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Ian F. Pollack

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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.

开云体育世界杯赔率

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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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.

开云体育世界杯赔率

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

复发的骨性结合合成增加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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Frederick A. Boop

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马修·a·阿达莫丽莎·亚伯拉罕,伊恩·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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Kevin L. Stevenson, Matthew Wetzel, and Ian F. Pollack

✓延迟与层磷相关并发症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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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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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 toleratedin vivoat 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 linesin 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 medianin vitroPKC 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 vivostudies 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 proliferationin vitroandin vivoand has potential for clinical applicability in the treatment of human gliomas.

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Ian F. Pollack, Nina F. Schor, A. Julio Martinez, and Richard Towbin

✓ The authors report an unusual case of a 2-year-old boy with a 3-month history of episodic rightward anterolateral head tilt and large-amplitude positional anteroposterior head bobbing reminiscent of bobble—head doll syndrome. This child experienced a sudden onset of drop attacks and then, within several hours, deep coma. The causative lesion was a contrast-enhancing, partially cystic third ventricular mass, which ultimately obstructed the aqueduct, producing profound obstructive hydrocephalus. An emergency ventriculostomy and endoscopic fenestration of the septum pellucidum was performed. Four days later, the tumor was completely resected by a transcallosal—transforaminal approach. The lesion was freely mobile within the third ventricle and contained a large cyst within its posterior pole; following drainage of the cyst, the lesion was easily delivered through the foramen of Monro. The histopathological diagnosis was choroid plexus papilloma.

The child's neurological deficits, head tilt, and head bobbing resolved immediately after operation. To the best of the authors' knowledge, this represents the first well-documented report of bobble—head doll syndrome and drop attacks secondary to a choroid plexus papilloma. The highly mobile nature of the cystic lesion presumably led to its intermittent impaction within the foramen of Monro and/or proximal aqueduct; this produced the intermittent head tilt and bobble-head symptoms and, ultimately, resulted in acute obstruction of the aqueduct, causing the child's precipitous neurological decline.

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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.

症状恶化的区间中值7.8years 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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