Preoperative risk stratification models after radical cystectomy for bladder cancer: A multi-center study.

OBJECTIVE: We investigated preoperative patient factors associated with prognosis in 263 bladder cancer (BC) patients undergoing radical cystectomy (RC). We also developed new risk stratification models for prognosis. METHODS: This retrospective study included patients treated at Tottori University Hospital and affiliated hospitals between January 2010 and December 2019. The relationship between preoperative patient factors and overall recurrence-free and cancer-specific survival (CSS) was analyzed. The modified Glasgow prognosis score (mGPS) was calculated using serum albumin and C-reactive protein (CRP) levels. Statistical analyses included the log-rank test and Cox proportional hazards regression. RESULTS: Eastern Cooperative Oncology Group performance status (ECOG-PS), mGPS, and clinical tumor stage independently predicted CSS in multivariate analysis. A new risk stratification model included ECOG-PS ≥2, clinical tumor stage ≥3, serum albumin <3.5 g/dL, and serum CRP >0.5 mg/dL. Risk groups were defined as 0 factors (low risk), 1-2 factors (intermediate risk), and 3-4 factors (high risk). High-risk patients showed significantly poorer 3-year cancer-free survival: 86.9% (low risk), 76.7% (intermediate risk), and 50.0% (high risk). CONCLUSIONS: ECOG-PS, clinical tumor stage, and mGPS are predictive of poor cancer-free survival post-RC for BC. Our model offers the potential for prognostic prediction in these patients.

The Benefits of Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma Require at Least Three Cycles.

Background: Upper urinary tract urothelial carcinoma (UTUC) is uncommon. In advanced cases, radical nephroureterectomy (RNU) alone is not curative, and recurrence and metastasis are likely to occur. Adjuvant chemotherapy (AC) is an evidence-based treatment. However, the optimal number of AC cycles is not clear. This multicenter study investigated the number of cycles required for the beneficial effects of AC in Japanese patients with UTUC. Methods: Patients who were diagnosed with UTUC and underwent RNU at our hospital and affiliated hospitals from January 2010 to September 2020 were included in the study. Patients with pathological T3 or higher or lymph node metastasis were observed or given AC, and their responses were compared. The AC regimens included gemcitabine and cisplatin or carboplatin. Patients were also classified into two groups: the observation and two cycles of AC group and the three to four cycles of AC group. The survival curves for recurrence-free survival (RFS) and cancer-specific survival (CSS) were evaluated using Kaplan-Meier analyses. Results: Of the 133 patients enrolled in the study, 24 received 2 cycles of AC, 37 received 3-4 cycles, and 72 were observed only. The 5-year RFS was 67.1% for the 3-4 cycles of AC group and 41.7% for the observation and two cycles of AC group. The 5-year CSS was 72.2% for the 3-4 cycles of AC group and 35.9% for the observation and two cycles of AC group. RFS and CSS were significantly longer in the 3-4 cycles of AC group compared to the observation and 2 cycles group (P = 0.048 and P = 0.005 respectively). Conclusion: AC prolonged RFS and CSS in the real-world setting. However, at least three cycles of AC are required to achieve beneficial effects in patients with UTUC.

Implementation of optically simulated luminescent dosimeter for quality control of gamma ray dose of an accelerator-based neutron source.

BACKGROUND: Neutron beams utilized for performing BNCT are composed of a mixture of neutrons and gamma rays. Although much of the dose delivered to the cancer cells comes from the high LET particles produced by the boron neutron capture reaction, the dose delivered to the healthy tissues from unwanted gamma rays cannot be ignored. With the increase in the number of accelerators for BNCT, a detector system that is capable of measuring gamma ray dose in a mixed neutron/gamma irradiation field is crucial. Currently, BeO TLDs encased in quartz glass are used to measure gamma ray dose in a BNCT irradiation field. However, this type of TLD is no longer commercially available. A replacement dosimetry system is required to perform the recommended ongoing quality assurance of gamma ray measurement for a clinical BNCT system. PURPOSE: The purpose of this study is to evaluate the characteristics of a BeO OSLD detector system under a mixed neutron and gamma ray irradiation field and to assess the suitability of the system for routine quality assurance measurements of an accelerator-based BNCT facility. METHODS: The myOSLD system by RadPro International GmbH was evaluated using the accelerator-based neutron source designed for clinical BNCT (NeuCure BNCT system). The readout constancy, linearity, dose rate effect, and fading effect of the OSLD were evaluated. Free-in-air and water phantom measurements were performed and compared with the TLD results and Monte Carlo simulation results. The PHITS Monte Carlo code was used for this study. RESULTS: The readout constancy was found to be stable over a month-long period and similar to the TLD results. The OSLD readout signal was found to be linear, with a high coefficient of determination (R2 ≥ 0.999) up to a proton charge of 3.6 C. There was no significant signal fading or dose rate dependency. The central axis depth dose and off-axis dose profile measurements agreed with both the TLD and Monte Carlo simulation results, within one standard deviation. CONCLUSION: The myOSLD system was characterized using an accelerator system designed for clinical BNCT. The experimental measurements confirmed the OSLD achieved similar, if not superior to, the currently utilized dosimetry system for routine QA of an accelerator-based BNCT system. The OSLD system would be a suitable replacement for the current TLD system for performing routine QA of gamma ray dose measurement in a BNCT irradiation field.

Boron neutron capture therapy as a larynx-preserving treatment for locally recurrent laryngeal carcinoma after conventional radiation therapy: A preliminary report.

OBJECTIVE: Laryngeal preservation and a radical cure are the treatment goals for laryngeal carcinoma, and larynx-preserving therapy is generally preferred for early-stage laryngeal carcinoma. When laryngeal carcinoma recurs locally, patients are often forced to undergo total laryngectomy, resulting in loss of vocal function. However, many patients with laryngeal carcinoma who have residual or recurrent disease after radiotherapy wish to preserve their voice. The purpose of this study was to investigate the possibility of using BNCT as a larynx-preserving treatment for residual or recurrent laryngeal carcinomas following radical irradiation. PATIENTS AND METHODS: This study included 15 patients who underwent BNCT for residual or recurrent laryngeal carcinoma after radical laryngeal carcinoma irradiation. The number of treatment sessions for all patients was one irradiation. Before BNCT, the recurrent laryngeal carcinoma stage was rT1aN0, rT2N0, rT2N1, rT3N0, rT3N1, and rT4aN0 in one, six, one, three, one, and three patients, respectively. The median maximum tumor diameter before BNCT was 15 mm (8-22 mm). All patients underwent a tracheostomy before BNCT to mitigate the risk of upper airway stenosis due to laryngeal edema after BNCT. Treatment efficacy was evaluated retrospectively using monthly laryngoscopy after BNCT and contrast-enhanced CT scans at 3 months. The safety of treatment was evaluated based on examination findings and interviews with patients. RESULTS: The median hospital stay after BNCT was 2 days (1-6). The response rate at three months after BNCT in 15 patients with locally recurrent laryngeal carcinoma was 93.3 %, and the CR rate was 73.3 %. The most frequent adverse event associated with BNCT was laryngeal edema, which occurred in nine patients the day after BNCT. The average course of laryngeal edema peaked on the second day after BNCT and almost recovered after 1 week in all patients. One patient had bilateral vocal fold movement disorders. None had dyspnea because of prophylactic tracheostomy. No grade four or higher adverse events occurred. Other grade 2 adverse events included pharyngeal mucositis, diarrhea, and sore throat. Three months after BNCT, tracheostomy tubes were removed in nine patients, retinal cannulas were placed in three patients, and voice cannulas were placed in three patients. CONCLUSIONS: BNCT for locally recurrent laryngeal carcinoma can safely deliver radical irradiation to tumor tissues, even in patients undergoing radical irradiation. BNCT has shown antitumor effects against recurrent laryngeal carcinoma. However, further long-term observations of the treatment outcomes are required.

Preliminary outcomes of boron neutron capture therapy for head and neck cancers as a treatment covered by public health insurance system in Japan: Real-world experiences over a 2-year period.

PURPOSE: Since June 2020, boron neutron capture therapy (BNCT) has been a health care service covered by health insurance in Japan to treat locally advanced or recurrent unresectable head and neck cancers. Therefore, we aimed to assess the clinical outcomes of BNCT as a health insurance treatment and explore its role among the standard treatment modalities for head and neck cancers. MATERIALS AND METHODS: We retrospectively analyzed data from patients who were treated using BNCT at Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, between June 2020 and May 2022. We assessed objective response rates based on the Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events based on the Common Terminology Criteria for Adverse Events, version 5.0. Additionally, we conducted a survival analysis and explored the factors that contributed to the treatment results. RESULTS: Sixty-nine patients (72 treatments) were included in the study, with a median observation period of 15 months. The objective response rate was 80.5%, and the 1-year locoregional control, progression-free survival, and overall survival rates were 57.1% (95% confidence interval [CI]: 43.9%-68.3%), 42.2% (95% CI: 30.1%-53.8%), and 75.4% (95% CI: 62.5%-84.5%), respectively. Locoregional control was significantly longer in patients with earlier TNM staging and no history of chemotherapy. CONCLUSIONS: BNCT may be an effective treatment option for locally advanced or recurrent unresectable head and neck cancers with no other definitive therapies. If definitive surgery or radiation therapy are not feasible, BNCT should be considered at early disease stages.

Nonclinical pharmacodynamics of boron neutron capture therapy using direct intratumoral administration of a folate receptor targeting novel boron carrier.

Background: Boron neutron capture therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via convection-enhanced delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional nonclinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration. Methods: In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration. Results: The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols. Conclusions: This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.

Application of stoichiometric CT number calibration method for dose calculation of tissue heterogeneous volumes in boron neutron capture therapy.

BACKGROUND: Monte Carlo simulation code is commonly used for the dose calculation of boron neutron capture therapy. In the past, dose calculation was performed assuming a homogeneous mass density and elemental composition inside the tissue, regardless of the patient's age or sex. Studies have shown that the mass density varies with patient to patient, particularly for those that have undergone surgery or radiotherapy. A method to convert computed tomography numbers into mass density and elemental weights of tissues has been developed and applied in the dose calculation process using Monte Carlo codes. A recent study has shown the variation in the computed tomography number between different scanners for low- and high-density materials. PURPOSE: The aim of this study is to investigate the effect of the elemental composition inside each calculation voxel on the dose calculation and the application of the stoichiometric CT number calibration method for boron neutron capture therapy planning. METHODS: Monte Carlo simulation package Particle and Heavy Ion Transport code System was used for the dose calculation. Firstly, a homogeneous cubic phantom with the material set to ICRU soft tissue (four component), muscle, fat, and brain was modelled and the NeuCure BNCT system accelerator-based neutron source was used. The central axis depth dose distribution was simulated and compared between the four materials. Secondly, a treatment plan of the brain and the head and neck region was simulated using a dummy patient dataset. Three models were generated; (1) a model where only the fundamental materials were considered (simple model), a model where each voxel was assigned a mass density and elemental weight using (2) the Nakao20 model, and (3) the Schneider00 model. The irradiation conditions were kept the same between the different models (irradiation time and irradiation field size) and the near maximum (D1%) and mean dose to the organs at risk were calculated and compared. RESULTS: A maximum percentage difference of approximately 5% was observed between the different materials for the homogeneous phantom. With the dummy patient plan, a large dose difference in the bone (greater than 12%) and region near the low-density material (mucosal membrane, 7%-11%) was found between the different models. CONCLUSIONS: A stoichiometric CT number calibration method using the newly developed Nakao20 model was applied to BNCT dose calculation. The results indicate the importance of calibrating the CT number to elemental composition for each individual CT scanner for the purpose of BNCT dose calculation along with the consideration of heterogeneity of the material composition inside the defined region of interest.

Impact of Collaborative Nursing Care Delivery on Patient Safety Events in an Emergency Intensive Care Unit: A Retrospective Observational Study.

OBJECTIVES: Patient safety events (PSEs) have detrimental consequences for patients and healthcare staff, highlighting the importance of prevention. Although evidence shows that nurse staffing affects PSEs, the role of an appropriate nursing care delivery system remains unclear. The current study aimed to investigate whether nursing care delivery systems could prevent PSEs. METHODS: This retrospective study was conducted in Japan. The study examined the collaborative 4:2 nursing care delivery system in which 2 nurses are assigned to care for 4 patients, collaborating to perform tasks, and provide care. The cohort receiving care from a collaborative 4:2 nursing care delivery system was labeled the postintervention, whereas the cohort receiving care from a conventional individualized system, in which one nurse provides care for 2 patients, was labeled the preintervention. The primary outcome was the occurrence of PSEs. RESULTS: The preintervention and postintervention comprised 561 and 401 patients, respectively, with the latter consisting of a younger and more critically ill population. The number of PSEs per 1000 patient-days was not significantly different between the 2 groups (10.3 [95% confidence interval, 7.1-13.5] versus 6.0 [95% confidence interval, 3.2-8.9], P = 0.058). Multiple logistic regression analysis showed that the collaborative 4:2 nursing care delivery system was significantly associated with PSEs (adjusted odds ratio, 0.53; 95% confidence interval, 0.29-0.95; P = 0.037). CONCLUSIONS: These findings suggest that in an emergency intensive care unit, a collaborative nursing care delivery system was associated with a decrease in PSEs.

Safety of Boron Neutron Capture Therapy with Borofalan(10B) and Its Efficacy on Recurrent Head and Neck Cancer: Real-World Outcomes from Nationwide Post-Marketing Surveillance.

BACKGROUND: This study was conducted to evaluate the real-world safety and efficacy of boron neutron capture therapy (BNCT) with borofalan(10B) in Japanese patients with locally advanced or locally recurrent head and neck cancer (LA/LR-HNC). METHODS: This prospective, multicenter observational study was initiated in Japan in May 2020 and enrolled all patients who received borofalan(10B) as directed by regulatory authorities. Patient enrollment continued until at least 150 patients were enrolled, and adverse events attributable to drugs, treatment devices, and BNCT were evaluated. The patients with LA/LR-HNC were systematically evaluated to determine efficacy. RESULTS: The 162 patients enrolled included 144 patients with squamous cell carcinoma of the head and neck (SCCHN), 17 patients with non-SCCHN (NSCCHN), and one patient with glioblastoma. Treatment-related adverse events (TRAEs) were hyperamylasemia (84.0%), stomatitis (51.2%), sialoadenitis (50.6%), and alopecia (49.4%) as acute TRAEs, and dysphagia (4.5%), thirst (2.6%), and skin disorder (1.9%) as more common late TRAEs. In patients with LA/LR-HNC, the overall response rate (ORR) was 72.3%, with a complete response (CR) in 63 (46.0%) of 137 patients with SCCHN. Among 17 NSCCHN patients, the ORR was 64.7%, with eight cases (47.1%) of CR. One- and two-year OS rates in patients with recurrent SCCHN were 78.8% and 60.7%, respectively. CONCLUSIONS: This post-marketing surveillance confirmed the safety and efficacy of BNCT with borofalan(10B) in patients with LA/LR-HNC in a real-world setting.

Feasibility study of optical imaging of the boron-dose distribution by a liquid scintillator in a clinical boron neutron capture therapy field.

BACKGROUND: Evaluation of the boron dose is essential for boron neutron capture therapy (BNCT). Nevertheless, a direct evaluation method for the boron-dose distribution has not yet been established in the clinical BNCT field. To date, even in quality assurance (QA) measurements, the boron dose has been indirectly evaluated from the thermal neutron flux measured using the activation method with gold foil or wire and an assumed boron concentration in the QA procedure. Recently, we successfully conducted optical imaging of the boron-dose distribution using a cooled charge-coupled device (CCD) camera and a boron-added liquid scintillator at the E-3 port facility of the Kyoto University Research Reactor (KUR), which supplies an almost pure thermal neutron beam with very low gamma-ray contamination. However, in a clinical accelerator-based BNCT facility, there is a concern that the boron-dose distribution may not be accurately extracted because the unwanted luminescence intensity, which is irrelevant to the boron dose is expected to increase owing to the contamination of fast neutrons and gamma rays. PURPOSE: The purpose of this research was to study the validity of a newly proposed method using a boron-added liquid scintillator and a cooled CCD camera to directly observe the boron-dose distribution in a clinical accelerator-based BNCT field. METHOD: A liquid scintillator phantom with 10 B was prepared by filling a small quartz glass container with a commercial liquid scintillator and boron-containing material (trimethyl borate); its natural boron concentration was 1 wt%. Luminescence images of the boron-neutron capture reaction were obtained in a water tank at several different depths using a CCD camera. The contribution of background luminescence, mainly due to gamma rays, was removed by subtracting the luminescence images obtained using another sole liquid scintillator phantom (natural boron concentration of 0 wt%) at each corresponding depth, and a depth profile of the boron dose with several discrete points was obtained. The obtained depth profile was compared with that of calculated boron dose, and those of thermal neutron flux which were experimentally measured or calculated using a Monte Carlo code. RESULTS: The depth profile evaluated from the subtracted images indicated reasonable agreement with the calculated boron-dose profile and thermal neutron flux profiles, except for the shallow region. This discrepancy is thought to be due to the contribution of light reflected from the tank wall. The simulation results also demonstrated that the thermal neutron flux would be severely perturbed by the 10 B-containing phantom if a relatively larger container was used to evaluate a wide range of boron-dose distributions in a single shot. This indicates a trade-off between the luminescence intensity of the 10 B-added phantom and its perturbation effect on the thermal neutron flux. CONCLUSIONS: Although a partial discrepancy was observed, the validity of the newly proposed boron-dose evaluation method using liquid-scintillator phantoms with and without 10 B was experimentally confirmed in the neutron field of an accelerator-based clinical BNCT facility. However, this study has some limitations, including the trade-off problem stated above. Therefore, further studies are required to address these limitations.

Out-of-field dosimetry using a validated PHITS model and computational phantom in clinical BNCT.

BACKGROUND: The out-of-field radiation dose for boron neutron capture therapy (BNCT), which results from both neutrons and γ-rays, has not been extensively evaluated. To safely perform BNCT, the neutron and γ-ray distributions inside the treatment room and the whole-body dose should be evaluated during commissioning. Although, certain previous studies have evaluated the whole-body dose in the clinical research phase, no institution providing BNCT covered by health insurance has yet validated the neutron distribution inside the room and the whole-body dose. PURPOSE: To validate the Monte Carlo model of the BNCT irradiation room extended for the whole-body region and evaluate organ-at-risk (OAR) doses using the validated model with a human-body phantom. METHODS: First, thermal neutron distribution inside the entire treatment room was measured by placing Au samples on the walls of the treatment room. Second, neutron and gamma-ray dose-rate distributions inside a human-body water phantom were measured. Both lying and sitting positions were considered. Bare Au, Au covered by Cd (Au+Cd), In, Al, and thermoluminescent dosimeters were arranged at 11 points corresponding to locations of the OARs inside the phantom. After the irradiation, γ-ray peaks emitted from the samples were measured by a high-purity germanium detector. The measured counts were converted to the reaction rate per unit charge of the sample. These measurements were compared with results of simulations performed with the Particle and Heavy Ion Transport code System (PHITS). A male adult mesh-type reference computational phantom was used to evaluate OAR doses in the whole-body region. The relative biological effectiveness (RBE)-weighted doses and dose-volume histograms (DVHs) for each OAR were evaluated. The median dose (D50% ) and near-maximum dose (D2% ) were evaluated for 14 OARs in a 1-h-irradiation process. The evaluated RBE-weighted doses were converted to equivalent doses in 2 Gy fractions. RESULTS: Experimental results within 60 cm from the irradiation center agreed with simulation results within the error bars except at ±20, 30 cm, and those over 70 cm corresponded within one digit. The experimental results of reaction rates or γ-ray dose rate for lying and sitting positions agreed well with the simulation results within the error bars at 8, 4, 11, 7 and 7, 4, 7, 6, 5, 6 out of 11 points, respectively, for Au, Au+Cd, In, Al, and TLD. Among the detectors, the discrepancies in reaction rates between experiment and simulation were most common for Au+Cd, but were observed randomly for measurement points (brain, lung, etc.). The experimental results of γ-ray dose rates were systematically lower than simulation results at abdomen and waist regions for both positions. Extending the PHITS model to the whole-body region resulted in higher doses for all OARs, especially 0.13 Gy-eq increase for D50% of the left salivary gland. CONCLUSION: The PHITS model for clinical BNCT for the whole-body region was validated, and the OAR doses were then evaluated. Clinicians and medical physicists should know that the out-of-field radiation increases the OAR dose in the whole-body region.

Optimal conversion coefficient from easily measurable dose to effective dose with consideration to radiation quality for posterior-anterior chest radiography.

Effective dose is sometimes used to compare medical radiation exposure to patients and natural radiation for providing explanations about radiation exposure to patients, but its calculation is lengthy and requires dedicated measuring devices. The purpose of this study was to identify the most suitable conversion coefficient for conversion of easily measurable dose to effective dose in posterior-anterior chest radiography, and to evaluate its accuracy by direct measurement. We constructed an examination environment using Monte Carlo simulation, and evaluated the variation in conversion coefficients from incident air kerma (IAK), entrance-surface air kerma (ESAK), and air kerma-area product (KAP) to effective dose when the irradiation field size and radiation quality were changed. Effective doses were also measured directly using thermoluminescence dosimeters and compared with the effective dose obtained from conversion coefficients. The KAP conversion coefficient most effectively suppressed the effect of irradiation field size, and was then used to set conversion coefficients for various half-value layers. The optimal conversion coefficient was 0.00023 [mSv/(mGy·cm2)] at 120 kVp (half-value layer = 5.5 mmAl). Evaluation of the direct measurements obtained with various radiation qualities revealed that the accuracy of the conversion coefficient was maintained at ≤ 11%. The proposed conversion coefficient can be easily calculated even in facilities that do not have equipment for measuring effective dose, and might enable the use of effective dose for providing explanations about radiation exposure to patients.

Proposal of recommended experimental protocols for in vitro and in vivo evaluation methods of boron agents for neutron capture therapy.

Recently, boron neutron capture therapy (BNCT) has been attracting attention as a minimally invasive cancer treatment. In 2020, the accelerator-based BNCT with L-BPA (Borofalan) as its D-sorbitol complex (Steboronine®) for head and neck cancers was approved by Pharmaceutical and Medical Devices Agency for the first time in the world. As accelerator-based neutron generation techniques are being developed in various countries, the development of novel tumor-selective boron agents is becoming increasingly important and desired. The Japanese Society of Neutron Capture Therapy believes it is necessary to propose standard evaluation protocols at each stage in the development of boron agents for BNCT. This review summarizes recommended experimental protocols for in vitro and in vivo evaluation methods of boron agents for BNCT based on our experience with L-BPA approval.

Experimentally determined relative biological effectiveness of cyclotron-based epithermal neutrons designed for clinical BNCT: in vitro study.

A neutron beam for boron neutron capture therapy (BNCT) of deep-seated tumours is designed to maintain a high flux of epithermal neutrons, while keeping the thermal and fast neutron component as low as possible. These neutrons (thermal and fast) have a high relative biological effectiveness in comparison with high energy photon beams used for conventional X-ray radiotherapy. In the past, neutrons for the purpose of BNCT were generated using nuclear reactors. However, there are various challenges that arise when installing a reactor in a hospital environment. From 2006, the Kyoto University Research Reactor Institute, in collaboration with Sumitomo Heavy Industries, began the development of an accelerator-based neutron source for clinical BNCT in a bid to overcome the shortcomings of a nuclear reactor-based neutron source. Following installation and beam performance testing, in vitro studies were performed to assess the biological effect of the neutron beam. Four different cell lines were prepared and irradiated using the accelerator-based neutron source. Following neutron and gamma ray irradiation, the survival curve for each cell line was calculated. The biological end point to determine the relative biological effectiveness (RBE) was set to 10% cell survival, and the D10 for each cell line was determined. The RBE of the accelerator-based neutron beam was evaluated to be 2.62.

The effects of BPA-BNCT on normal bone: determination of the CBE value in mice‡.

Boron neutron capture therapy (BNCT) with p-boronophenylalanine (BPA) is expected to have less effect on the decrease in normal bone strength than X-ray therapy. However, the compound biological effectiveness (CBE) value necessary to convert the boron neutron capture reaction (BNCR) dose into a bioequivalent X-ray dose has not been determined yet. The purpose of this study was to evaluate the influence of BNCT on normal bone in mice and to elucidate the CBE factor. We first searched the distribution of BPA in the normal bone of C3H/He mice and then measured the changes in bone strength after irradiation. The CBE value was determined when the decrease in bone strength was set as an index of the BNCT effect. The 10B concentrations in the tibia after subcutaneous injection of 125, 250 and 500 mg/kg BPA were measured by prompt gamma-ray spectroscopy and inductively coupled plasma (ICP)-atomic emission spectrometry. The 10B mapping in the tibia was examined by alpha-track autoradiography and laser ablation-ICP-mass spectrometry. The 10B concentration increased dose-dependently; moreover, the concentrations were maintained until 120 min after BPA administration. The administered 10B in the tibia was abundantly accumulated in the growth cartilage, trabecular bone and bone marrow. The bone strength was analyzed by a three-point bending test 12 weeks after irradiation. The bending strength of the tibia decreased dose-dependently after the irradiation of X-ray, neutron and BNCR. The CBE factor was obtained as 2.27 by comparing these dose-effect curves; the value determined in this study will enable an accurate dosimetry of normal bone.

Effects of Alfaxalone on the Induction and Maintenance of Total Intravenous Anesthesia in Gentoo Penguins (Pygoscelis papua).

Systemic anesthesia in penguins is often achieved using inhalation anesthetic agents alone, and information on injectable drugs for systemic anesthesia is limited. General anesthesia with a minimal effect on circulatory dynamics is necessary to perform noninvasive examinations and treatments in animals, including penguins. In this study, alfaxalone (ALFX), an injectable anesthetic agent, was examined to establish the optimal anesthetic method for gentoo penguins (Pygoscelis papua). Alfaxalone was administered intravenously through the metatarsal vein, and anesthesia was maintained by a constant rate infusion (CRI). A biological monitor was used to record numerous clinical indices, and the anesthetic depth was evaluated every 5 minutes during anesthesia; the CRI was adjusted until the optimal anesthetic depth was obtained. Anesthesia depth was assessed, and the CRI rate was adjusted. The CRI was stopped, and the time until recovery was recorded. Blood samples were collected to analyze plasma concentrations of ALFX. The mean total dose of ALFX required for anesthetic induction was 9 ± 1.9 mg/kg, the intubation time was 126 ± 21 seconds, and the maintenance infusion rate of ALFX was 0.3 ± 0.08 mg/kg/min. The time from discontinuation of anesthesia to extubation was 42 ± 23 minutes, and the time to recovery was 90 ± 33 minutes. Significant changes in the heart rate and blood pressure were not observed during the anesthetic events. The plasma concentration of ALFX under stable anesthesia was 6734 ± 4386 ng/mL (range, 3315-14 326 ng/mL). Although anesthesia using ALFX tended to result in a prolonged time to recovery in gentoo penguins, rapid induction of anesthesia and stable hemodynamics during anesthetic maintenance were achieved. Therefore, ALFX may be considered a suitable anesthetic method for noninvasive examinations and treatments in penguins.

Pharmacokinetic Study of 14C-Radiolabeled p-Boronophenylalanine (BPA) in Sorbitol Solution and the Treatment Outcome of BPA-Based Boron Neutron Capture Therapy on a Tumor-Bearing Mouse Model.

BACKGROUND AND OBJECTIVE: Boron neutron capture therapy (BNCT) is a binary cancer treatment that combines boron administration and neutron irradiation. The tumor cells take up the boron compound and the subsequent neutron irradiation results in a nuclear fission reaction caused by the neutron capture reaction of the boron nuclei. This produces highly cytocidal heavy particles, leading to the destruction of tumor cells. p-boronophenylalanine (BPA) is widely used in BNCT but is insoluble in water and requires reducing sugar or sugar alcohol as a dissolvent to create an aqueous solution for administration. The purpose of this study was to investigate the pharmacokinetics of 14C-radiolabeled BPA using sorbitol as a dissolvent, which has not been reported before, and confirm whether neutron irradiation with a sorbitol solution of BPA can produce an antitumor effect of BNCT. MATERIALS AND METHODS: In this study, we evaluated the sugar alcohol, sorbitol, as a novel dissolution aid and examined the consequent stability of the BPA for long-term storage. U-87 MG and SAS tumor cell lines were used for in vitro and in vivo experiments. We examined the pharmacokinetics of 14C-radiolabeled BPA in sorbitol solution, administered either intravenously or subcutaneously to a mouse tumor model. Neutron irradiation was performed in conjunction with the administration of BPA in sorbitol solution using the same tumor cell lines both in vitro and in vivo. RESULTS: We found that BPA in sorbitol solution maintains stability for longer than in fructose solution, and can therefore be stored for a longer period. Pharmacokinetic studies with 14C-radiolabeled BPA confirmed that the sorbitol solution of BPA distributed through tumors in much the same way as BPA in fructose. Neutron irradiation was found to produce dose-dependent antitumor effects, both in vitro and in vivo, after the administration of BPA in sorbitol solution. CONCLUSION: In this report, we demonstrate the efficacy of BPA in sorbitol solution as the boron source in BNCT.

Quantitative Analysis of the Clinical Reasons Influencing the Frequency of Pediatric Head CT Examinations: A Single-Center Observation Study.

Epidemiological studies on radiation exposure from pediatric CT scans have attracted attention in terms of radiological protection. These studies have not taken into account the reasons why CT examinations were performed. It is presumed that there are clinical reasons that justify more frequent CT examinations in children. The purpose of this study was to characterize the clinical reasons why relatively high numbers of head CT examinations (NHCT) are frequently performed and to conduct a statistical analysis to determine the factors governing the NHCT. Patient information, the date of examination, and medical conditions for examination data stored on the radiology information system were used to investigate the reasons for undergoing CT examinations. The target facility was National Children's Hospital; data were obtained from March 2002 to April 2017, and the age of the study population was less than 16 years old. Quantitative analysis of the factors associated with frequent examinations was conducted by Poisson regression analysis. Among all patients who had a CT scan, 76.6% had head CT examinations, and 43.4% of children were under 1 year old at the time of the initial examination. There were marked differences in the number of examinations depending on the disease. The average NHCT was higher for children younger than 5 days of age. Among children less than 1 year of age with surgery, there was a marked difference between hydrocephalus, with a mean = 15.5 (95% CI 14.3,16.8), and trauma, with a mean = 8.3 (95% CI 7.2,9.4). In conclusion, this study revealed that NHCT was significantly higher in children who had undergone surgery than in those who had not been to the hospital. The clinical reasons behind patients with higher NHCT should be considered in investigating a causal relationship between CT exposure and brain tumors.

The impact of TP53 status of tumor cells including the type and the concentration of administered 10B delivery agents on compound biological effectiveness in boron neutron capture therapy.

Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or neo vector (SAS/neo) were inoculated subcutaneously into left hind legs of nude mice. After the subcutaneous administration of a 10B-carrier, boronophenylalanine-10B (BPA) or sodium mercaptododecaborate-10B (BSH), at two separate concentrations, the 10B concentrations in tumors were measured using γ-ray spectrometry. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) tumor cells, then were administered with BPA or BSH. Subsequently, the tumors were irradiated with reactor neutron beams during the time of which 10B concentrations were kept at levels similar to each other. Following irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled quiescent (Q) and total (= P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU. In both SAS/neo and SAS/mp53 tumors, the compound biological effectiveness (CBE) values were higher in Q cells and in the use of BPA than total cells and BSH, respectively. The higher the administered concentrations were, the smaller the CBE values became, with a clearer tendency in SAS/neo tumors and the use of BPA than in SAS/mp53 tumors and BSH, respectively. The values for BPA that delivers into solid tumors more dependently on uptake capacity of tumor cells than BSH became more alterable. Tumor micro-environmental heterogeneity might partially influence on the CBE value. The CBE value can be regarded as one of the indices showing the level of intratumor heterogeneity.