Takuya Kaminuma

Cranial irradiation induces bone marrow-derived microglia in adult mouse brain tissue.

Postnatal hematopoietic progenitor cells do not contribute to microglial homeostasis in adult mice under normal conditions. However, previous studies using whole-body irradiation and bone marrow (BM) transplantation models have shown that adult BM cells migrate into the brain tissue and differentiate into microglia (BM-derived microglia; BMDM). Here, we investigated whether cranial irradiation alone was sufficient to induce the generation of BMDM in the adult mouse brain. Transgenic mice that express green fluorescent protein (GFP) under the control of a murine stem cell virus (MSCV) promoter (MSCV-GFP mice) were used. MSCV-GFP mice express GFP in BM cells but not in the resident microglia in the brain. Therefore, these mice allowed us to detect BM-derived cells in the brain without BM reconstitution. MSCV–GFP mice, aged 8–12 weeks, received 13.0 Gy irradiation only to the cranium, and BM-derived cells in the brain were quantified at 3 and 8 weeks after irradiation. No BM-derived cells were detected in control non-irradiated MSCV-GFP mouse brains, but numerous GFP-labeled BM-derived cells were present in the brain stem, basal ganglia and cerebral cortex of the irradiated MSCV-GFP mice. These BM-derived cells were positive for Iba1, a marker for microglia, indicating that GFP-positive BM-derived cells were microglial in nature. The population of BMDM was significantly greater at 8 weeks post-irradiation than at 3 weeks post-irradiation in all brain regions examined. Our results clearly show that cranial irradiation alone is sufficient to induce the generation of BMDM in the adult mouse.

Comparison of the radiosensitivities of neurons and glial cells derived from the same rat brain

Non-proliferating cells, such as mature neurons, are generally believed to be more resistant to X-rays than proliferating cells, such as glial and vascular endothelial cells. Therefore, the late adverse effects of radiotherapy on the brain have been attributed to the radiation-induced damage of glial and vascular endothelial cells. However, little is known about the radiosensitivities of neurons and glial cells due to difficulties in culturing these cells, particularly neurons, independently. In the present study, primary dissociated neurons and glial cultures were prepared separately from the hippocampi and cerebrum, respectively, which had been obtained from the same fetal rat on embryonic day 18. X-irradiations of 50 Gy were performed on the cultured neurons and glial cells at 7 and 21 days in vitro (DIV). The cells were fixed at 24 h after irradiation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was then performed to measure the apoptotic indices (AIs). The AIs of non-irradiated and irradiated neurons at 7 DIV were 23.7±6.7 and 64.9±4.8%, and those at 21 DIV were 52.1±17.4 and 44.6±12.5%, respectively. The AIs of non-irradiated and irradiated glial cells at 7 DIV were 5.8±1.5 and 78.4±3.3% and those at 21 DIV were 9.6±2.6 and 86.3±4.9%, respectively. Glial cells and neurons were radiosensitive at 7 DIV. However, while glial cells were radiosensitive at 21 DIV, neurons were not.

Clinical outcomes of helical tomotherapy for super-elderly patients with localized and locally advanced prostate cancer: comparison with patients under 80 years of age

We investigated the clinical outcomes of helical tomotherapy in 23 patients aged ≥80 years with localized and locally advanced prostate cancer and compared the results with data from 171 patients under 80 years. All patients received helical tomotherapy in our hospital between September 2009 and October 2012. The median follow-up periods were 35 months in the aged group and 34 months in the younger group. The median prescribed dose in helical tomotherapy was 78 Gy in 39 fractions (range, 72–78 Gy). The 3-year overall survival and biochemical relapse-free rates were 92% and 96% in the aged group and 99.4% and 97.3% in the younger group, respectively. There was no significant difference between the two groups in the biochemical relapse-free rates. The 3-year cumulative incidences of late Grade 2 or higher rectal toxicity and urinary toxicity were 13% and 4.8% in the aged group and 7.0% and 1.2% in the younger group, respectively. There was no significant difference between the aged group and the younger group in the cumulative incidence rates of rectal toxicity or urinary toxicity. No patients exhibited Grade 4 or higher toxicity, and all patients improved with conservative therapy. Helical tomotherapy in super-elderly patients with localized and locally advanced prostate cancer had good biochemical control rates without severe late toxicity. Definitive helical tomotherapy may be the treatment of choice for patients with localized and locally advanced prostate cancer, even in those older than 80 years of age.

Tumor-specific CD8-positive T cell-mediated antitumor immunity is implicated in the antitumor effect of local hyperthermia

Abstract Purpose: This study aimed to elucidate the contribution of T cell-mediated antitumor immunity in the antitumor effect of local hyperthermia (LH). Materials and methods: C57BL/6J mice were injected with the mouse lymphoma cell line, E.G7-OVA, in the right femur on day 0. LH was induced by immersing the right femur in a water bath at 42 °C for 60 min on day 7, followed by administration of anti-CD8 monoclonal antibodies (mAb) or anti-CTLA-4 mAb (days 8, 11, and 14). The effect of LH on tumor growth (TG) was assessed by measuring the duration until tumor volume reached 1000 mm3 and survival time. Tumor-specific T cell responses were measured using enzyme-linked immunospot (ELISpot) assay. Results: TG with and without LH treatment was 9.0 ± 9.6 and 7.0 ± 1.6 days, respectively. TG was significantly slower with LH treatment (p = .01). The therapeutic effect of LH was mitigated by addition of anti-CD8 mAb (p < .05 for both TG and survival) compared with the untreated (control) group. Furthermore, addition of anti-CTLA-4 mAb did not significantly affect the therapeutic effect of LH. The ELISpot assay showed that the number of spots in the LH group (276.3 ± 14.5) was significantly greater than in the control group (59.0 ± 4.5, p < .001). Conclusion: CD8-positive T cell-mediated antitumor immunity significantly contributes to the antitumor effect of LH.