RESUMEN
Pediatric pineal region tumors consist of tumors of pineal gland origin and parapineal origin. The former are comprised of germ cell tumor (GCT) and pineal parenchymal tumor. The latter originate from the surrounding neural structures, such as the midbrain and thalamus; thus, they are often benign gliomas during childhood. Pineal region tumors often cause obstructive hydrocephalus, which is the main cause of presenting symptoms. Advanced imaging discloses precise location and extension of the tumor and associated anomalies such as hydrocephalous, dissemination, hemorrhage, etc. Hydrocephalus has been managed with CSF diversion, mostly using an endoscopic third ventriculostomy. Because of different treatment paradigms for each tumor type, histological confirmation is needed either through biopsy, tumor markers for GCTs, and/or surgical resection sampling. Radical resection of these tumors remains a challenge due to their deep-seated location and involvement of delicate neural and vascular structures. Comparison of common craniotomy approaches, occipital transtentorial (OT) and infratentorial supracerebellar (ITSC), is reviewed for their advantages and disadvantages. Surgical area exposure and blind spots are important factors for successful tumor removal. The surgical techniques and nuances that the author employs for tumor resection via a posterior interhemispheric transtentorial approach are presented.
RESUMEN
Over the last half a century, diagnostic neuroimaging has made tremendous strides following the introduction of computerized tomography (CT) and subsequent magnetic resonance imaging (MR). Prior to that time, the neurological diagnosis was conducted with careful history taking, physical examinations, and invasive testing such as cerebral angiography, encephalography, and myelography. Techniques and contrast media for these tests have been refined and progressed over time. However, these invasive tests have diminished and are rarely used for daily practice in pediatric neurosurgery since the introduction of CT and MR. Nuclear brain scan and ultrasonography are non-invasive. A nuclear brain scan using radioactive tracers was used to demonstrate the laterality of the lesion without an intact blood-brain barrier, but was rarely performed after the CT era. On the other hand, improved ultrasonography made strides because of its portability and the lack of radiation exposure and sedation. It is often a first-line investigatory tool for neonatal evaluation. This article describes a review of developments and progresses of pediatric neuroimaging in the pre-CT era.
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Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Recién Nacido , Humanos , Niño , Angiografía Cerebral , Neuroimagen , Medios de ContrasteRESUMEN
OBJECTIVES: In the past 50 years, pediatric neurosurgery has made tremendous strides, and gained its own identity as a distinct subspecialty. I have personally observed this progress and evolution in pediatric neurosurgery in multiple dimensions, which are described based upon my own experience and reflection. METHODS: The development and evolutions of multiple domains of pediatric neurosurgery, including neuroimaging, hydrocephalus, pediatric brain tumor, spinal dysraphism, craniosynostosis, vascular malformation, functional neurosurgery and spinal disorders were reviewed and commented on based upon my own experience and reflection. RESULTS: The field of pediatric neurosurgery has grown in all aspects of diagnosis and therapy owing to the introduction of computers, innovative techniques and technologies and new discoveries of scientific data including molecular investigations. CONCLUSION: A minimally invasive approach and molecular target therapy are a current trend. The past half century's clinical experience and advances in biomedical knowledge and techniques provide foundation for further improvement in the care of children of the next generation. Prospective artificial intelligence will likely promote further advances in pediatric neurosurgery.
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Hidrocefalia , Neurocirugia , Niño , Humanos , Neurocirugia/historia , Inteligencia Artificial , Estudios Prospectivos , Procedimientos Neuroquirúrgicos/métodos , Hidrocefalia/cirugíaRESUMEN
INTRODUCTION: Intracranial germ cell tumor (iGCT) is a rare disorder and often occurs during childhood and adolescence. iGCTs are frequently localized in pineal region and hypothalamic-neurohypophyseal axis (HNA). In spite of well-established clinical and pathological entity, histogenesis of iGCTs remains unsettled. Current theories of histogenesis of iGCTs include germ cell theory (from primordial germ cells (PGCs) of aberrant migration) and stem cell theory (transformed embryonic stem (ES) cells). In order to comprehend the histogenesis, we revisit the origin, migration, and fate of the human PGCs, and their transformation processes to iGCT. DISCUSSION: In "germ cell theory," transformation of ectopic PGCs to iGCT is complex and involves multiple transcription factors. Germinoma is derived from ectopic PGCs and is considered a prototype of all GCTs. Non-germinomatous germ cell tumors (NGGCTs) develop from more differentiated counterparts of embryonic and extra-embryonic tissues. However, there is a distinct genomic/epigenomic landscape between germinoma and NGGCT. ES cells transformed from ectopic PGCs through molecular dysregulation or de-differentiation may become the source of iGCT. "Stem cell theory" is transformation of endogenous ES cells or primitive neural stem cell to iGCTs. It supports histological diversity of NGGCTs because of ES cell's pluripotency. However, neural stem cells are abundantly present along the subependymal zone; therefore, it does not explain why iGCTs almost exclusively occur in pineal and HNA locations. Also, the vast difference of methylation status between germinoma and NGGCT makes it difficult to theorize all iGCTs derive from the common cellular linage. CONCLUSION: Transformation of PGCs to ES cells is the most logical mechanism for histogenesis of iGCT. However, its detail remains an enigma and needs further investigations.
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Neoplasias Encefálicas , Germinoma , Neoplasias de Células Germinales y Embrionarias , Adolescente , Humanos , Neoplasias Encefálicas/patología , Germinoma/patología , Células Madre Embrionarias/patología , Células Madre Embrionarias/fisiologíaRESUMEN
PURPOSE: Resecting pineal region tumors in children is often challenging. Several approaches have been proposed and practiced. A personal series of pediatric pineal region tumors resected through craniotomy with posterior interhemispheric occipital transtentorial (OT) approach are reviewed. We present the surgical techniques, pitfalls, and their results. MATERIAL AND METHODS: Eighty patients ranging in age from 3 months to 21 years old, and treated over 3 decades were reviewed. Hydrocephalus caused the main presenting symptoms and was noted in 74 patients. It was treated prior to the craniotomy for tumor resection with endoscopic third ventriculostomy (ETV) in 33, external ventricular drainage in 26, and precraniotomy shunt in 15. Nine patients had ETV together with endoscopic biopsy. All patients had a parieto-occipital craniotomy in a prone position. Through a tentorial section, a gross total resection of the tumor was attempted except for germinomas. RESULTS: The tumor pathology showed 32 germ cell tumors (GCT), 22 benign astrocytomas, 13 pineal parenchymal tumors, 5 ATRTs, 3 papillary tumors, and 5 others. Of GCTs, 18 were teratomas. The extent of resection consisted of 55 gross total resections, 13 subtotal resections, 10 partial, and 2 biopsies with one postoperative death. Hemiparesis in 2, cerebellar ataxia in another 2, and hemiballismus in 1 were transient and improved over time. One had permanent hemisensory loss and another patient had bilateral oculomotor palsy. Postoperative homonymous hemianopia occurred in 2 patients but subsided over a short period of time. Parinaud's sign was noted in 24 patients, of which 16 were transient. CONCLUSION: The posterior interhemispheric OT approach provides a safe route and comfortable access to the pineal region in children. A great majority of postoperative neurological complications are the results of direct manipulations of the midbrain at tumor resection. Identification and preservation of the tumor-brain interface are of paramount importance. GCTs other than teratomas are treated with neoadjuvant chemotherapy and may eliminate the need for craniotomy. Exophytic midbrain JPAs are amenable to resection.
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Neoplasias Encefálicas , Glándula Pineal , Pinealoma , Teratoma , Niño , Humanos , Pinealoma/cirugía , Pinealoma/patología , Estudios Retrospectivos , Neoplasias Encefálicas/cirugía , Glándula Pineal/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
OBJECTIVES: Controversy remains regarding surgical managements of sylvian fissure arachnoid cyst (SFAC). This review presents our experience in the microsurgical fenestration of pediatric patients with SFAC to define surgical indication, and risks and benefits with special emphasis on postoperative subdural fluid collection (SDFC) and cyst size reduction. METHODS: Thirty-four children with SFAC who underwent microsurgical cyst fenestration at a single institution over a 10-year period were retrospectively reviewed for their clinical presentation, neuroimaging findings, and postsurgical course. The SFACs were classified by a novel grading system based on the degree of arachnoid cyst extension from the sylvian fissure to the insular cistern shown on MR images: grade 0 - little or no prominence of sylvian fissure, grade I - SFAC confined to the sylvian fissure, grade II - SFAC partially extending to the insular cistern, grade III - SFAC extending to the entire insular cistern. RESULTS: There were 26 males and 8 females. SFAC was present in the left side in 24. Twelve patients presented with cyst rupturing to the subdural space. Cyst grading did not show significant difference compared with rupture status (p > 0.9). All patients underwent microsurgical cyst fenestration. Postoperative SDFC is common but often resolved overtime in two-thirds of the cases with the mean average of 6 months. However, 3 patients had symptomatic postoperative SDFC and needed reoperation shortly after the first operation. Microsurgical cyst fenestrations for SFAC effectively resolved the presenting symptoms and often showed restorations of intracranial structures on follow-up imaging. Cyst resolution or reduction greater than 75% was noted in 61.8% of the patients postoperatively which was noted in a half of the SFAC of children even with age of 11 years or older. During the follow-up, no cyst recurrence or SDFC was noted. Patients with greater surgical reduction of cyst size tended to occur in younger children, and those with lower MR grade. CONCLUSION: Our results showed a high reduction rate of SFAC and brain re-expansion after microsurgical fenestration together with symptomatic improvements regardless the patient's age. Considering the developing CNS during childhood, reductions of a large space-occupying lesion followed by restorations of the structural integrity of the developing brain are very desirable. However, a multi-center cooperative prospective longitudinal study on long-term comparative data of those treated and untreated of neuro-psychological outcome and cyst rupture incidence is needed.
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Quistes Aracnoideos , Espacio Subdural , Masculino , Femenino , Niño , Humanos , Espacio Subdural/patología , Estudios Retrospectivos , Estudios Prospectivos , Estudios Longitudinales , Quistes Aracnoideos/cirugía , Resultado del TratamientoRESUMEN
PURPOSE: The aim of this study is to analyze rates of ventriculopleural (VPL) shunt failure and complications among patients with pediatric hydrocephalus, and to analyze which factors may predict early (< 1 year) or late (> 1 year) VPL shunt failure in this sample. METHODS: A retrospective chart review was conducted of all consecutive VPL shunt placements from 2000 to 2019 at our institution. Data was collected on patient characteristics, shunt history, and shunt type. Primary endpoints include rates of VPL shunt survival and rates of symptomatic pleural effusion. The Kaplan-Meier method was used to calculate shunt survival, and Fisher's exact test and t-test were used to compare differences between categorical variables and means, respectively (p < 0.05). RESULTS: Thirty-one patients with pediatric hydrocephalus underwent VPL shunt placement (mean age 14.2 years). Of the 27 patients with long-term follow-up (mean 46 months), VPL shunt revision was required in 19, seven of which were due to pleural effusion. Overall shunt survival rates at 1, 3, 5, and 7 years were 76%, 62%, 55%, and 46%, respectively. Mean duration of shunt survival was 26.74 months. Overall pleural effusion rate was 26%. No patient-specific factors, including shunt valve type, were significantly associated with shunt survival, risk of early revision, or risk of pleural effusion. CONCLUSIONS: Our results are comparable to those reported in the literature and represent one of the largest case series on the topic. VPL shunts are a viable second-line option when ventriculoperitoneal (VP) shunt placement is not possible or desirable, though there are high rates of shunt revision and pleural effusion.
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Hidrocefalia , Derrame Pleural , Niño , Humanos , Adolescente , Derivaciones del Líquido Cefalorraquídeo/efectos adversos , Estudios Retrospectivos , Derivación Ventriculoperitoneal/efectos adversos , Derivación Ventriculoperitoneal/métodos , Derrame Pleural/cirugía , Derrame Pleural/complicaciones , Hidrocefalia/etiología , Resultado del Tratamiento , ReoperaciónRESUMEN
In a previous study, we showed that folate receptor-α (FRα) translocates to the nucleus where it acts as a transcription factor and upregulates Hes1, Oct4, Sox2, and Klf4 genes responsible for pluripotency. Here, we show that acetylation and phosphorylation of FRα favor its nuclear translocation in the presence of folate and can cause a phenotypic switch from differentiated glial cells to dedifferentiated cells. shRNA-FRα mediated knockdown of FRα was used to confirm the role of FRα in dedifferentiation. Ocimum sanctum hydrophilic fraction-1 treatment not only blocks the folate mediated dedifferentiation of glial cells but also promotes redifferentiation of dedifferentiated glial cells, possibly by reducing the nuclear translocation of ~38 kDa FRα and subsequent interaction with chromatin assembly factor-1. Stem Cells 2019;37:1441-1454.
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Receptor 1 de Folato/metabolismo , Cresta Neural/efectos de los fármacos , Cresta Neural/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Desdiferenciación Celular/efectos de los fármacos , Desdiferenciación Celular/genética , Línea Celular , Línea Celular Tumoral , Receptor 1 de Folato/genética , Ácido Fólico/análogos & derivados , Ácido Fólico/farmacología , Humanos , Factor 4 Similar a Kruppel , Técnicas de Transferencia Nuclear , Ocimum sanctum/química , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , ARN Interferente Pequeño/genética , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: Choroid plexus tumors (CPTs) are rare pediatric intracranial neoplasms, and mostly occur in the lateral ventricle. CPTs located in the infratentorial location are considered to be rare in the pediatric population. We present a series of eight patients treated in the last decade at our institution focusing on clinical presentations and their outcome after excision. METHODS: We performed an institutional retrospective review of patients who underwent surgical resection of infratentorial CPTs during the period from 2008 to 2017. Patients' charts were reviewed for demographic data, clinical presentation, surgical treatment, and follow-up. RESULTS: There were eight patients (6 females and 2 males), with mean age for the cohort at presentation was 9.0 years. They represent 75% of 12 CPTs of all locations treated at the same period in our institution. These 8 infratentorial CPTs were in the fourth ventricle in seven, and in the cerebellopontine angle (CPA) in one. Seven patients had choroid plexus papillomas (WHO grade I) and 1 had an atypical choroid plexus papilloma (WHO grade II). Gross total resection was attempted in all patients. However, two of 3 patients with fourth ventricle floor invasion had subtotal resection with a thin layer of tumor left on the floor. The remaining 6 had a gross total resection. Six patients with preoperative hydrocephalus had a perioperative external ventricular drainage but none required permanent shunting after tumor resection. None showed recurrence/tumor progression without adjuvant therapy during the follow-up period of 20 months to 11 years. CONCLUSION: Infratentorial dominance among pediatric CPTs in this series contradicts previous reports. Infratentorial CPTs are amenable to surgical resection. Unresected small residuals due to invasion to the fourth ventricle floor showed no regrowth during 2 to 3 years follow-up without adjuvant therapy. However, these patients with incomplete resection need watchful observations.
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Neoplasias del Plexo Coroideo , Papiloma del Plexo Coroideo , Niño , Neoplasias del Plexo Coroideo/diagnóstico por imagen , Neoplasias del Plexo Coroideo/cirugía , Femenino , Cuarto Ventrículo/diagnóstico por imagen , Cuarto Ventrículo/cirugía , Humanos , Masculino , Recurrencia Local de Neoplasia , Papiloma del Plexo Coroideo/diagnóstico por imagen , Papiloma del Plexo Coroideo/cirugía , Estudios RetrospectivosRESUMEN
PURPOSE: This manuscript describes our management philosophy of Chiari I malformation in children based on a single neurosurgeon's personal experience. METHODS: Based on 61 infants and children with Chiari I malformation treated from 2007 to 2017, typical symptoms, surgical indications, types of surgery, and evaluation of surgical decompression are reviewed. RESULTS: Sixty-one patients had 69 decompressions, with 90% having symptom improvement. Seven (11.5%) needed reoperation, 1 of which needed 2 reoperations for recurrence. The recurrence rates were 20% (5 of 25) after dural scoring and 5.6% (2 of 36) after duraplasty (p = 0.1116, Fisher's exact test). Six (16%) of 36 patients developed pseudomeningocele or CSF leak. CONCLUSIONS: We recommend surgical intervention for Chiari I malformation for clearly symptomatic patients and those with significant hydromyelia regardless of symptoms. A bony decompression with dural scoring is recommended for patients with typical occipital headaches with a lesser degree of tonsillar descent, while an expansile duraplasty is standard for those with high-grade tonsillar descent, medullary kink, or hydromyelia. Intraoperative ultrasound is often helpful to ensure the adequacy of the decompression. Most patients will have improvements in symptom and imaging after either type of decompressive surgery.
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Malformación de Arnold-Chiari/diagnóstico por imagen , Malformación de Arnold-Chiari/cirugía , Toma de Decisiones Clínicas/métodos , Descompresión Quirúrgica/métodos , Manejo de la Enfermedad , Niño , Descompresión Quirúrgica/tendencias , Femenino , Humanos , Masculino , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Neuroquirúrgicos/tendencias , Procedimientos de Cirugía Plástica/métodos , Procedimientos de Cirugía Plástica/tendenciasRESUMEN
Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT.
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Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Activación Enzimática , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We describe 2 cases of rapidly progressive primary central nervous system malignant melanoma, and summarize 18 previously reported cases of this extremely rare tumor in children. Both patients presented with focal neurologic symptoms, with no evidence of skin or other organ system involvement. One patient was treated with temozolomide and etoposide, whereas the other was treated with multiple surgical resections, radiation therapy, and a trial of ipilimumab. New molecularly targeted and immune-based therapies used in metastatic melanoma in adults are potential new treatment options, but their efficacy and safety in pediatric patients needs to be established.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Nervioso Central , Quimioradioterapia , Melanoma , Adolescente , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/terapia , Preescolar , Etopósido/administración & dosificación , Humanos , Ipilimumab/administración & dosificación , Masculino , Melanoma/metabolismo , Melanoma/patología , Melanoma/terapia , Temozolomida/administración & dosificaciónRESUMEN
OBJECTIVES: Chiari I malformation has been a well-recognized clinical entity; however, its occurrence among infants and toddlers is unusual. Their clinical presentations may be different from other age groups due to their lack of effective verbal communication. The authors analyze their personal series of patients focusing on symptomatology and MRI characteristics. Treatment methods, results, and outcome are analyzed in order to identify appropriate surgical management among infants and toddlers with Chiari I malformation. METHODS: The authors retrospectively reviewed 16 patients who were diagnosed and surgically treated between 2007 and 2014 during the first 3 years of life with minimum follow-up of 3 years. We focused on the presenting symptoms, magnetic resonance imaging findings, and surgical techniques used for posterior fossa decompression (PFD) and their postoperative outcome. RESULTS: Twelve patients (75%) presented with signs of headaches such as irritability, inconsolable crying, head grabbing, and/or arching back. Ten patients (62.5%) presented with oropharyngeal and/or respiratory symptoms such as emesis, choking, gagging, snoring, sleep apnea, breathing pause, and/or vocal cord palsy. Only one patient had segmental cervical hydromyelia. At the first surgery, ten patients had PFD with dural scoring (Type 1 procedure), while six others had PFD with duraplasty (Type 2 procedure) with thermal reduction of the cerebellar tonsils in four. Following the first operation, all initially had varying degrees of symptomatic improvement; however, seven patients subsequently had symptomatic recurrence. Persistent crowding at the PFD site on the postoperative imaging indicated greater risk of recurrences in both Type 1 procedure and Type 2 procedure groups. Of seven patients who needed a second operation, fivewere after Type 1 procedure and the two were after Type 2 procedure. The difference of recurrence rates between these two groups is not significant. CSF-related complications occurred in 4 out of 11 patients who had Type 2 procedure (one after primary decompression and three after the second decompression for recurrence). CONCLUSION: Young patients lacking effective verbal communication often present their Chiari I malformation differently from olderage groups. Behavioral changes indicative of headaches/irritability and oropharyngeal/respiratory symptoms are the primary presenting symptoms. The recurrence rate tends to be higher among the patients after Type 1 procedure (particularly those younger than 18 months) than after Type 2 procedure. We observed that duraplasty at primary or at redo PFD provides for better decompression and long-term outcome. However, one should keep it in mind that there is risk of CSF-related complications following duraplasty, particularly higher tendency after redo PFD.
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Malformación de Arnold-Chiari/diagnóstico , Malformación de Arnold-Chiari/cirugía , Preescolar , Descompresión Quirúrgica/métodos , Femenino , Humanos , Lactante , Masculino , Procedimientos Neuroquirúrgicos/métodos , Complicaciones Posoperatorias/epidemiología , Recurrencia , Estudios RetrospectivosRESUMEN
OBJECTIVE: Endoscopic third ventriculostomy (ETV) provides a shunt-free treatment for obstructive hydrocephalus children. With rapidly evolving technology, the semi-rigid fiber optic neuroendoscopy shows a potential application in ETV by blunt fenestration. A retrospective analysis of our experience is reviewed. METHODS: The authors review infants and children who underwent ETV using this technique from June 2004 to June 2016 with radiological and clinical follow-up done by a single surgeon. Patients who underwent ETV with channel scope were excluded. Demographic variables and operative reports were collected. Improvement of preoperative symptoms and avoidance of additional cerebrospinal fluid (CSF) diversion procedures were considered a success. The ETV success score (ETVSS) was used to correlate with clinical outcomes. RESULTS: A total of 79 patients were included with a mean age of 8.3 ± 5.5 years, and 40.5% were female. The mean clinical and radiographic follow-up was 38.6 ± 40.9 months. The overall complication rate was 6.3%, while 73.4% were considered successful. The ETV failure cases received conversion to ventriculoperitoneal shunt or redo of ETV with a median time of 2 months. The mean ETV success score was 74.3 ± 11.8 with positive correlation between success rate (P < 0.05). Kaplan-Meier failure-free survival rates of 30-day, 90-day, 6-month, 1-year, and 2-year were 89.9, 83.5, 78.5, 75.9, and 74.6%. Eight patients required redo ETV, and five of these patients required eventual shunt placements. Approximately 61.9% of failure occurred within 3 months. Patients with post-intraventricular hemorrhage (IVH) /infection, and age younger than 12 months had the poorest outcome (P < 0.05). CONCLUSIONS: Blunt dissection of the third ventricle floor under endoscopic vision with the stylet tip of a fiber optic neuroendoscopy is safe and requires less equipment in the pediatric population. This technique is successful with an optimistic long-term outcome except for infants and the post-IVH and infectious subgroups.
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Tecnología de Fibra Óptica/métodos , Hidrocefalia/cirugía , Neuroendoscopía/métodos , Ventriculostomía/métodos , Adolescente , Niño , Preescolar , Femenino , Tecnología de Fibra Óptica/instrumentación , Estudios de Seguimiento , Humanos , Hidrocefalia/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Ventriculostomía/instrumentaciónRESUMEN
OBJECTIVE: In this study, we investigate a neuroprotective agent, erythropoietin (EPO), in animal hydrocephalus model and its potential reversal effects on hydrocephalus by altering the expression of aquaporin-4 (AQP4). METHODS: Obstructive hydrocephalus was induced in 2-week-old rat pups by injecting kaolin (50 µl, 10 mg/ml in saline) into the cisterna magna, while the control pups received only saline. Kaolin-injected pups were divided into two groups on the fifth day after kaolin injection; one group received intra-peritoneal (i.p.) EPO (1 µg/pup) for 5 consecutive days, while other group received i.p. saline for 5 days. The effects of EPO on hydrocephalus were investigated by studying cerebral ventricle size and structural ependymal changes. We examined also the EPO effects on AQP4 expression and microRNA expression. RESULTS: EPO treatment significantly reduced dilation of the cerebral ventricle and denudation of ependymal line in hydrocephalic pups comparing with the control group. Increased expression of AQP4 in periventricular ependymal lining and cultured astrocytes and increased vascular formation were noted after EPO treatment. Additionally, we identified miR-668 as an endogenous regulator of AQP4 in response to EPO. Anti-miR-668 dampened EPO-induced activation of AQP4 expression. CONCLUSIONS: Together, our results show that EPO-mediated upregulation of AQP4 significantly reduces dilation of the cerebral ventricles in obstructive hydrocephalus pups and may lead to potential therapeutic options for hydrocephalus.
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Acuaporina 4/efectos de los fármacos , Acuaporina 4/metabolismo , Eritropoyetina/farmacología , Hidrocefalia/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hidrocefalia/patología , MicroARNs , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system neoplasms. In the majority of cases these tumors are benign and receive favorable prognosis following gross total surgical resection. In patients with progressive or symptomatic tumors, aggressive surgical resection is generally not feasible, thus radiation or chemotherapy are accepted initial or adjuvant interventions. Due to serious long-lasting side-effects, radiation is limited in young children; therefore, chemotherapy is widely practiced as an adjuvant treatment for these patients. However, chemotherapy can promote the emergence of multidrug resistant tumor cells that are more malignant than those of the original tumor. CD133, a putative stem cell marker in normal tissue and malignant brain tumors, enhances multidrug resistant gene 1 (MDR1) expression following chemotherapy in adult malignant glioblastomas. This study examines the relationship between CD133 and MDR1 in pediatric PAs exposed to chemotherapy, with the goal of identifying therapeutic targets that manifest as a result of chemotherapy. METHODS: Slides were obtained for 15 recurrent PAs, seven of which had received chemotherapy prior to surgical treatment for the recurrent tumor. These samples, as well as primary tumor tissue slides from the same patients were used to investigate CD133 and MDR1 expression via immunofluorescence. Archived frozen tissue samples from the same patients were used to examine CD133, MDR1 and PI3K-Akt-NF-κB signaling mediators, via western blot. Two drug resistant pediatric PA cell lines Res186 and Res199 were also used to evaluate the role of CD133 on cell response to cytotoxic therapy. RESULTS: CD133 and MDR1 were co-expressed and their expression was elevated in recurrent PAs from patients that had received chemotherapy, compared to patients that had not received chemotherapy. PI3K-Akt-NF-κB signaling mediator expression was also elevated in recurrent, chemotherapy-treated PA. Suppressing CD133 expression with siCD133 decreased levels of PI3K-Akt-NF-κB signaling mediators and MDR1, while increasing cell chemosensitivity, as indicated by quantification of apoptotic cells following chemotherapy. CONCLUSIONS: CD133 contributes to multidrug resistance by regulating MDR1 levels via the PI3K-Akt-NF-κB signal pathway not only in adult glioblastomas, but also in pediatric PAs. Targeting CD133, adjuvant to conventional chemotherapy may improve outcomes for children with recurrent PA.
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Antígeno AC133/metabolismo , Astrocitoma/metabolismo , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/metabolismo , Regulación hacia Arriba , Antígeno AC133/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adolescente , Astrocitoma/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quimioterapia Adyuvante , Niño , Preescolar , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Masculino , FN-kappa B/genética , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
Prenatal folic acid (FA) supplementation prevents neural tube defects. Folate receptor alpha (FRα) is critical for embryonic development, including neural crest (NC) development. Previously we showed that FRα translocates to the nucleus in response to FA, where it acts as a transcription factor. In this study, we examined if FA through interaction with FRα regulates stem cell characteristics of cranial neural crest cells (CNCCs)-critical for normal development. We hypothesized that FRα upregulates coding genes and simultaneously downregulates non-coding miRNA which targets coding genes in CNCCs. Quantitative RT-PCR and chromatin immunoprecipitation showed that FRα upregulates Oct4, Sox2, and Klf4 by binding to their cis-regulator elements-5' enhancer/promoters defined by H3K27Ac and p300 occupancy. FA via FRα downregulates miRNAs, miR-138 and miR-let-7, which target Oct4 and Trim71 (an Oct4 downstream effector), respectively. Co-immunoprecipitation data suggests that FRα interacts with the Drosha-DGCR8 complex to affect pre-miRNA processing. Transfecting anti-miR-138 or anti-miR-let-7 into non-proliferating neural crest cells (NCCs) derived from Splotch (Sp-/- ), restored their proliferation potential. In summary, these results suggest a novel pleiotropic role of FRα: (a) direct activation of Oct4, Sox2, and Klf4 genes; and (b) repression of biogenesis of miRNAs that target these genes or their effector molecules. Stem Cells 2016;34:2721-2732.
Asunto(s)
Receptor 1 de Folato/genética , Factores de Transcripción de Tipo Kruppel/genética , MicroARNs/genética , Células-Madre Neurales/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factores de Transcripción SOXB1/genética , Animales , Antagomirs/genética , Antagomirs/metabolismo , Femenino , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/metabolismo , Ácido Fólico/metabolismo , Ácido Fólico/farmacología , Regulación del Desarrollo de la Expresión Génica , Histonas/genética , Histonas/metabolismo , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/agonistas , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Noqueados , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Cresta Neural/citología , Cresta Neural/efectos de los fármacos , Cresta Neural/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Factor 3 de Transcripción de Unión a Octámeros/agonistas , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Factor de Transcripción PAX3/deficiencia , Factor de Transcripción PAX3/genética , Regiones Promotoras Genéticas , Unión Proteica , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Ribonucleasa III/genética , Ribonucleasa III/metabolismo , Factores de Transcripción SOXB1/agonistas , Factores de Transcripción SOXB1/metabolismo , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional , Factores de Transcripción p300-CBP/genética , Factores de Transcripción p300-CBP/metabolismoRESUMEN
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.
Asunto(s)
Neoplasias Encefálicas/fisiopatología , Proteínas de Unión al ADN/biosíntesis , Proteínas Musculares/biosíntesis , Tumor Rabdoide/fisiopatología , Teratoma/fisiopatología , Factores de Transcripción/biosíntesis , Adolescente , Western Blotting , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Proteínas de Unión al ADN/genética , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación in Situ , Lactante , Masculino , Proteínas Musculares/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Tumor Rabdoide/genética , Factores de Transcripción de Dominio TEA , Teratoma/genética , Factores de Transcripción/genética , Regulación hacia ArribaRESUMEN
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.