Determining a methodology of dosimetric quality assurance for commercially available accelerator-based boron neutron capture therapy system

The irradiation field of boron neutron capture therapy (BNCT) consists of multiple dose components including thermal, epithermal and fast neutron, and gamma. The objective of this work was to establish a methodology of dosimetric quality assurance (QA), using the most standard and reliable measurement methods, and to determine tolerance level for each QA measurement for a commercially available accelerator-based BNCT system. In order to establish a system of dosimetric QA suitable for BNCT, the following steps were taken. First, standard measurement points based on tissue-administered doses in BNCT for brain tumors were defined, and clinical tolerances of dosimetric QA measurements were derived from the contribution to total tissue relative biological effectiveness factor-weighted dose for each dose component. Next, a QA program was proposed based on TG-142 and TG-198, and confirmed that it could be assessed whether constancy of each dose component was assured within the limits of tolerances or not by measurements of the proposed QA program. Finally, the validity of the BNCT QA program as an evaluation system was confirmed in a demonstration experiment for long-term measurement over 1 year. These results offer an easy, reliable QA method that is clinically applicable with dosimetric validity for the mixed irradiation field of accelerator-based BNCT.     

Analysis of boron neutron capture reaction sensitivity using Monte Carlo simulation and proposal of a new dosimetry index in boron neutron capture therapy

Boron neutron capture therapy is a cellular-scale heavy-particle therapy. The factor determining the biological effects in the boron neutron capture reaction (BNCR) is the value of , which is the alpha component in the Linear Quadratic (LQ) model. Recently, the factor determining the value of has been revealed to correspond to the structural features of the tumor tissue. However, the relationship and mechanism have yet to be thoroughly studied. In this study, we simulated BNCR in tissues using the Monte Carlo simulation technique and examined the factors that determine the value of . According to this simulation, the nuclear-cytoplasmic (N/C) ratio, nuclear diameter and heterogeneity of the distribution of boron in the tissue have been suggested to determine the value of . Moreover, we proposed Biological Effectivity (BE) as a new dosimetry index based on the surviving fraction (SF), extending the concept of absolute biological effectiveness (ABE) in a previous report.     

Boron neutron capture therapy outcomes for advanced or recurrent head and neck cancer

We retrospectively review outcomes of applying boron neutron capture therapy (BNCT) to unresectable advanced or recurrent head and neck cancers. Patients who were treated with BNCT for either local recurrent or newly diagnosed unresectable head or neck cancers between December 2001 and September 2007 were included. Clinicopathological characteristics and clinical outcomes were retrieved from hospital records. Either a combination of borocaptate sodium and boronophenylalanine (BPA) or BPA alone were used as boron compounds. In all the treatment cases, the dose constraint was set to deliver a dose <10–12 Gy-eq to the skin or oral mucosa. There was a patient cohort of 62, with a median follow-up of 18.7 months (range, 0.7–40.8). A total of 87 BNCT procedures were performed. The overall response rate was 58% within 6 months after BNCT. The median survival time was 10.1 months from the time of BNCT. The 1- and 2-year overall survival (OS) rates were 43.1% and 24.2%, respectively. The major acute Grade 3 or 4 toxicities were hyperamylasemia (38.6%), fatigue (6.5%), mucositis/stomatitis (9.7%) and pain (9.7%), all of which were manageable. Three patients died of treatment-related toxicity. Three patients experienced carotid artery hemorrhage, two of whom had coexistent infection of the carotid artery. This study confirmed the feasibility of our dose-estimation method and that controlled trials are warranted.     

Dosimetric effect of set-up error in accelerator-based boron neutron capture therapy for head and neck cancer

The dosimetric effect of set-up error in boron neutron capture therapy (BNCT) for head and neck cancer remains unclear. In this study, we analyzed the tendency of dose error by treatment location when simulating the set-up error of patients. We also determined the tolerance level of the set-up error in BNCT for head and neck cancer. As a method, the distal direction was shifted with an interval of 2.5 mm, from 0.0 mm to +20.0 mm and compared with the dose at the reference position. Similarly, the horizontal direction and vertical direction were shifted, with an interval of 5.0 mm, from −20.0 mm to +20.0 mm. In addition, cases with 3.0 mm and 5.0 mm simultaneous shifts in all directions were analyzed as the worst-case scenario. The dose metrics of the minimum dose of the tumor and the maximum dose of the mucosa were evaluated. From unidirectional set-up error analysis, in most cases, the set-up errors with dose errors within ±5% were Δdistal < +2.5 mm, Δhorizontal < ±5.0 mm and Δvertical < ±5.0 mm. In the simulation of 3.0 mm shifts in all directions, the errors in the minimum tumor dose and maximum mucosal dose were −3.6% ±1.4% (range, −5.4% to −0.6%) and 2% ±1.4% (range, 0.4% to 4.5%), respectively. From these results, if the set-up error was within ±3.0 mm in each direction, the dose errors of the tumor and mucosa could be suppressed within approximately ±5%, which is suggested as a tolerance level.     

Application of an ultraminiature thermal neutron monitor for irradiation field study of accelerator-based neutron capture therapy

Phantom experiments to evaluate thermal neutron flux distribution were performed using the Scintillator with Optical Fiber (SOF) detector, which was developed as a thermal neutron monitor during boron neutron capture therapy (BNCT) irradiation. Compared with the gold wire activation method and Monte Carlo N-particle (MCNP) calculations, it was confirmed that the SOF detector is capable of measuring thermal neutron flux as low as 10⁵ n/cm²/s with sufficient accuracy. The SOF detector will be useful for phantom experiments with BNCT neutron fields from low-current accelerator-based neutron sources.     

Relation between lineal energy distribution and relative biological effectiveness for photon beams according to the microdosimetric kinetic model

Our cell survival data showed the obvious dependence of RBE on photon energy: The RBE value for 200 kV X-rays was approximately 10% greater than those for mega-voltage photon beams. In radiation therapy using mega-voltage photon beams, the photon energy distribution outside the field is different with that in the radiation field because of a large number of low energy scattering photons. Hence, the RBE values outside the field become greater. To evaluate the increase in RBE, the method of deriving the RBE using the Microdosimetric Kinetic model (MK model) was proposed in this study. The MK model has two kinds of the parameters, tissue-specific parameters and the dose-mean lineal energy derived from the lineal energy distributions measured with a Tissue-Equivalent Proportional Counter (TEPC). The lineal energy distributions with the same geometries of the cell irradiations for 200 kV X-rays, (60)Co γ-rays, and 6 MV X-rays were obtained with the TEPC and Monte Carlo code GEANT4. The measured lineal energy distribution for 200 kV X-rays was quite different from those for mega-voltage photon beams. The dose-mean lineal energy of 200 kV X-rays showed the greatest value, 4.51 keV/μm, comparing with 2.34 and 2.36 keV/μm for (60)Co γ-rays and 6 MV X-rays, respectively. By using the results of the TEPC and cell irradiations, the tissue-specific parameters in the MK model were determined. As a result, the RBE of the photon beams (y(D): 2~5 keV/μm) in arbitrary conditions can be derived by the measurements only or the calculations only of the dose-mean lineal energy.     

Evaluation of useful neutron flux for accelerator boron neutron capture therapy using the 7Li(p,n) reaction

Accelerator neutron sources for epithermal neutron capture therapy utilising the 7Li(p,n) nuclear reaction are proposed to operate in the range of 1.88 to 2.5 MeV proton energy. Operation with proton energies closer to the reaction threshold decreases neutron yield but allows for smaller reflector and moderator, with less reduction of the epithermal flux, whereas high energies allow thicker targets to be used. The neutron yields for thick lithium targets are estimated in the energy range of 1.881 MeV to 2.5 MeV and useful neutron flux determined. The optimal range of proton energy is found to be 1.89-1.95 MeV, and this is recommended for more detailed studies of neutron transport properties for accelerator BNCT.     

Relative biological effects of neutron mixed-beam irradiation for boron neutron capture therapy on cell survival and DNA double-strand breaks in cultured mammalian cells

Understanding the biological effects of neutron mixed-beam irradiation used for boron neutron capture therapy (BNCT) is important in order to improve the efficacy of the therapy and to reduce side effects. In the present study, cell viability and DNA double-strand breaks (DNA-DSBs) were examined in Chinese hamster ovary cells (CHO-K1) and their radiosensitive mutant cells (xrs5, Ku80-deficient), following neutron mixed-beam irradiation for BNCT. Cell viability was significantly impaired in the neutron irradiation groups compared to the reference gamma-ray irradiation group. The relative biological effectiveness for 10% cell survival was 3.3 and 1.2 for CHO-K1 and xrs5 cells, respectively. There were a similar number of 53BP1 foci, indicators of DNA-DSBs, in the neutron mixed-beam and the gamma-ray groups. In addition, the size of the foci did not differ between groups. However, neutron mixed-beam irradiation resulted in foci with different spatial distributions. The foci were more proximal to each other in the neutron mixed-beam groups than the gamma-ray irradiation groups. These findings suggest that neutron beams may induce another type of DNA damage, such as clustered DNA-DSBs, as has been indicated for other high-LET irradiation.     

The effectiveness of painting therapy program for the treatment of externalizing behaviors in children with intellectual disability

Externalizing behaviors are prevalent among children with intellectual disability (ID). This study was conducted to identify the effectiveness of painting therapy program in alleviating the externalizing behaviors of male children with ID. In a randomized clinical trial, 60 children with ID were separated into intervention group and control group. The intervention group received the painting therapy program (12 weeks; two sessions per week), while the control group did not receive any program. The questionnaires were completed by their parents in order to evaluate the externalizing behaviors of children at the beginning and at the end of the painting therapy program. A two-way repeated-measure Analysis of Variance showed that the mean levels of externalizing behaviors in the intervention group decreased after the painting therapy program. In addition, the analysis showed that the mean levels of externalizing behaviors between the intervention group and the control group were significantly different. The findings revealed that painting therapy program could alleviate the externalizing behaviors of children with ID.     

Methods to elicit experts' beliefs over uncertain quantities: application to a cost effectiveness transition model of negative pressure wound therapy for severe pressure ulceration

We can use decision models to estimate cost effectiveness, quantify uncertainty regarding the adoption decision and provide estimates of the value of further research. In many cases, the existence of only limited data with which to populate a decision model can mean that a cost-effectiveness analysis either does not proceed or may misrepresent the degree of uncertainty associated with model inputs. An example is the case of negative pressure wound therapy (NPWT) used to treat severe pressure ulceration, for which the evidence base is limited and sparse. There is, however, substantial practical experience of using this treatment and its comparators. We can capture this knowledge quantitatively to inform a cost-effectiveness model by eliciting beliefs from experts. This paper describes the design and conduct of an elicitation exercise to generate estimates of multiple uncertain model inputs and validate analytical assumptions for a decision model on the use of NPWT. In designing the exercise, the primary focus was the use of elicitation to inform decision models (multistate models), where representations of uncertain beliefs need to be probabilistically coherent. This paper demonstrates that it is feasible to collect formally elicited evidence to inform decision models.     

Estimation of the range of excess death associated with influenza epidemics: application of a model using annual mortality rates and the seasonal index for determining minimum excess mortality estimates

OBJECTIVE: To determine the range of excess death associated with influenza in Japan. METHODS: The monthly rates for mortality from all causes other than accidents (ICD9: E800-E949, ICD-10: V01-X59) were determined from the Japanese national vital statistics for 1987-2003. By employing a model using the annual mortality rates and the seasonal index, the number of expected deaths and the 95% range of mortality in the absence of influenza-associated deaths (normal range) were obtained. Point estimation of excess mortality during an influenza season was performed by calculation of differences between the number of deaths observed and the number of deaths expected. The range of excess death was defined: the lower limit of the excess death was performed by calculation of difference between the number of deaths observed and the upper limit of the normal range. The upper limit of the excess death, on the contrary, was performed by calculation of difference between the number of deaths observed and the lower limit of the normal range. Based on the results of a survey of tendencies in the occurrence of infectious diseases, months showing a high prevalence of influenza and associated deaths were regarded as "months when the rate of death from influenza was 0.9 deaths/100,000 person-years or higher". RESULTS: The excess death determined by point estimation was largest in 1999, followed by 1995, 1993, 1997, 2000, and 2003. The point estimation (range of excess death) in 1999 was approximately 49,000 (approximate range, 37,000-60,000). Correspondingly, the excess death in 1995 was approximately 38,000 (approximate range, 27,000-48,000). While values in 1993, 1997, 2000, and 2003 were in the approximate range of 21,000 to 25,000, the range of excess death of each year showed the differences: approximate range from 15,000 to 36,000 in 1993, from 18,000 to 31,000 in 1997, from 18,000 to 28,000 in 2000, and from 11,000 to 34,000 in 2003, respectively. From comparison of the range of excess deaths by year, that in 1995 appeared to be the largest among the examined years. CONCLUSION: By considering the range of variation in the number of deaths in the years when no influenza epidemics occurred, the increase (the largest number and smallest number of deaths) associated with elevation the prevalence of influenza could be determined. Estimation of the range of excess deaths can be considered a useful method for understanding the influence of influenza on public health.     

Prediction of post-radiotherapy survival for bone metastases: a comparison of the 3-variable number of risk factors model with the new Katagiri scoring system

We investigated patient survival after palliative radiotherapy for bone metastases while comparing the prognostic accuracies of the 3-variable number of risk factors (NRF) model and the new Katagiri scoring system (Katagiri score). Overall, 485 patients who received radiotherapy for bone metastases were grouped as per the NRF model (groups I, II and III) and Katagiri score (low-, intermediate- and high-risk). Survival was compared using the log-rank or log-rank trend test. Independent prognostic factors were identified using multivariate Cox regression analyses (MCRA). MCRA and receiver operating characteristic (ROC) curves were used to compare both models’ accuracy. For the 376 evaluable patients, the overall survival (OS) rates decreased significantly in the higher-tier groups of both models (P < 0.001). All evaluated factors except ‘previous chemotherapy status’ differed significantly between groups. Both models exhibited independent predictive power (P < 0.001). Per NRF model, hazard ratios (HRs) were 1.44 (P = 0.099) and 2.944 (P < 0.001), respectively, for groups II and III, relative to group I. Per Katagiri score, HRs for intermediate- and high-risk groups were 4.02 (P < 0.001) and 7.09 (P < 0.001), respectively, relative to the low-risk group. Areas under the curve (AUC) for predicting 6-, 18- and 24-month mortality were significantly higher when using the Katagiri score (P = 0.036, 0.039 and 0.022). Both models predict survival. Prognostic accuracy of the Katagiri score is superior, especially in patients with long-term survival potential; however, in patients with short prognosis, no difference occurred between both models; simplicity and patient burden should also be considered.     

Analysis of late toxicity associated with external beam radiation therapy for prostate cancer with uniform setting of classical 4-field 70 Gy in 35 fractions: a survey study by the Osaka Urological Tumor Radiotherapy Study Group

We aimed to analyse late toxicity associated with external beam radiation therapy (EBRT) for prostate cancer using uniform dose-fractionation and beam arrangement, with the focus on the effect of 3D (CT) simulation and portal field size. We collected data concerning patients with localized prostate adenocarcinoma who had been treated with EBRT at five institutions in Osaka, Japan, between 1998 and 2006. All had been treated with 70 Gy in 35 fractions, using the classical 4-field technique with gantry angles of 0°, 90°, 180° and 270°. Late toxicity was evaluated strictly in terms of the Common Terminology Criteria for Adverse Events Version 4.0. In total, 362 patients were analysed, with a median follow-up of 4.5 years (range 1.0–11.6). The 5-year overall and cause-specific survival rates were 93% and 96%, respectively. The mean ± SD portal field size in the right–left, superior–inferior, and anterior–posterior directions was, respectively, 10.8 ± 1.1, 10.2 ± 1.0 and 8.8 ± 0.9 cm for 2D simulation, and 8.4 ± 1.2, 8.2 ± 1.0 and 7.7 ± 1.0 cm for 3D simulation (P < 0.001). No Grade 4 or 5 late toxicity was observed. The actuarial 5-year Grade 2–3 genitourinary and gastrointestinal (GI) late toxicity rates were 6% and 14%, respectively, while the corresponding late rectal bleeding rate was 23% for 2D simulation and 7% for 3D simulation (P < 0.001). With a uniform setting of classical 4-field 70 Gy/35 fractions, the use of CT simulation and the resultant reduction in portal field size were significantly associated with reduced late GI toxicity, especially with less rectal bleeding.     

A new combined predicting model using a non-invasive score for the assessment of liver fibrosis in patients presenting with chronic hepatitis B virus infection

ObjectivesSeveral non-invasive markers have recently been proposed to predict liver fibrosis without percutaneous liver biopsy (PLB). We aimed to evaluate the performance of non-invasive scores and to highlight the value of a new combined score in the prediction of liver fibrosis in chronic hepatitis B (CHB) patients.Patients and methodsWe performed a retrospective study of patients presenting with CHB who underwent PLB between 2008 and 2016. We calculated ASAT/Platelet Ratio Index (APRI), Fibrosis-4 Score (FIB4), GGT-to-platelet ratio (GPR), and ASAT/ALAT Ratio (AAR). Then, we combined APRI and FIB-4 scores into a new combined score. We assessed their performance in predicting liver fibrosis according to the Metavir score.ResultsA total of 179 patients presenting with CHB were included. Multivariate analysis showed that the APRI score was the only independent factor of significant fibrosis (OR = 3.78; P = 0.02), whereas the FIB-4 score was the only independent factor for severe fibrosis (OR = 2.85; P < 0.001) and cirrhosis (OR = 2.5; P = 0.001). At a threshold of severe fibrosis, APRI had the best specificity (75%) and FIB-4 had the greatest sensitivity (74%). Using the combined score, we improved the diagnostic performance of APRI and FIB-4 scores at the three thresholds of liver fibrosis. With this combined score, maximum 25.1% of patients presenting with CHB would undergo PLB.ConclusionAPRI, FIB-4, and GPR scores were well performing to predict liver fibrosis during CHB. The new combined score using APRI and FIB-4 was more accurate at the three-fibrosis thresholds.