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A novel intramedullary spinal cord tumor model: functional, radiological, and histopathological characterization

Gaurav Mavinkurve, Gustavo Pradilla, Federico G. Legnani, Betty M. Tyler, Carlos A. Bagley, Henry Brem, and George Jallo

Object

Survival rates for high-grade intramedullary spinal cord tumors (IMSCTs) are approximately 30%, and optimal therapy has yet to be determined. Development of a satisfactory intramedullary tumor model is necessary for testing new therapeutic paradigms that may prolong survival. The authors report the technique, functional progression, radiological appearance, and histopathological features of a novel intramedullary model in rabbits.

Methods

Ten New Zealand white rabbits were randomized to receive an intramedullary injection of either 25 µl of VX2 carcinoma cells (500,000 cells; six rabbits) or 25 ml of medium (Dulbecco modified Eagle medium; four rabbits) into the midthoracic spinal cord. Postoperatively the rabbits were evaluated twice daily for neurological deficits. High-resolution magnetic resonance (MR) images were acquired preoperatively and weekly postoperatively until onset of paraparesis, at which point the animals were killed, and the midthoracic spines were processed for histopathological examination.

The VX2-carcinoma cells grew in 100% of animals injected and resulted in a statistically significant mean onset of paraparesis of 16.8 ± 1.7 days (p = 0.0035, log-rank test), compared with animals in the control group in which neurological deficits were absent by Day 45. Contrast-enhanced T1-weighted MR imaging best demonstrated space-occupying intramedullary lesions and histopathological findings confirmed the intramedullary location of the tumor. Animals in the control group exhibited no functional, radiographic, or pathological signs of tumor.

Conclusions

Progression to paraparesis was consistent in all the VX2-injected animals, with predictable onset of paraparesis occurring approximately 17 days postinjection. Histopathological and radiological characteristics of the VX2 intramedullary tumor are comparable with those of aggressive primary human IMSCTs. Establishment of this novel animal tumor model will facilitate the testing of new therapeutic paradigms for the treatment of IMSCTs.

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Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel

Laboratory investigation

Betty M. Tyler, Alia Hdeib, Justin Caplan, Federico G. Legnani, Kirk D. Fowers, Henry Brem, George Jallo, and Gustavo Pradilla

Object

Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma.

Methods

Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 μl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 μl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis.

Results

OncoGel was safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml of paclitaxel; a dose of 5 μl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5.

Conclusions

OncoGel is safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings.

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A novel rat model for the study of intraosseous metastatic spine cancer

Ajay Mantha, Federico G. Legnani, Carlos A. Bagley, Gary L. Gallia, Ira Garonzik, Gustavo Pradilla, Eric Amundson, Betty M. Tyler, Henry Brem, and Ziya L. Gokaslan

Object. Although metastatic spinal disease constitutes a significant percentage of all spinal column tumors, an accessible and reproducible animal model has not been reported. In this study the authors describe the technique for creating an intraosseous spinal tumor model in rats and present a functional and histological analysis.

Methods. Eighteen female Fischer 344 rats were randomized into two groups. Group 1 animals underwent a transabdominal exposure and implantation of CRL-1666 breast adenocarcinoma into the L-6 vertebral body (VB). Animals in Group 2 underwent a sham operation. Hindlimb function was tested daily by using the Basso-Beattie-Bresnahan scale. Sixteen days after tumor implantation, animals were killed and their spines were removed for histological assessment. Statistical analysis was performed using the Wilcoxon signed-rank test.

By Day 15 functional analysis showed a significant decrease in motor function in Group 1 animals (median functional score 2 of 21) compared with Group 2 rats (median functional score 21 of 21) (p = 0.0217). The onset of paraparesis in Group 1 occurred within 14 to 16 days of surgery. Histopathological analysis showed tumor proliferation through the VB and into the spinal canal, with marked osteolytic activity and spinal cord compression.

Conclusions. Analysis of these findings demonstrates the consistency of tumor growth in this model and validates the utility of functional testing for onset of paresis. This new rat model allows for the preclinical evaluation of novel therapeutic treatments for patients harboring metastatic spine disease.