Tadanori Tomita

Spina bifida outcome: A 25-year prospective

Background: Open spina bifida is the most complex congenital abnormality compatible with long-term survival. This report outlines the 20- to 25-year outcome for our original cohort of patients with a myelomeningocele treated in a nonselective, prospective manner. Methods: Of the initial 118 children, 71 patients were available for our most recent review. Nineteen patients have been lost to follow-up and 28 patients have died. Data were collected on: motor level, shunt status, education/employment, seizure history, mobility, bladder/bowel continence, tethered cord, scoliosis, latex allergy, posterior cervical decompression, tracheostomy and/or gastrostomy tube. Results: Mortality (24%) continues to climb into young adulthood. Eighty-six percent of the cohort have cerebrospinal fluid diversion, with 95% having undergone at least one shunt revision. Thirty-two percent have undergone a tethered cord release, with 97% having an improvement or stabilization in their preoperative symptoms. Forty-nine percent have scoliosis, with 43% eventually requiring a spinal fusion. Sixteen patients (23%) have had at least one seizure. Eighty-five percent are attending or have graduated from high school and/or college. More than 80% of young adults have social bladder continence. Approximately 1/3 of patients are allergic to latex, with 6 patients having experienced a life-threatening reaction. Conclusion: At least 75% of children born with a myelomeningocele can be expected to reach their early adult years. Late deterioration is common. One of the greatest challenges in medicine today is establishing a network of care for these adults with spina bifida.

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Surgical results of posterior fossa decompression for patients with Chiari I malformation

IntroductionAn increasing number of children with Chiari I malformations are coming to the attention of neurosurgeons today, although a consensus on the surgical approach to these lesions has yet to be found.MethodsWe present a retrospective analysis of posterior fossa decompression (PFD) performed at our institution on 96 patients from 1989 to 2001. Statistical analyses based on clinical and radiographic presentation and the types of surgical procedures used formed the basis for our review.ResultsMost of the patients with hydromyelia underwent duraplasty procedures with or without tonsillar manipulation. In contrast, most patients without hydromyelia underwent bony decompression with dural scoring and intraoperative ultrasound. PFD with bony decompression and dural scoring showed a 72% success rate, compared with 68% for duraplasty. Dural opening was not more likely to improve or arrest hydromyelia. The group subjected to duraplasty, however, had a significantly higher complication rate. Patients under the age of 8 fared better than their older counterparts.ConclusionsOverall, we favor a tailored posterior fossa craniectomy with dural scoring as the initial surgical procedure in children with Chiari I malformation with or without a syrinx. This less invasive approach minimizes complications associated with dural opening and offers comparable success rates.

Craniopharyngiomas in children: Surgical experience at Children's Memorial Hospital

ObjectivesCraniopharyngioma during childhood poses difficulty in management because of the high incidence of surgical complications and treatment failure. In order to identify less detrimental and more effective treatment, a personal series of craniopharyngioma was reviewed in regard to various clinical factors, patient factors (age and sex), tumor factors (location and extension, relationship with chiasm, and hydrocephalus), and therapeutic modes [extent of resection and radiation therapy (RT)].Materials and methodsFifty-four childhood craniopharyngiomas treated from 1984 to 2003 were reviewed. Preoperative neuroimaging studies were classified depending upon tumor location and extension. In this series of 54 patients, 43 had total tumor resection and 11 had subtotal resection. Of the total resection group, ten showed evidence of residual tumor on postoperative neuroimaging studies. Following the initial resection, 46 did not have RT whereas 8 with subtotal resection received RT.ResultsThere were no surgical deaths. Postoperative complications included pseudoaneurysm in 1, hemiparesis in 3, severe obesity in 5, panhypopituitarism in 50, and worsening of visual function in 7. During follow-up ranging from 12 months to 21 years, 24 patients had recurrence. Of the 33 patients with radiographic total resection, 9 (27.3%) had recurrence. Among the patients with total resection but radiographic residual and those with subtotal resection, the craniopharyngioma recurred in 90% and 100%, respectively. Three (37.5%) of eight patients with subtotal resection with RT had recurrence. Overall recurrence-free survival was 62% at 5 years and 49% at 10 years. The sex and age, location and extension of the tumor, nature of the optic chiasm, and hydrocephalus did not influence survival with statistical significance. However, the extent of surgical resection and use of RT showed significant differences for survival. Patients with total resection had a recurrence-free survival rate of 83% and 70% at 5 and 10 years, respectively. Patients with subtotal resection with RT had 71% at 5 years and 36% at 10 years. Patients who had subtotal resection or radiographically residual tumor without RT had a recurrence-free survival rate of only 9%. Among 22 patients whose recurrent tumor was treated with RT, a second recurrence-free survival rate was 90% at 5 years.ConclusionTotal resection provided the best outcome. However, recurrence rates and surgical complications remained high following radical tumor resection. RT was effective for recurrent tumors and should be considered being the primary treatment for recurrences or difficult tumors, which are not amenable to total resections.

Neurodevelopment of children with single suture craniosynostosis: a review

IntroductionRates of neurocognitive risk range from 35–50% of school-aged children with isolated single suture craniosynostosis (SSC). It has been hypothesized that early surgical intervention to release suture fusion reduces risk for increased intracranial pressure (ICP) and the corresponding risk to neurodevelopment. However, studies assessing children with SSC have been inconsistent in finding an association between neurocognitive development, age of surgery, and ICP.ReviewSSC produces notable distortion of the cranial vault and underlying brain mass. Although a linear relationship between skull distortion, ICP, and neurocognitive deficits has generally been assumed, recent studies have postulated an interactive process between the skull and developing brain that results in neuroanatomical changes that are not limited to areas directly beneath the fused suture. The specific neuropsychological deficits identified in children with SSC including problems with attention and planning, processing speed, visual spatial skills, language, reading, and spelling may be related to the anatomic differences that persist after correction of suture fusion.ConclusionsAvailable literature on neurocognitive development of children with SSC is suggestive of mild but persistent neuropsychological deficits, which become more significant as cognitive demands increase at school age. Anatomical studies of children without SSC are beginning to identify particular groups of brain structures that if disrupted or malformed, may be associated with specific cognitive deficits. Controlled research investigating the relationship between persistent anatomical changes and neurocognitive functioning of school-aged children with SSC is needed.

Spinal lipomas in children: Outcome of 270 procedures?

Spinal lipomas are a common cause of spinal cord tethering. Recently, prophylactic surgical removal of spinal lipomas has been questioned, especially of the conus medullaris. Unfortunately, few statistically significant series have been reported. A total of 213 children with spinal lipomas were operated on at the Childrens Memorial Hospital in Chicago, Ill., USA, on whom 270 procedures were carried out between 1975 and 1995. The status of these children was retrospectively reviewed to determine the differences in outcome between patients prophylactically operated on before the onset of symptoms and those operated on after the onset of symptoms. Fifty-five patients presented with a lipoma of the filum terminale and 158 with a lipoma of the conus medullaris. In the filum terminale group, 28 were asymptomatic at the initial operation, and 27 presented with symptoms. Of the asymptomatic children with filum terminale lipomas, none worsened after surgery, and all remained asymptomatic throughout follow-up (mean follow-up: 3.4 years). Benefits were also observed for the symptomatic patients in this group as no cases of further deterioration were noted, and 5 patients returned to normal clinical status. In the conus group, 71 patients were asymptomatic at initial surgery, and 87 presented with symptoms. In the case of conus medullaris lipomas, 9 of the 71 children who were operated on prophylactically, later deteriorated (mean follow-up: 6.2 years) and required a second untethering operation which resolved all symptoms in 4 cases. Thus, 5 of 71 deteriorated, while 66 remained normal (93%) throughout the period of follow-up. On the other hand, of the 87 patients operated on after the onset of symptoms, 36 (41%) deteriorated further and required subsequent reoperations. In these 87 children, the final outcome at the end of follow-up (mean follow-up: 6.6 years) showed that 20 (23%) patients had deteriorated compared to initial presentation and 44 (51%) remained at initial clinical baseline, while 23 (26%) improved or returned to normal clinical status. Prophylactic surgery in the case of the asymptomatic infant with a spinal lipoma showed a clear benefit. Good outcome was also observed when surgery was carried out after the onset of symptoms. Prophylactic surgery also had a better general outcome by actuarial calculations when only patients with a follow-up of more than 5 years were considered. Deterioration occurred in 5 (16.7%) of the 30 children with a follow-up of more than 5 years, while 25 (83.3%) remained normal. Furthermore, in cases which had prophylactic surgery, there was not only a smaller incidence of deterioration requiring a reoperation, but this group of patients also experienced a longer time interval between initial surgery and the need for reoperation compared to the patients operated on after the onset of symptoms. The authors conclude that spinal lipomas should be operated on as soon as possible on a prophylactic basis, and careful and constant follow-up should be carried out to permit prompt reintervention in cases with deterioration.

Radical Resections of Childhood Craniopharyngiomas

A series of 27 children with craniopharyngiomas is presented. All the craniopharyngiomas were detected by computed tomography, and radical total resection was attempted. Postoperative evaluations were done by a series of computed tomography and magnetic resonance imaging scans. Twenty patients who had total resection confirmed by surgical and radiographic observations showed no recurrence during the follow-up period of from 1 to 12 years. It is emphasized that total resection using modern diagnostic and surgical methods is the mainstay for childhood craniopharyngiomas.

Optic Pathway Hypothalamic Gliomas in Children under Three Years of Age: The Role of Chemotherapy

Objectives: Optic pathway/hypothalamic gliomas (OPHGs) tend to occur in young children. Treatment options consist of surgical resection, radiation therapy (RT) and chemotherapy. Due to complications induced by surgery and RT, chemotherapy has gained significant recognition for the treatment of OPHG in young children. Chemosensitivity of OPHG in very young children under 3 years of age has not been well documented. We analyzed 14 patients who were treated with chemotherapy with or without surgery. Materials and Methods: Fourteen children younger than 3 years (median age of 10 months) with OPHG were treated between 1988 and 1998. Magnetic resonance imaging was obtained in all cases. Hydrocephalus was present in 8 patients and diencephalic syndrome was noted in 6. Only 3 of these had evidence of neurofibromatosis-1. Five patients had partial tumor resection and 4 had endoscopic biopsy at the time of ventriculoperitoneal shunt placement. Pathological examination revealed low-grade astrocytoma in 5 and juvenile pilocytic astrocytoma in 4. All patients received chemotherapy: carboplatin in 8, a combination of carboplatin and vincristine in 4 and a combination of other agents in 2. Results: Eight (57%) of 14 patients had a sustained reduction of tumor during the follow-up time between 15 months and 8 years. The 5-year progression-free survival was 63%. These tumor reductions were often accompanied by clinical improvements. Diencephalic syndrome responded to chemotherapy alone in 4 of 6 patients. However, 5 others had progressive disease; 3 during the treatment and 2 following the treatment (9 months and 2 years, respectively). All these 5 patients had a partial tumor resection prior to chemotherapy. Conclusion: A majority of OPHGs responds to chemotherapy. Due to slow progression of these tumors and adverse effects of other therapeutic modalities, we recommend chemotherapy as a primary treatment for OPHGs. Our present data indicates that partial surgical resection does not enhance chemotherapy effectiveness for OPHGs in infants or children younger than 3 years.

Medulloblastoma in Childhood

51 medulloblastomas under 12 years of age were treated from 1966 through 1977. 50 patients underwent craniotomy and 39 of them completed postoperative radiation therapy. Surgical mortality rate of primary posterior fossa craniotomy was 8%. One year survival rate was 71.4%, 3 years 45.6% and 5 years 34.5%. Extent of surgical resection was found to affect the survival, and a group of radical or visibly total resection showed higher postoperative survival. Female patients enjoyed longer survival. The patients under 12 months of age showed poor prognosis. Reexploration of the posterior fossa failed to prolong the survival by more than 3 months.

Identification of MicroRNAs as Potential Prognostic Markers in Ependymoma

Introduction We have examined expression of microRNAs (miRNAs) in ependymomas to identify molecular markers of value for clinical management. miRNAs are non-coding RNAs that can block mRNA translation and affect mRNA stability. Changes in the expression of miRNAs have been correlated with many human cancers. Materials and Methods We have utilized TaqMan Low Density Arrays to evaluate the expression of 365 miRNAs in ependymomas and normal brain tissue. We first demonstrated the similarity of expression profiles of paired frozen tissue (FT) and paraffin-embedded specimens (FFPE). We compared the miRNA expression profiles of 34 FFPE ependymoma samples with 8 microdissected normal brain tissue specimens enriched for ependymal cells. miRNA expression profiles were then correlated with tumor location, histology and other clinicopathological features. Results We have identified miRNAs that are over-expressed in ependymomas, such as miR-135a and miR-17-5p, and down-regulated, such as miR-383 and miR-485-5p. We have also uncovered associations between expression of specific miRNAs which portend a worse prognosis. For example, we have identified a cluster of miRNAs on human chromosome 14q32 that is associated with time to relapse. We also found that miR-203 is an independent marker for relapse compared to the parameters that are currently used. Additionally, we have identified three miRNAs (let-7d, miR-596 and miR-367) that strongly correlate to overall survival. Conclusion We have identified miRNAs that are differentially expressed in ependymomas compared with normal ependymal tissue. We have also uncovered significant associations of miRNAs with clinical behavior. This is the first report of clinically relevant miRNAs in ependymomas.