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1.
J Neurosurg Pediatr ; 32(2): 141-148, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37119101

RESUMO

OBJECTIVE: The aim of this study was to evaluate the incidence of spinal inclusion cyst (sIC) formation after open fetal myelomeningocele (fMMC) repair and the effect of dural patch closure. METHODS: The authors conducted a retrospective review of patients who underwent open fMMC repair at their institution between March 2011 and June 2020. All patients met the criteria for intervention defined by the Management of Myelomeningocele Study (MOMS). The primary outcomes investigated were development of sIC and need for surgical intervention. Secondary outcomes included need for CSF diversion, extent of reversal of hindbrain herniation, and ambulatory status. RESULTS: Of 56 patients who underwent open fMMC repair, 52 had adequate spinal imaging for review. Twelve of these patients (23%) developed sIC (95% CI 0.11-0.35). Six patients experienced symptoms and required surgical detethering with sIC resection. Six additional patients had evidence of sIC on surveillance MRI but remained asymptomatic. The authors found a statistically significant relationship between the use of a dural allograft patch and sIC formation (p = 0.05). In terms of sIC development, there was no statistically significant difference between patients who underwent primary closure and those who received an allograft at the level of the fascia (p = 0.34) or skin (p = 0.26). The rate of hydrocephalus requiring CSF diversion was 52%. Interestingly, 98% of patients had improvement in extent of hindbrain herniation. Dural patch closure did not have any effect on the rate of progressive hydrocephalus (p = 0.33) or degree of reversal of hindbrain herniation (p > 0.99). CONCLUSIONS: This study suggested that children with prenatally repaired MMC are at higher risk for development of sIC and associated symptoms than those who undergo postnatal repair. The presentation of symptoms was also earlier in these patients than previously reported after postnatal repair. The use of a dural allograft patch appears to have a positive correlation with sIC formation. Future investigations evaluating the incidence of sIC after fetoscopic MMC repair, in which primary dural closure typically cannot be achieved and a dural patch is most often utilized, will be helpful in facilitating prenatal counseling for patients considering fetal intervention.


Assuntos
Cistos , Hidrocefalia , Meningomielocele , Gravidez , Criança , Feminino , Humanos , Meningomielocele/complicações , Incidência , Hidrocefalia/cirurgia , Aloenxertos , Cistos/diagnóstico por imagem , Cistos/epidemiologia , Cistos/etiologia
2.
Nature ; 612(7941): 787-794, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36450980

RESUMO

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.


Assuntos
Neoplasias Encefálicas , Transformação Celular Neoplásica , Feto , Meduloblastoma , Humanos , Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Cerebelares/patologia , Cerebelo/citologia , Cerebelo/patologia , Feto/citologia , Feto/patologia , Meduloblastoma/patologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/patologia , Prognóstico
3.
Neurooncol Adv ; 4(1): vdac055, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35611273

RESUMO

Background: Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG. Methods: Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed. Results: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression. Conclusion: The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.

4.
Pediatr Neurol ; 127: 1-5, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34864371

RESUMO

BACKGROUND: We report the clinical, radiological, laboratory, and neuropathological findings in support of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. PATIENT DESCRIPTION: A previously healthy, eight-year-old Hispanic girl presented with subacute left-sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was positive. Magnetic resonance imaging revealed an enhancing right frontal lobe lesion with significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, she experienced neurological decline and died 93 days after presentation. SARS-CoV-2 testing revealed positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Postmortem brain autopsy remained consistent with vasculitis. CONCLUSION: This is the first pediatric presentation to suggest that SARS-CoV-2 can lead to a fatal, postinfectious, inflammatory small-vessel cerebral vasculitis. Our patient uniquely included supportive cerebrospinal fluid and postmortem tissue analysis. While most children recover from the neurological complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for severe disease.


Assuntos
COVID-19/sangue , COVID-19/diagnóstico por imagem , SARS-CoV-2/isolamento & purificação , Vasculite do Sistema Nervoso Central/sangue , Vasculite do Sistema Nervoso Central/diagnóstico por imagem , COVID-19/complicações , Criança , Evolução Fatal , Feminino , Humanos , Vasculite do Sistema Nervoso Central/etiologia
5.
J Neurosurg Pediatr ; 27(4): 391-399, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33545679

RESUMO

OBJECTIVE: The aim of this study was to investigate diffusion tensor imaging (DTI), an objective and noninvasive neuroimaging technique, for its potential as an imaging biomarker to predict the need and timing of CSF diversion surgery in patients after prenatal myelomeningocele (MMC) repair. METHODS: This was a retrospective analysis of data based on 35 pediatric patients after prenatal MMC repair (gestational age at birth 32.68 ± 3.42 weeks, range 24-38 weeks; 15 females and 20 males). A logistic regression analysis was used to classify patients to determine the need for CSF diversion surgery. The model performance was compared between using the frontooccipital horn ratio (FOHR) alone and using the FOHR combined with DTI values (the genu of the corpus callosum [gCC] and the posterior limb of the internal capsule [PLIC]). For patients who needed to be treated surgically, timing of the procedure was used as the clinical outcome to test the predictive value of DTI acquired prior to surgery based on a linear regression analysis. RESULTS: Significantly lower fractional anisotropy (FA) values in the gCC (p = 0.014) and PLIC (p = 0.037) and higher mean diffusivity (MD) values in the gCC (p = 0.013) were found in patients who required CSF diversion surgery compared with those who did not require surgery (all p values adjusted for age). Based on the logistic regression analysis, the FOHR alone showed an accuracy of performance of 0.69 and area under the receiver operating characteristic curve (AUC) of 0.60. The performance of the model was higher when DTI measures were used in the logistic regression model (accuracy = 0.77, AUC = 0.84 for using DTI values in gCC; accuracy = 0.75, AUC = 0.84 for using DTI values in PLIC). Combining the DTI values of the gCC or PLIC and FOHR did not improve the model performance when compared with using the DTI values alone. In patients who needed CSF diversion surgery, significant correlation was found between DTI values in the gCC and the time interval between imaging and surgery (FA: ρ = 0.625, p = 0.022; MD: ρ = -0.6830, p = 0.010; both adjusted for age and FOHR). CONCLUSIONS: The authors' data demonstrated that DTI could potentially serve as an objective biomarker differentiating patients after prenatal MMC repair regarding those who may require surgery for MMC-associated hydrocephalus. The predictive value for the need and timing of CSF diversion surgery is highly clinically relevant for improving and optimizing decision-making for the treatment of hydrocephalus in this patient population.


Assuntos
Imagem de Tensor de Difusão/métodos , Hidrocefalia/cirurgia , Meningomielocele/diagnóstico por imagem , Meningomielocele/cirurgia , Neuroimagem/métodos , Derivações do Líquido Cefalorraquidiano , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/cirurgia , Terapias Fetais , Humanos , Hidrocefalia/etiologia , Recém-Nascido , Masculino , Meningomielocele/complicações , Estudos Retrospectivos
6.
Childs Nerv Syst ; 37(5): 1613-1621, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33392653

RESUMO

INTRODUCTION: The objective of this study was to evaluate the utility of three-dimensional (3D) versus conventional two-dimensional (2D) endoscopy for fetal myelomeningocele repair using a low-fidelity fetoscopic surgical simulator. METHODS: A low-fidelity fetoscopic box trainer was developed for surgical simulation of myelomeningocele repair. Participants with varying surgical experience were recruited and completed three essential tasks (cutting skin, dural patch placement, and suturing skin) using both 2D and 3D endoscopic visualization. Participants were randomized to begin all tasks in either 2D or 3D. Time to completion was measured for each task, and each participant subsequently completed the NASA Load Index test and a questionnaire evaluating their experience. RESULTS: Sixteen participants completed the study tasks using both 2D and 3D endoscopes in the simulator. While the mean performance time across all tasks was shorter with 3D versus 2D endoscopy (cutting skin, 47 vs. 54 seconds; dural patch placement, 38 vs. 52 seconds; and suturing skin, 424 vs. 499 seconds), the results did not reach statistical significance. When comparing times to completion of each of the three tasks between levels of expertise, participants in the expert category were faster when suturing skin on the 2D modality (P = 0.047). Under 3D visualization, experts were faster at cutting the skin (P = 0.008). When comparing experiences using the NASA-TLX test, participants felt that their performance was better using 3D over the 2D system (P = 0.045). Overall, 13 of 16 (81.3%) participants preferred 3D over 2D visualization. CONCLUSIONS: Three-dimensional endoscopes could potentially be used in the near future for relative improvement in visualization and possibly performance during complex fetoscopic procedures such as prenatal repair of myelomeningocele defects. Further studies utilizing 3D scopes for other related procedures may potentially support clinical implementation of this technology in fetal surgery and also prove to be a useful tool in surgical training.


Assuntos
Meningomielocele , Feminino , Fetoscopia , Feto/cirurgia , Humanos , Imageamento Tridimensional , Meningomielocele/diagnóstico por imagem , Meningomielocele/cirurgia , Projetos Piloto , Gravidez , Cuidado Pré-Natal
7.
Oper Neurosurg (Hagerstown) ; 20(2): E131-E132, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33047136

RESUMO

Myelomeningocele (MMC) is the most common open neural tube defect associated with long-term survival. In 2011, The Management of Myelomeningocele Study (MOMS) trial demonstrated that fetal repair for MMC reduced the rate of shunted hydrocephalus and improved developmental, motor, and ambulation outcomes at 30 mo compared to postnatal intervention.1 Recent studies have demonstrated the safety and feasibility of fetoscopic MMC repair as well as reduction in preterm birth, lower risk of uterine dehiscence, and the option of vaginal delivery with this approach compared to open fetal repair.2-4 The patient is a 25-yr-old female, G4 P2, who presented at 20 wk's gestation with ultrasound findings concerning for MMC and Chiari II malformation. These findings were further corroborated with fetal magnetic resonance imaging. After extensive prenatal counseling in a multidisciplinary fashion and discussion regarding risks and benefits of prenatal closure of the MMC, the patient chose to undergo prenatal repair and surgical consent was obtained. At 25 wk's gestation, the patient underwent a fetoscopic multilayer closure with dural patch repair using a standardized, 3-port, carbon dioxide insufflation technique for the intrauterine treatment of MMC without any postoperative complications. The duration of the entire procedure was 275 min. At 36 wk's and 1 d's gestational age, the patient had a spontaneous vaginal delivery, resulting in a healthy male newborn. The surgical site was well healed without complications, and follow-up radiographic imaging was reassuring. This edited, 2-dimensional operative video highlights the key steps of the fetoscopic closure with follow-up postnatal clinical and radiographic outcomes.


Assuntos
Hidrocefalia , Meningomielocele , Nascimento Prematuro , Feminino , Fetoscopia , Idade Gestacional , Humanos , Hidrocefalia/cirurgia , Recém-Nascido , Masculino , Meningomielocele/diagnóstico por imagem , Meningomielocele/cirurgia , Gravidez
8.
J Matern Fetal Neonatal Med ; 34(10): 1651-1657, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-31345076

RESUMO

OBJECTIVE: This study compared the morbidities and financial burden associated with prenatal open myelomeningocele repair versus postnatal repair. MATERIALS AND METHODS: The retrospective study cohort included 23 mother-infant dyads undergoing prenatal repair and 30 with postnatal repair. Financial, demographic, and medical information were obtained for mother-infant dyads from each infant's birth through the first year of life. RESULTS: Infants in the prenatal repair group were significantly affected by sequelae of prematurity, including apnea, bronchopulmonary dysplasia, and retinopathy of prematurity. Importantly, fewer of these infants required ventriculoperitoneal shunt procedures and the overall improved composite outcome of shunting or death. Infants in the postnatal repair group required more hospital readmissions in the first year of life. Financial costs for mother-infant dyads in the prenatal repair group were higher, driven by the length of stay in the neonatal intensive care unit and maternal hospital admissions. Kaplan-Meier curves analyzing the relative contributions of the length of stay and total charges in the population were constructed. The maternal contribution was markedly different between groups due to postoperative hospitalization, readmission, and close fetal surveillance required. Though these differences did not reach statistical significance, it highlights an important burden on families and the medical system. CONCLUSIONS: This is the first study to report the contributions of prematurity in relation to maternal and infant morbidity and financial costs. The benefits of prenatal myelomeningocele repair include lower risk for ventriculoperitoneal shunting and fewer hospital readmissions. The risk of preterm birth and its neonatal sequelae continue to be a significant burden.


Assuntos
Meningomielocele , Nascimento Prematuro , Feminino , Humanos , Lactente , Recém-Nascido , Meningomielocele/cirurgia , Morbidade , Gravidez , Estudos Retrospectivos , Derivação Ventriculoperitoneal
9.
Acta Neuropathol Commun ; 8(1): 182, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33153497

RESUMO

Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs' genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , Progressão da Doença , Feminino , Deleção de Genes , Genoma , Genômica , Glioma/patologia , Glioma/terapia , Humanos , Lactente , Isocitrato Desidrogenase/genética , Masculino , Glicoproteínas de Membrana/genética , Gradação de Tumores , Recidiva Local de Neoplasia/terapia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myb/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor trkB/genética , Transativadores/genética
10.
J Neurooncol ; 149(3): 511-522, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33034839

RESUMO

PURPOSE: Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients. METHODS: Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m2; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively. RESULTS: The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ . CONCLUSIONS: Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies. TRIAL REGISTRATION: NCT02607124.


Assuntos
Aminopiridinas/uso terapêutico , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia/métodos , Glioma Pontino Intrínseco Difuso/terapia , Purinas/uso terapêutico , Adolescente , Adulto , Aminopiridinas/farmacocinética , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Glioma Pontino Intrínseco Difuso/patologia , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Prognóstico , Purinas/farmacocinética , Distribuição Tecidual , Adulto Jovem
11.
Mol Cancer Res ; 18(11): 1711-1723, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32801164

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor with a median survival of less than 1 year. No effective therapy is currently available, and no therapeutic advances have been made in several decades. We have previously identified BMI-1 as a potential therapeutic target in DIPG and have shown that BMI-1 is highly expressed in DIPG tumors regardless of histone 3 subtype. In the present study, we show that the modulation of BMI-1 leads to DNA damage, M phase cell-cycle arrest, chromosome scattering, and cell death. Interestingly, EZH2 inhibition did not alter these effects. Furthermore, modulation of BMI-1 sensitizes DIPG patient-derived stem-like cells to ionizing radiation (IR). Treatment of DIPG stem-like cells with PTC596, a BMI-1 modulator, and IR impairs the kinetics of DNA damage response (DDR). Both DDR foci formation and resolution were delayed, resulting in further reduction in cell viability compared with either treatment alone. In vivo, treatment of mice bearing DIPG xenografts with PTC596 leads to decreased tumor volume and growth kinetics, increased intratumoral apoptosis, and sustained animal survival benefit. Gene expression analysis indicates that BMI-1 expression correlates positively with DIPG stemness and BMI-1 signature. At the single-cell level, the analysis reveals that BMI-1 pathway is upregulated in undifferentiated cells and positively correlates with stemness in DIPG tumors. IMPLICATIONS: Together, our findings indicate that BMI-1 modulation is associated with mitotic abnormalities, impaired DDR, and cell death, supporting the combination of BMI-1 modulation and radiation as a promising novel therapy for children with DIPG.


Assuntos
Glioma Pontino Intrínseco Difuso/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Mitose , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Prenat Diagn ; 40(1): 49-57, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31351017

RESUMO

PURPOSE: The purpose of the study is to examine MRI findings of the brain and spine on prenatal and postnatal MRI following intrauterine repair of open spinal dysraphism (OSD) by open hysterotomy and fetoscopic approaches. MATERIALS AND METHODS: This study is a single-center HIPAA-compliant and IRB-approved retrospective analysis of fetal MRIs with open spinal dysraphism from January 2011 through December 2018 that underwent subsequent prenatal repair of OSD. RESULTS: Sixty-two patients met inclusion criteria: 47 underwent open repair, and 15 underwent fetoscopic repair, with an average gestational age of 22.6 ± 1.4 weeks at initial MRI. On postnatal MRI, spinal cord syrinx was seen in 34% (16/47) of patients undergoing open versus 33.3% (5/15) undergoing fetoscopic repair (P = 0.96). Postnatally, there was no significant difference in hindbrain herniation between the open versus fetoscopic repair groups (P = 0.28). Lateral ventricular size was significantly larger in the open (20.9 ± 6.7 mm) versus the fetoscopic repair (16.1 ± 4.9 mm) group (P = 0.01). CONCLUSION: Though lateral ventricular size in the open repair group was larger than the fetoscopic repair group, this can likely be explained by initial selection criteria used for fetoscopic repair. Other postoperative imaging parameters on postnatal MRI were not significantly different between the two groups.


Assuntos
Encefalocele/diagnóstico por imagem , Terapias Fetais/métodos , Fetoscopia/métodos , Hemorragias Intracranianas/diagnóstico por imagem , Meningomielocele/diagnóstico por imagem , Espinha Bífida Cística/diagnóstico por imagem , Siringomielia/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/cirurgia , Idade Gestacional , Humanos , Histerotomia/métodos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico por imagem , Doenças do Recém-Nascido/cirurgia , Ventrículos Laterais/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Meningomielocele/cirurgia , Seleção de Pacientes , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , Espinha Bífida Cística/cirurgia , Medula Espinal/diagnóstico por imagem , Ultrassonografia Pré-Natal
13.
Childs Nerv Syst ; 36(4): 827-833, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31399765

RESUMO

PURPOSE: To investigate white matter microstructural abnormality based on diffusion tensor imaging (DTI) in pediatric patients with fetal repair for myelomeningocele (MMC). METHODS: This was a retrospective analysis of DTI data from 8 pediatric patients with prenatal MMC repair (age range 1.64-33.70 months; sex 3F/5M) and 8 age-matched controls (age 2.24-31.20 months; sex 5F/2M). All participants were scanned on 1.5T GE Signa MR scanner (GE Healthcare, Milwaukee, WI) with the same sequence specifications. Two DTI measures, including fractional anisotropy (FA) and mean diffusivity (MD), were calculated from the genu of corpus callosum (gCC) and the posterior limb of internal capsule (PLIC). DTI values and fronto-occipital horn ratio (FOHR) were tested for group difference based on two-tailed paired t test. RESULTS: The ventricle size based on FOHR in patients with prenatal MMC repair was significantly larger than that in the age-matched control group (p < 0.001). Statistically significant group difference in DTI (lower FA and higher MD in patient group) was found in gCC (p = 0.007 and 0.003, respectively). A trend level increase in MD was also found (p = 0.065) in PLIC in patients when compared with the age-matched controls. CONCLUSION: Our data showed white matter abnormality based on DTI in pediatric patient with fetal repair for MMC. The sensitivity of DTI in detecting white matter abnormality, as shown in the present study, may help to serve as an imaging biomarker for assessing hydrocephalus and improve and optimize decision making for the treatment of hydrocephalus in this patient population.


Assuntos
Hidrocefalia , Meningomielocele , Anisotropia , Encéfalo , Criança , Pré-Escolar , Imagem de Tensor de Difusão , Feminino , Humanos , Lactente , Meningomielocele/diagnóstico por imagem , Meningomielocele/cirurgia , Gravidez , Estudos Retrospectivos
15.
Acta Neuropathol Commun ; 5(1): 78, 2017 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-29084603

RESUMO

Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Adulto , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Metilação de DNA , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Adulto Jovem
16.
Oncotarget ; 8(38): 62962-62975, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28968963

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor. No effective curative therapy is currently available and no therapeutic advances have been made in several decades. BMI-1 is a member of the multimeric protein complex Polycomb repressor complex 1. It is highly expressed in a number of diseases and malignancies and has been implicated in self-renewal of normal and cancer cells, and in DNA damage signaling. The role of BMI-1 in DIPG is largely unknown. Here, we show that BMI-1 is highly expressed in tumor tissue samples of DIPG patients and in patient-derived cancer stem-like cells. BMI-1 downregulation leads to the inhibition of DIPG patient-derived neurosphere cell proliferation, cell cycle signaling, self-renewal, telomerase expression and activity, and suppresses DIPG cell migration. Moreover, targeted inhibition of BMI-1 sensitizes DIPG cells to radiomimetic drug-induced DNA damage. Together, our data validate BMI-1 as a potential therapeutic target to treat children with DIPG.

17.
Pediatr Neurol ; 72: 81-85, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28511812

RESUMO

BACKGROUND: Subependymal giant cell astrocytomas (SEGA) are slow-growing tumors, which can cause obstructive hydrocephalus in patients with tuberous sclerosis complex (TSC). These tumors require routine surveillance with magnetic resonance imaging. Current consensus guidelines recommend treatment of asymptomatic SEGAs with an mechanistic target of rapamycin (mTOR) inhibitor because these medications have demonstrated efficacy and safety in multiple prospective clinical trials. For symptomatic SEGAs, standard therapy typically involves surgical resection of the tumor to relieve mass effect and resolve hydrocephalus. However, resection can be associated with significant perioperative morbidity and complications. There are anecdotal reports of using mTOR inhibitors to reduce tumor size in preparation for surgery, but prospective studies comparing sole mTOR inhibitor therapy with surgical management have not been completed. METHODS: Here, we present a seven-year-old boy with a large, symptomatic SEGA which was treated acutely with everolimus. RESULTS: Everolimus treatment resulted in rapid reduction in tumor size, symptomatic improvement, and decrease in cerebrospinal fluid protein. CONCLUSIONS: Everolimus can effectively reduce tumor size, decrease cerebrospinal fluid protein, and allow successful ventriculoperitoneal shunt placement without the need for surgical resection of a symptomatic SEGA.


Assuntos
Antineoplásicos/uso terapêutico , Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Everolimo/uso terapêutico , Hidrocefalia/tratamento farmacológico , Astrocitoma/complicações , Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Pré-Escolar , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Imageamento por Ressonância Magnética , Masculino , Resultado do Tratamento
18.
Curr Neuropharmacol ; 15(1): 129-133, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27109746

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a malignant brain tumor of childhood that carries an extremely poor prognosis. There are ~200-300 new cases diagnosed each year, [1, 2] and little progress has been made in changing the prognosis and outcome of the tumor since it was first documented in the literature in 1926 [3]. The median overall survival is 8-11 months [4], with an overall survival rate of 30% at 1 year, and less than 10% at 2 years [4]. This review will provide background information on DIPGs, a historical look at the trends in caring for DIPG, and current trends in diagnosis and treatment. By changing the way we care for these terminal tumors, we can work towards having a better understanding of the underlying molecular biology, and attempt to develop better chemotherapeutic tools to combat the disease.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico , Glioma/diagnóstico , Pediatria , Ponte/patologia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Feminino , Glioma/patologia , Glioma/terapia , Humanos , Lactente , Masculino
19.
J Neurooncol ; 129(3): 443-451, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27350411

RESUMO

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioma/tratamento farmacológico , Indóis/uso terapêutico , Niacinamida/análogos & derivados , Telomerase/metabolismo , Adolescente , Alanina Transaminase/metabolismo , Contagem de Células Sanguíneas , Neoplasias do Sistema Nervoso Central/cirurgia , Criança , Pré-Escolar , Feminino , Glioma/cirurgia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Niacinamida/uso terapêutico , Oligonucleotídeos , Telomerase/genética , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
20.
Acta Neuropathol Commun ; 4: 13, 2016 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-26860432

RESUMO

Through inadvertent oversight of the authors, the paper failed to acknowledge funding support from Genome Canada. The Acknowledgement section should include the text: "This work was supported by the Canadian Centre for Computational Genomics (C3G), part of the Genome Innovation Network (GIN), funded by Genome Canada through Genome Quebec and Ontario Genomics".

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