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Ian F. Pollack

Object

Brain tumors are the most common category of childhood solid tumors. In the 1970s and 1980s, treatment protocols for benign tumors focused almost exclusively on surgery, with radiation treatment as a salvage modality, whereas the management of malignant tumors employed a combination of surgery, radiation therapy, and chemotherapy, with therapeutic approaches such as “8-in-1” chemotherapy often applied across histological tumor subsets that are now recognized to be prognostically distinct. During the ensuing years, treatment has become increasingly refined, based on clinical and, more recently, molecular factors, which have supported risk-adapted treatment stratification. The goal of this report is to provide an overview of recent progress in the field.

Methods

A review of the literature was undertaken to examine recent advances in the management of the most common childhood brain tumor subsets, and in particular to identify instances in which molecular categorization and treatment stratification offer evidence or promise for improving outcome.

Results

For both medulloblastomas and infant tumors, refinements in clinical and molecular stratification have already facilitated efforts to achieve risk-adapted treatment planning. Current treatment strategies for children with these tumors focus on improving outcome for tumor subsets that have historically been relatively resistant to therapy and reducing treatment-related sequelae for children with therapy-responsive tumors. Recent advances in molecular categorization offer the promise of further refinements in future studies. For children with ependymomas and low-grade gliomas, clinical risk stratification has facilitated tailored approaches to therapy, with improvement of disease control and concomitant reduction in treatment sequelae, and recent discoveries have identified promising therapeutic targets for molecularly based therapy. In contrast, the prognosis remains poor for children with diffuse intrinsic pontine gliomas and other high-grade gliomas, despite recent identification of biological correlates of tumor prognosis and elucidation of molecular substrates of tumor development.

Conclusions

Advances in the clinical and molecular stratification for many types of childhood brain tumors have provided a foundation for risk-adapted treatment planning and improvements in outcome. In some instances, molecular characterization approaches have also yielded insights into new therapeutic targets. For other tumor types, outcome remains discouraging, although new information regarding the biological features critical to tumorigenesis are being translated into novel therapeutic approaches that hold promise for future improvements.

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Frederick A. Boop

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Matthew A. Adamo and Ian F. Pollack

Object

Sagittal synostosis accounts for the most common form of craniosynostosis, occurring with an incidence of 1 in 2000–5000 live births. In most cases of single-suture, nonsyndromic sagittal synostosis, a single operation is all that is required to achieve a reasonable cosmetic result. However, there are a number of patients who may experience symptomatic postoperative calvarial growth restriction secondary to fibrosis of newly formed bone and pericranium that replace the surgically removed sagittal suture, or due to fusion of other previously open sutures leading to increased intracranial pressure, necessitating a second operation.

Methods

A retrospective review was conducted of all cases involving infants who had undergone an extended sagittal strip craniectomy with bilateral parietal wedge osteotomies at our institution between 1990 and 2006 for single-suture, nonsyndromic sagittal craniosynostosis. The frequency with which subsequent operations were required for cranial growth restriction was then defined.

Results

There were a total of 164 patients with single-suture nonsyndromic sagittal synostosis. Follow-up data were available for 143 of these patients. The average age at time of initial operation was 5.25 months, and the mean duration of follow-up was 43.85 months. There were 2 patients (1.5%) who required a second operation for symptomatic postoperative calvarial growth restriction.

Conclusions

Recurrence of synostosis with resultant increased intracranial pressure in cases of single-suture, nonsyndromic sagittal craniosynostosis is an uncommon event, but does occur sporadically and unpredictably. Therefore, we recommend routine neurosurgical follow up for at least 5 years, with regular ophthalmological examinations to assess for papilledema.

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Ian F. Pollack, Dachling Pang and Robert Sclabassi

✓ Spinal cord injury without radiographic abnormality is a well-known entity in the pediatric age group. Agerelated elasticity of the vertebral ligaments as well as immaturity of the osseous structures in the pediatric spine allow momentary subluxation in response to deforming forces. The resultant neurological injuries range from transient dorsal column dysfunction to complete cord transection. Between 1960 and 1985, 42 such injuries were treated at the Children's Hospital of Pittsburgh. Management of these radiographically occult spinal cord injuries consisted of cervical immobilization for 2 months in a hard collar and restriction of contact sports. Recurrent cord injury occurred in eight cases during the 2-month immobilization period. A clearly defined traumatic episode was identified in seven of the eight patients, although in four children the recurrent trauma to the spine was trivial. Five of the children removed their collars briefly before the second injury, and two children incurred reinjury with the hard collar in place. The remaining child was too young for hard-collar immobilization, and recurrent neurological deterioration occurred during sleep. Serial flexion-extension films failed to detect frank instability in any of the eight cases. The children most susceptible to reinjury were those who sustained mild or transient neurological deficits from an initial cord injury and who rapidly resumed normal activities. Radiographically occult spinal instability resulting from the initial injury to the vertebral and paravertebral soft tissues presumably made these children vulnerable to recurrent spinal cord injury, often from otherwise insignificant trauma. During the last 21 months, 12 additional children have been managed with a more stringent protocol combining neck immobilization in a rigid cervical brace for 3 months and restriction of both contact and noncontact sports, together with a major emphasis on patient compliance. With this new protocol, no recurrent cord injuries have been documented.

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Ian F. Pollack

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Ian F. Pollack, Dachling Pang and A. Leland Albright

✓ Benign intrinsic tumors arising in the dorsal midbrain have long been recognized as a potential cause of late-onset aqueductal stenosis. Where histopathological studies of such lesions have been performed, the majority have been reported to be low-grade gliomas. Because these tumors often present with a paucity of neurological findings and a characteristic radiographic appearance and because there has been substantial uncertainty regarding their potential for long-term progression, the authors have routinely deferred biopsy and/or radiotherapy for these lesions until there has been clear-cut evidence of disease progression. Herein, the authors report their experience with 16 children manifesting this syndrome who were treated between 1979 and 1992. The patients ranged in age from 6 months to 14 years at presentation (median 9.75 years). In general, symptoms of increased intracranial pressure developed insidiously; three of the older children had exhibited profound macrocephaly since infancy, which predated the onset of other symptoms of hydrocephalus by several years. Only one of the 16 children showed evidence of brain-stem dysfunction at presentation, a partial Parinaud's syndrome that resolved following placement of a ventriculoperitoneal shunt. In 12 patients, the tumor was detected by magnetic resonance (MR) imaging at initial evaluation as a bulbous enlargement of the tectal plate. In four patients who presented before the advent of MR imaging, initial computerized tomography (CT) scans failed to delineate the tectal lesion convincingly; however, subsequent MR studies clearly demonstrated the presence of an intrinsic tectal mass. All 16 patients underwent cerebrospinal fluid diversion initially, with conservative management of the tectal lesion and close long-term follow-up monitoring. Four children ultimately demonstrated clinical signs of progressive tumor growth with the insidious onset of partial or complete Parinaud's syndrome, despite the presence of a functioning shunt.

The median interval to symptom progression was 7.8 years from the time of shunt insertion and 11.5 years from the onset of initial symptoms and signs of hydrocephalus. Follow-up CT and MR studies demonstrated obvious tumor enlargement in three of the four patients who then underwent stereotactic or open biopsy. The histological diagnosis in these three was benign mixed glioma, anaplastic astrocytoma, and low-grade astrocytoma. All four patients with clinical evidence of disease progression were treated with conventional radiotherapy; the patient with an anaplastic astrocytoma also received focal stereotactic radiosurgery. These patients subsequently remained clinically stable, with three showing tumor regression and one showing stable disease on serial MR studies (median follow-up period from tumor progression, 4.25 years). One other child was noted to have progressive tumor enlargement during the 2 years after shunt insertion; she remains asymptomatic and has not yet undergone biopsy or radiotherapy.

It is concluded that benign intrinsic tectal tumors, although generally indolent, merit conscientious long-term follow-up monitoring since these lesions may ultimately show evidence of progressive growth and require therapeutic intervention to maintain disease control. These tumors are best visualized on MR imaging, which should be included in the workup of all patients with late-onset aqueductal stenosis.

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Ian F. Pollack, Stephanie Kawecki and John S. Lazo

✓ Seven-hydroxystaurosporine (UCN-01) is a derivative of the nonselective protein kinase inhibitor staurosporine that exhibits significant selectivity for protein kinase C (PKC) in comparison to a variety of other intracellular kinases and appears to be well tolerated in vivo at concentrations sufficient to achieve effective inhibition of PKC. Because recent studies have indicated that the proliferation of malignant gliomas may result from activation of PKC-mediated pathways and, conversely, may be inhibited by blocking PKC, the authors examined the efficacy of this agent as an inhibitor of proliferation in three established and three low-passage malignant glioma cell lines in vitro. A striking inhibition of proliferation was produced by UCN-01 in each of the cell lines, with a median effective concentration of 20 to 100 nM, which correlated with the median in vitro PKC inhibitory concentration of 20 to 60 nM for this agent in the U-87 and SG-388 glioma cell lines. Inhibition-recovery studies of clonogenic activity indicated that UCN-01 had both cytostatic and cytotoxic effects on the treated cells. Proliferation resumed after short-term (6- and 24-hour) exposures to this agent; in contrast, with longer exposures, recovery of proliferative activity was severely compromised. In addition, UCN-01 enhanced the inhibition of glioma cell proliferation achieved with conventional chemotherapeutic agents, exhibiting synergistic effects with cisplatin and additive effects with 1,3-bis(2-chloroethyl)-1-nitrosourea. In vivo studies in which UCN-01 was administered by continuous intraperitoneal infusion in subcutaneous and intracranial intraparenchymal nude rat models demonstrated significant activity against U-87 glioma xenografts at dose levels that were well tolerated. It is concluded that UCN-01 is an effective agent for the inhibition of glioma proliferation in vitro and in vivo and has potential for clinical applicability in the treatment of human gliomas.

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Ian F. Pollack, H. Wolfgang Losken and Dennis J. Hurwitz

✓ The management of infants with bilateral coronal synostosis and resultant brachyturricephaly poses a significant therapeutic challenge. The application of total calvarial reconstruction to the treatment of this problem has represented a major recent innovation that has substantially improved the cosmetic results in this patient population. However, rigid fixation of the reconstructed calvaria is often required to maintain the correction achieved and to provide protection for the underlying brain. The requirement for extensive fixation constitutes a significant disadvantage for the use of this procedure in infants and young children. In this report, the authors describe an approach to the treatment of this problem that incorporates a series of tongue-in-groove osteotomies to provide increased stability to advancements of both the frontal and occipital regions in conjunction with cranial height reduction, while minimizing the need for metallic fixation. With this approach, the reconstructed skull is sturdy enough to resist the compressive force applied by the weight of the child's head immediately after surgery, but retains the ability to expand progressively. The authors have found the cosmetic results to be extremely gratifying. In this article they present their experience with this technique in seven children.

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Ian F. Pollack, Dachling Pang and Kenneth E. Schuit

✓ A patient is described with osteomyelitis of the cranium and epidural abscess due to Aspergillus fumigatus as the presenting manifestations of chronic granulomatous disease. The diagnosis was suggested by the unusual nature of the organism isolated and confirmed by appropriate laboratory studies. The details of diagnostic assessment and therapeutic management are discussed, and the central nervous system manifestations of chronic granulomatous disease are reviewed.