Study of charged particle activation analysis (II): Determination of boron concentration in human blood samples.

Boron Neutron Capture Therapy (BNCT) is a radiotherapy for the treatment of intractable cancer. In BNCT precise determination of 10B concentration in whole blood sample before neutron irradiation of the patient, as well as accurate neutron dosimetry, is crucial for control of the neutron irradiation time. For this purpose ICP-AES and neutron induced prompt γ-ray analysis are generally used. In Ibaraki Neutron Medical Research Center (iNMRC), an intense proton beam will be accelerated up to 8 MeV, which can also be used for Charged Particle Activation Analysis (CPAA). Thus, in this study, we apply the CPAA utilizing the proton beam to non-destructive and accurate determination of 10B concentration in whole blood sample. A CPAA experiment is performed by utilizing an 8 MeV proton beam from the tandem accelerator of Nuclear Science Research Institute in Japan Atomic Energy Agency. The 478 keV γ-ray of 7Be produced by the 10B(p, α)7Be reaction is used to quantify the 10B in human blood. The 478 keV γ-ray intensity is normalized by the intensities of the 847 keV and 1238 keV γ-rays of 56Co originating from Fe in blood. The normalization methods were found to be linear in the range of 3.27 µg 10B/g to 322 µg 10B/g with correlation coefficients of better than 0.9999.

Investigation of the neutron spectrum measurement method for dose evaluation in boron neutron capture therapy.

In boron neutron capture therapy, it is important to evaluate the dose administered to a patient's body outside the tumour area. The exposure dose is evaluated by calculation; however, the calculated value must be validated using a measured value. The dose evaluations based on the measured neutron spectrum are investigated. Multi-foil activation, combined with a LiCaAlF6 scintillation detector and an imaging plate, is proposed as a measurement method. The proposed method can measure the neutron spectrum at various points quickly.

Fatal carotid blowout syndrome after BNCT for head and neck cancers.

Boron neutron capture therapy (BNCT) is high linear energy transfer (LET) radiation and tumor-selective radiation that does not cause serious damage to the surrounding normal tissues. BNCT might be effective and safe in patients with inoperable, locally advanced head and neck cancers, even those that recur at previously irradiated sites. However, carotid blowout syndrome (CBS) is a lethal complication resulting from malignant invasion of the carotid artery (CA); thus, the risk of CBS should be carefully assessed in patients with risk factors for CBS after BNCT. Thirty-three patients in our institution who underwent BNCT were analyzed. Two patients developed CBS and experienced widespread skin invasion and recurrence close to the carotid artery after irradiation. Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion from recurrent lesions after irradiation is an ominous sign of CBS onset and lethal consequences.

Long-term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide-naïve chronic hepatitis B patients.

Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long-term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide-naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12-243 000 IU/mL), and median follow-up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed-up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was -0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87-55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80-333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.

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.

Correlation between radiation dose and histopathological findings in patients with gliblastoma treated with boron neutron capture therapy (BNCT).

The purpose of this study was to clarify the correlation between the radiation dose and histopathological findings in patients with glioblastoma multiforme (GBM) treated with boron neutron capture therapy (BNCT). Histopathological studies were performed on specimens from 8 patients, 3 had undergone salvage surgery and 5 were autopsied. For histopathological cure of GBM at the primary site, the optimal minimal dose to the gross tumor volume (GTV) and the clinical target volume (CTV) were 68Gy(w) and 44Gy(w), respectively.

Virological response and safety of 24-week telaprevir alone in Japanese patients infected with hepatitis C virus subtype 1b.

Hepatitis C virus (HCV) subtype 1b, which infects approximately 70% of Japanese carriers, is likely to be more eradicable by a telaprevir regimen than subtype 1a because of the higher genetic barrier of Val(36) and Arg(155) substitutions. The aims of this exploratory study were to evaluate the virological response and safety of 24-week oral administration of telaprevir alone in chronic HCV subtype 1b infection. Fifteen treatment-naïve patients were treated with telaprevir 750 mg every 8 h for 24 weeks. All patients were Japanese whose median age was 58.0 years (range: 45-68), and six patients (40%) were men. Median baseline HCV RNA level was 6.80 log(10) IU/mL (range: 3.55-7.10). The HCV RNA levels decreased to undetectable in five patients (33%) within 8 weeks. Three patients (20%) with negative HCV RNA by Week 4 achieved end of treatment response. One patient (7%) who achieved sustained virological response had a low baseline viraemia of 3.55 log(10) IU/mL. Most of the adverse events including anaemia and skin disorders were mild to moderate. Developed variants were T54A and A156V/T/F/Y with or without secondary substitutions rather than V36M ± R155K. Telaprevir alone for 24 weeks in Japanese patients with HCV subtype 1b resulted in an sustained viral response rate of 7% (1/15) and was well tolerated for 24 weeks. These results will support the implementation of further studies on oral combination of telaprevir with other direct-acting antiviral agents in patients infected with HCV subtype 1b.

Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection.

BACKGROUND: Telaprevir in combination with peginterferon and ribavirin is a promising advancement in chronic hepatitis C treatment. However, the safety, tolerability, pharmacokinetics and antiviral profiles of telaprevir alone beyond 2 weeks have not been studied. METHODS: In a phase 1b study in Japan, 10 treatment-naïve patients infected with hepatitis C virus genotype 1b with high viral load (>5 log(10) IU/mL) received telaprevir 750 mg every 8 h (q8h) for 12 weeks. We examined the safety, tolerability, pharmacokinetics, hepatitis C virus (HCV) RNA levels and resistant variants of telaprevir. RESULTS: Neither serious adverse events nor discontinuations of study drug owing to an adverse event occurred. The most common adverse drug reactions were rash (80%) and anaemia (70%). Telaprevir concentration reached its steady state within 2 days after the first administration without abnormal accumulation. Telaprevir alone provided potent antiviral activity: a median log(10) decrease of 2.325 at 16 h and 5.175 on Day 14. During the treatment, HCV RNA levels at the nadir were below the limit of the quantification in seven patients and undetectable in three of 10 patients. Viral breakthrough associated with mainly Ala(156) -substituted variants occurred in eight patients, and only one patient showed end-of-treatment response. The selected variants reverted to the wild-type during the 24-week follow-up period. CONCLUSION: Telaprevir alone was well tolerated at 750 mg q8h for up to 12 weeks. The safety profile and emergence of resistant variants of genotype 1b under telaprevir monotherapy for 12 weeks will become increasingly important in evaluating an oral combination of telaprevir with other direct-acting antiviral agents.

Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C.

The aims of this phase III study were to assess the efficacy and safety of telaprevir in combination with peginterferon alfa-2b (PEG-IFN) and ribavirin (RBV) for difficult-to-treat patients who had not achieved sustained virological response (SVR) to prior regimens in Japan. The subjects were 109 relapsers (median age of 57.0 years) and 32 nonresponders (median age of 57.5 years) with hepatitis C virus genotype 1. Patients received telaprevir (750 mg every 8 h) for 12 weeks and PEG-IFN/RBV for 24 weeks. The SVR rates for relapsers and nonresponders were 88.1% (96/109) and 34.4% (11/32), respectively. Specified dose modifications of RBV that differed from that for the standard of care were introduced to alleviate anaemia. RBV dose reductions were used for 139 of the 141 patients. The SVR rates for relapsers did not depend on RBV dose reduction for 20-100% of the planned dose (SVR rates 87.5-100%, P < 0.05). Skin disorders were observed in 82.3% (116/141). Most of the skin disorders were controllable by anti-histamine and/or steroid ointments. The ratios of discontinuation of telaprevir only or of all the study drugs because of adverse events were 21.3% (30/141) and 16.3% (23/141), respectively. A frequent adverse event leading to discontinuation was anaemia. Telaprevir in combination with PEG-IFN/RBV led to a high SVR rate for relapsers and may offer a potential new therapy for nonresponders even with a shorter treatment period.

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.

Clinical results of boron neutron capture therapy (BNCT) for glioblastoma.

The purpose of this study was to evaluate the clinical outcome of BSH-based intra-operative BNCT (IO-BNCT) and BSH and BPA-based non-operative BNCT (NO-BNCT). We have treated 23 glioblastoma patients with BNCT without any additional chemotherapy since 1998. The median survival time (MST) of BNCT was 19.5 months, and 2-year, 3-year and 5-year survival rates were 26.1%, 17.4% and 5.8%, respectively. This clinical result of BNCT in patients with GBM is superior to that of single treatment of conventional radiotherapy compared with historical data of conventional treatment.

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.

Resumption of JRR-4 and characteristics of neutron beam for BNCT.

The clinical trials of Boron Neutron Capture Therapy (BNCT) have been conducted using Japan Research Reactor No. 4 (JRR-4) at Japan Atomic Energy Agency (JAEA). On December 28th, 2007, a crack of a graphite reflector in the reactor core was found on the weld of the aluminum cladding. For this reason, specifications of graphite reflectors were renewed; dimensions of the graphite were reduced and gaps of water were increased. All existing graphite reflectors of JRR-4 were replaced by new graphite reflectors. In February 2010 the resumption of JRR-4 was carried out with new graphite reflectors. We measured the characteristics of neutron beam at the JRR-4 Neutron Beam Facility. A cylindrical water phantom of 18.6 cm diameter and 24 cm depth was set in front of the beam port with 1cm gap. TLDs and gold wires were inserted within the phantom when the phantom was irradiated. The results of the measured thermal neutron flux and the gamma dose in water were compared with that of MCNP calculation. The neutron energy spectrum of the calculation model with new reflector had little variation compared to that with old reflector, but intensities of the neutron flux and gamma dose with new reflector were rather smaller than those with old reflector. The calculated results showed the same tendency as that of the experimental results. Therefore, the clinical trials of BNCT in JRR-4 could be restarted.

Investigation of irradiation conditions for recurrent breast cancer in JRR-4.

Clinical trials of boron neutron capture therapy (BNCT) for recurrent breast cancers are considered at Japan Research Reactor No. 4 (JRR-4). In this study, the irradiation technique for a total mastectomy patient with recurrent cancer was optimized by dosimetric calculations using JAEA computational dosimetry system (JCDS). The evaluation was performed using an en face technique and a tangents technique with thermal neutron beam mode at JRR-4. The results revealed that equivalent doses of lung, heart, liver and skin were similar in each irradiation technique due to the isotropic scattering of thermal neutrons in the body. On the other hand, the irradiation time with the tangents technique was a few times longer than with the en face technique. We concluded that the en face technique was an optimal irradiation technique for recurrent breast cancers using thermal neutron beam mode in terms of shorter irradiation time and easier patient positioning.

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.

Long-survivors of glioblatoma treated with boron neutron capture therapy (BNCT).

The purpose of this study was to compare the radiation dose between long-survivors and non-long-survivors in patients with glioblatoma (GBM) treated with boron neutron capture therapy (BNCT). Among 23 GBM patients treated with BNCT, there were five patients who survived more than three years after diagnosis. The physical and weighted dose of the minimum gross tumor volume (GTV) of long-survivors was much higher than that of non-long survivors with significant statistical differences.

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.

Comparative study of dose calculations with SERA and JCDS treatment planning systems.

Three treatment planning systems developed for clinical boron neutron capture therapy (BNCT) use are SERA developed by INL/Montana State University, NCTPlan developed by the Harvard-MIT and the CNEA group and JAEA computational dosimetry system (JCDS) developed by Japan Atomic Energy Agency (JAEA) in Japan. Previously, performance of the SERA and NCTPlan has been compared in various studies. In this preliminary study, the dose calculations performed with SERA and JCDS systems were compared in single brain cancer patient case with the FiR 1 epithermal neutron beam. A two-field brain cancer treatment plan was performed with the both codes. The dose components to normal brain, tumor and planning target volume (PTV) were calculated and compared in case of one radiation field and combined two fields. The depth dose distributions and the maximum doses in regions of interest were compared. Calculations with the treatment planning systems for the thermal neutron induced ((10)B and nitrogen) dose components and photon dose were in good agreement. Higher discrepancy in the fast neutron dose calculations was found. In case of combined two-field treatment plan, overall discrepancy of the maximum weighted dose was approximately 3% for normal brain and PTV and approximately 4% for tumor dose.

Dosimetric evaluation of neutron capture therapy for local advanced breast cancer.

Local recurrence breast cancer is one of the most difficult conditions to cure and there is a need for new therapy. If sufficient boron compound can be targeted to the tumor, boron neutron capture therapy (BNCT) can be applied to local recurrent breast cancer. In this study, we performed a preliminary dosimetry with a phantom model of the mammary gland at Kyoto University Research Reactor (KUR), and a feasibility dosimetry with JAERI Computational Dosimetry System (JCDS) at JRR4 reactor of Japan Atomic Research Institute. We performed preliminary dosimetry of a phantom model of the mammary gland with thermal neutron irradiation (OO-0011 mode) on LiF collimation at KUR. The thermal neutron flux was 5.16 E+08 cm(-2)s(-1) at the surface of phantom. The blood boron concentration is estimated to be 30 ppm; tumor boron concentration is also estimated to be 90 ppm according to tumor/blood ratio 3 and skin/blood ratio 1.2. Tumor RBE dose is estimated to be 47 Gy/h, and skin RBE dose is 12.4 Gy/h. In case of advanced breast cancer, we performed the feasibility estimation of 3D construction of tumor according to the MRI imaging of a patient with epithermal neutron mode at JRR4. The blood boron concentration (ppm) and tumor/normal tissue ratio are estimated to be 24 and 3.5, respectively. Skin RBE dose is restricted to 10 Gy/h, the maximum tumor RBE dose, minimum tumor RBE dose, and mean tumor RBE dose are 42.2, 11.3, and 28.9 Gy-Eq, respectively, in half hour irradiation. In this study, we showed the possibility to apply BNCT to local recurrent breast cancer. We can irradiate tumors selectively and as safely as possible, reducing the effects on neighboring healthy tissues.

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.