The uptake of boron into tumor cells is a key factor in the biological effects of boron neutron capture therapy (BNCT). The uptake of boron agents is suppressed in hypoxic conditions, but the mechanism of hypoxia-induced modulation of suppression of boron uptake is not clear. Therefore, we evaluated whether hypoxia-inducible factor 1α (HIF-1α) contributes to attenuation of the antitumor effects of BNCT in hypoxic tumor cells. We also tested whether YC-1, a HIF-1α-targeting inhibitor, has therapeutic potential with BNCT. To elucidate the mechanism of attenuation of the effects of BNCT caused by hypoxia, deferoxamine (DFO) was used in experiments. Cells were incubated in normal oxygen, hypoxic conditions (1% O2) or 5 μM DFO for 24 h. Then, cells were treated with 10B-boronophenylalanine (BPA) for 2 h and boron accumulation in cells was evaluated. To clarify the relationship between HIF-1α and L-type amino acid transporter 1 (LAT1), gene expression was evaluated by a using HIF-1α gene knockdown technique. Finally, to improve attenuation of the effects of BNCT in hypoxic cells, BNCT was combined with YC-1. Boron uptake was continuously suppressed up to 2 h after administration of BPA by 5 μM DFO treatment. In cells treated with 5 μM DFO, LAT1 expression was restored in HIF-1α-knocked down samples in all cell lines, revealing that HIF-1α suppresses LAT1 expression in hypoxic cells. From the results of the surviving fraction after BNCT combined with YC-1, treatment with YC-1 sensitized the antitumor effects of BNCT in cells cultured in hypoxia.

The output constancy of the accelerator used for boron neutron capture therapy (BNCT) is essential to ensuring anti-tumor efficacy and safety. BNCT as currently practiced requires a wide variety of beam quality assessments to ensure that RBE dose errors are maintained within 5%. However, the necessity of maintaining a constant beam dose rate has not been fully discussed. We therefore clarified the effect of different physical dose rates of the accelerator BNCT on biological effects. SAS and A172 cells exposed to ¹⁰B-boronophenylalanine were irradiated using a neutron beam (normal operating current, 100 μA) at the Aomori Quantum Science Center. Thermal neutron flux was attenuated to 50.0 ± 0.96% under 50 μA irradiation compared to that under 100 μA irradiation. Cells were given physical doses of 1.67 and 3.36 Gy at 30 and 60 mC, respectively, and survival was significantly increased after 50 μA irradiation for both cell types (p = 0.0052 for SAS; p = 0.046 for A172, for 60 mC). Differences in accelerator BNCT beam dose rates have non-negligible effects on biological effects. Dose rate fluctuations and differences should not be easily permitted to obtain consistent biological effects.

The purpose of this study was to evaluate the impact of markerless on-board kilovoltage (kV) cone-beam computed tomography (CBCT)-based positioning uncertainty on determination of the planning target volume (PTV) margin by comparison with kV on-board imaging (OBI) with gold fiducial markers (FMs), and to validate a methodology for the evaluation of PTV margins for markerless kV-CBCT in prostate image-guided radiotherapy (IGRT). A total of 1177 pre- and 1177 post-treatment kV-OBI and 1177 pre- and 206 post-treatment kV-CBCT images were analyzed in 25 patients who received prostate IGRT with daily localization by implanted FMs. Intrafractional motion of the prostate was evaluated between each pre- and post-treatment image with these two different techniques. The differences in prostate deviations and intrafractional motions between matching by FM in kV-OBI (OBI-FM) and matching by soft tissues in kV-CBCT (CBCT-ST) were compared by Bland-Altman limits of agreement. Compensated PTV margins were determined and compensated by references. Mean differences between OBI-FM and CBCT-ST in the anterior to posterior (AP), superior to inferior (SI), and left to right (LR) directions were − 0.43 ± 1.45, − 0.09 ± 1.65, and − 0.12 ± 0.80 mm, respectively, with R2 = 0.85, 0.88, and 0.83, respectively. Intrafractional motions obtained from CBCT-ST were 0.00 ± 1.46, 0.02 ± 1.49, and 0.15 ± 0.64 mm, respectively, which were smaller than the results from OBI-FM, with 0.43 ± 1.90, 0.12 ± 1.98, and 0.26 ± 0.80 mm, respectively, with R2 = 0.42, 0.33, and 0.16, respectively. Bland-Altman analysis showed a significant proportional bias. PTV margins of 1.5 mm, 1.4 mm, and 0.9 mm for CBCT-ST were calculated from the values of CBCT-ST, which were also smaller than the values of 3.15 mm, 3.66 mm, and 1.60 mm from OBI-FM. The practical PTV margin for CBCT-ST was compensated with the values from OBI-FM as 4.1 mm, 4.8 mm, and 2.2 mm. PTV margins calculated from CBCT-ST might be underestimated compared to the true PTV margins. To determine a reliable CBCT-ST-based PTV margin, at least the systemic error Σ and the random error σ for on-line matching errors need to be investigated by supportive preliminary FM evaluation at least once.