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I. Jonathan Pomeraniec, Alexander Ksendzovsky, Scott Ellis, Sarah E. Roberts and John A. Jane Jr.

OBJECTIVE

Intraventricular hemorrhage (IVH) is a common complication of premature neonates with small birth weight, which often leads to hydrocephalus and treatment with ventriculoperitoneal (VP) shunting procedures. Trapped fourth ventricle (TFV) can be a devastating consequence of the subsequent occlusion of the cerebral aqueduct and foramina of Luschka and Magendie.

METHODS

The authors retrospectively reviewed 8 consecutive cases involving pediatric patients with TFV following VP shunting for IVH due to prematurity between 2003 and 2012. The patients ranged in gestational age from 23.0 to 32.0 weeks, with an average age at first shunting procedure of 6.1 weeks (range 3.1–12.7 weeks). Three patients were managed with surgery. Patients received long-term radiographic (mean 7.1 years; range 3.4–12.2 years) and clinical (mean 7.8 years; range 4.6–12.2 years) follow-up.

RESULTS

The frequency of TFV following VP shunting for neonatal posthemorrhagic hydrocephalus was found to be 15.4%. Three (37.5%) patients presented with symptoms of posterior fossa compression and were treated surgically. All of these patients showed signs of radiographic improvement with stable or improved clinical examinations during postoperative follow-up. Of the 5 patients treated conservatively, 80% experienced stable ventricular size and 1 patient experienced a slight increase (3 mm) on imaging. All of the nonsurgical patients showed stable to improved clinical examinations over the follow-up period.

CONCLUSIONS

The frequency of TFV among premature IVH patients is relatively high. Most patients with TFV are asymptomatic at presentation and can be managed without surgery. Symptomatic patients may be treated surgically for decompression of the fourth ventricle.

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I. Jonathan Pomeraniec, Alexander Ksendzovsky, Ahmed J. Awad, Francis Fezeu and John A. Jane Jr.

OBJECT

The natural and surgical history of Chiari malformation Type I (CM-I) in pediatric patients is currently not well described. In this study the authors discuss the clinical and radiological presentation and outcomes in a large cohort of pediatric CM-I patients treated with either conservative or surgical management.

METHODS

The authors retrospectively reviewed 95 cases involving pediatric patients with CM-I who presented between 2004 and 2013. The patients ranged in age from 9 months to 18 years (mean 8 years) at presentation. The cohort was evenly split between the sexes. Twenty-five patients underwent posterior fossa decompression (PFD) with either dural splitting or duraplasty. Seventy patients were managed without surgery. Patients were followed radiologically (mean 44.8 months, range 1.2–196.6 months) and clinically (mean 66.3 months, range 1.2–106.5 months).

RESULTS

Seventy patients were treated conservatively and followed with serial outpatient neurological and radiological examinations, whereas 25 patients were treated with PFD. Of these 25 surgical patients, 11 were treated with duraplasty (complete dural opening) and 14 were treated with a dura-splitting technique (incomplete dural opening). Surgical intervention was associated with better clinical resolution of symptoms and radiological resolution of tonsillar ectopia and syringomyelia (p = 0.0392). Over the course of follow-up, 20 (41.7%) of 48 nonsurgical patients who were symptomatic at presentation experienced improvement in symptoms and 18 (75%) of 24 symptomatic surgical patients showed clinical improvement (p = 0.0117). There was no statistically significant difference in resolution of symptoms between duraplasty and dura-splitting techniques (p = 0.3572) or between patients who underwent tonsillectomy and tonsillopexy (p = 0.1667). Neither of the 2 patients in the conservative group with syrinx at presentation showed radiological evidence of resolution of the syrinx, whereas 14 (87.5%) of 16 patients treated with surgery showed improvement or complete resolution of syringomyelia (p = 0.0392). In the nonsurgical cohort, 3 patients (4.3%) developed new or increased syrinx.

CONCLUSIONS

The overwhelming majority of CM-I patients (92.9%) managed conservatively do not experience clinical or radiological progression, and a sizeable minority (41.7%) of those who present with symptoms improve. However, appropriately selected symptomatic patients (sleep apnea and dysphagia) and those presenting with syringomyelia should be considered surgical candidates because of the high rates of clinical (75%) and radiological improvement (87.5%).

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Jie Lu, Alexander Ksendzovsky, Chunzhang Yang, Gautam U. Mehta, Raymund L. Yong, Robert J. Weil, Deric M. Park, Harry M. Mushlin, Xueping Fang, Brian M. Balgley, Dae-Hee Lee, Cheng S. Lee, Russell R. Lonser and Zhengping Zhuang

Object

Tumor-initiating cells are uniquely resilient to current treatment modalities and play an important role in tumor resistance and recurrence. The lack of specific tumor-initiating cell markers to identify and target these cells presents a major obstacle to effective directed therapy.

Methods

To identify tumor-initiating cell markers in primary brain tumors, the authors compared the proteomes of glioma tumor-initiating cells to their differentiated progeny using a novel, nongel/shotgun-based, multidimensional liquid-chromatography protein separation technique. An in vivo xenograft model was used to demonstrate the tumorigenic and stem cell properties of these cells. Western blot and immunofluorescence analyses were used to confirm findings of upregulated ciliary neurotrophic factor receptor subunit–α (CNTFRα) in undifferentiated tumor-initiating cells and gliomas of increasing tumor grade. Sequencing of the CNTFRα coding regions was performed for mutation analysis. Finally, antibody-dependent cell-mediated cytotoxicity was used to establish the role of CNTFRα as a potential immunotherapeutic target.

Results

Ciliary neurotrophic factor receptor subunit–α expression was increased in tumor-initiating cells and was decreased in the cells' differentiated progeny, and expression levels increased with glioma grade. Mutations of CNTFRα are not common in gliomas. Functional studies using CNTF treatment in glioma tumor-initiating cells showed induction of differentiation through the CNTFRα pathway. Treatment with anti-CNTFRα antibody resulted in increased antibody-dependent cell-mediated cytotoxicity in CNTFRα expressing DAOY cells but not in cell lines that lack CNTFRα.

Conclusions

These data indicate that CNTFRα plays a role in the formation or maintenance of tumor-initiating cells in gliomas, is a marker that correlates with histological grade, may underlie treatment resistance in some cases, and is a potential therapeutic target.

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Alexander Ksendzovsky, Stuart Walbridge, Richard C. Saunders, Ashok R. Asthagiri, John D. Heiss and Russell R. Lonser

Object

Recent studies indicate that M13 bacteriophage, a very large nanoparticle, binds to β-amyloid and α-synuclein proteins, leading to plaque disaggregation in models of Alzheimer and Parkinson disease. To determine the feasibility, safety, and characteristics of convection-enhanced delivery (CED) of M13 bacteriophage to the brain, the authors perfused primate brains with bacteriophage.

Methods

Four nonhuman primates underwent CED of M13 bacteriophage (900 nm) to thalamic gray matter (4 infusions) and frontal white matter (3 infusions). Bacteriophage was coinfused with Gd-DTPA (1 mM), and serial MRI studies were performed during infusion. Animals were monitored for neurological deficits and were killed 3 days after infusion. Tissues were analyzed for bacteriophage distribution.

Results

Real-time T1-weighted MRI studies of coinfused Gd-DTPA during infusion demonstrated a discrete region of perfusion in both thalamic gray and frontal white matter. An MRI-volumetric analysis revealed that the mean volume of distribution (Vd) to volume of infusion (Vi) ratio of M13 bacteriophage was 2.3 ± 0.2 in gray matter and 1.9 ± 0.3 in white matter. The mean values are expressed ± SD. Immunohistochemical analysis demonstrated mean Vd:Vi ratios of 2.9 ± 0.2 in gray matter and 2.1 ± 0.3 in white matter. The Gd-DTPA accurately tracked M13 bacteriophage distribution (the mean difference between imaging and actual bacteriophage Vd was insignificant [p > 0.05], and was –2.2% ± 9.9% in thalamic gray matter and 9.1% ± 9.5% in frontal white matter). Immunohistochemical analysis revealed evidence of additional spread from the initial delivery site in white matter (mean Vd:Vi, 16.1 ± 9.1). All animals remained neurologically intact after infusion during the observation period, and histological studies revealed no evidence of toxicity.

Conclusions

The CED method can be used successfully and safely to distribute M13 bacteriophage in the brain. Furthermore, additional white matter spread after infusion cessation enhances distribution of this large nanoparticle. Real-time MRI studies of coinfused Gd-DTPA (1 mM) can be used for accurate tracking of distribution during infusion of M13 bacteriophage.

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J. Bradley Elder and E. Antonio Chiocca

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Russell R. Lonser, Alexander Ksendzovsky, Joshua J. Wind, Alexander O. Vortmeyer and Edward H. Oldfield

Object

Dural invasion by adrenocorticotropic hormone (ACTH)-secreting adenomas is a significant risk factor for incomplete resection and recurrence in Cushing disease (CD). Since ACTH-producing adenomas are often the smallest of the various types of pituitary tumors at the time of resection, examining their invasion provides the best opportunity to identify the precise sites of early dural invasion by pituitary adenomas. To characterize the incidence and anatomical distribution of dural invasion by ACTH-secreting adenomas, the authors prospectively and systematically analyzed features of dural invasion in patients with CD.

Methods

The authors prospectively studied consecutive patients with CD undergoing the systematic removal of ACTH-secreting adenoma and histological analysis of the anterior sella dura as well as other sites of dural invasion that were evident at surgery. Clinical, imaging, histological, and operative findings were analyzed.

Results

Eighty-seven patients with CD (58 females and 29 males) were included in the study. Overall, dural invasion by an ACTH-positive adenoma was histologically confirmed in 30 patients (34%). Eighteen patients (60% of dural invasion cases, 21% of all patients) had evidence of cavernous sinus wall invasion (4 of these patients also had other contiguous sites of invasion), and 12 patients (40% of dural invasion cases) had invasion of the sella dura excluding the cavernous sinus wall. Eleven patients (13% all patients) had invasion of the routinely procured anterior sella dura specimen. Preoperative MR imaging revealed an adenoma in 64 patients (74%) but accurately predicted dural invasion in only 4 patients (22%) with cavernous sinus invasion and none of the patients with non–cavernous sinus invasion. Adenomas associated with dural invasion (mean ± SD, 10.9 ± 7.8 mm, range 2–37 mm) were significantly larger than those not associated with dural invasion (5.7 ± 2.1 mm, range 2.5–12 mm; p = 0.0006, Mann-Whitney test).

Conclusions

Dural invasion by ACTH-producing adenomas preferentially occurs laterally into the wall of the cavernous sinus. Preoperative MR imaging infrequently detects dural invasion, including cavernous sinus invasion. Invasion is directly associated with tumor size. To provide a biochemical cure and avoid recurrence after resection, identification and removal of invaded sella dura, including the medial cavernous sinus wall, are necessary.

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Alexander Ksendzovsky, Roberta Glick, Manuel Utset, Tadanori Tomita and Gopa Srinivasan

Hemangiomas of infancy (HOIs) are among the most common benign tumors of childhood and classically appear as a vascular stain or small vascular papule at birth. They are unique tumors due to their propensity to proliferate, involute, and finally regress. These lesions can be associated with visceral malformations that have been shown to affect mainly the liver and the gastrointestinal tract, but rarely the spinal cord. The authors report a rare case of a spinal HOI in a 2-month-old infant presenting with quadriplegia due to intratumoral hemorrhage. Following resection of the lesion, the child regained function. This first reported case of spinal HOI suggests another location for hemangiomatosis. Spinal HOI should be included in the differential diagnosis of acute intraspinal hemorrhage in infants.