Experimental study on Compton camera for boron neutron capture therapy applications.

Boron neutron capture therapy (BNCT) is a high-dose-intensive radiation therapy that has gained popularity due to advancements in accelerator neutron sources. To determine the dose for BNCT, it is necessary to know the difficult-to-determine boron concentration and neutron fluence. To estimate this dose, we propose a method of measuring the prompt γ-rays (PGs) from the boron neutron capture reaction (BNCR) using a Compton camera. We performed a fundamental experiment to verify basic imaging performance and the ability to discern the PGs from 511 keV annihilation γ-rays. A Si/CdTe Compton camera was used to image the BNCR and showed an energy peak of 478 keV PGs, separate from the annihilation γ-ray peak. The Compton camera could visualize the boron target with low neutron intensity and high boron concentration. This study experimentally confirms the ability of Si/CdTe Compton cameras to image BNCRs.

Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Additive effect of BPA and Gd-DTPA for application in accelerator-based neutron source.

Because of its fast metabolism gadolinium as a commercial drug was not considered to be suitable for neutron capture therapy. We studied additive effect of gadolinium and boron co-administration using colony forming assay. As a result, the survival of tumor cells with additional 5 ppm of Gd-DTPA decreased to 1/10 compared to the cells with boron only. Using gadolinium to increase the effect of BNCT instead of additional X-ray irradiation might be beneficial, as such combination complies with the short-time irradiation regimen at the accelerator-based neutron source.

Pretreatment with buthionine sulfoximine enhanced uptake and retention of BSH in brain tumor.

To determine the influence of buthionine sulfoximine (BSO) on boron biodistribution after sulfhydryl borane (BSH) administration for boron neutron capture therapy, the effectiveness of the combination of BSO with sulfhydril- (BSH) and non-sulfhydril (B12H12 and BNH3) boron compounds, and the interval between BSO and BSH administration, the retention of boron in tissues have been evaluated using a 9L rat tumor model. Simultaneous administration of BSH and BSO showed significantly higher boron accumulation compared to that without BSO, however there was no difference in tissue boron level between B12H12 and BNH3 administration with BSO or without BSO. The longer interval (6h) between BSH and BSO administration related to the highest boron concentration in the brain and subcutaneous tumors compared to shorter intervals (0.5, 3h). Boron concentration in subcutaneous and brain tumors was maintained for 6 and 12h after the administration of BSH following BSO pretreatment.

Project for the development of the linac based NCT facility in University of Tsukuba.

A project team headed by University of Tsukuba launched the development of a new accelerator based BNCT facility. In the project, we have adopted Radio-Frequency Quadrupole (RFQ)+Drift Tube Linac (DTL) type linac as proton accelerators. Proton energy generated from the linac was set to 8MeV and average current was 10mA. The linac tube has been constructed by Mitsubishi Heavy Industry Co. For neutron generator device, beryllium is selected as neutron target material; high intensity neutrons are generated by the reaction with beryllium and the 80kW proton beam. Our team chose beryllium as the neutron target material. At present beryllium target system is being designed with Monte-Carlo estimations and heat analysis with ANSYS. The neutron generator consists of moderator, collimator and shielding. It is being designed together with the beryllium target system. We also acquired a building in Tokai village; the building has been renovated for use as BNCT treatment facility. It is noteworthy that the linac tube had been installed in the facility in September 2012. In BNCT procedure, several medical devices are required for BNCT treatment such as treatment planning system, patient positioning device and radiation monitors. Thus these are being developed together with the linac based neutron source. For treatment planning system, we are now developing a new multi-modal Monte-Carlo treatment planning system based on JCDS. The system allows us to perform dose estimation for BNCT as well as particle radiotherapy and X-ray therapy. And the patient positioning device can navigate a patient to irradiation position quickly and properly. Furthermore the device is able to monitor movement of the patient׳s position during irradiation.

Reirradiation for recurrent malignant brain tumor with radiotherapy or proton beam therapy. Technical considerations based on experience at a single institution.

BACKGROUND AND PURPOSE: Radiotherapy for recurrent malignant brain tumors is usually limited because of the dose tolerance of the normal brain tissue. The goal of the study was to evaluate the efficacy and feasibility of reirradiation for patients with recurrent malignant brain tumors. PATIENTS AND METHODS: The subjects comprised 26 patients with recurrent malignant brain tumors treated with conventional radiotherapy (RT, n = 8), stereotactic radiotherapy (SRT, n = 10), and proton beam therapy (PBT, n = 8) at our institute. Fifteen patients had glioblastoma, 6 had WHO grade 3 glioma, and 5 had other tumors. The dose of initial radiotherapy was 34.5-94.4 Gy. Different radiation schedules were compared using the equivalent dose in 2-Gy fractions. RESULTS: Reirradiation was completed in all patients without a severe acute reaction. The reirradiation doses were 30-60 Gy (median, 42.3 Gy) and the total doses for the initial and second treatments were 64.5-150.4 Gy (median, 100.0 Gy). Currently, 11 patients are alive (median follow-up period, 19.4 months) and 15 are dead. The median survival and local control periods after reirradiation of the 26 patients were 18.3 and 9.3 months, respectively. For the 15 patients with glioblastoma, these periods were 13.1 and 11.0 months, respectively. Two patients showed radiation necrosis that was treated by surgery or conservative therapy. CONCLUSION: Reirradiation for recurrent malignant brain tumor using conventional RT, SRT, or PBT was feasible and effective in selected cases. Further investigation is needed for treatment optimization for a given patient and tumor condition.

Evaluation of three-dimensional polymer gel dosimetry using X-ray CT and R2 MRI.

It is difficult to obtain images of thin slices from measurement of spin-spin relaxation (R2) with magnetic resonance imaging (MRI) using the traditional dose reading method of polymer gel dosimetry. In this study, the dose reading method was performed using X-ray computed tomography (CT) for proton beam measurements in order to enable collection of thin slices. In addition, three-dimensional (3D) images of polymer gels were constructed using volume rendering. As a result of acquisition of thin slices, more detailed 3D data consisting of smaller voxel sizes compared to R2 were acquired. However, it was found that with thin slice thicknesses and small voxels, the signal-to-noise ratio around the voxels deteriorated. In addition, the coefficient of variation of non-irradiated gels with CT was smaller than that with R2 MRI.

A clinical trial protocol for second line treatment of malignant brain tumors with BNCT at University of Tsukuba.

We have evaluated the efficacy and safety of boron neutron capture therapy (BNCT) for recurrent glioma and malignant brain tumor using a new protocol. One of the two patients enrolled in this trial is a man with recurrent glioblastoma and the other is a woman with anaplastic meningioma. Both are still alive and no severe adverse events have been observed. Our findings suggest that NCT will be safe as a palliative therapy for malignant brain tumors.

Boron neutron capture therapy combined with fractionated photon irradiation for glioblastoma: a recursive partitioning analysis of BNCT patients.

Eight patients to received Boron Neuron Capture Therapy (BNCT) were selected from 33 newly diagnosed glioblastoma patients (NCT(+) group). Serial 42 glioblastoma patients (NCT(-) group) were treated without BNCT. The median OS of the NCT(+) group and NCT (-) group were 24.4 months and 14.9 months. In the high risk patients (RPA class V), the median OS of the NCT(+) group tended to be better than that of NCT(-) group. 50% of BNCT patients were RPA class V.

Multistep Lattice-Voxel method utilizing lattice function for Monte-Carlo treatment planning with pixel based voxel model.

Treatment planning for boron neutron capture therapy generally utilizes Monte-Carlo methods for calculation of the dose distribution. The new treatment planning system JCDS-FX employs the multi-purpose Monte-Carlo code PHITS to calculate the dose distribution. JCDS-FX allows to build a precise voxel model consisting of pixel based voxel cells in the scale of 0.4×0.4×2.0 mm(3) voxel in order to perform high-accuracy dose estimation, e.g. for the purpose of calculating the dose distribution in a human body. However, the miniaturization of the voxel size increases calculation time considerably. The aim of this study is to investigate sophisticated modeling methods which can perform Monte-Carlo calculations for human geometry efficiently. Thus, we devised a new voxel modeling method "Multistep Lattice-Voxel method," which can configure a voxel model that combines different voxel sizes by utilizing the lattice function over and over. To verify the performance of the calculation with the modeling method, several calculations for human geometry were carried out. The results demonstrated that the Multistep Lattice-Voxel method enabled the precise voxel model to reduce calculation time substantially while keeping the high-accuracy of dose estimation.

Prognostic factors in glioblastoma multiforme patients receiving high-dose particle radiotherapy or conventional radiotherapy.

The aim of this study was to evaluate the influence of prognostic factors related to patient selection on survival outcomes. Survival outcomes were retrospectively analysed in a consecutive series of 67 newly diagnosed glioblastoma multiforme (GBM) patients who had received either conventional fractionated photon radiotherapy (CRT) or high-dose particle radiotherapy (HDT). In the CRT protocol, a total dose of 60.0-61.2 Gy was administered. In the HDT protocol, an average dose of approximately 30 GyE in a single session and additional fractionated photon irradiation of total dose 30 Gy were administered to patients receiving boron neutron capture therapy; and a total dose of 96.6 GyE was administered to patients receiving proton therapy. Most of the patients had received chemotherapy with nimustine hydrochloride (ACNU) alone or with ACNU, procarbazine and vincristine. The median overall survival (OS) and progression-free survival times for all patients were 17.7 months [95% confidence interval (CI), 14.6-20.9 months] and 7.8 months (95% CI, 5.7-9.9 months), respectively. The 1- and 2-year survival rates were 67.2% and 33.7%, respectively. For patients treated with HDT, the median OS was 24.4 months (95% CI, 18.2-30.5 months), compared with 14.2 months (95% CI, 10.0-18.3 months) for those treated with CRT. The Cox proportional hazards model revealed radiation modality (HDT vs CRT) and European Organisation for Research and Treatment of Cancer recursive partitioning analysis class to be the significant prognostic factors. Age, sex, pre-operative performance status, treatment with or without advanced neuroimaging, extent of surgery and regimen of chemotherapy were not statistically significant factors in predicting prognosis. The median OS was 18.5 months (95% CI, 9.9-27.1 months) in patients of 65 years and older, compared with 16.8 months (95% CI, 13.6-20.1 months) in those 64 years and younger (p=0.871). The positive effect of HDT treatment is unlikely to reflect patient selection alone. Randomised trials with strictly controlled inclusion criteria to ensure the comparable selection of patients are required to demonstrate conclusively that prolonged survival can be attributed to high-dose particle radiotherapies.

The status of Tsukuba BNCT trial: BPA-based boron neutron capture therapy combined with X-ray irradiation.

The phase II trial has been prepared to assess the effectiveness of BPA (250 mg/kg)-based NCT combined with X-ray irradiation and temozolomide (75 mg/m(2)) for the treatment of newly diagnosed GBM. BPA uptake is determined by (18)F-BPA-PET and/or (11)C-MET-PET, and a tumor with the lesion to normal ratio of 2 or more is indicated for BNCT. The maximum normal brain point dose prescribed was limited to 13.0 Gy or less. Primary end point is overall survival.

Highly efficient eradication of intracranial glioblastoma using Eg5 siRNA combined with HVJ envelope.

Hemagglutinating virus of Japan envelope (HVJ-E) vector with inactivated replication-defective Sendai virus was originally developed as a versatile drug delivery system. Recently, we have shown the direct tumor-killing activity of HVJ-E itself without therapeutic molecules in prostate cancer cells. Although human glioblastoma cells were also sensitive to HVJ-E treatment, complete eradication was not achieved using HVJ-E alone. Here, to develop more effective therapeutic strategy of glioblastoma, we enhanced the anti-tumor activity by incorporating Short interfering RNA (siRNA) of mitotic motor protein Eg5 into HVJ-E. Treatment with HVJ-E-containing Eg5 siRNA induced monopolar spindle formation and resulted in cell-cycle arrest and apoptosis. When HVJ-E-containing Eg5 siRNA was directly injected into an intradermal tumor xenograft, all mice became tumor-free. Similar results were observed in the intracranial tumor xenografts. The survival time of treated mice was significantly prolonged when HVJ-E was used. Histological examination showed that tumors remained in the brain after treatment with HVJ-E-containing negative control siRNA, but no tumors were detected after treatment with HVJ-E-containing Eg5 siRNA. This remarkable anti-tumor response was likely due to a synergistic effect of Eg5 siRNA and HVJ-E. Thus, this combination shows promise as an attractive novel therapy for glioblastoma.

Intracellular uptake of a new boronated porphyrin EC032.

We measured the toxicity and intracellular uptake of a newly developed boronated porphyrin EC032, and verified the fluorescence-based boron concentration measuring methods. Toxicity study showed that concentration required to produce a 50% reduction in viability (IC(50)) of EC032 was more than 0.25 mM. Fluorescence study showed the intracellular uptake of EC032 increased up until 24 h after its exposure to C6, 9L, U87, and U251 cells. There was also a linear correlation between ICP-AES and fluorescence intensity as an arbitrary unit about measurement of boron concentration. Fluorescence-based boron concentration measuring methods are very simple and useful methods, especially for screening of slight test dose of porphyrin compounds.

Development of boron nanocapsules for neutron capture therapy.

High accumulation and selective delivery of boron into tumor tissues are the most important requirements to achieve efficient neutron capture therapy of cancers. We focused on liposomal boron delivery system in order to achieve a large amount of boron delivery to tumor. We synthesized the double-tailed boron cluster lipid 4c according to our reported procedure with modification. Size distribution of liposomes prepared from the boron cluster lipid 4c, DMPC, PEG-DSPE, and cholesterol was determined as 100 nm in diameter by an electrophoretic light scattering spectrophotometer. A high level of (10)B concentration (22 ppm) was observed in tumor tissue at 24 h after the administration of boron liposomes.

Performance measurement of the scintillator with optical fiber detector for boron neutron capture therapy.

The thermal neutron flux can be easily measured in real time by using the scintillator with optical fiber (SOF) detector. However the irradiation damage under high-intensity neutron flux causes deterioration of the SOF detector due to radiation damage to the plastic scintillator in which (6)LiF is blended. After irradiating the SOF detector for 4 h (thermal neutron fluence is approximately 2.0 x 10(13)neutrons/cm(2)), the sensitivity of the SOF detector decreased by 3.0%. After irradiating the SOF detector for 2 months (thermal neutron fluence approximately 6.4 x 10(14)neutrons/cm(2)), the sensitivity was reduced to 42% of baseline. Supposing that the thermal neutron fluence is 2 x 10(12)neutrons/cm(2) on the surface of a patient in a BNCT treatment, the sensitivity of the SOF detector is reduced by approximately 0.3%. This report presents investigations on the deterioration of the SOF detector in irradiation experiments.

Development of a new multi-modal Monte-Carlo radiotherapy planning system.

A new multi-modal Monte-Carlo radiotherapy planning system (developing code: JCDS-FX) is under development at Japan Atomic Energy Agency. This system builds on fundamental technologies of JCDS applied to actual boron neutron capture therapy (BNCT) trials in JRR-4. One of features of the JCDS-FX is that PHITS has been applied to particle transport calculation. PHITS is a multi-purpose particle Monte-Carlo transport code. Hence application of PHITS enables to evaluate total doses given to a patient by a combined modality therapy. Moreover, JCDS-FX with PHITS can be used for the study of accelerator based BNCT. To verify calculation accuracy of the JCDS-FX, dose evaluations for neutron irradiation of a cylindrical water phantom and for an actual clinical trial were performed, then the results were compared with calculations by JCDS with MCNP. The verification results demonstrated that JCDS-FX is applicable to BNCT treatment planning in practical use.

Boron neutron capture therapy for newly diagnosed glioblastoma: a pilot study in Tsukuba.

Neutron capture therapy (NCT) theoretically allows an unique tumor-cell-selective high-LET particle radiotherapy. The survival benefits and safety of NCT were evaluated in 15 patients with newly diagnosed glioblastoma multiforme (GBM). Seven patients received intra-operative (IO-) NCT and eight patients received external beam (EB-) NCT. Sulfhydryl borane (BSH, 5 g/body) was administered intravenously 12 h before neutron irradiation. Additionally, p-dihydroxyboryl-phenylalanine (BPA, 250 mg/kg) was given 1 h before irradiation to the eight patients who underwent EB-NCT. EB-NCT was combined with fractionated photon irradiation. Five of 15 patients were alive at analysis for a mean follow-up time of 20.3 M. In 11 of 15 patients followed up for more than 1-year, eight (72.7%) maintained their Karnofsky performance status (KPS; 90 in 6 and 100 in 2). The median overall survival (OS) and time to magnetic resonance (MR) change (TTM) for all patients were 25.7 and 11.9 M, respectively. There was no difference in TTM between the IO-NCT (12.0 M) and EB-NCT (11.9 M) groups. The 1- and 2-year survival rates were 85.7% and 45.5%, respectively. This NCT pilot study in 15 patients with newly diagnosed GBM showed survival benefits, suggesting that the neutron capture reaction may function sufficiently to control tumors locally, and that further optimized studies in large series of patients are warranted.

Dose distribution and clinical response of glioblastoma treated with boron neutron capture therapy.

The dose distribution and failure pattern after treatment with the external beam boron neutron capture therapy (BNCT) protocol were retrospectively analyzed. BSH (5 g/body) and BPA (250 mg/kg) based BNCT was performed in eight patients with newly diagnosed glioblastoma. The gross tumor volume (GTV) and clinical target volume (CTV)-1 were defined as the residual gadolinium-enhancing volume. CTV-2 and CTV-3 were defined as GTV plus a margin of 2 and 3 cm, respectively. As additional photon irradiation, a total X-ray dose of 30 Gy was given to the T2 high intensity area on MRI. Five of the eight patients were alive at analysis for a mean follow-up time of 20.3 months. The post-operative median survival time of the eight patients was 27.9 months (95% CI=21.0-34.8). The minimum tumor dose of GTV, CTV-2, and CTV-3 averaged 29.8+/-9.9, 15.1+/-5.4, and 12.4+/-2.9 Gy, respectively. The minimum tumor non-boron dose of GTV, CTV-2, and CTV-3 averaged 2.0+/-0.5, 1.3+/-0.3, and 1.1+/-0.2 Gy, respectively. The maximum normal brain dose, skin dose, and average brain dose were 11.4+/-1.5, 9.6+/-1.4, and 3.1+/-0.4 Gy, respectively. The mean minimum dose at the failure site in cases of in-field recurrence (IR) and out-field recurrence (OR) was 26.3+/-16.7 and 14.9 GyEq, respectively. The calculated doses at the failure site were at least equal to the tumor control doses which were previously reported. We speculate that the failure pattern was related to an inadequate distribution of boron-10. Further improvement of the microdistribution of boron compounds is expected, and may improve the tumor control by BNCT.

Direct comparison of thallium-201 and technetium-99m MIBI SPECT of a glioma by receiver operating characteristic analysis.

The diagnostic value of single photon-emission computed tomography (SPECT) has been assessed using arbitrarily determined sensitivity and specificity cut-off values. The diagnostic accuracy of thallium-201 (Tl-201) SPECT and technetium-99m methoxyisobutylisonitrile (Tc-MIBI) SPECT were compared for patients with primary glioma using receiver operating characteristic (ROC) analysis. The study population included 59 patients with gliomas. Tl and Tc-MIBI SPECT images were obtained using a multi-detector SPECT machine 15 min (early) and 3 hours (delayed) after intravenous injection of 74 MBq of Tl-chloride or 740 MBq of Tc-MIBI. The regions of interest were set on the tumor and contralateral normal white matter and tumor : normal ratios were calculated. The area z-score (A(z)) values were calculated from the areas under the ROC curves. All A(z) values were high and no statistical difference was observed between the two modalities. Both Tl and Tc-MIBI SPECT are useful imaging modalities for the evaluation of glioma malignancy.