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Quoc-Anh Thai, Gustavo Pradilla, Federico G. Legnani, Ryan M. Kretzer, Wesley Hsu and Rafael J. Tamargo

Object

Currently no adequate surgical treatment exists for spontaneous intracerebral hemorrhage (ICH). Implantable polymers can be used effectively to deliver therapeutic agents to the local site of the pathological process, thus reducing adverse systemic effects. The authors report the use of stereotactically implanted polymers loaded with tissue plasminogen activator (tPA) to induce lysis of ICH in a rabbit model.

Methods

Ethylene vinyl acetate (EVAc) polymers were loaded with bovine serum albumin (BSA) only or with BSA plus tPA. In vitro pharmacokinetic (three polymers) and thrombolysis (12 polymers) studies were performed. For the in vivo study, 12 rabbits were fixed in a stereotactic frame, and 0.2 ml of clotted autologous blood was injected into the right frontal lobe parenchyma. After 20 minutes, control BSA polymers were stereotactically implanted at the hemorrhage site in six rabbits, and experimental BSA plus tPA polymers were implanted in six rabbits. Animals were killed at 3 days, and blood clot volume was assessed.

The pharmacokinetic study showed release of 146 ng of tPA over 3 days. The tPA activity correlated with in vitro thrombolysis. In the in vivo study, the six animals treated with tPA polymers had a mean (± standard error of the mean [SEM]) thrombus volume of 1.43 ± 0.29 mm3 at 3 days, whereas the six animals treated with blank (BSA-only) polymers had a mean (± SEM) thrombus volume of 19.99 ± 3.74 mm3 (p < 0.001).

Conclusions

Ethylene vinyl acetate polymers release tPA over the course of 3 days. Stereotactic implantation of tPA-loaded EVAc polymers significantly reduced ICH volume. Polymers loaded with tPA may be useful clinically for lysis of ICH without the side effects of systemic administration of tPA.

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Veit Rohde and Uzma Samadani

Object

Currently no adequate surgical treatment exists for spontaneous intracerebral hemorrhage (ICH). Implantable polymers can be used effectively to deliver therapeutic agents to the local site of the pathological process, thus reducing adverse systemic effects. The authors report the use of stereotactically implanted polymers loaded with tissue plasminogen activator (tPA) to induce lysis of ICH in a rabbit model.

Methods

Ethylene vinyl acetate (EVAc) polymers were loaded with bovine serum albumin (BSA) only or with BSA plus tPA. In vitro pharmacokinetic (three polymers) and thrombolysis (12 polymers) studies were performed. For the in vivo study, 12 rabbits were fixed in a stereotactic frame, and 0.2 ml of clotted autologous blood was injected into the right frontal lobe parenchyma. After 20 minutes, control BSA polymers were stereotactically implanted at the hemorrhage site in six rabbits, and experimental BSA plus tPA polymers were implanted in six rabbits. Animals were killed at 3 days, and blood clot volume was assessed.

The pharmacokinetic study showed release of 146 ng of tPA over 3 days. The tPA activity correlated with in vitro thrombolysis. In the in vivo study, the six animals treated with tPA polymers had a mean (±standard error of the mean [SEM]) thrombus volume of 1.43 ±0.29 mm3 at 3 days, whereas the six animals treated with blank (BSA-only) polymers had a mean (±SEM) thrombus volume of 19.99 ±3.74 mm3 (p <0.001).

Conclusions

Ethylene vinyl acetate polymers release tPA over the course of 3 days. Stereotactic implantation of tPA-loaded EVAc polymers significantly reduced ICH volume. Polymers loaded with tPA may be useful clinically for lysis of ICH without the side effects of systemic administration of tPA.

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Philippe Metellus, Wesley Hsu, Siddharth Kharkar, Sumit Kapoor, William Scott and Daniele Rigamonti

The authors report their experience using preoperative chest radiography and intraoperative ultrasonography for percutaneous positioning of the distal end of the catheter when placing ventriculoatrial (VA) shunts in patients with hydrocephalus. The distal portion of VA shunt catheters were percutaneously placed into the internal jugular vein with the aid of intraoperative ultrasonography in 14 consecutive adults. In all cases, the technique was easy, there were no postoperative complications, and postoperative chest radiography demonstrated good positioning of the distal catheter tip. One patient presented with a shunt infection and needed a shunt replacement. The authors therefore conclude that percutaneous placement of a VA shunt under preoperative radiographic guidance and ultrasonographic monitoring is a safe, effective, and reliable technique that is simple to learn.

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Wesley Hsu, Khan W. Li, Markus Bookland and George I. Jallo

In the early 1920s, Walter E. Dandy began translating the field of endoscopy to neurosurgery. In the ensuing years, Dandy, who would become known as the “Father of Neuroendoscopy,” applied his own ingenuity in combination with guidance from prominent medical contemporaries in the development of the early neuroendoscope. This paper reviews his contributions to the early evolution of this growing and important field of neurosurgery.

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Wesley Hsu, Thomas A. Kosztowski, Hasan A. Zaidi, Ziya L. Gokaslan and Jean-Paul Wolinsky

Chordomas are rare tumors that arise from the sacrum, spine, and skull base. Surgical management of these tumors can be difficult, given their locally destructive behavior and predilection for growing near delicate and critical structures. En bloc resection with negative margins can be difficult to perform without damaging adjacent structures and causing significant clinical morbidity. For chordomas of the upper cervical spine, surgical options traditionally involve transoral or submandibular approaches. The authors report the use of the image-guided, endoscopic, transcervical approach to the upper cervical spine as an alternative to traditional techniques for addressing upper cervical spine tumors, particularly for tumors where gross-total resection is not feasible.

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Michael J. Dorsi, Wesley Hsu and Allan J. Belzberg

Object

The aim of this study was to estimate the prevalence of brachial plexus injury (BPI) in pediatric multitrauma patients.

Methods

The National Pediatric Trauma Registry was queried using the ICD-9 code 953.4, injury to brachial plexus, to identify cases of BPI. The patient demographics, mechanism of trauma, and associated ICD-9 diagnoses were analyzed.

Results

Brachial plexus injuries were identified in 113 (0.1%) of the 103,434 injured children entered in the registry between April 1, 1985, and March 31, 2002. Sixty-nine patients (61%) were male. Injuries were most often caused by motor vehicle accidents involving passengers (36 cases [32%]) or pedestrians (19 cases [17%]). Head injuries were diagnosed in 47% of children and included concussion in 27%, intracranial bleeds in 21%, and skull fractures in 14%. Upper-extremity vascular injury occurred in 16%. The most common musculoskeletal injuries were fractures of the humerus (16%), ribs (16%), clavicle (13%), and scapula (11%). Spinal fractures occurred in 12% of patients, and spinal cord injury occurred in 4%. The Injury Severity Score ranged from 1 to 75, with a mean score of 10, and 6 patients (5%) died as a result of injuries sustained during a traumatic event.

Conclusions

Brachial plexus injuries occur in 0.1% of pediatric multitrauma patients. Motor vehicle accidents and pedestrians struck by a motor vehicle are the most common reasons for BPIs in this population. Common associated injuries include head injuries, upper-extremity vascular injuries, and fractures of the spine, humerus, ribs, scapula, and clavicle.

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Wesley Hsu, Ahmed Mohyeldin, Sagar R. Shah, Colette M. ap Rhys, Lakesha F. Johnson, Neda I. Sedora-Roman, Thomas A. Kosztowski, Ola A. Awad, Edward F. McCarthy, David M. Loeb, Jean-Paul Wolinsky, Ziya L. Gokaslan and Alfredo Quiñones-Hinojosa

Object

Chordoma is a malignant bone neoplasm hypothesized to arise from notochordal remnants along the length of the neuraxis. Recent genomic investigation of chordomas has identified T (Brachyury) gene duplication as a major susceptibility mutation in familial chordomas. Brachyury plays a vital role during embryonic development of the notochord and has recently been shown to regulate epithelial-to-mesenchymal transition in epithelial-derived cancers. However, current understanding of the role of this transcription factor in chordoma is limited due to the lack of availability of a fully characterized chordoma cell line expressing Brachyury. Thus, the objective of this study was to establish the first fully characterized primary chordoma cell line expressing gain of the T gene locus that readily recapitulates the original parental tumor phenotype in vitro and in vivo.

Methods

Using an intraoperatively obtained tumor sample from a 61-year-old woman with primary sacral chordoma, a chordoma cell line (JHC7, or Johns Hopkins Chordoma Line 7) was established. Molecular characterization of the primary tumor and cell line was conducted using standard immunostaining and Western blotting. Chromosomal aberrations and genomic amplification of the T gene in this cell line were determined. Using this cell line, a xenograft model was established and the histopathological analysis of the tumor was performed. Silencing of Brachyury and changes in gene expression were assessed.

Results

The authors report, for the first time, the successful establishment of a chordoma cell line (JHC7) from a patient with pathologically confirmed sacral chordoma. This cell line readily forms tumors in immunodeficient mice that recapitulate the parental tumor phenotype with conserved histological features consistent with the parental tumor. Furthermore, it is demonstrated for the first time that silencing of Brachyury using short hairpin RNA renders the morphology of chordoma cells to a more differentiated-like state and leads to complete growth arrest and senescence with an inability to be passaged serially in vitro.

Conclusions

This report represents the first xenograft model of a sacral chordoma line described in the literature and the first cell line established with stable Brachyury expression. The authors propose that Brachyury is an attractive therapeutic target in chordoma and that JHC7 will serve as a clinically relevant model for the study of this disease.

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Wesley Hsu, Ryan M. Kretzer, Michael J. Dorsi and Ziya L. Gokaslan

Wrong-site surgery (WSS) is a rare occurrence that can have devastating consequences for patient care. There are several factors inherent to spine surgery that increase the risk of WSS compared with other types of surgery. Not only can a surgeon potentially operate on the wrong side of the spine or the wrong level, but there are unique issues related to spinal localization that can be challenging for even the most experienced clinicians. The following review discusses important issues that can help prevent WSS during spinal procedures.

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Wesley Hsu, I-Mei Siu, Gustavo Pradilla, Ziya L. Gokaslan, George I. Jallo and Gary L. Gallia

Object

Advances in the diagnosis and management of patients with spinal cord tumors have been limited because of the rarity of the disease and the limitations of current animal models for spinal cord glioma. The ideal spinal cord tumor model would possess a number of characteristics, including the use of human glioma cells that capture the growth pattern and local invasive nature of their human counterpart. In this study, the authors' goal was to develop a novel spinal cord tumor model using a human neurosphere cell line.

Methods

Eighteen female athymic rats were randomized into 3 experimental groups. Animals in the first group (6 rats) received a 3-ml intramedullary injection containing DMEM and were used as controls. Animals in the second group (6 rats) received a 3-ml intramedullary injection containing 100,000 glioblastoma multiforme (GBM) neurosphere cells in 3 ml DMEM. Animals in the third group (6 rats) received a 3-ml intramedullary injection containing 9L gliosarcoma cells in 3 ml DMEM. Functional testing of hindlimb strength was assessed using the Basso-Beattie-Bresnahan (BBB) scale. Once the functional BBB score of an animal was less than or equal to 5 (slight movement of 2 joints and extensive movement of the third), euthanasia was performed.

Results

Animals in the GBM neurosphere group had a mean survival of 33.3 ± 2.0 days, which was approximately twice as long as animals in the 9L gliosarcoma group (16.3 ± 2.3 days). There was a significant difference between survival of the GBM neurosphere and 9L gliosarcoma groups (p < 0.001). None of the control animals died (p < 0.001 for GBM neurosphere group vs controls and 9L vs controls). Histopathological examination of the rats injected with 9L gliosarcoma revealed that all animals developed highly cellular, well-circumscribed lesions causing compression of the surrounding tissue, with minimal invasion of the surrounding gray and white matter. Histopathological examination of animals injected with GBM neurospheres revealed that all animals developed infiltrative lesions with a high degree of white and gray matter invasion along with areas of necrosis.

Conclusions

The authors have established a novel animal model of spinal cord glioma using neurospheres derived from human GBM. When injected into the spinal cords of athymic nude rats, neurospheres gave rise to infiltrative, actively proliferating tumors that were histologically identical to spinal cord glioma in humans. On the basis of their results, the authors conclude that this is a reproducible animal model of high-grade spinal cord glioma based on a human GBM neurosphere line. This model represents an improvement over other models using nonhuman glioma cell lines. Novel therapeutic strategies can be readily evaluated using this model.