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Gamma knife surgery as monotherapy with clinically relevant doses prolongs survival in a human GBM xenograft model.

Skeie BS, Wang J, Dodoo E, Heggdal JI, Grønli J, Sleire L, Bragstad S, Ganz JC, Chekenya M, Mørk S, Pedersen PH, Enger PØ - Biomed Res Int (2013)

Bottom Line: However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments.In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P < 0.006).Polynuclear macrophages and fibrosis was seen in groups subjected to GKS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Haukeland University Hospital, 5021 Bergen, Norway ; Institute of Surgical Sciences, Haukeland University Hospital, 5021 Bergen, Norway ; Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, 5021 Bergen, Norway.

ABSTRACT

Object: Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS.

Methods: GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12 Gy or 18 Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test.

Results: In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls (P < 0.001). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P < 0.006). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment (P = 0.04).

Conclusion: GKS administered with clinically relevant doses prolongs survival in rats harboring GBM xenografts, and the associated toxicity is mild.

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Related in: MedlinePlus

GKS of nude rats harboring GBM xenografts. The rats are fixed in a stereotactic frame (a) attached to a transparent hood prior CT scanning (b). These scans are merged with MRI images (c). Shown is a dose administered with a 4 mm collimator (red) and the accompanying 80% isodose curve (yellow).
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fig1: GKS of nude rats harboring GBM xenografts. The rats are fixed in a stereotactic frame (a) attached to a transparent hood prior CT scanning (b). These scans are merged with MRI images (c). Shown is a dose administered with a 4 mm collimator (red) and the accompanying 80% isodose curve (yellow).

Mentions: Animals were irradiated with the Leksell Gamma Knife Perfexion (Elekta Instrument AB, Stockholm, Sweden) anesthetized with intramuscular Hypnorm-Dormicum (0, 4 mL/kg). One day after MRI, the rats were immobilized in a Regis-Valliccioni stereotactic frame 5 (Neuropace, Neuilly, France (Figure 1(a))) [16] and underwent CT scanning with the frame attached. The MRI images of the tumors were coaligned with the CT scans in the Gammaplan, aided by anatomical landmarks and the visible trajectory from the tumor implantation (Figure 1(b)). The rats were randomized to different treatment groups and treated with a tumor margin dose of 12 Gy or 18 Gy to the 50–88% (mean 74.6%) isodose, using collimator size 4 (Figure 1(c)), or they were randomized to no treatment. The mean treatment time was 5.0 minutes. In the radiotoxicity experiment, the rats received early GKS only 9 days after implantation to allow for a long follow-up time. These animals received 12 Gy to the 80% isodose, centered at the site of the implantation (Figure 1(c)).


Gamma knife surgery as monotherapy with clinically relevant doses prolongs survival in a human GBM xenograft model.

Skeie BS, Wang J, Dodoo E, Heggdal JI, Grønli J, Sleire L, Bragstad S, Ganz JC, Chekenya M, Mørk S, Pedersen PH, Enger PØ - Biomed Res Int (2013)

GKS of nude rats harboring GBM xenografts. The rats are fixed in a stereotactic frame (a) attached to a transparent hood prior CT scanning (b). These scans are merged with MRI images (c). Shown is a dose administered with a 4 mm collimator (red) and the accompanying 80% isodose curve (yellow).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3842058&req=5

fig1: GKS of nude rats harboring GBM xenografts. The rats are fixed in a stereotactic frame (a) attached to a transparent hood prior CT scanning (b). These scans are merged with MRI images (c). Shown is a dose administered with a 4 mm collimator (red) and the accompanying 80% isodose curve (yellow).
Mentions: Animals were irradiated with the Leksell Gamma Knife Perfexion (Elekta Instrument AB, Stockholm, Sweden) anesthetized with intramuscular Hypnorm-Dormicum (0, 4 mL/kg). One day after MRI, the rats were immobilized in a Regis-Valliccioni stereotactic frame 5 (Neuropace, Neuilly, France (Figure 1(a))) [16] and underwent CT scanning with the frame attached. The MRI images of the tumors were coaligned with the CT scans in the Gammaplan, aided by anatomical landmarks and the visible trajectory from the tumor implantation (Figure 1(b)). The rats were randomized to different treatment groups and treated with a tumor margin dose of 12 Gy or 18 Gy to the 50–88% (mean 74.6%) isodose, using collimator size 4 (Figure 1(c)), or they were randomized to no treatment. The mean treatment time was 5.0 minutes. In the radiotoxicity experiment, the rats received early GKS only 9 days after implantation to allow for a long follow-up time. These animals received 12 Gy to the 80% isodose, centered at the site of the implantation (Figure 1(c)).

Bottom Line: However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments.In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P < 0.006).Polynuclear macrophages and fibrosis was seen in groups subjected to GKS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Haukeland University Hospital, 5021 Bergen, Norway ; Institute of Surgical Sciences, Haukeland University Hospital, 5021 Bergen, Norway ; Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, 5021 Bergen, Norway.

ABSTRACT

Object: Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS.

Methods: GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12 Gy or 18 Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test.

Results: In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls (P < 0.001). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P < 0.006). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment (P = 0.04).

Conclusion: GKS administered with clinically relevant doses prolongs survival in rats harboring GBM xenografts, and the associated toxicity is mild.

Show MeSH
Related in: MedlinePlus