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  • Author or Editor: Lung-Kuo Tai x
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Hsin-I Ma, Shih-Hwa Chiou, Dueng-Yuan Hueng, Lung-Kuo Tai, Pin-I Huang, Chung-Lan Kao, Yi-Wei Chen and Huey-Kang Sytwu

Object

Glioblastoma, the most common primary brain tumor, has a poor prognosis, even with aggressive resection and chemoradiotherapy. Recent studies indicate that CD133+ cells play a key role in radioresistance and recurrence of glioblastoma. Cyclooxygenase-2 (COX-2), which converts arachidonic acid to prostaglandins, is over-expressed in a variety of tumors, including CD133+ glioblastomas. The COX-2–derived prostaglandins promote neovascularization during tumor development, and conventional radiotherapy increases the proportion of CD133+ cells rather than eradicating them. The aim of the present study was to investigate the role of celecoxib, a selective COX-2 inhibitor, in enhancing the therapeutic effects of radiation on CD133+ glioblastomas.

Methods

Cells positive for CD133 were isolated from glioblastoma specimens and characterized by flow cytometry, then treated with celecoxib and/or ionizing radiation (IR). Clonogenic assay, cell irradiation, cell cycle analysis, Western blot, and xenotransplantation were used to assess the effects of celecoxib alone, IR alone, and IR with celecoxib on CD133+ and CD133 glioblastoma cells. Three separate xenotransplantation experiments were carried out using 310 severe combined immunodeficient (SCID) mice: 1) an initial tumorigenicity evaluation in which 3 different quantities of untreated CD133 cells or untreated or pretreated CD133+ cells (5 treatment conditions) from 7 different tumors were injected into the striatum of 2 mice (210 mice total); 2) a tumor growth study (50 mice); and 3) a survival study (50 mice). For these last 2 studies the same 5 categories of cells were used as in the tumorigenicity (untreated CD133 cells, untreated or pretreated CD133+ cells, with pretreatment consisting of celecoxib alone, IR alone, or IR and celecoxib), but only 1 cell source (Case 2) and quantity (5 × 104 cells) were used.

Results

High levels of COX-2 protein were detected in the CD133+ but not the CD133 glioblastoma cells. The authors further demonstrated that 30 μM celecoxib was able to effectively enhance the IR effect in inhibiting colony formation and increasing IR-mediated apoptosis in celecoxib-treated CD133+ glioblastoma cells. Furthermore, reduction in radioresistance was correlated with the induction of G2/M arrest, which was partially mediated through the increase in the level of phosphorylated-cdc2. In vivo xenotransplant analysis further confirmed that CD133+-associated tumorigenicity was significantly suppressed by celecoxib treatment. Importantly, pretreatment of CD133+ glioblastoma cells with a combination of celecoxib and IR before injection into the striatum of SCID mice resulted in a statistically significant reduction in tumor growth and a statistically significant increase in the mean survival rate of the mice.

Conclusions

Celecoxib combined with radiation plays a critical role in the suppression of growth of CD133+ glioblastoma stemlike cells. Celecoxib is therefore a radiosensitizing drug for clinical application in glioblastoma.

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Shiuh-Lin Hwang, Chih-Lung Lin, Ann-Shung Lieu, Kung-Shing Lee, Tai-Hung Kuo, Yan-Fen Hwang, Yu-Feng Su and Shen-Long Howng

Object. Cage-assisted anterior cervical discectomy and fusion (ACDF) has proven to be a safe and effective procedure for the treatment of one- and two-level degenerative disc disease (DDD). To the authors' knowledge, clinical results after three- and four-level interbody cage—augmented ACDF have not been reported in the literature. The authors investigated the safety and effectiveness of titanium cages used in such procedures and evaluated the results in cases with or without plate fixation.

Methods. Fifty-six patients suffering from cervical DDD were divided into two groups. Group 1 included 32 patients who underwent titanium cage—assisted ACDF; Group 2 included 24 patients who underwent the same procedure, supplemented with plate fixation. The cervical DDD was confirmed by radiography and magnetic resonance imaging. The patients underwent radiographic evaluation to assess cervical lordosis, segmental height of cervical spine, the height of the foramina, and spinal stability. Neurological outcomes were assessed using the Japanese Orthopaedic Association (JOA) scores. Neck pain was graded using a 10-point visual analog scale (VAS). The follow-up period ranged from 13 to 28 months (mean 17.2 months).

In both Groups 1 and 2 significant increase (p < 0.001) was demonstrated in the JOA scores (preoperatively 10.7 ± 2.4 and 11.1 ± 2, postoperatively 13.9 ± 2.2 and 14.1 ± 2.3, respectively) and VAS pain scores (preoperatively 8.8 ± 0.9 and 8.5 ± 1, postoperatively 3.1 ± 2.1 and 2.8 ± 1.8, respectively); however, there was no significant intergroup difference. A significant increase in the cervical lordosis, foraminal height, and segmental height was observed in both groups. Good stability of cage fusion was obtained in both groups 12 months postoperatively (90.6% in Group 1 and 91.7% in Group 2); however, there were no statistically significant intergroup differences. The complication rate in Group 2 was higher than that in Group 1. The hospital length of stay in Group 1 was significantly lower than in Group 2 (p < 0.001).

Conclusions. Analysis of these findings demonstrated that titanium cage—assisted ACDF provided long-term stabilization, increased lordosis, increased segmental height, and increased foraminal height. In both groups good neurological outcomes were achieved and donor site morbidity was avoided. The lower complication rate and shorter hospital stay, however, make the cage-assisted fusion without plate fixation better than with plate fixation.