (LOH) in TSC2. SEGAs are benign, slowly growing tumors that rarely have significant mitotic activity. However, histopathological examination in the present case revealed high mitotic activity and necrosis besides the typical large plump cells arranged in sheets. This may be the first genetically proven case of a solitary SEGA with histopathological anaplastic features. In this report, we reviewed solitary SEGAs and histopathological malignancy in SEGA.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Esclerose Tuberosa , Anaplasia , Astrocitoma/diagnóstico por imagem , Astrocitoma/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Pré-Escolar , Feminino , Humanos , Mutação , Esclerose Tuberosa/genéticaRESUMO
Idiopathic normal pressure hydrocephalus (iNPH) is a condition resulting from impaired cerebrospinal fluid (CSF) absorption and excretion characterized by a triad of symptoms comprising dementia, gait disturbance (impaired trunk balance), and urinary incontinence. CSF biomarkers not only assist in diagnosis but are also important for analyzing the pathology and understanding appropriate treatment indications. As the neuropathological findings characteristic of iNPH have yet to be defined, there remains no method to diagnose iNPH with 100% sensitivity and specificity. Neurotoxic proteins are assumed to be involved in the neurological symptoms of iNPH, particularly the appearance of cognitive impairment. The symptoms of iNPH can be reversed by improving CSF turnover through shunting. However, early diagnosis is essential as once neurodegeneration has progressed, pathological changes become irreversible and symptom improvement is minimal, even after shunting. Combining a variety of diagnostic methods may lead to a more definitive diagnosis and accurate prediction of the prognosis following shunt treatment. Identifying comorbidities in iNPH using CSF biomarkers does not contraindicate shunting-based intervention, but does limit the improvement in symptoms it yields, and provides vital information for predicting post-treatment prognosis.
Assuntos
Hidrocefalia de Pressão Normal , Biomarcadores , Derivações do Líquido Cefalorraquidiano , Diagnóstico Precoce , Humanos , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/epidemiologia , Hidrocefalia de Pressão Normal/cirurgia , PrognósticoRESUMO
Glioblastoma (GBM) is pathologically characterized by highly malignant neoplastic cells, focal necrosis and aberrant blood vessels composed of disorganized endothelial cells and pericytes. The recent cancer microarray database revealed upregulation of fibulin-7 (Fbln7), a member of the fibulin family, but provided no information on the tissue localization or biological function. In the present study, we demonstrated that Fbln7 is markedly overexpressed by the GBM tissue among astrocytic tumors, and immunolocalized mainly to endothelial cells and pericytes of the glomeruloid and hypertrophied microvessels. The production of Fbln7 by endothelial cells and pericytes was confirmed in cultured human umbilical vein endothelial cells (HUVEC) and human brain vascular pericytes (HBVP) and vascular endothelial growth factor (VEGF) stimulated the Fbln7 expression in HUVEC. Fbln7 bound to angiopoietin-1, but not angiopoietin-2 or Tie2 receptor, through interaction between the N-terminal portions of Fbln7 and angiopoietin-1, and it blocked phosphorylation of Tie2 receptor in HUVEC. In a coculture assay using HUVEC and HBVP, multilayered and irregular-shaped tube-like structures of HUVEC were induced by treatment with a high concentration of VEGF. This was accompanied by Fbln7 overproduction by HUVEC and angiopoietin-1 expression by HBVP. The production of aberrant VEGF-induced tube-like structures was attenuated by treatment with antibody or synthetic peptides specific to the Fbln7 N-terminal domain or knockdown of Fbln7. These data demonstrate that Fbln7 is overexpressed by endothelial cells and pericytes of the abnormal microvessels in GBM, and suggest that Fbln7 may contribute to the aberrant vessel formation by modulation of the angiopoietin-1/angiopoietin-2-Tie2 axis.
Assuntos
Angiopoietina-1/genética , Neoplasias Encefálicas/genética , Proteínas de Ligação ao Cálcio/genética , Glioblastoma/genética , Neovascularização Patológica/genética , Angiopoietina-1/metabolismo , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica , Glioblastoma/irrigação sanguínea , Glioblastoma/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Pericitos/citologia , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Ligação Proteica , Fator A de Crescimento do Endotélio Vascular/farmacologiaAssuntos
Germinoma , Neoplasias do Nervo Óptico , Humanos , Nervo Óptico/diagnóstico por imagem , Neoplasias do Nervo Óptico/complicações , Neoplasias do Nervo Óptico/diagnóstico , Germinoma/complicações , Germinoma/diagnóstico , Erros de Diagnóstico , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia , Imageamento por Ressonância MagnéticaRESUMO
The extracranial-intracranial (EC-IC) bypass using the maxillary artery (MA) has been successfully completed using a radial artery (RA) graft but the complicated anatomy and narrow exposure make it difficult. The purpose of this article is to define the microsurgical exposure of the MA through the middle fossa and describe the branches, diameter, and length of the MA available for the EC-IC bypass in the sphenopalatine fossa and anterior part of the infratemporal fossa. 5 cadaveric specimens were dissected bilaterally (10 MA dissections) to define the microsurgical anatomy of the MA through an intracranial approach. The exposable branches of the MA at the level of the infratemporal and sphenopalatine fossae were the anterior deep temporal, posterior superior alveolar, and infraorbital arteries. The origin of each branch could be exposed. The available section of the MA for use as a donor vessel is between the origin of the anterior deep temporal artery and the infraorbital artery. The mean exposable length of the MA was 19.4 mm. The mean outer diameter of the donor MA was 3.2 mm. Tension-free EC-IC bypass was possible using a RA graft between the MA and the middle cerebral artery, the MA and the supraclinoid internal carotid artery (ICA), or the MA and the petrous ICA. Exposure of the MA at the infratemporal and sphenopalatine fossae is complicated but provides length and diameter suitable as a donor artery for the EC-IC bypass. Clin. Anat. 31:724-733, 2018. © 2017 Wiley Periodicals, Inc.
Assuntos
Revascularização Cerebral/métodos , Artéria Maxilar/anatomia & histologia , Artéria Maxilar/transplante , Adulto , Fossa Craniana Média/anatomia & histologia , Humanos , Microcirurgia , Fossa Pterigopalatina/anatomia & histologiaRESUMO
BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown. PROCEDURE: We performed high-throughput copy number variation analysis of primary cell lines generated from primary and relapsed tumors from one of our patients to identify new genes involved in AT/RT biology. The expression of the identified gene was validated in 29 AT/RT samples by gene expression profiling, quantitative real-time polymerase chain reaction, and immunohistochemistry (IHC). Furthermore, we investigated the function of this gene by mutating it in rhabdoid tumor cells. RESULTS: TEAD4 amplification was detected in the primary cell lines and its overexpression was confirmed at mRNA and protein levels in an independent cohort of AT/RT samples. TEAD4's co-activator, YAP1, and the downstream targets, MYC and CCND1, were also found to be upregulated in AT/RT when compared to medulloblastoma. IHC showed TEAD4 and YAP1 overexpression in all samples. Cell proliferation and migration were significantly reduced in TEAD4-mutated cells. CONCLUSIONS: We report the overexpression of TEAD4 in AT/RT, which is a key component of Hippo pathway. Recent reports revealed that dysregulation of the Hippo pathway is implicated in tumorigenesis and poor prognosis of several human cancers. Our results suggest that TEAD4 plays a role in the pathophysiology of AT/RT, which represents a new insight into the biology of this aggressive tumor.
Assuntos
Neoplasias Encefálicas/fisiopatologia , Proteínas de Ligação a DNA/biossíntese , Proteínas Musculares/biossíntese , Tumor Rabdoide/fisiopatologia , Teratoma/fisiopatologia , Fatores de Transcrição/biossíntese , Adolescente , Western Blotting , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização In Situ , Lactente , Masculino , Proteínas Musculares/genética , Reação em Cadeia da Polimerase em Tempo Real , Tumor Rabdoide/genética , Fatores de Transcrição de Domínio TEA , Teratoma/genética , Fatores de Transcrição/genética , Regulação para CimaRESUMO
PURPOSE: Malignant rhabdoid tumors (MRTs) are deadly embryonal tumors of the infancy. With poor survival and modest response to available therapies, more effective and less toxic treatments are needed. We hypothesized that a systematic screening of the kinome will reveal kinases that drive rhabdoid tumors and can be targeted by specific inhibitors. METHODS: We individually mutated 160 kinases in a well-characterized rhabdoid tumor cell line (MON) using lentiviral clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The kinase that most significantly impaired cell growth was further validated. Its expression was evaluated by microarray gene expression (GE) within 111 pediatric tumors, and functional assays were performed. A small molecule inhibitor was tested in multiple rhabdoid tumor cell lines and its toxicity evaluated in zebrafish larvae. RESULTS: The Polo-like kinase 4 (PLK4) was identified as the kinase that resulted in higher impairment of cell proliferation when mutated by CRISPR/Cas9. PLK4 CRISPR-mutated rhabdoid cells demonstrated significant decrease in proliferation, viability, and survival. GE showed upregulation of PLK4 in rhabdoid tumors and other embryonal tumors of the brain. The PLK4 inhibitor CFI-400945 showed cytotoxic effects on rhabdoid tumor cell lines while sparing non-neoplastic human fibroblasts and developing zebrafish larvae. CONCLUSIONS: Our findings indicate that rhabdoid tumor cell proliferation is highly dependent on PLK4 and suggest that targeting PLK4 with small-molecule inhibitors may hold a novel strategy for the treatment of MRT and possibly other embryonal tumors of the brain. This is the first time that PLK4 has been described as a potential target for both brain and pediatric tumors.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Sistemas CRISPR-Cas/genética , Ensaios de Triagem em Larga Escala/métodos , Indazóis/farmacologia , Indóis/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Tumor Rabdoide/tratamento farmacológico , Sequência de Aminoácidos , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Larva/crescimento & desenvolvimento , Larva/metabolismo , Mutação/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Alinhamento de Sequência , Células Tumorais Cultivadas , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismoRESUMO
BACKGROUND: It is extremely rare to see cerebrospinal fluid dissemination of intraventricular meningioma, particularly with the development of acute, progressive brainstem/cerebellar dysfunction with an absence of mass formation in the corresponding anatomical sites. CASE PRESENTATION: An 81-year-old man was admitted because of double vision, right facial nerve palsy and truncal ataxia. Brain magnetic resonance imaging showed normal findings except for a tumor mass in the left lateral ventricle, which had been noted over 6 months previously. The patient developed hiccups, hyperventilation, and drowsiness, which worsened progressively, and did not respond to corticosteroid or intraventricular immunoglobulin therapy. Cerebrospinal fluid study revealed a mild elevation of protein, and cytology was negative. The patient died and an autopsy was performed. Postmortem investigation disclosed a malignant transformation of benign fibroid meningioma with cerebrospinal fluid dissemination of the malignant cells, diversely involving the surface of brainstem, cerebellum, and spinal cords, secondarily resulting in extensive ischemia in the brain parenchyma by vessel occlusion. CONCLUSION: If a patient with an intraventricular tumor develops acute, progressive neurological symptoms, the possibility that it is be caused by cerebrospinal fluid dissemination of tumor cells, after malignant transformation, should be considered.
Assuntos
Encefalopatias/patologia , Doenças dos Nervos Cranianos/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Idoso de 80 Anos ou mais , Tronco Encefálico/patologia , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
OBJECTIVE: The rhomboid lip is a neural tissue encountered during cerebellopontine angle surgery, with differing shape and extent among individuals. This study aimed to investigate the variation of rhomboid lips during posterior fossa surgery. METHODS: In this retrospective study, we examined posterior cranial fossa surgeries performed using a retrosigmoid approach. Rhomboid lips were classified according to thickness, extent, and appearance, with some subjected to histological analysis. T2-weighted magnetic resonance imaging of rhomboid lips was conducted. RESULTS: Among 304 surgeries, rhomboid lips were observed in 75 patients who underwent schwannoma or meningioma resection, facial spasm-related neurovascular decompression, and other surgeries (37, 2, 32, and 4 patients, respectively). Rhomboid lips were categorized based on apparent thickness: thin membranous type, resembling an arachnoid membrane, and thick parenchymal type. Rhomboid lip extension was classified by position relative to the choroid plexus: nonextension, lateral extension, and jugular foramen (41, 22, and 12 patients, respectively). Veins were observed on the rhomboid lip surface in 37 cases. The rhomboid lip was visible in only 1 case (parenchymal jugular foramen type) on magnetic resonance imaging. Histologically, the rhomboid lip comprised an ependymal cell layer, a glial layer, and connecting tissue. The glial layer thickness determined the rhomboid lip thickness, which was greater in the parenchymal type than in the membrane type. In 42 patients, the rhomboid lip was dissected with no complications observed. CONCLUSIONS: Morphological classification of the rhomboid lip and understanding of its anatomical details contribute to safe surgical field development for neurosurgeons.