Chronic pathophysiological changes in the normal brain parenchyma caused by radiotherapy accelerate glioma progression.

Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-ß1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.

Evaluation of a novel sodium borocaptate-containing unnatural amino acid as a boron delivery agent for neutron capture therapy of the F98 rat glioma.

BACKGROUND: Boron neutron capture therapy (BNCT) is a unique particle radiation therapy based on the nuclear capture reactions in boron-10. We developed a novel boron-10 containing sodium borocaptate (BSH) derivative, 1-amino-3-fluorocyclobutane-1-carboxylic acid (ACBC)-BSH. ACBC is a tumor selective synthetic amino acid. The purpose of this study was to assess the biodistribution of ACBC-BSH and its therapeutic efficacy following Boron Neutron Capture Therapy (BNCT) of the F98 rat glioma. METHODS: We evaluated the biodistribution of three boron-10 compounds, ACBC-BSH, BSH and boronophenylalanine (BPA), in vitro and in vivo, following intravenous (i.v.) administration and intratumoral (i.t.) convection-enhanced delivery (CED) in F98 rat glioma bearing rats. For BNCT studies, rats were stratified into five groups: untreated controls, neutron-irradiation controls, BNCT with BPA/i.v., BNCT with ACBC-BSH/CED, and BNCT concomitantly using BPA/i.v. and ACBC-BSH/CED. RESULTS: In vitro, ACBC-BSH attained higher cellular uptake F98 rat glioma cells compared with BSH. In vivo biodistribution studies following i.v. administration and i.t. CED of ACBC-BSH attained significantly higher boron concentrations than that of BSH, but much lower than that of BPA. However, following convection enhanced delivery (CED), ACBC-BSH attained significantly higher tumor concentrations than BPA. The i.t. boron-10 concentrations were almost equal between the ACBC-BSH/CED group and BPA/i.v. group of rats. The tumor/brain boron-10 concentration ratio was higher with ACBC-BSH/CED than that of BPA/i.v. group. Based on these data, BNCT studies were carried out in F98 glioma bearing rats using BPA/i.v. and ACBC-BSH/CED as the delivery agents. The corresponding mean survival times were 37.4 ± 2.6d and 44.3 ± 8.0d, respectively, and although modest, these differences were statistically significant. CONCLUSIONS: Our findings suggest that further studies are warranted to evaluate ACBC-BSH/CED as a boron delivery agent.

Localized radiation necrosis model in mouse brain using proton ion beams.

Brain radiation necrosis is the most serious late adverse event that occurs after 6 months following radiation therapy. Effective treatment for this irreversible brain necrosis has not been established yet. This study tries to establish brain radiation necrosis mouse model using proton or helium beam. The right cerebral hemispheres of C57BL/6J mouse brains were irradiated at doses of 40, 50, 60 Gy with charged particles. In 60 Gy group, brain necrosis that recapitulates human disease was detected after 8 months.

Intratumoral and peritumoral post-irradiation changes, but not viable tumor tissue, may respond to bevacizumab in previously irradiated meningiomas.

The efficacy of bevacizumab has not been determined for treatment-refractory meningiomas. We treated meningiomas with low-dose bevacizumab and compared the radiological responses of non-irradiated meningiomas with previously irradiated meningiomas. In addition, we assessed intraparenchymal radiation necrosis following bevacizumab treatment.Six patients with meningiomas (three anaplastic, one atypical, and two grade I) who were previously treated with multiple sessions of radiotherapy and subsequently developed perilesional edema were treated with bevacizumab. Of six patients, two patients with anaplastic meningiomas developed three tumors following radiotherapy, which were defined as non-irradiated tumors. There were 12 pre-existing extra-axial tumors that were previously irradiated. Some of these tumors demonstrated adjacent intraparenchymal contrast enhancement. These tumors were defined as post-irradiated tumors. Four patients had intraparenchymal radiation necrosis. Low-dose bevacizumab was administered biweekly over 3-6 cycles to all patients.Four tumors decreased in contrast-enhanced volume, nine tumors were unchanged, and two tumors progressed. Of the three non-irradiated tumors, two tumors increased in volume (126 % and 198 %) and one tumor was stable (-5 %). The median reduction rates determined by contrast volume were -31 % and -71 % in post-irradiated tumors and radiation necrosis, respectively. Non-irradiated tumors had a significantly poorer response to bevacizumab than post-irradiated tumors and radiation necrosis (p = 0.0013 and p = 0.0005, respectively, Tukey-Kramer test).Low-dose bevacizumab did not demonstrate efficacy in the treatment of non-irradiated meningiomas. Responses to low-dose bevacizumab could be related to its effect on post-irradiation changes, rather than its effect on biologically active tumor tissue in post-irradiated meningiomas. Radiological responses to low-dose bevacizumab may distinguish biologically active tumors from post-irradiation changes in progressive meningiomas following radiotherapy.

The roles of platelet-derived growth factors and their receptors in brain radiation necrosis.

BACKGROUND: Brain radiation necrosis (RN) occurring after radiotherapy is a serious complication. We and others have performed several treatments for RN, using anticoagulants, corticosteroids, surgical resection and bevacizumab. However, the mechanisms underlying RN have not yet been completely elucidated. For more than a decade, platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been extensively studied in many biological processes. These proteins influence a wide range of biological responses and participate in many normal and pathological conditions. In this study, we demonstrated that PDGF isoforms (PDGF-A, B, C, and D) and PDGFRs (PDGFR-α and ß) are involved in the pathogenesis of human brain RN. We speculated on their roles, with a focus on their potential involvement in angiogenesis and inflammation in RN. METHODS: Seven surgical specimens of RN, obtained from 2006 to 2013 at our department, were subjected to histopathological analyses and stained with hematoxylin and eosin. We qualitatively analyzed the protein expression of each isoform of PDGF by immunohistochemistry. We also examined their expression with double immunofluorescence. RESULTS: All PDGFs were expressed in macrophages, microglia, and endothelial cells in the boundary of the core of RN, namely, the perinecrotic area (PN), as well as in undamaged brain tissue (UB). PDGF-C, D and PDGFR-α were also expressed in reactive astrocytes in PN. PDGFs and PDGFR-α were scarcely detected in UB, but PDGFR-ß was specifically expressed in endothelial cells not only in PN but also in UB. CONCLUSIONS: PDGFs/PDGFRs play critical roles in angiogenesis and possibly in inflammation, and they contribute to the pathogenesis of RN, irrespective of the original tumor pathology and applied radiation modality. Treatments for the inhibition of PDGF-C, PDGF-D, and PDGFR-α may provide new approaches for the treatment of RN induced by common radiation therapies.

Intracranial extravasation of contrast medium during diagnostic CT angiography in the initial evaluation of subarachnoid hemorrhage: report of 16 cases and review of the literature.

INTRODUCTION: Three-dimensional CT angiography (3D-CTA) is increasingly used in the initial evaluation of subarachnoid hemorrhage (SAH). However, there is a risk of aneurysm re-rupture in the hyperacute phase. We sought to clarify the incidence of re-rupture and characterize the subgroup in which extravasation of contrast media was seen on 3D-CTA. METHODS: We examined the records of 356 consecutive patients presenting to our institution with non-traumatic SAH between October 2003 and December 2011. After resuscitation, patients with poor grade SAH underwent CT then 3D-CTA while sedated, mechanically ventilated and with a target systolic blood pressure of 120 mmHg. RESULTS: 336 patients underwent 3D-CTA; 20 died without return of spontaneous circulation. Extravasated contrast medium was seen in 16 (4.8%), 15 (4.5%) at the initial evaluation. Their World Federation of Neurosurgical Societies Grade was V; one patient was resuscitated from cardiac arrest. The mean times from onset to arrival and to CTA were 43.7 minutes and 71.8 minutes, respectively. Ten patients (62.5%) had episodes suggestive of aneurysm re-rupture before 3D-CTA. Surgical clipping, evacuation of hematoma and wide decompressive craniectomy was completed in six patients and one underwent coil embolization. Two of 16 patients survived: one with moderate disability and one made a good recovery. CONCLUSIONS: Contrast extravasation was detected by 3D-CTA in 4.5% of cases despite intensive resuscitation, suggesting that continuous or intermittent rebleeding may occur frequently in the hyperacute phase. The consequences of rebleeding are devastating; however, favorable results can be obtained with immediate aneurysm repair with decompression and intensive neurocritical care.