Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates.

PURPOSE: MP470 is a multi-targeted tyrosine kinase inhibitor with potent activity against mutant c-Kit, PDGFRα, Flt3, c-Met and c-Ret that is being evaluated as an anticancer agent. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of MP470 were studied in a non-human primate model that is highly predictive of CSF penetration in humans. METHODS: Oral MP470, 300 mg, was administered to four non-human primates. Serial samples of blood were collected from four animals and CSF samples from three animals for pharmacokinetic studies. Plasma and CSF concentrations were measured using an LC-MS/MS assay. Both model-independent and model-dependent methods were used to analyze the pharmacokinetic data. RESULTS: Following a one-time oral dose of 300 mg, the MP470 plasma area under the curve (AUC) was 1,690 ± 821 nM h (mean ± SD). The half-life of MP470 in the plasma was 11.0 ± 3.4 h. There was no measurable MP470 in the CSF. CONCLUSIONS: Although CSF penetration is minimal, MP470 has demonstrated potent activity against cancer cell lines in vitro and in vivo, and further clinical investigation is warranted.

Antineuronal nuclei immunohistochemical staining patterns in childhood ependymomas.

NeuN, the mouse-derived monoclonal antibody to the reportedly neuron-specific nuclear protein, has been observed to react with many different types of normal, postmitotic neurons throughout the central and peripheral nervous systems. We retrospectively examined 23 surgical specimens (collected from 20 patients) originally diagnosed at our institution between 1983 and 1999 as ependymoma (9), myxopapillary ependymoma (1), anaplastic/malignant ependymoma (10), and primitive neuroectodermal tumor with ependymal differentiation (3). The ependymomas included lesions from the spine (3), cerebrum (5), and posterior fossa (15). Representative formalin-fixed, paraffin-embedded sections from each tumor were subjected to immunohistochemical staining with antibody against NeuN (Chemicon International, Inc, Temecula, CA). Five astrocytomas, four primitive neuroectodermal tumors, and normal cerebral cortex and ependyma from autopsy brains of premature newborns, term infants, and older children served as controls. Thirteen ependymal tumors had positive nuclear staining ranging from rare tumor cells to numerous groups of cells; of these, 9 were anaplastic ependymomas and had the most staining. These studies suggest that some ependymomas arise from a pluripotential neuroglial cell.

Pituitary adenoma in children.

Pituitary adenoma is an uncommon intracranial tumor of children. The authors retrospectively reviewed the records of 10 patients younger than 17 years of age with pituitary adenoma. Five patients had visual loss at presentation. Four of these five patients with visual loss and extrasellar tumor extension were adolescents (12-15 years of age). Seven of 10 patients underwent neurosurgery. Of the five patients with visual loss, three patients experienced visual improvement, one patient was unchanged, and one patient did not have follow-up. The visual loss in these patients tended to be more severe and more likely to be associated with optic atrophy than adult patients. Although they are relatively uncommon, ophthalmologists should be aware that pituitary adenomas may occur in children and that these tumors when present in the pubertal period may be more likely to exhibit extrasellar extension or invasiveness.

Dural inversion procedure for moyamoya disease. Technical note.

A variety of surgical procedures have been proposed for the treatment of moyamoya disease, but few have used the potential of the middle meningeal artery to any great extent. During the period of spontaneous collateral formation, patients with this disease are at risk for the development of transient ischemic attacks and strokes. Surgical treatments aimed at increasing collateral flow to the brain from the external carotid system have included both direct and indirect anastomotic methods. In this report, the authors describe a technique that used the middle meningeal artery circulation as a source of collateral blood supply by inverting dural flaps that are located on a large meningeal vessel, allowing the richly vascularized outer dural surface to contact a large surface area of the ischemic cortex. An extensive degree of revascularization was observed.

Surgical management of calcified cephalhematoma and associated skull defect in infancy.

Cephalhematoma is a collection of blood under the periosteum of the skull and is frequently associated with traumatic delivery. The distinct calcified form of this disease is rare and has not been reported in the plastic surgery literature. In this report, we present an infant with a large calcified cephalhematoma associated with a skull defect and discuss its management.

Bone formation within a choroid plexus papilloma.

Bone formation within the choroid plexus papillomas is rare, with only 4 previous cases reported. We present a case of a 12-year-old boy who presented with papilledema, visual loss and hydrocephalus who was found to have a choroid plexus papilloma. Histological analysis of the tumor revealed foci of cancellous bone formation with hematopoietic cells within the marrow spaces. We review the proposed mechanisms for bone formation within neuroepithelial brain tumors.

Pediatric midbrain tumors: a benign subgroup of brainstem gliomas.

The presentation, radiographic findings and course of 17 children with MRI-documented intrinsic midbrain lesions are reviewed. The anatomic centers of all the lesions were tectal, peritectal, or tegmental. Lesions centered at the pineal gland were excluded. Signs of increased intracranial pressure from hydrocephalus requiring shunt placement were present in 14 patients. Histopathological diagnosis was confirmed in three tumors; these were low grade astrocytomas and all received focal irradiation, as did one unbiopsied tumor. The remaining 13 patients with no histopathological diagnosis received no therapy other than shunt placement in 11. All but one of the lesions have remained clinically and radiographically stable, with a 4-year progression-free and total survival of 94 and 100%, respectively. We conclude that mass lesions originating in the upper midbrain are a subset of intrinsic brainstem tumors with a relatively benign course, usually presenting with hydrocephalus after infancy. They may remain stable for considerable periods and may require no further therapy after treatment of hydrocephalus. Surgical biopsy and/or resection can usually be reserved for progressive or atypical lesions which may also require further adjuvant therapy.

Critical analysis of results of craniofacial surgery for nonsyndromic bicoronal synostosis.

We retrospectively assessed the intermediate and long-term results of craniofacial surgery in 22 consecutive patients with nonsyndromic bicoronal synostosis to determine the outcome of corrective surgery. The study population consisted of 13 males and 9 females whose ages ranged from 6 weeks to 24 months (mean, 5.6 months) at the time of initial surgery. All patients had been assigned a diagnosis of nonsyndromic bicoronal synostosis. Each patient underwent resection of both coronal sutures and frontal orbital advancement with cranial vault remodeling using a floating forehead technique. Age at initial operation was 5 months or less in 13 patients and 6 months or more in 9. Complications occurred in 5 patients (23%), and 1 patient with an associated metabolic disorder died from respiratory arrest postoperatively. Follow-up ranged from 6 to 168 months (mean, 53.2 months). Results were graded according to the need for and extent of reoperation. Residual aesthetic deformities were documented in 12 patients (55%). Three patients (14%) required calvarial recontouring or cranioplasty to achieve satisfactory forehead contour or bony continuity. Total reoperation for recurrent deformity was required at a mean age of 29.7 months in 8 patients (36%) and is pending in another (4%). Four patients (18%) required a third operation (two total reoperations and two cranioplasties) to achieve satisfactory results. Eight of 13 patients (62%) operated on at 5 months of age or younger required total reoperation compared with 1 of 9 (11%) operated at 6 months of age or older. When analyzed alone, age of operation was a statistically significant determinant of the need for reoperation (p < 0.03). However, when subjected to multivariate analysis, neither age at operation nor the presence of an associated anomaly or positive family history had a significant effect on outcome.

Sources of human Schwann cells and the influence of donor age.

We evaluated several tissues as possible sources for culturing human Schwann cells. The average cell yield (total cell number/mg of nerve fascicle) obtained from adult autopsy cases and transplant organ donors was similar (2 x 10(4) and 2.9 x 10(4), respectively), but significantly higher yields were obtained from dorsal roots of pediatric patients undergoing selective dorsal rhizotomy (6.1 x 10(4)). Fresh tissue was not essential since cells isolated from 0 to 20 h postmortem were equally viable. However, we found evidence that donor age affects the intrinsic growth rate of Schwann cells and perineurial fibroblasts in culture.

Metopic synostosis: evaluation of aesthetic results.

Analysis of intermediate- and long-term results of surgical treatment of metopic synostosis is lacking. We therefore retrospectively studied 23 patients with metopic synostosis (14 males, 9 females) who have been followed from 3 months to 8.1 years (mean 42.5 months) after operation. Age at first operation ranged from 2 to 56 months (mean 8.2 months), with 15 patients operated on before 6 months and 8 after 7 months. Fronto-orbital remodeling and calvarial vault reshaping with floating forehead techniques were carried out in all patients. Stabilization of bony segments was accomplished with microplates and screws in 7 patients (30 percent), wires in 15 (65 percent), and absorbable sutures in 1. Complications included minor wound dehiscence (n = 1), seizures (n = 1), and increased intracranial pressure (n = 1). Postoperative photographic documentation of surgical results was available in 17 of the 23 patients. Aesthetic outcome in these 17 patients was graded (I = none or minor contour irregularities; II = moderate; and III = severe) by one of the authors (Cohen) and by a lay panel (n = 3) according to the degree of residual cranio-orbital deformity. Judged by the surgeon, grade I results were present in 53 percent, grade II in 35 percent, and grade III in 12 percent. To date, total reoperation (reoperative fronto-orbital remodeling and calvarial vault reshaping) was necessary in 2 patients (9 percent), one of whom had signs of increased intracranial pressure 3 years after the original craniofacial procedure, while partial reoperation (temporal cranioplasty) was carried out (n = 2) or recommended (n = 3) in another 5 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Shunt failure without ventriculomegaly proclaimed by ophthalmic findings.

Four patients who developed increased intracranial pressure from ventricular shunt failure suffered a delay in diagnosis because magnetic resonance imaging of the brain did not show ventriculomegaly and because ophthalmic findings were initially overlooked or misinterpreted. None of the patients had the conventional manifestations of shunt failure: severe headache, nausea, vomiting, and depressed consciousness. Three patients suffered marked, permanent vision loss from chronic papilledema. These cases affirm that increased intracranial pressure may occur in shunt dependency without producing either conventional clinical symptoms or signs on imaging of the brain. Because ophthalmic manifestations may be the major clues to diagnosis, and because irreversible loss of vision is possible if these clues are overlooked, consideration should be given to periodic ophthalmological examination of shunt-dependent patients.

Congenital mesoblastic nephroma metastatic to the brain.

BACKGROUND: Congenital mesoblastic nephroma (CMN) is generally considered to be a benign neoplasm requiring only total excision. Rare local recurrences have usually been related to incomplete removal, and distant metastases to the lung have been reported three times. METHODS: The authors reported the first case of CMN metastatic to the brain, illustrating a comparison of the histopathology of the primary and secondary lesions. RESULTS: The gross appearance of the renal tumor was that of a benign CMN. On histopathologic examination, there was a single nodule of more cellular tissue with focal necrosis. This area was diagnosed as within the designation "cellular" mesoblastic nephroma. The appearance of the brain metastasis corresponded to that of the cellular nodule. CONCLUSIONS: This report expands the spectrum of metastatic potential of CMN. Though a rare event, this case underscores the need for close follow-up of infants with CMN.

Analysis of 153 patients with myelomeningocele or spinal lipoma reoperated upon for a tethered cord. Presentation, management and outcome.

After primary repair of myelomeningoceles or lipomyelomeningoceles, late progressive neurologic deterioration commonly occurs due to a treatable cause. In our experience many of these patients have a tethered cord. With early untethering, most patients are stabilized and a significant percent of the patients show improvement in their clinical status. Of 341 tethered cord releases done from 1981 to 1988, we report on 153 patients reoperated upon following primary repair. One hundred were performed after primary closure of a myelomeningocele and 53 after repair of a lipomyelomeningocele. The average age of the patients with a myelomeningocele was 6 years old, and for the spinal lipoma patients, 8 years old. The presenting symptoms were similar; weakness, deterioration in gait, scoliosis, orthopedic deformities, and urinary incontinence represented the most common complaints. All 153 patients were noted to have a tethered cord at operation. Additional pathology (dermoid tumors, hydromyelia, tight filum and diastematomyelia) was present in 30% of the cases. With the use of the CO2 laser for dissection, all but 10 patients could be untethered. Follow-up over an average of 4 years revealed 93% of the patients with a myelomeningocele had stabilization or improvement of their presenting complaints, and 7% had progression of their presenting complaints. All of the lipomyelomeningocele patients had either stabilization or improvement of their presenting complaints. There were no mortalities. Close follow-up and early treatment of this patient population is indicated. With release of the cord a significant portion of the population will have relief or improvement of their presenting complaints.

Surgical techniques of cranial vault expansion for increases in intracranial pressure in older children.

Standard craniofacial techniques to expand the cranial vault were successful in treating elevations of intracranial pressure (ICP) in 7 older children. Of the 7 patients, a diagnosis of craniosynostosis was made in 6 and deformational head deformity with slit ventricle syndrome in 1. There were 5 boys and 2 girls, whose ages ranged from 3 1/2 to 8 years (mean, 5.2 yr). Three patients had previously undergone surgical treatment of craniosynostosis. One patient presented with visual changes and papilledema. Another with a deformational skull deformity was shunt-dependent and was diagnosed with slit ventricle syndrome. This patient had undergone several temporal craniectomies to control recurrent symptoms of increased ICP. The remaining 2 patients appeared to have craniosynostosis as an explanation for reduced cranial vault size and elevated ICP, but the specific sites of sutural fusion could not be identified. Total follow-up ranged from 3 to 18 months, and evidence of resolution of signs and symptoms of increased ICP was achieved in each of the 7 patients. Plastic surgeons involved in caring for children with craniosynostosis should be particularly aware of the possibility of increased ICP developing or recurring following craniofacial surgery.

Insidious onset of familial craniosynostosis.

A mother, son, and daughter are presented, in whom serial photographs document an insidious and late onset of exorbitism and midfacial retrusion consistent with a diagnosis of familial nonsyndromic craniosynostosis. Papilledema was found in the 4.5-year-old daughter because of increased intracranial pressure secondary to a reduction in cranial vault size, whereas optic nerve sheath swelling on CT scan was found in the son.

Intramedullary lesions of the pediatric spinal cord: correlation of findings from MR imaging, intraoperative sonography, surgery, and histologic study.

Findings of preoperative magnetic resonance (MR) imaging and radiologist-directed intraoperative sonography (IOS) were correlated with surgical and pathologic findings in 11 pediatric patients with intramedullary spinal cord lesions. There were seven gliomas and one each of primitive neuroectodermal tumor, venous vascular malformation, neuroenteric cyst, and active schistosomiasis. MR imaging provided discrete preoperative anatomic localization and excluded multicentric lesions but did not reliably distinguish between solid and cystic lesions. IOS helped (a) define the limits of intramedullary mass before the dura mater was opened and (b) differentiate cystic from solid components. The internal architecture of intramedullary lesions, as shown with MR imaging and sonography, was strikingly similar, allowing discrete correlative localization for biopsy or tissue resection. Gadolinium-enhanced MR imaging and IOS are complementary imaging techniques that should be used in concert for the evaluation and management of intramedullary lesions of the pediatric spinal cord. Both techniques display regions of cord abnormality, but neither definitively characterizes underlying tissue histology.

Eosinophilic granuloma of the cervicothoracic junction. Case report.

A case is reported of eosinophilic granuloma at the cervicothoracic junction presenting with profound quadriparesis preoperatively. The patient underwent excision via an anterior approach, with splitting of the sternum to gain access to the T-1 vertebra. Postoperatively, he has had an excellent return of function.

Atlanto-axial rotational limitation secondary to osteoid osteoma of the axis. Case report.

An unusual case of atlanto-axial rotational limitation secondary to an osteoid osteoma of the axis is presented. Transoral microsurgical resection followed by physical therapy improved the clinical symptoms. This case illustrates several unique problems within the cervical spine as well as the efficacy of the transoral approach to the axis.