Yoshihiko Yoshii

Pathological review of late cerebral radionecrosis

Late cerebral radionecrosis may be considered to be a specific chronic inflammatory response, although it is unknown whether the initial damage by brain irradiation is to an endothelial cell or a glial cell. I discuss the pathological specificity of late cerebral radionecrosis by studying the published literature and a case that I experienced. In late cerebral radionecrosis, there are typical coagulation necrosis areas containing fibrinoid necrosis with occlusion of the lumina and poorly active inflammatory areas with many inflammatory ghost cells, focal perivascular lymphocytes, hyalinized vessels, and telangiectatic vascularization near and in the necrotic tissue, and more active inflammatory areas formed as a partial rim of the reactive zone by perivascular lymphocytes, much vascularization, and GFAP-positive astrocytes at the corticomedullary border adjacent to necrotic tissue in the white matter. It is difficult to believe that coagulation necrosis occurs without first disordering the vascular endothelial cells because fibrinoid necrosis is a main feature and a diffusely multiple lesion in late cerebral radionecrosis. Because various histological findings do develop, progress, and extend sporadically at different areas and times in the irradiated field of the brain for a long time after radiation, uncontrolled chronic inflammation containing various cytokine secretions may also play a key role in progression of this radionecrosis. Evaluation of the mechanism of the development/aggravation of late cerebral radionecrosis requires a further study for abnormal cytokine secretions and aberrant inflammatory reactions.

Apoptotic effect in the glioma cells induced by specific protein extracted from Okinawa Habu (Trimeresurus flavoviridis) venom in relation to oxidative stress

Okinawa Habu (Trimeresurus flavoviridis) venom is well known for its toxic efficacy, from which one kind of specific protein, Okinawa Habu apoxin protein-1 (OHAP-1) has been extracted. The purpose of this study was to investigate whether OHAP-1 could induce apoptosis in some glioma cells, and if so, to elucidate the possible mechanism involved. Three malignant glioma cell lines were tested. The malignant glioma cell lines were rat C6 and human RBR 17T, U251. OHAP-1 inhibited growth of all cell lines. Whether or not the apoptosis had been induced was determined by using DNA gel electrophoresis, DNA flow cytometry and TUNEL assay. After OHAP-1 treatment, DNA fragmentation, an increase in the percentage of subdiploid DNA content, and TUNEL positive cells were found in the C6, RBR17T, and U251 cells. Furthermore, OHAP-1 showed L-amino acid oxidase (LAAO) activity. In order to study the mechanism of apoptosis induced by OHAP-1, the changes of intracellular reactive oxygen species (ROS) were measured using flow cytometry, and the expression of p53 protein was examined using immunohistochemistry. OHAP-1 was found to generate ROS and increase the expression of p53 protein in glioma cells. The inhibiting effect of OHAP-1 on three tested cells was reversed when an antioxidant of either catalase or reduced glutathione (GSH) was added; its apoptotic effect correspondingly became weaker. In this study, the apoptotic effect of OHAP-1 on some malignant glioma cells was confirmed, and it could be that this effect might be mediated through promoting the generation of intracellular ROS and p53 protein expression in glioma cells. It was suggested that OHAP-1 is promising as a potential candidate for clinical tumor therapy.

Treatment and prognosis of brain metastases from breast cancer.

Background To analyze retrospectively the results of treatments for patients with brain metastases from breast cancer. Materials and Methods The records of 65 breast cancer patients with brain metastases who were treated between 1985 and 2005 were reviewed. For brain metastases, 11 patients (17%) were treated with surgical resection followed by radiotherapy, and the remaining 54 patients were treated with radiotherapy alone. Systemic chemotherapy was also administered to 11 patients after brain radiotherapy. Results The overall median survival for all patients was 6.1xa0months (range, 0.4–82.2xa0months). In univariate analysis, treatment modality, Karnofsky performance status (KPS), administration of systemic chemotherapy, extracranial disease status and total radiation dose each had significant impact on overall survival, and in multivariate analysis, treatment modality, KPS and administration of systemic chemotherapy were significant prognostic factors. Eight patients survived for more than 2xa0years after the diagnosis of brain metastases, and all these patients were treated with surgical resection and/or systemic chemotherapy in addition to radiotherapy. For the 45 patients treated with palliative radiotherapy (without systemic chemotherapy), the improvements in neurological symptoms were observed in 35 patients (78%), with the median duration of improvement of 3.1xa0months (range, 1.5–4.4xa0months). Conclusions The prognoses for patients with brain metastases from breast cancer were generally poor, although selected patients may survive longer with intensive brain tumor treatment, such as surgical resection and/or systemic chemotherapy in addition to brain radiotherapy. For patients with unfavorable prognoses, palliative radiotherapy was effective in improving the quality of the remaining lifetime.

Apoptosis induced by box jellyfish (Chiropsalmus quadrigatus) toxin in glioma and vascular endothelial cell lines.

This study was made to investigate whether Chiropsalmus Quadrigatus toxins (CqTX), which isolated from box jellyfish C. Quadrigatus venom, could induce apoptosis in human U251 and rat C6 malignant glioma cells and transformed vascular endothelial ECV 304 cell lines. Cell viability was estimated by MTT assay. Apoptosis was evaluated using TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labeling (TUNEL) method and DNA gel electrophoresis. Furthermore, the expression of p53 protein was examined immunohistochemically in the U251 cells. After the CqTX treatment, the growth of all cell lines was inhibited, the fragmented DNA was observed and some cells became TUNEL positive. The expression of p53 protein was increased in the tested U251 cells. The results suggested that CqTX induced apoptosis in these cell lines. The promotion of the p53 expression might be one mechanism of apoptosis induced by CqTX in the glioma cells.

Spinal recurrence from intracranial germinoma: risk factors and treatment outcome for spinal recurrence.

PURPOSEnTo analyze retrospectively the risk factors of spinal recurrence in patients with intracranial germinoma and clinical outcomes of patients who developed spinal recurrence.nnnMETHODS AND MATERIALSnBetween 1980 and 2007, 165 patients with no evidence of spinal metastases at diagnosis were treated with cranial radiotherapy without spinal irradiation. The median follow-up in all 165 patients was 61.2 months (range, 1.2-260.1 months).nnnRESULTSnAfter the initial treatment, 15 patients (9.1%) developed spinal recurrences. Multivariate analysis revealed that large intracranial disease (>/=4 cm) and multifocal intracranial disease were independent risk factors for spinal recurrence. Radiation field, total radiation dose, and the use of chemotherapy did not affect the occurrence of spinal recurrences. Of the 15 patients who experienced spinal recurrence, the 3-year actuarial overall survival and disease-free survival (DFS) rates from the beginning of salvage treatments were 65% and 57%, respectively. In the analysis, presence of intracranial recurrence and salvage treatment modality (radiotherapy with chemotherapy vs. radiotherapy alone) had a statistically significant impact on DFS. The 3-year DFS rate in patients with no intracranial recurrence and treated with both spinal radiotherapy and chemotherapy was 100%, whereas only 17% in patients with intracranial recurrence or treated with radiotherapy alone (p = 0.001).nnnCONCLUSIONnLarge intracranial disease and multifocal intracranial disease were risk factors for spinal recurrence in patients with intracranial germinoma with no evidence of spinal metastases at diagnosis. For patients who developed spinal recurrence alone, salvage treatment combined with spinal radiotherapy and chemotherapy was effective in controlling the recurrent disease.

Prospective trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas

Twenty-one patients with high-grade gliomas were enrolled in a prospective trial of radiotherapy after hyperbaric oxygenation (HBO). Radiotherapy was administered in daily 2-Gy fractions up to a total dose of 60 Gy, and each fraction was delivered immediately after HBO. The current study indicated that radiotherapy immediately after HBO with chemotherapy was feasible for high-grade gliomas.

Anaplastic meningioma with papillary, rhabdoid, and epithelial features: a case report

A 74-year-old man manifested disturbed consciousness and right hemiparesis. Computed tomography revealed a left frontal parasagittal meningeal tumor with extensive peritumoral brain edema and skull invasion. Subtotal removal was performed. Five years later, he underwent two more operations of massive recurrences. Pathological studies revealed anaplastic meningioma with two different histological areas. One was an epithelial and meningothelial area, and the other was a papillary and rhabdoid area. In the papillary and rhabdoid area, small tumor cells with a high nucleus/cytoplasm ratio proliferated densely around the dilated central capillaries with a pseudopapillary pattern. Many rhabdoid cells (vimentin ++, cytokeratin AE1/AE3+, epithelial membrane antigen [EMA]++) tended to be distributed far from the central capillaries. There were many mitotic figures near the central vessels. Dense MIB1-positive nuclei were also observed near the central vessels. The trabecular pattern of the tumor cells in the epithelial area was quite different from the histological features of chordoid meningioma.

Copper/Zinc Superoxide Dismutase, Nuclear DNA Content, and Progression in Human Gliomas

To our knowledge, there have been no previous reports regarding the immunohistochemistry and image cytometry to demonstrate elevated Copper/zinc superoxide dismutase (Cu/Zn SOD) expression and numbers of the clonal cells in human gliomas. In 30 well-studied patients with gliomas, immunoreactivity for Cu/Zn SOD and cytometric evidence of DNA ploidy in the G2M cell cycle phase were evaluated from routinely prepared tissue blocks.Cu/Zn SOD positive tumor cells were shown in 8 of 13 glioblastomas (mean quantitative immunoreactivity SOD score; 1), 3 of 8 anaplastic gliomas (score; 0.6), and none of 9 low-grade gliomas. The differences in SOD score was not significant. In hypertetraploid glioblastomas, time to progression was shorter than for hypertetraploid of anaplastic gliomas, while SOD scores were not significantly different. The same relationship held for tetraploid specimens. Considering variables in combination, hypertetraploid gliomas with high SOD immunoreactivity showed a significantly short time to progression (p<0.05) (1–5 months after radiotherapy and chemotherapy) compared with hypertetraploid, low-SOD immunoreactivity gliomas or tetraploid, low-SOD immunoreactivity gliomas.The tumor cells with high SOD activity also tended to be resistant for radiotherapy and anticancer drugs. Those results were suggested that the high grade glioma with a single clone and low SOD activity were effective for radiotherapy associated with oxidative stress, and that the high grade gliomas with more than two clones and high SOD activity were very less effective for same therapy.Cu/Zn SOD activity and the degree of the clonality in human gliomas should be very important factors influencing a choice of oxidative cytotoxic treatment.

Cytotoxic effect through fas/APO-1 expression due to vitamin K in human glioma cells.

Congeners of vitamin K have been found to inhibit growth in various rodent and human tumor cells, but the mechanisms of the inhibitory action are still not well understood. To investigate the modes of actions of vitamin K, we used several vitamin K analogs and examined their cytotoxic effect for human glioma cell lines RBR17T and U251. The analogs included vitamin K1 (VK1), vitamin K2 (VK2), vitamin K3 (VK3), and geranylgeraniol (GGO) which form an unsaturated side chain of VK2. Cell viability was estimated by MTT assay. DNA fragmentation was demonstrated by gel electrophoresis and flow cytometry. In order to study the mechanism of apoptosis, we measured the changes of intracellular reactive oxygen intermediates (ROI) and Fas/APO-1 expression by flow cytometry. The results showed: (1) VK2, VK3, and GGO inhibited cell growth; (2) VK3 had a more potent cytotoxic effect than VK2, and VK3 enhanced the cytotoxic effect of antitumor agents (ACNU and IFN-beta) in RBR17T cells; (3) VK2, VK3, and GGO induce apoptosis; (4) VK3 increased the expression of Fas/APO-1 although VK2 and GGO did not increase its expression in glioma cells; (5) VK3 increased the production of intracellular ROI. Catalase and reduced glutathione (GSH) inhibited production of intracellular ROI and antagonized inhibition of cell-growth induced by VK2, but failed to antagonize that of VK2 and GGO. We hypothesize that VK3 induces apoptosis by promoting the generation of intracellular ROI and Fas/APO-1 expression. On the other hand, VK2 and GGO induce apoptosis but most likely by some other unknown pathway.

The Corpus Callosum and Epileptic Seizures: Experimental Results in Cats

Purpose: Corpus callosotomy (CC) has recently been recognized as an effective treatment for patients with intractable generalized seizures. Experimental studies also reported the same seizure‐suppressive effects. We investigated the effects of sectioning the corpus callosum in models of epilepsy in cats.