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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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Ian F. Pollack, Sameer Agnihotri and Alberto Broniscer

Brain tumors are the most common solid tumors in children, and, unfortunately, many subtypes continue to have a suboptimal long-term outcome. During the last several years, however, remarkable advances in our understanding of the molecular underpinnings of these tumors have occurred as a result of high-resolution genomic, epigenetic, and transcriptomic profiling, which have provided insights for improved tumor categorization and molecularly directed therapies. While tumors such as medulloblastomas have been historically grouped into standard- and high-risk categories, it is now recognized that these tumors encompass four or more molecular subsets with distinct clinical and molecular characteristics. Likewise, high-grade glioma, which for decades was considered a single high-risk entity, is now known to comprise multiple subsets of tumors that differ in terms of patient age, tumor location, and prognosis. The situation is even more complex for ependymoma, for which at least nine subsets of tumors have been described. Conversely, the majority of pilocytic astrocytomas appear to result from genetic changes that alter a single, therapeutically targetable molecular pathway. Accordingly, the present era is one in which treatment is evolving from the historical standard of radiation and conventional chemotherapy to a more nuanced approach in which these modalities are applied in a risk-adapted framework and molecularly targeted therapies are implemented to augment or, in some cases, replace conventional therapy. Herein, the authors review advances in the categorization and treatment of several of the more common pediatric brain tumors and discuss current and future directions in tumor management that hold significant promise for patients with these challenging tumors.

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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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Kevin L. Stevenson, Matthew Wetzel and Ian F. Pollack

✓ Delayed complications associated with sublaminar and interspinous wiring in the pediatric cervical spine are rare. The authors present a case of delayed complication in which a cervical fusion wire migrated into the cerebellum, causing subsequent cerebellar abscess 2 years after posterior cervical arthrodesis. A craniotomy was required to remove the wire and drain the abscess. Despite their history of safety and successful fusion, procedures involving sublaminar and interspinous wiring carry a risk of neurological injury secondary to wire migration. A thorough neuroimaging evaluation is required in patients who have undergone fusion and who have neurological complaints to detect late instrumentation-related sequelae.

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Matthew A. Adamo, Lisa Abraham and Ian F. Pollack

Herpesviruses can cause an acute, subacute, or chronic disease state in both immunocompetent and immunocompromised individuals. Herpes simplex virus (HSV) encephalitis is most often an acute monophasic disease process. Rarely, however, it may progress to a chronic state, and more rarely still to a granulomatous encephalitis. Prior studies have suggested that antiviral immunity with Toll-like receptors determines susceptibility to herpesviruses. The authors report the case of a 14-year-old girl with a remote history of treated HSV encephalitis, who had intractable seizures and worsening MR imaging changes that were concerning for either a neoplastic or an inflammatory process. She was found to have granulomatous herpes simplex encephalitis and had a low cytokine response to Toll-like receptor 3 stimulation.

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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, Peter J. Jannetta and David J. Bissonette

✓ Thirty-five patients with trigeminal neuralgia (TN) bilaterally underwent posterior fossa microvascular decompression (MVD) between 1971 and 1984. They comprised 5.0% of a larger series of 699 patients with TN who underwent MVD during that interval. Compared to the subgroup of 664 patients with only unilateral symptoms, the population with bilateral TN included a greater percentage of females (74% vs. 58%, p < 0.1), a higher rate of “familial” TN (17% vs. 4.1%, p < 0.001), and an increased incidence of additional cranial nerve dysfunction (17% vs. 6.6%, p < 0.05) and hypertension (34% vs. 19%, p < 0.05).

Of the 35 patients with bilateral TN, 10 underwent bilateral MVD (22 procedures) and 25 underwent unilateral MVD (30 procedures). In the latter patients, pain on the nonoperative side was well controlled with medication alone or had previously been treated by ablative procedures. Good or excellent pain control was achieved after one MVD was performed in 40 of the 45 sides treated (89%), and was maintained 1, 5, and 10 years after surgery in 82%, 66%, and 60%, respectively, based on life-table analysis. Six of 10 patients with recurrent symptoms underwent repeat unilateral MVD. Good or excellent long-term pain control was maintained in all six. With these repeat procedures included, symptom control at 1, 5, and 10 years after initial surgery was maintained in 87%, 78%, and 78% of the treated sides, respectively. Overall, 26 of 35 patients (74%) maintained good or excellent pain relief throughout the duration of the study (mean follow-up period 75 months) without resumption of regular medication usage. Although preoperative neurological deficits resulting from previous ablative procedures were seen in the majority of patients before MVD, no patient developed new major trigeminal sensory loss or masseter weakness after MVD. Operative mortality was zero. The results indicate that posterior fossa MVD is an effective and relatively safe treatment for the majority of patients with bilateral “idiopathic” TN, avoiding the risks of bilateral trigeminal nerve injury seen with other approaches.