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Dueng-Yuan Hueng, Hsin-I Ma and Huey-Kang Sytwu

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Dueng-Yuan Hueng, Hsin-I Ma, Huey-Kang Sytwu and Ming-Ying Liu

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Dueng-Yuan Hueng, Hsin-I Ma and Chien-Min Chen

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Ichiro Nakano and E. Antonio Chiocca

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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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Dueng-Yuan Hueng, Chia-Lin Tsai, Shih-Wei Hsu and Hsin-I Ma

Object

The purpose of this study was to investigate publication patterns for comparative effectiveness research (CER) on spine neurosurgery.

Methods

The authors searched the PubMed database for the period 1980–2012 using the key words “cost analysis,” “utility analysis,” “cost-utility,” “outcomes research,” “practical clinical research,” “comparator trial,” and “comparative effectiveness research,” linked with “effectiveness” and “spine neurosurgery.”

Results

From 1980 through April 9, 2012, neurosurgery CER publications accounted for 1.38% of worldwide CER publications (8657 of 626,330 articles). Spine neurosurgery CER accounted for only 0.02%, with 132 articles. The journal with the greatest number of publications on spine neurosurgery CER was Spine, followed by the Journal of Neurosurgery: Spine. The average annual publication rate for spine neurosurgery CER during this period was 4 articles (132 articles in 33 years), with 68 (51.52%) of the 132 articles being published within the past 5 years and a rising trend beginning in 2008. The top 3 contributing countries were the US, Turkey, and Japan, with 68, 8, and 7 articles, respectively. Only 8 regular articles (6.06%) focused on cost analysis.

Conclusions

There is a paucity of publications using CER methodology in spine neurosurgery. Few articles address the issue of cost analysis. The promotion of continuing medical education in CER methodology is warranted. Further investigations to address cost analysis in comparative effectiveness studies of spine neurosurgery are crucial to expand the application of CER in public health.

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Dueng-Yuan Hueng, Ph.D. Chang-Min Liang, Ph.D. Huey-Kang Sytwu and Ph.D. Hsin-I Ma

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Dueng-Yuan Hueng, Ming-Ying Liu and Hsin-I Ma

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Jung-Chun Lin, Te-Jung Liu, Shih-Wei Hsu, Kuan-Yin Tseng, Tung-Han Tsai, Hsin-I Ma and Dueng-Yuan Hueng