Radiation damage to the normal monkey brain: experimental study induced by interstitial irradiation.

Radiation damage to normal brain tissue induced by interstitial irradiation with iridium-192 seeds was sequentially evaluated by computed tomography (CT), magnetic resonance imaging (MRI), and histological examination. This study was carried out in 14 mature Japanese monkeys. The experimental area received more than 200-260 Gy of irradiation developed coagulative necrosis. Infiltration of macrophages to the periphery of the necrotic area was seen. In addition, neovascularization, hyalinization of vascular walls, and gliosis were found in the periphery of the area invaded by the macrophages. All sites at which the vascular walls were found to have acute stage fibrinoid necrosis eventually developed coagulative necrosis. The focus of necrosis was detected by MRI starting 1 week after the end of radiation treatment, and the size of the necrotic area did not change for 6 months. The peripheral areas showed clear ring enhancement with contrast material. Edema surrounding the lesions was the most significant 1 week after radiation and was reduced to a minimum level 1 month later. However, the edema then expanded once again and was sustained for as long as 6 months. CT did not provide as clear of a presentation as MRI, but it did reveal similar findings for the most part, and depicted calcification in the necrotic area. This experimental model is considered useful for conducting basic research on brachytherapy, as well as for achieving a better understanding of delayed radiation necrosis.</p

Long-term Multidisciplinary Rehabilitation Efficacy in Older Patients After Traumatic Brain Injury: Assessed by the Functional Independence Measure

Instances of traumatic brain injury (TBI) in the elderly have been increasing along with the aging of popula-tions. In the present study, we examined the effect of aging on long-term multidisciplinary in-patient rehabili-tation efficacy after TBI. Sixty-three patients with physical and cognitive impairments after TBI were enrolled in this study. Patients were divided into 4 age groups (≤ 24, 25-44, 45-64, ≥ 65 years) and the clinical charac-teristics and rehabilitation efficacy of each age group were determined. Functional disability was evaluated using motor and cognitive Functional Independence Measure (FIM) scores. Rehabilitation efficacy was assessed by FIM gains during rehabilitation and compared among the groups. There were no statistically significant dif-ferences in motor and cognitive FIM gains among the age groups. However, cognitive FIM gain was limited in a subset of ≥ 65 patients, and initial cognitive measures could not predict cognitive FIM improvement. These results indicate that chronological age is insufficient to accurately predict rehabilitation efficacy in older TBI patients, and that such patients should be considered candidates for intensive rehabilitation programs based on these results. Accurate prognostication of rehabilitation efficacy with continuing data collection is important when using rehabilitation resources for older TBI patients

Resistance to topoisomerase II inhibitors in human glioma cell lines overexpressing multidrug resistant associated protein (MRP) 2

For understanding of the resistance to topoisomerase II inhibitors, 50 sublines were isolated as single clones from parental glioma cell lines by exposure to VP-16 or m-AMSA. The quantitative aspects of topoisomerase IIα,multi drug resistant gene (MDR)-1,breast cancer resistance protein (BCRP), and multidrug resistant associated protein (MRP)1-5were studied by Northern blotting in 50 resistant cell lines. By understanding the function of MRP2, we picked up three drug resistant sublines (T98G-m1, T98G-m2, and gli36-VP1) that overexpressed MRP2, but did not overexpress MDR-1 orMRP1-5 except 2. Moreover, in the results of northern blot analysis of mRNA for topoisomerase IIα identical results are observed in parental cell lines and their resistant cell lines, suggesting that alterations in topoisomerase II do not account for the resistance in these cells. To determine whether the cellular sensitivity to anticancer agents was closely associated with the cellular levels of MRP2, we established cell lines with the same levels of MRP2 as their parental cells by introducing the MRP2 antisense expression plasmid into resistant cells. Etoposide (VP-16) accumulation and efflux studies were carried out in the parental cell lines and their drug resistant cell lines. Decreases in the H3-VP-16 accumulation and increases in the efflux were observed in these drug resistant cell lines. In the cytotoxicity assay, these drug resistant cell lines were resistant to multiple topoisomerase II inhibitors with little cross resistance to vincristine, and display efflux of VP-16. We found that the resistant cells transfected with MRP2 antisense cDNA displayed increased cellular levels of VP-16 and enhanced sensitivities to topoisomerase II inhibitors. In this study on the T98G-m1, T98G-m2, and gli36-VP1 cell lines, we showed a high correlation between MRP2 mRNA and VP-16 efflux, suggesting that MRP2 could be a new transporter for topoisomerase II inhibitors

Usefulness of FDG, MET and FLT-PET Studies for the Management of Human Gliomas

The use of positron imaging agents such as FDG, MET, and FLT is expected to lead the way for novel applications toward efficient malignancy grading and treatment of gliomas. In this study, the usefulness of FDG, MET and FLT-PET images was retrospectively reviewed by comparing their histopathological findings. FDG, MET, and FLT-PET were performed in 27 patients with WHO grade IV, 15 patients with WHO grade III, and 12 patients with WHO grade II during 5.5 years. The resulting PET images were compared by measuring SUVs and T/N ratios (tumor to normal tissue ratios). Although there were no significant differences in FDG-PET, there were significant differences in the T/N ratios in the MET-PET between WHO grades II and IV and in the FLT-PET between the WHO grades III and IV. In glioblastoma patients, the SUVs of the areas depicted by MRI in the MET-PET were different from those SUVs in the FLT-PET. Importantly, the areas with high SUVs in both MET-PET and FLT-PET were also high in Ki-67 index and were histologically highly malignant. PET imaging is a noninvasive modality that is useful in determining a tumor area for removal as well as improving preoperative diagnosis for gliomas

Effect of intracarotid infusion of etoposide: modification of the permeability of the blood-brain barrier and the blood-tumor barrier in rat brain tumor model

The effect of intracarotid infusion of etoposide on the permeability of the blood-brain barrier (BBB) and brain-tumor barrier (BTB) was investigated using a model of rats injected with C6 glioma cells. Fifty four glioma-bearing rats were divided into 3 groups and treated with 0, 3, or 15 mg/kg of etoposide infused into the internal carotid artery. BBB or BTB permeability was evaluated qualitatively by the leakage of Evans blue (6 animals in each group) or quantitatively by the diffusion of carboplatin [cis-diammine (1,1-cyclobutane-dicarboxylato) platinum(II); CBDCA] (12 animals in each group) into the normal brain or the tumor tissue. BBB and BTB disruption augmented significantly in proportion to the dose of etoposide. The degree of disruption of BTB was greater than that of BBB, but the rate of disruption of BBB in proportion to increasing the dose of etoposide was higher than that in the BTB. Histopathologically, no obvious changes were observed in the animals of either the control group or the 3 mg/kg group but degenerative changes in the neurons of the hippocampus of the infused hemisphere were seen in the 15 mg/kg group. This change is thought to be caused by apoptosis because of the positive reaction with TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. Our results suggest that intracarotid infusion of etoposide can increase drug delivery of concurrent antitumor agents into tumor tissue, but cerebral parenchymal cell damage is expected with a higher dosage of etoposide. Therefore, the dosage of etoposide for intracarotid infusion should be lower than 15 mg/kg in order to reduce neurotoxicity of both etoposide and concurrent anticancer drugs.</p

Perioperative Clinical Course Variables Associated with Length of Hospital Stay after Primary Intracranial Meningioma Resection

The relationship between perioperative clinical course variables and postoperative length of hospital stay (LOS) in patients undergoing primary intracranial meningioma resection has not been fully elucidated. We therefore aimed to identify the perioperative clinical course variables that predict postoperative LOS in such patients. We retrospectively collected data concerning demographics, tumor characteristics, and perioperative clinical course variables in 76 patients who underwent primary intracranial meningioma resection between January 2010 and December 2019, and tested for associations with postoperative LOS. Univariate analyses showed that younger age, fewer days to postoperative initiation of standing/walking, preoperative independence in activities of daily living (ADL), and ADL independence one week after surgery were associated with shorter postoperative LOS. Multiple regression analyses with these factors identified that days to stand/walk initiation and ADL independence one week after surgery were associated with postoperative LOS. Based on these results, we conclude that rehabilitation programs that promote early mobilization and the early acquisition of independence may reduce postoperative LOS in patients who undergo primary intracranial meningioma resection

Reduction of expression of the multidrug resistance protein (MRP)1 in glioma cells by antisense phosphorothioate oligonucleotides

The tumor cells’ acquisition of resistance to multiple drugs due to overexpression of the multidrug resistance protein(MRP) 1gene is one of major obstacles in cancer chemotherapy. We have attempted to reverse the multidrug resistance (MDR) phenotype by treating etoposide resistant glioma cell lines (T98G-VP and Gli36-VP) with MRP1 antisense oligonucleotides. 20-mer phosphorothioate oligodeoxynucleotide (0.3μM), complementary to the coding region in the MRP cDNA sequence, could significantly inhibit the growth of multidrug resistant cell lines, T98G-VP and Gli36-VP, cultured in etoposide containing medium. No such effect was observed for the parental T98G and Gli36 cell lines. Further investigations by the reverse transcription-polymerase chain reaction and immunoblotting revealed that antisense oligomer could result in a reduction in the level of MRP1 mRNA, probably through hindering MRP1 gene transcription. This study demonstrates that the antisense oligonucleotides can increase the sensitivity of the tumor cells to the anticancer drug by decreasing the expression of the MRP gene. This strategy may be applicable to cure cancer patients with MRP mediated MDR phenotype

Histidine-rich Glycoprotein Could Be an Early Predictor of Vasospasm after Aneurysmal Subarachnoid Hemorrhage

Cerebral vasospasm (CVS) is a major contributor to the high morbidity and mortality of aneurysmal subarachnoid hemorrhage (aSAH) patients. We measured histidine-rich glycoprotein (HRG), a new biomarker of aSAH, in cerebrospinal fluid (CSF) to investigate whether HRG might be an early predictor of CVS. A total of seven controls and 14 aSAH patients (8 males, 6 females aged 53.4±15.4 years) were enrolled, and serial CSF and serum samples were taken. We allocated these samples to three phases (T1-T3) and measured HRG, interleukin (IL)-6, fibrinopeptide A (FpA), and 8-hydroxy-2’-deoxyguanosine (8OHdG) in the CSF, and the HRG in serum. We also examined the release of HRG in rat blood incubated in artificial CSF. In contrast to the other biomarkers examined, the change in the CSF HRG concentration was significantly different between the nonspasm and spasm groups (p<0.01). The rat blood/CSF model revealed a time course similar to that of the human CSF samples in the non-spasm group. HRG thus appears to have the potential to become an early predictor of CVS. In addition, the interaction of HRG with IL-6, FpA, and 8OHdG may form the pathology of CVS

Differences in the neuronal stem cells survival, neuronal differentiation and neurological improvement after transplantation of neural stem cells between mild and severe experimental traumatic brain injury

We developed a novel protocol for generation and selective amplification of neural progenitor cells regionally specified to the rostral brain but not the spinal cord from mouse embryonic stem cells (ESCs). The neural progenitors could differentiate in vitro and in vivo into many cholinergic and a few GABAergic neurons but rarely into astrocytes. The transplanted neurospheres could survive in the hippocampus (CA3) of animals with mild traumatic brain injury (TBI). Twelve weeks after transplantation (a week after the behavioral test), we found significant cholinergic differentiation recognized as ChAT immunoreactivity in the eGFP+ transplanted cells. Moreover, the grafts contained a few GAD67+cells. However, we barely found GFAP+ astrocytes within the grafts. Furthermore, presynaptic formations of graft-derived neurons were recognized by immunohistochemistry of near the grafts aroundCA3. However, these findings were not observed in severe TBI group. So, we examined NGF, BDNF, and FGF-2 mRNA by RT-PCR in 12 mice including normal, mild TBI and severe TBI group. Increases in the neurotrophic factors’ mRNA were evident in the hippocampus on the ipsilateral side in the mild TBI group. Statistical analysis revealed significant differences between the mild and severe TBI groups. The data also revealed significant differences between the mild TBI and normal groups. The transplanted neurospheres could survive in the mild TBI animals, but not in the severe TBI group