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BACKGROUND: Patients are commonly monitored for hyponatremia after intracranial procedures, yet the prevalence of hyponatremia after cranial vault reconstruction (CVR) remains unclear. The purpose of this study is to define the prevalence, risk factors, and complications of hyponatremia after CVR to optimize postoperative sodium surveillance protocols. METHODS: Patients with nonsyndromic, single-suture craniosynostosis who underwent primary CVR between 2009 and 2020 at Michigan Medicine were included (n = 231). Demographic, intraoperative, and postoperative characteristics were compared by postoperative hyponatremia status at P < 0.05 significance. Hyponatremia was defined as mild (<135 mEq/L), moderate (<130 mEq/L), or severe (<125 mEq/L) based on the lowest postoperative laboratory draw. RESULTS: Twenty-three patients (10.0%) developed mild postoperative hyponatremia. No patient developed moderate or severe postoperative hyponatremia. On multivariable regression, decreased preoperative sodium level (P = 0.03) and decreased preoperative weight (P = 0.02) were significantly associated with mild postoperative hyponatremia. No patient developed complications or required hospital readmission because of hyponatremia. CONCLUSIONS: This large retrospective cohort study of patients with nonsyndromic single-suture craniosynostosis demonstrated a 10% prevalence of mild, clinically inconsequential hyponatremia and 0% prevalence of moderate or severe, clinically significant hyponatremia after primary CVR. Patients with low preoperative sodium level or weight were at increased risk for developing mild postoperative hyponatremia. The results suggest that patients with preoperative sodium greater than 140 mEq/L or preoperative weight greater than 10 kg may be candidates for limited postoperative sodium surveillance; however, future prospective studies are warranted before implementation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.
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Craniossinostoses , Hiponatremia , Procedimentos de Cirurgia Plástica , Complicações Pós-Operatórias , Humanos , Hiponatremia/epidemiologia , Hiponatremia/etiologia , Craniossinostoses/cirurgia , Feminino , Masculino , Estudos Retrospectivos , Prevalência , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Procedimentos de Cirurgia Plástica/efeitos adversos , Procedimentos de Cirurgia Plástica/métodos , Lactente , Fatores de Risco , Michigan/epidemiologia , Crânio/cirurgiaRESUMO
OBJECTIVE: Given the lack of a definitive treatment and the poor prognosis of patients with diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG), socioeconomic status (SES) may affect treatment access and therefore survival. Therefore, this study aimed to examine the relationship between SES and treatment modalities, progression-free survival (PFS), and overall survival (OS) in children with DMG/DIPG. METHODS: A retrospective, single-institution review was conducted of medical records of patients ≤ 18 years of age who had DMG or DIPG that was diagnosed between 2000 and 2022. Patient demographics, surgical interventions, chemotherapy, radiation therapy, clinical trial enrollment, and medical care-related travel were extracted. SES variables (education and mean income) for associated patient census tracts were collected and stratified. Statistical analysis using unpaired t-tests, chi-square analysis, and log-rank tests was conducted. RESULTS: Of the 96 patients who met the inclusion criteria, the majority were female (59%) and non-Hispanic White (57%). The median PFS, median OS, and time from diagnosis to treatment did not differ between races/ethnicities or sex. Ninety-one of 96 patients had census tract data available. Patients from higher-income census tracts (> 50% of families with annual household income greater than $50,000) had a longer median OS (480 vs 235 days, p < 0.001) and traveled significantly longer distances for medical care (1550 vs 1114 miles, p = 0.048) than families from lower-income census tracts. Patients from the highest education quartile traveled significantly farther for treatment than the lowest education quartile (mean 2964 vs 478 miles, p = 0.047). Patients who received both oral and intravenous chemotherapy were more likely to be from higher-income census tracts than those who received intravenous or no chemotherapy. Duration of PFS, rates of clinical trial enrollment, biopsy rates, H3K27 mutation status, ventriculoperitoneal shunt placement rates, and radiotherapy rates were not associated with SES variables. CONCLUSIONS: Patients from families from higher-income census tracts experienced longer OS and traveled farther for treatment. Patients from families from higher-education-level census tracts traveled more often for treatment. The authors' findings suggest that SES influences DMG and DIPG OS. More studies should be done to understand the role of SES in the outcomes of children with DMG/DIPG.
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Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Classe Social , Humanos , Feminino , Masculino , Neoplasias do Tronco Encefálico/terapia , Neoplasias do Tronco Encefálico/patologia , Criança , Estudos Retrospectivos , Glioma Pontino Intrínseco Difuso/terapia , Pré-Escolar , Glioma/terapia , Glioma/patologia , Glioma/mortalidade , Adolescente , Resultado do Tratamento , Lactente , Intervalo Livre de ProgressãoRESUMO
Recent clinical trials for H3K27-altered diffuse midline gliomas (DMGs) have shown much promise. We present a consensus roadmap and identify three major barriers: (1) refinement of experimental models to include immune and brain-specific components; (2) collaboration among researchers, clinicians, and industry to integrate patient-derived data through sharing, transparency, and regulatory considerations; and (3) streamlining clinical efforts including biopsy, CNS-drug delivery, endpoint determination, and response monitoring. We highlight the importance of comprehensive collaboration to advance the understanding, diagnostics, and therapeutics for DMGs.
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Neoplasias Encefálicas , Glioma , Humanos , Criança , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/diagnóstico , Glioma/genética , Glioma/terapia , Mutação , Encéfalo/patologia , BiópsiaRESUMO
BACKGROUND: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. METHODS: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. FINDINGS: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1). INTERPRETATION: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. FUNDING: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.
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Antineoplásicos , Glioblastoma , Glioma , Adulto , Feminino , Humanos , Masculino , Quimiorradioterapia , Terapia Genética , Glioblastoma/genética , Glioblastoma/terapia , Glioma/genética , Glioma/terapia , Adolescente , Pessoa de Meia-Idade , IdosoRESUMO
OBJECTIVE: Necrotizing enterocolitis (NEC) and posthemorrhagic hydrocephalus are both conditions that can affect preterm infants. The peritoneum is the preferred terminus for shunt placement, but another terminus is sometimes used due to subjective concerns about infection and complications related to NEC. The aim of this study was to examine the rates of ventriculoatrial (VA) and ventriculoperitoneal (VP) shunt infection and failure in pediatric patients with a history of NEC. METHODS: A single-center retrospective review of medical records from 2009 to 2021 was performed to identify pediatric patients with NEC who underwent shunt placement before 2 years of age. Patients were excluded if shunt placement preceded NEC diagnosis. Patient demographic characteristics, timing of shunt placement, type of shunt, shunt infections or revisions, and timing and management of NEC were extracted. The Student t-test and Fisher exact test were used to calculate significance. Kaplan-Meier curves were calculated. RESULTS: Twenty-two patients met the inclusion criteria. Most patients underwent VP shunt placement (16 [71.4%]). Patients who underwent surgical management of NEC compared with those who underwent medical management were more likely to have a VA shunt placed (p = 0.02). One VA shunt and 3 VP shunts became infected during follow-up (p = 0.7). The mean time until infection was not significantly different between VA and VP shunts (p = 0.73). Significantly more VA shunts required revision (83% vs 31%, p = 0.04), and VA shunts had a significantly shorter time until failure (3.0 ± 0.8 vs 46.3 ± 7.55 months, p = 0.03). CONCLUSIONS: VP shunts had a significantly longer time until failure than VA shunts; these shunts had similar infection rates in infants with prior NEC. When feasible, neurosurgeons and pediatric general surgeons can consider placing a VP shunt even if the patient has a history of NEC.
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Enterocolite Necrosante , Hidrocefalia , Recém-Nascido , Criança , Humanos , Lactente , Derivação Ventriculoperitoneal/efeitos adversos , Enterocolite Necrosante/complicações , Enterocolite Necrosante/cirurgia , Recém-Nascido Prematuro , Hidrocefalia/cirurgia , Hidrocefalia/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Currently, there is no consensus recommendation regarding the safety of sports participation for pediatric patients with arachnoid cysts (ACs). OBJECTIVE: To prospectively survey patients with ACs to define the risk of sports-associated neurologic injury in untreated and treated patients. METHODS: A prospectively administered survey was given to all patients diagnosed with an AC who presented to a single pediatric neurosurgery clinic between December 2010 and December 2021. Data were recorded on demographic information, imaging characteristics, treatment, sports participation, and presence of sports-related neurologic injury. The type and date of surgery for the AC were noted if surgery was performed. RESULTS: Of the 303 patients with completed surveys, 189 patients participated in sports, and 94 patients had prospective data available. There was no significant difference in cyst location or Galassi score between patients who did and did not participate in contact vs noncontact sports and those who did and did not experience a concussion. A cumulative total of 2700.5 seasons of sports were played (2499.7 in untreated and 200.8 in treated patients). There were 44 sports-related concussions among 34 patients: 43 in untreated patients and 1 in a treated patient. For all participants, the concussion rate was 16.3 per 1000 seasons of all sports and 14.8 per 1000 seasons of contact sports. The concussion rate after AC treatment was 4.9 per 1000 seasons of all sports. Three patients experienced sports-related AC rupture or hemorrhage, none of which required surgery or resulted in lasting neurologic symptoms or deficits. CONCLUSION: The rates of sports-related concussion and cyst rupture in patients with AC in both treated and untreated populations were low. We advocate for a generally permissive posture toward sports participation in this population.
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Cistos Aracnóideos , Traumatismos em Atletas , Concussão Encefálica , Esportes , Humanos , Criança , Cistos Aracnóideos/epidemiologia , Cistos Aracnóideos/cirurgia , Estudos Prospectivos , Traumatismos em Atletas/diagnóstico , Concussão Encefálica/diagnósticoRESUMO
INTRODUCTION: Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. Access to timely molecular diagnostic testing for brain tumor patients is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. METHODS: By combining stimulated Raman histology (SRH), a rapid, label-free, non-consumptive, optical imaging method, and deep learning-based image classification, we are able to predict the molecular genetic features used by the World Health Organization (WHO) to define the adult-type diffuse glioma taxonomy, including IDH-1/2, 1p19q-codeletion, and ATRX loss. We developed a multimodal deep neural network training strategy that uses both SRH images and large-scale, public diffuse glioma genomic data (i.e. TCGA, CGGA, etc.) in order to achieve optimal molecular classification performance. RESULTS: One institution was used for model training (University of Michigan) and four institutions (NYU, UCSF, Medical University of Vienna, and University Hospital Cologne) were included for patient enrollment in the prospective testing cohort. Using our system, called DeepGlioma, we achieved an average molecular genetic classification accuracy of 93.2% and identified the correct diffuse glioma molecular subgroup with 91.5% accuracy within 2 minutes in the operating room. DeepGlioma outperformed conventional IDH1-R132H immunohistochemistry (94.2% versus 91.4% accuracy) as a first-line molecular diagnostic screening method for diffuse gliomas and can detect canonical and non-canonical IDH mutations. CONCLUSIONS: Our results demonstrate how artificial intelligence and optical histology can be used to provide a rapid and scalable alternative to wet lab methods for the molecular diagnosis of brain tumor patients during surgery.
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Neoplasias Encefálicas , Glioma , Adulto , Humanos , Inteligência Artificial , Estudos Prospectivos , Glioma/diagnóstico por imagem , Glioma/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Imuno-Histoquímica , Isocitrato Desidrogenase/genética , Mutação/genéticaRESUMO
BACKGROUND: Currently, there is no consensus recommendation regarding the safety of sports participation for pediatric patients with Chiari I malformation (CM-I). OBJECTIVE: To prospectively survey the treated and untreated patients with CM-I to define the risk of sports-associated neurological injury. METHODS: A prospective survey was administered to 744 pediatric patients at one neurosurgery clinic between 2010 and 2021. Data were recorded on demographic information, imaging characteristics, treatment, sports participation, and presence of sports-related neurological injury. Patients with incomplete data were called. Two hundred seven patients completed at least 1 subsequent survey and were prospectively followed (mean 1.6 years). RESULTS: Of 744 patients with completed surveys, 462 participated in sports. Sports participants were more likely to be older at presentation ( P < .001) and have rounded cerebellar tonsil morphology ( P < .001). Seasons of sports played before and after CM-I decompression (CMD) totaled 5918.7 and 936, respectively. There were 84 sports-related concussions among 55 patients; 79 in untreated patients and 5 after CMD. For all sports participants, the concussion rate was 12.3/1000 seasons of all sports, 9.2/1000 seasons of limited-contact sports, and 13.8/1000 of contact sports. The concussion rate after CMD was 5.3/1000 seasons of all sports, 9.2/1000 seasons of limited-contact sports, and 7.1/1000 seasons of contact sports. There were no reports of long-lasting neurological issues postconcussion or of permanent spinal cord injury. CONCLUSION: No permanent or catastrophic sports-associated neurological injuries were reported. The concussion rates in treated and untreated patients with CM-I were low. Therefore, sports participation in this population should be permitted in most cases.
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Traumatismos em Atletas , Concussão Encefálica , Esportes , Humanos , Criança , Estudos Prospectivos , Traumatismos em Atletas/epidemiologia , Traumatismos em Atletas/terapia , Traumatismos em Atletas/complicações , Concussão Encefálica/complicaçõesRESUMO
Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal. 39, 942-956.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Mutação , Glioma/genética , Glioma/metabolismo , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismoRESUMO
PURPOSE: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. EXPERIMENTAL DESIGN: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. RESULTS: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFß signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. CONCLUSIONS: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.
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Neoplasias Encefálicas , Glioblastoma , Animais , Camundongos , Humanos , Glioblastoma/metabolismo , Linhagem Celular Tumoral , Neoplasias Encefálicas/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Temozolomida/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos Alquilantes/farmacologiaRESUMO
Chiari I malformation is a common condition seen by adult and pediatric neurosurgeons. With increased utilization of MRI over time, incidental findings of Chiari I malformation are occurring more frequently. The prevalence of symptomatic Chiari I malformation is much smaller than that of asymptomatic Chiari I malformation. The prevalence of Chiari I malformation-associated syringomyelia is likely overestimated in the literature. The epidemiology of Chiari I malformation and associated syringomyelia differs based on age, sex, ethnicity, race, and socioeconomic status. The natural history of Chiari I malformation and associated syringomyelia appears to be quite benign as few patients who are managed nonsurgically later require surgical intervention.
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Malformação de Arnold-Chiari , Siringomielia , Adulto , Humanos , Criança , Siringomielia/complicações , Siringomielia/epidemiologia , Siringomielia/cirurgia , Malformação de Arnold-Chiari/complicações , Malformação de Arnold-Chiari/epidemiologia , Malformação de Arnold-Chiari/cirurgia , Imageamento por Ressonância MagnéticaRESUMO
An abnormal or absent superficial abdominal reflex (SAR) may be associated with an underlying spinal cord syrinx. The sensitivity of an abnormal or absent SAR and the relationship to Chiari malformation type I (CM-I) or syrinx morphology has not been studied. We aimed to describe the relationship between SAR abnormalities and syrinx size, location, and etiology. Children who underwent brain or c-spine MRI over 11 years were reviewed in this retrospective cohort study. Patients with idiopathic and CM-I-associated syringes (axial diameter ≥ 3 mm) were included. Clinical examination findings (including SAR) and imaging characteristics were analyzed. Of 271 patients with spinal cord syrinx, 200 had either CM-I-associated or idiopathic syrinx, and 128 of these patients had SAR-evaluation documentation. Forty-eight percent (62/128) had an abnormal or absent reflex. Abnormal/absent SAR was more common in patients with CM-I-associated syrinx (61%) compared with idiopathic syrinx (22%) (P < 0.0001). Abnormal/absent SAR was associated with wider syringes (P < 0.001), longer syringes (P < 0.05), and a more cranial location of the syrinx (P < 0.0001). Controlling for CM-I, scoliosis, age, sex, cranial extent of syrinx, and syrinx dimensions, CM-I was independently associated with abnormal or absent SAR (OR 4.2, 95% CI 1.4-14, P < 0.01). Finally, the sensitivity of SAR for identifying a patient with syrinx was 48.1%. An abnormal/absent SAR was present in most patients with CM-I-associated syrinx but in a minority of patients with idiopathic syrinx. This has implications for pathophysiology of CM-I-associated syrinx and in guiding clinical care of patients presenting with syrinx.
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Malformação de Arnold-Chiari , Escoliose , Siringomielia , Malformação de Arnold-Chiari/complicações , Malformação de Arnold-Chiari/diagnóstico por imagem , Criança , Humanos , Imageamento por Ressonância Magnética/efeitos adversos , Reflexo Abdominal/fisiologia , Reflexo Anormal , Estudos Retrospectivos , Escoliose/etiologia , Siringomielia/complicações , Siringomielia/diagnóstico por imagemRESUMO
Elizabeth Crosby (1888-1983) is a beloved and well-respected titan of neuroanatomy. Her contributions to our understanding of neuroanatomy are rooted in her seminal text, The Comparative Anatomy of the Nervous System of Vertebrates, Including Man, published in 1936, which is a masterful and comprehensive account of comparative neuroanatomy. Her later texts, Correlative Neurosurgery and Correlative Anatomy of the Nervous System, are standard reference texts to this day. Her mentorship of graduate students, close work with the University of Michigan neurosurgery department, and the quality of her research and scientific publications were recognized with many awards, culminating in the National Medal of Science presented by President Carter in 1980.
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Neuroanatomia , Neurocirurgia , Animais , Amigos , Humanos , Masculino , Mentores , Neurocirurgia/educação , Procedimentos NeurocirúrgicosRESUMO
The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.
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Internato e Residência , Neurocirurgia , Educação de Pós-Graduação em Medicina , Bolsas de Estudo , Humanos , Neurocirurgiões/educação , Neurocirurgia/educação , Estados UnidosRESUMO
Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cyclerelated genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WTexpressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.
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Ependimoma , Histonas , Animais , Criança , Ependimoma/genética , Epigênese Genética , Epigenômica , Histonas/genética , Humanos , Redes e Vias Metabólicas , CamundongosRESUMO
OBJECTIVE: The objective of this study was to understand the natural history of scoliosis in patients with Chiari malformation type I (CM-I) with and without syringomyelia. METHODS: A retrospective review of data was conducted. Patients with CM-I were identified from a cohort of 14,118 individuals age 18 years or younger who had undergone MRI over an 11-year period at the University of Michigan. Patients eligible for study inclusion had a coronal curve ≥ 10° on radiography, associated CM-I with or without syringomyelia, and at least 1 year of clinical follow-up prior to any surgery. Curve magnitude at initial diagnosis, prior to posterior fossa decompression (PFD; if applicable), and at the last follow-up (prior to any surgical correction of scoliosis) was recorded, and clinical and radiographic characteristics were noted. The change in curve magnitude by 10° was defined as curve progression (increase by 10°) or regression (decrease by 10°). RESULTS: Forty-three patients met the study inclusion criteria and were analyzed. About one-third (35%) of the patients presented with symptoms attributed to their CM-I. The mean degree of scoliosis at presentation was 32.6° ± 17.7°. Twenty-one patients (49%) had an associated syrinx. The mean tonsil position below the level of the foramen magnum was 9.8 ± 5.8 mm. Patients with a syrinx were more likely to have a curve > 20° (86% vs 41%, p = 0.002). Curve magnitude remained stable (≤ ±10°) in 77% of patients (33/43), progressed in 16% (7/43), and regressed in 7% (3/43). Mean age was higher (14.8 ± 0.59 years) among patients with regressed curves (p = 0.026). All regressed curves initially measured ≤ 20° (mean 14° ± 5.3°), and none of the patients with regressed curves had a syrinx. The change in curve magnitude was statistically similar in patients with (7.32° ± 17.7°) and without (5.32° ± 15.8°) a syrinx (p = 0.67). After a mean follow-up of 3.13 ± 2.04 years prior to surgery, 27 patients (63%) ultimately underwent posterior fossa or scoliosis correction surgery. For those who eventually underwent PFD only, the rate of change in curve magnitude prior to surgery was 0.054° ± 0.79°. The rate of change in curve magnitude was statistically similar before (0.054° ± 0.79°) and after (0.042° ± 0.33°) surgery (p = 0.45) for patients who underwent PFD surgery only. CONCLUSIONS: The natural history of scoliosis in the presence of CM-I is variable, though most curves remained stable. All curves that regressed were ≤ 20° at initial diagnosis, and most patients in such cases were older at scoliosis diagnosis. Patients who underwent no surgery or PFD only had similar profiles for the change in curve magnitude, which remained relatively stable overall, as compared to patients who underwent PFD and subsequent fusion, who demonstrated curve progression. Among the patients with a syrinx, no curves regressed, most remained stable, and some progressed. Understanding this variability is a first step toward building a prediction model for outcomes for these patients.
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Malformação de Arnold-Chiari/epidemiologia , Escoliose/epidemiologia , Siringomielia/epidemiologia , Malformação de Arnold-Chiari/complicações , Malformação de Arnold-Chiari/cirurgia , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Escoliose/complicações , Escoliose/cirurgia , Siringomielia/complicações , Siringomielia/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Cephalohematoma of infancy is the result of a subperiosteal blood collection that usually forms during birth-related trauma. A small proportion of cephalohematomas can calcify over time, causing a permanent calvarial deformity that is only correctable with surgery. The authors present a technique for the excision and reconstruction of calcified cephalohematoma and their management experience over the past 25 years. METHODS: All patients with a diagnosis of calcified cephalohematoma between 1994 and 2019 were identified. Patients were included if the diagnosis was confirmed by a pediatric plastic surgeon or a neurosurgeon. All patients underwent surgical evaluation followed by surgical intervention or observation. Patient demographics and potential risk factors for both surgical and nonsurgical groups were compared using chi-square or Fisher's exact test. Additional data were collected for the surgical cohort. RESULTS: Of 160 infants diagnosed with cephalohematoma, 72 met inclusion criteria. Thirty patients underwent surgical treatment. There was no significant difference in demographics, baseline characteristics, or potential risk factors between the operative and nonoperative groups. Mean age at the time of surgery was 8.6 months. Twenty-one surgical patients (70 percent) required inlay bone grafting. All surgery patients had improvement in calvarial shape. The main risk of surgery was blood loss requiring transfusion [eight patients (26.7 percent)]. Thirteen percent of patients experienced minor complications. CONCLUSIONS: This series of 72 children with calcified cephalohematomas, 30 of whom required surgical intervention, is one of the largest to date. The technique presented herein demonstrated excellent surgical outcomes by restoring normal cranial contours and was associated with a low complication profile. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
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Traumatismos do Nascimento/complicações , Transplante Ósseo/métodos , Calcinose/terapia , Traumatismos Cranianos Fechados/complicações , Hematoma/terapia , Traumatismos do Nascimento/patologia , Traumatismos do Nascimento/terapia , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Transfusão de Sangue/estatística & dados numéricos , Transplante Ósseo/efeitos adversos , Transplante Ósseo/estatística & dados numéricos , Calcinose/epidemiologia , Calcinose/etiologia , Calcinose/patologia , Tratamento Conservador/estatística & dados numéricos , Traumatismos Cranianos Fechados/patologia , Traumatismos Cranianos Fechados/terapia , Hematoma/etiologia , Hematoma/patologia , Humanos , Lactente , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Crânio/patologia , Crânio/cirurgia , Resultado do TratamentoRESUMO
PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Meduloblastoma/tratamento farmacológico , Meduloblastoma/radioterapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Clinical findings in children with unilateral coronal craniosynostosis are characteristic, and therefore clinicians have questioned the need for confirmatory imaging. Preoperative computed tomographic imaging is a powerful tool for diagnosing associated anomalies that can alter treatment management and surgical planning. The authors' aim was to determine whether and how routine preoperative imaging affected treatment management in unilateral coronal craniosynostosis patients within their institution. METHODS: A retrospective, single-center review of all patients who underwent cranial vault remodeling for unilateral coronal craniosynostosis between 2006 and 2014 was performed. Patient data included demographics, age at computed tomographic scan, age at surgery, results of the radiographic evaluation, and modification of treatment following radiologic examination. RESULTS: Of 194 patients diagnosed with single-suture craniosynostosis, 29 were diagnosed with unilateral coronal craniosynostosis. Additional radiographic anomalies were found in 19 unilateral coronal craniosynostosis patients (65.5 percent). These included severe deviation of the anterior superior sagittal sinus [n = 12 (41.4 percent)], Chiari I malformation [n = 1 (3.4 percent)], and benign external hydrocephalus [n = 2 (6.9 percent)]. The radiographic anomalies resulted in a change in management for 48.3 percent of patients. Specifically, alteration in frontal craniotomy design occurred in 12 patients (41.4 percent), and two patients (6.9 percent) required further radiographic studies. CONCLUSIONS: Although clinical findings in children with unilateral coronal craniosynostosis are prototypical, preoperative computed tomographic imaging is still of great consequence and continues to play an important role in surgical management. Preoperative imaging enabled surgeons to alter surgical management and avoid inadvertent complications such as damage to a deviated superior sagittal sinus. Imaging findings of Chiari malformation and hydrocephalus also permitted judicious follow-up. CLINICAL QUESTIONS/LEVEL OF EVIDENCE: Therapeutic, IV.