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  • Author or Editor: Wesley Hsu x
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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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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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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, 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.