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The stereotactic procedure in neurosurgery is a minimally invasive technique used to treat intracranial lesions. The fiducial markers of a frame-based stereotactic procedure are important for defining the stereotactic coordinate system and in locating the target. These markers are often defective in stereotactic images owing to the presence of air bubbles in the imaging indicator. We have assessed the effect of these defects on the registration of an image and on the localization of a target. The virtual phantom method was employed to simulate various types of defect. The virtual images were registered using the Leksell GammaPlan® (LGP) radiosurgery planning system, and the image definition and the target localization errors were assessed. As a result, the effect of the defects was most severe when the majority of the marker disappeared, but not all, especially in the posterior region. The mean and maximum image definition errors were 0.1 and 1.4 mm, which caused the mean target localization error to be 0.2 and 0.0 mm in LGP version 5.34 and 8.3.1, respectively. It is recommended to exclude images with defective fiducial markers during the image definition procedure to minimize subsequent errors, though the newest version of LGP (version 8.3.1) corrects localization errors.

We investigated pseudoprogression (psPD) in patients with malignant gliomas treated with radiotherapy (RT) and maintenance temozolomide (TMZ) in terms of incidence, outcomes, and predictive and prognostic factors. We evaluated p53 overexpression by immunohistochemical analysis of thirty-five tumor samples as a predictor for psPD. The time to progression and overall survival were compared between subgroups, psPD versus early progression (ePD) versus nonprogression (nonPD). Eight patients developed psPD among eighteen patients with lesion enlargement at the first MRI scan, and the others were classified as ePD. The remaining stable or improved patients were classified as nonPD. All patients with psPD were alive at last follow-up (median follow-up period was 12 months; range 5.8-58.5 months). Overall survival of psPD patients was significantly higher than ePD patients (P < 0.01). There was no significant survival difference between the psPD group and nonPD group (P = 0.25). Seven (87.5%) of eight tumors with psPD showed p53 overexpression, as compared to 3 (30%) of the ten tumors with ePD (P = 0.03). Our study indicates that psPD following chemoradiotherapy with TMZ is associated with significantly better overall survival compared to that of ePD, and is comparable to nonPD group. Overexpression of p53 was identified as a potential biomarker for predicting the development of psPD.

Purpose: We retrospectively evaluated the effect of brain atrophy on the outcome of patients after a large cerebral infarct., Methods: Between June 2003 and Oct 2008, 134 of 2975 patients with stroke were diagnosed as having a large cerebral infarct. The mean age of the patients was 70 (21-95) y. The mean infarct volume was 223.6±95.2 cm(3) (46.0-491.0). The inter-caudate distance (ICD) was calculated as an indicator of brain atrophy by measuring the hemi-ICD of the intact side and then multiplying by two to account for brain swelling at the infarct site. The mean ICD was 18.0±4.8 mm (9.6-37.6)., Results: Forty-nine (36.6%) patients experienced a malignant clinical outcome (MCO) during management in the hospital. Thirty-one (23.1%) patients had a favourable functional outcome (FO) (modified Rankin scale (mRS) ≤3) and 49 (36.6%) had an acceptable functional outcome (AO) (mRS≤4) at 6 months after stroke onset. In the multivariate analysis, brain atrophy (ICD≥20 mm) had a significant and independent protective effect on MCO (p=0.003; OR=0.137; 95% CI 0.037 to 0.503). With respect to FO, the age and infarct volume reached statistical significance (p<0.001, OR=0.844, 95% CI 0.781 to 0.913; p=0.006, OR=0.987, 95% CI 0.977 to 0.996, respectively). Brain atrophy (ICD≥20 mm) was negatively associated only with AO (p=0.022; OR=0.164; 95% CI 0.035 to 0.767)., Conclusions: Brain atrophy may have an association with clinical outcome after a large stroke by a trend of saving patients from an MCO but also by interfering with their functional recovery.

The purpose of this study is to determine the efficacy of Gamma Knife stereotactic radiosurgery (GK SRS) for intracranial hemangiopericytomas, and to investigate the optimal dose for successful tumor control without adverse effects. We evaluated 17 hemangiopericytomas of nine patients treated with GK SRS between 1999 and 2008. The mean tumor volume was 2.2 cm(3) (range 0.2-9.9 cm(3)), and the mean and median marginal doses were 18.1 and 20 Gy (range 11-22 Gy), respectively, at the 50% isodose line. Mean clinical and radiological follow-up periods were 49 and 34 months, respectively. Successful tumor control was achieved in 14 of 17 lesions (82.4%) at time of last follow-up after GK SRS. Actuarial local tumor control rates at 1, 2, and 5 years after GK SRS were 100%, 84.6%, and 67.7%, respectively. No adverse effects, such as radiation necrosis or marked peritumoral edema, were observed in any patient. Marginal dose (>or=17 Gy) was the only statistically significant factor for local tumor control on univariate analysis. Extended analysis using lesion data available from previous studies revealed that higher marginal dose (>or=17 Gy) was also significant (P = 0.028). GK SRS provides an effective and safe adjuvant management option for patients with recurrent or residual hemangiopericytomas. Our results suggest that doses higher than previously used (around 15 Gy) are desirable to achieve better local tumor control of hemangiopericytomas. Close radiological follow-up is also necessary for early detection of small recurrent lesions.

Purpose: We retrospectively evaluated the survival of patients with brain metastases from advanced gastric cancer (AGC) after radiosurgery (RS)., Methods: Between 1998 and 2007, a total of 11 patients (median age, 61 years; range, 36-70) were diagnosed with brain metastasis from AGC and treated with RS. Each of five (46%) patients had two brain metastases. The median volume of the 16 lesions was 2.9 cm(3) (range, 0.1-33.8). The median marginal dose prescribed was 20 Gy (range, 10-25) at the 50% isodose line. RS was the primary treatment for brain metastases in six patients., Results: As of February 28, 2008, eight (73%) patients had died, and three (27%) were living with stable disease. The median survival time was 17.0 +/- 3.9 months (95% CI, 9.4-24.6). The median progression-free survival time was 9.0 +/- 2.5 months (95% CI, 4.2-13.8). Patients who did not undergo WBRT died within 8 months, and the other six patients treated with WBRT at various time intervals from the diagnosis of brain metastases survived, with a median survival time of 19.0 +/- 3.4 months (95% CI, 12.4-25.6)., Conclusions: Radiosurgery seems to be a good alternative to surgical resection for patients with brain metastases from AGC, when performed in conjunction with WBRT.

Pyrrolidine dithiocarbamate (PDTC) is a stable compound that acts as antioxidant or prooxidant, and is widely used to inhibit the activation of NF-kappaB. PDTC was also reported to activate NF-kappaB depending on its dose and metal ions in PC12 cells. In this work, we demonstrated a working mechanism of PDTC and its effects on the proinflammatory cytokine gene expression in a mouse macrophage cell line, RAW 264.7. PDTC alone induced NF-kappaB-independent MIP-2 promoter activation that can be assessed by transient transfection and confocal image analysis. The involvement of AP-1 transcription factor was noticed by promoter deletion/site-specific mutation analysis and electrophoretic mobility shift assay (EMSA). Among three different mitogen-activated protein kinase (MAPK) pathways tested, only the stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) pathway was significantly activated in RAW 264.7 cells after the stimulation with PDTC. Using pathway-specific inhibitors, we found that the SAPK/JNK pathway is clearly associated with PDTC-induced MIP-2 gene expression. Our experimental results indicate that PDTC-induced proinflammatory cytokine expressions are mediated by SAPK/JNK pathway, which activates AP-1.

Macrophage inflammatory protein-2 (MIP-2) is a mouse C-X-C chemokine that plays an important role in the recruitment of neutrophils. Transcription of the MIP-2 gene is rapidly induced by lipopolysaccharide (LPS) stimulation in cells of macrophage lineage. We show here that the MIP-2 promoter is transcriptionally activated in a macrophage cell line RAW 264.7 by LPS through a sequence located between -450 and -54 and this region contains two copies of activator protein-1 (AP-1) and one copy of nuclear factor-kappaB (NF-kappaB) binding site. A MIP-2 promoter-reporter was activated by ectopical expression of NF-kappaB p65 or c-Jun transcription factors. Inhibition of NF-kappaB nuclear localization by co-expression of a mutant IkappaBalpha protein (IkappaBalpha super repressor, IkappaBalphaSR) blocked LPS-induced transcription from a MIP-2 promoter-reporter construct, showing that NF-kappaB activation is required for MIP-2 gene expression in the LPS-signaling pathway. By deletion analysis of the MIP-2 promoter region, we show that NF-kappaB and c-Jun binding sites are essential for LPS-induced MIP-2 gene expression. Using transient transfection, NF-kappaB and c-Jun transcription factors were found to synergistically activate the MIP-2 promoter. In summary, our data suggest that both NF-kappaB and c-Jun contribute to LPS-induced mouse MIP-2 gene expression in RAW 264.7 cells.

Immunostimulatory activities of synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODNs) have gained attention as potentially useful immunotherapeutics. However, CpG-ODNs induce harmful and lethal shock effects because they greatly enhance the sequence-dependent induction of tumor necrosis factor-alpha (TNF-alpha). We have shown that phosphorothioate-modified oligodeoxynucleotides (PS-ODNs) of the CpG-ODN 1826 stimulate TNF-alpha gene expression, TNF-alpha promoter activity, IkappaB degradation, and NF-kappaB activation at higher levels compared with its phosphodiester ODN (PO-ODN). In contrast to the effects of CpG-ODN 1826, PS-ODN of the CpG-ODN 2006 showed lower stimulatory activities than its PO-ODN. Using transient transfection, it was found that myeloid differentiation protein (MyD88) and tumor necrosis factor receptor-associated factor 6 are commonly required for activation of the TNF-alpha promoter by various CpG-ODNs with different potencies. These results strongly suggest a possibility to optimally activate the innate immune responses by modulating the potency of CpG-ODNs via sequence rearrangement and phosphorothioate backbone modification.