Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.

BACKGROUND: Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT. MATERIALS AND METHODS: We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival. RESULTS: Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy. CONCLUSION: 'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.

Neutron emission and dose distribution from natural carbon irradiated with a 12 MeV amu-1 12C5+ ion beam.

Measured neutron energy distribution emitted from a thick stopping target of natural carbon at 0°, 30°, 60° and 90° from nuclear reactions caused by 12 MeV amu-1 incident 12C5+ ions were converted to energy differential and total neutron absorbed dose as well as ambient dose equivalent H *(10) using the fluence-to-dose conversion coefficients provided by the ICRP. Theoretical estimates were obtained using the Monte Carlo nuclear reaction model code PACE and a few existing empirical formulations for comparison. Results from the PACE code showed an underestimation of the high-energy part of energy differential dose distributions at forward angles whereas the empirical formulation by Clapier and Zaidins (1983 Nucl. Instrum. Methods 217 489-94) approximated the energy integrated angular distribution of H *(10) satisfactorily. Using the measured data, the neutron doses received by some vital human organs were estimated for anterior-posterior exposure. The estimated energy-averaged quality factors were found to vary for different organs from about 7 to about 13. Emitted neutrons having energies above 20 MeV were found to contribute about 20% of the total dose at 0° while at 90° the contribution was reduced to about 2%.

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study).

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85-90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36-5.21, P = 0.004 for cN2-3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15-2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22-3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43-4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16-4.20, P = 0.017 for cT3-4 vs. cT1-2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48-6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53-13.14, P = 0.005 for cN2-3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12-4.94, P = 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31-5.97, P = 0.006 and HR 3.86, 95 % CI 1.13-24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.

Landscape effects of a non-native grass facilitate source populations of a native generalist bug, Stenotus rubrovittatus, in a heterogeneous agricultural landscape.

Non-native plant species can provide native generalist insects, including pests, with novel food and habitats. It is hypothesized that local and landscape-level abundances of non-native plants can affect the population size of generalist insects, although generalists are assumed to be less sensitive to habitat connectivity than specialists. In a heterogeneous landscape in Japan, the relationship between the density of a native pest of rice (Stenotus rubrovittatus (Matsumura) (Heteroptera: Miridae)) and the abundance of Italian ryegrass (Lolium multiflorum Lam. (Poales: Poaceae)), a non-native meadow grass known to facilitate S. rubrovittatus, was analyzed. Statistical analyses of data on bug density, vegetation, and the spatial distribution of fallow fields and meadows dominated by Italian ryegrass, obtained by field surveys, demonstrated that local and landscape-level abundances of Italian ryegrass (the unmowed meadow areas within a few hundred meters of a sampling plot) positively affected bug density before its immigration into rice fields. Our findings suggest that a generalist herbivorous insect that prefers non-native plants responds to spatial availability and connectivity of plant species patches at the metapopulation level. Fragmentation by selective mowing that decreases the total area of source populations and increases the isolation among them would be an effective and environmentally-friendly pest management method.

Forensic identification using multiple lot numbers of an implanted device.

We report a case in which identification of a deceased individual was established using multiple lot numbers printed on a body implantable device. Autopsy of an unknown woman revealed an intramedullary nail inserted within her right femur. The device manufacturer was identified from the configuration of the intramedullary nail, and the "use history" was traced from lot numbers printed on the device's multiple parts. The deceased individual was thus identified as a woman who had attempted suicide by jumping from a height about a year previously and had been transported to a hospital and undergone surgery that included implantation of the intramedullary nail. The main factor contributing to the rapid identification was the manufacturer's and distributor's record of the use history (traceability) of the product, because of their accountability for purposes of quality control. A second contributing factor was multiple lot numbers, resulting in extremely low probability of the same combination of lot numbers being present in multiple individuals. This case confirmed the utility of multiple lot numbers of body implantable devices in forensic identification.

Predictions of the pathological response to neoadjuvant chemotherapy in patients with primary breast cancer using a data mining technique.

Nomogram, a standard technique that utilizes multiple characteristics to predict efficacy of treatment and likelihood of a specific status of an individual patient, has been used for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients. The aim of this study was to develop a novel computational technique to predict the pathological complete response (pCR) to NAC in primary breast cancer patients. A mathematical model using alternating decision trees, an epigone of decision tree, was developed using 28 clinicopathological variables that were retrospectively collected from patients treated with NAC (n = 150), and validated using an independent dataset from a randomized controlled trial (n = 173). The model selected 15 variables to predict the pCR with yielding area under the receiver operating characteristics curve (AUC) values of 0.766 [95 % confidence interval (CI)], 0.671-0.861, P value < 0.0001) in cross-validation using training dataset and 0.787 (95 % CI 0.716-0.858, P value < 0.0001) in the validation dataset. Among three subtypes of breast cancer, the luminal subgroup showed the best discrimination (AUC = 0.779, 95 % CI 0.641-0.917, P value = 0.0059). The developed model (AUC = 0.805, 95 % CI 0.716-0.894, P value < 0.0001) outperformed multivariate logistic regression (AUC = 0.754, 95 % CI 0.651-0.858, P value = 0.00019) of validation datasets without missing values (n = 127). Several analyses, e.g. bootstrap analysis, revealed that the developed model was insensitive to missing values and also tolerant to distribution bias among the datasets. Our model based on clinicopathological variables showed high predictive ability for pCR. This model might improve the prediction of the response to NAC in primary breast cancer patients.

Low Amino Acid Score of Breakfast is Associated with the Incidence of Cognitive Impairment in Older Japanese Adults: A Community-Based Longitudinal Study.

BACKGROUND: The protein digestibility-corrected amino acid score (PDCAAS) represents the degree of utilizable dietary protein, namely the protein quality. The PDCAAS of a diet is required to be evaluated on a meal-by-meal basis, as food digestion and absorption occur with each meal intake. Although a positive association between protein intake and cognitive function has been reported, no study has investigated the association between PDCAAS of a diet and cognitive function. OBJECTIVES: To investigate the relationship between PDCAAS of a diet and cognitive impairment in older adults. DESIGN: Longitudinal epidemiological study. SETTING: Community-based setting. PARTICIPANTS: We analyzed 541 community-dwellers who participated in both baseline and follow-up survey. They were 60-83 years of age without cognitive impairment at baseline. MEASUREMENTS: Cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score ≤27. Individual PDCAASs were calculated for each of three regular meals from the 3-day dietary records at baseline. Participants were classified into two groups according to the sex-specific tertiles (T1-T3) of the PDCAAS for each meal (i.e., T1 as the low score group and T2-T3 as the medium and high score group). The dependent variable was cognitive impairment observed after 4 years, and the explanatory variables were the PDCAAS groups for each meal (the medium and high group as the reference) and covariates (sex, age, body mass index, education, depressive symptoms, medical history, protein intake at each meal, and the MMSE score at baseline). Multivariable logistic regression analysis was performed to evaluate the low PDCAAS group for cognitive impairment after 4 years. RESULTS: A significant association was observed only between a low PDCAAS of breakfast and the incidence of cognitive impairment (the adjusted odds ratios [95% confidence intervals] of low PDCAAS for cognitive impairment for breakfast, lunch, and dinner were 1.58 [1.00-2.50], 0.85 [0.54-1.34], and 1.08 [0.71-1.65], respectively). CONCLUSION: A lower PDCAAS of breakfast, i.e., a diet with poor quality of protein, was associated with the incidence of cognitive impairment in older adults of the community.

The Association between Dietary Amino Acid Intake and Cognitive Decline 8 Years Later in Japanese Community-Dwelling Older Adults.

OBJECTIVES: Previous studies have reported a relationship between low protein intake and cognitive decline and have suggested that this association may be related to specific amino acid intake. However, the effects of amino acid intake on the maintenance of cognitive function have yet to be clarified. We examined the longitudinal association between dietary amino acid intake and cognitive function in community-dwelling older adults. DESIGN: Longitudinal epidemiological study. SETTING: Community-based setting. PARTICIPANTS: This study comprised 427 study participants aged 60-82 years with no cognitive decline, defined as a Mini-Mental State Examination (MMSE) score of >27 at baseline, who also participated in a follow-up. The average and standard deviation of the follow-up period was 8.2 ± 0.3 years. MEASUREMENTS: Dietary intake was assessed using three-day dietary records at baseline. Participants were classified into quartiles (Q1-Q4) based on the intake of 19 amino acids for males and females. Next, we classified participants into Q1 and Q2-Q4 groups. Cognitive function was assessed using the MMSE both at baseline and at follow-up. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between the Q1 group and cognitive decline (MMSE ≤27), using the Q2-Q4 group as a reference group. Covariates were age, sex, body mass index, years of education, severity of depressive symptoms, history of lifestyle diseases (hypertension, dyslipidemia, diabetes mellitus, stroke, and ischemic heart disease), energy intake (kcal/d), protein intake (g/d), and MMSE score at baseline. RESULTS: Cognitive decline was present in 133 (31.1%) participants. After adjustment for covariates, including total protein intake, the ORs (95% CIs) for cognitive decline were 2.40 (1.21-4.75) for lysine, 2.05 (1.02-4.09) for phenylalanine, 2.18 (1.09-4.34) for threonine, and 2.10 (1.06-4.15) for alanine. CONCLUSION: The results suggest that lysine, phenylalanine, threonine, and alanine intake is important for the maintenance of cognitive function in older people, independent of total protein intake.

Is response rate increment obtained by molecular targeted agents related to survival benefit in the phase III trials of advanced cancer?

BACKGROUND: It remains unclear whether response rate (RR) is related to survival benefit in phase III trials of advanced cancer treated with molecular targeted agents (MTA) in combination with standard therapies. MATERIALS AND METHODS: We carried out a systematic search of PubMed for randomized phase III trials of four solid tumors examining the efficacy of MTA when added to a standard therapy. We examined whether there were any associations between RR increment obtained by the addition of targeted agents (DeltaRR) and survival benefit in phase III trials. RESULTS: We identified 26 phase III trials of MTA with a total of 21 156 patients and 29 experimental arms of MTA. Studies which showed significant survival benefit had higher DeltaRR compared with those which did not show significant benefit. In the receiver operating characteristic curve analysis, using a 7% gain as threshold value for DeltaRR allowed assessment of survival benefit with high sensitivity and specificity. There were also significant relationships between DeltaRR and hazard ratios for overall survival and progression-free survival in the linear regression analysis. CONCLUSION: RR increment obtained by the addition of MTA to a standard therapy may be useful to predict survival benefit in clinical phase III trials of advanced cancer.

Risk of hypoglycemia associated with thyroid agents is increased in patients with liver impairment.

OBJECTIVE: To determine the risk of developing hypoglycemia from drugs that affect glucose homeostasis and evaluate the elevation of that risk by liver impairment as judged by a decrease of liver reserve or the severity of abnormal values in liver function tests. METHODS: A hospital-based case-control study was carried out. The base population consisted of all patients aged 20 years and older attending a university hospital in Japan from 2002 - 2004 who had received drugs and serum glucose measurements. Cases were defined as having had at least one episode of hypoglycemia as determined by a serum glucose concentration below 70 mg/dl. Up to 5 controls for each case were matched for the year of serum glucose measurement, out- or inpatient status, clinical departments visited, and age difference within 5 years, taken randomly from the base population without hypoglycemia. The odds ratio for developing hypoglycemia was estimated using conditional logistic regression analysis. RESULTS: From a base population of 10,011, 245 cases and 1,194 controls were enrolled. Of the drugs investigated, levothyroxine use was associated with an increased risk of hypoglycemia in patients with liver impairment (adjusted odds ratio; non-use with normal liver (reference), non-use with liver impairment 0.91 (95% CI 0.62, 1.33), use with normal liver 4.50 (0.58, 34.76), use with liver impairment 14.68 (1.57, 137.4), p for trend 0.007). The risk elevation likely depended on the lowering of liver reserve. CONCLUSION: Clinicians and pharmacists should carefully monitor serum glucose concentrations in levothyroxine users with liver impairment, especially those with lower liver reserve.

The effect of sevoflurane-induced hypotension in combination with acute hypervolaemic haemodilution on middle cerebral artery flow velocity in surgical patients.

BACKGROUND AND OBJECTIVE: This study was carried out to clarify the effect of the combination of acute hypervolaemic haemodilution and hypotensive anaesthesia induced with sevoflurane on human middle cerebral artery flow velocity using transcranial Doppler ultrasonography. METHODS: Thirty patients who were maintained with N2O-O2-sevoflurane anaesthesia undergoing hip surgery were randomly divided into two groups (no controlled hypotension group, Group A, and controlled hypotension group, Group B). Haemodilution was produced by acute preoperative infusion of 1000 mL of hydroxyethylstarch without removing blood in both groups. Mean arterial pressure was maintained at approximately 95 mmHg in Group A and at 55 mmHg for 80 min by increasing the inspired concentration of sevoflurane in Group B. Middle cerebral artery flow velocity was measured before haemodilution, after haemodilution, 80 min after starting hypotension, and 60 min after recovery from hypotension. RESULTS: Middle cerebral artery flow velocity significantly increased in both groups after haemodilution; by 28%, in Group A, P < 0.05 vs. before haemodilution and by 30% vs. before haemodilution in Group B, P < 0.05). During controlled hypotension, it decreased towards the pre-haemodilution value (P < 0.05 vs. after haemodilution). CONCLUSIONS: Sevoflurane-induced hypotension to a mean arterial pressure of 55 mmHg would reduce middle cerebral artery flow that had been increased by acute hypervolaemic haemodilution, such as haematocrit value of 26%, whereas it could preserve the flow in pre-haemodilution condition during normocapnia.

Gain-of-function mutation in PTPN11 in histiocytic sarcomas of Bernese Mountain Dogs.

Histiocytic sarcoma (HS) is an aggressive malignant neoplasm of dendritic cell origin that is common in certain breeds of dogs. High prevalence of fatal, disseminated HS has been described in Bernese Mountain Dogs (BMDs). Support for genetic predisposition to develop HS has been presented in several studies, but to date, causative genetic events have not been reported. In addition, no driver mutations have been identified in tumours. Recently, E76K gain-of-function mutation in SHP2 encoded by the PTPN11 gene has been described in human histiocytic malignancies. In our study, we identified the PTPN11E76K in HS of BMDs. Amplification of exon 3 of the PTPN11 gene followed by Sanger sequencing was used to detect the mutation and estimate the prevalence in HS from 30 BMDs, 13 Golden Retrievers and 10 other dog breeds. The overall prevalence of PTPN11E76K in HS of BMDs was 36.67% compared with 8.69% in other breeds. No mutation was identified in normal tissues from 10 BMDs with HS that carried the mutation and 12 control dogs with no neoplastic disease, including 6 BMDs. Increased immunoreactivity for AKT, phosphorylated ERK1/2 and phosphorylated AKT in a small subset of BMDs with PTPN11E76K suggests that a gain-of-function might be mediated by the ERK and AKT pathways. These data suggest PTPN11E76K as an important driver mutation of HS in BMDs. This information may not only aid in unravelling the tumourigenic events associated with HS in BMDs, but also help in identifying more promising therapeutic strategies.

Label-free photoacoustic imaging of human palmar vessels: a structural morphological analysis.

We analysed the vascular morphology of the palm using a photoacoustic tomography (PAT) instrument with a hemispherical detector array. The three-dimensional (3D) morphology of blood vessels was determined noninvasively. Overall, 12 females and 11 males were recruited as healthy volunteers. Their ages were distributed almost evenly from 22 to 59 years. In all cases, many vascular networks were observed just beneath the skin and were determined to be veins anatomically. To analyse the major arteries, the layer containing the subcutaneous venous network was removed from the image. The analysis focused on the common and proper palmar digital arteries. We used the curvature of these arteries as a parameter to analyse their morphologies. There was no significant difference in the curvature between genders when comparing the subjects as a whole. The blood vessel curvature increased with age. Good agreement was found between the 3D numerical analysis results and the subjective evaluation of the two-dimensional (2D) projection image. The PAT system enabled visualization of the 3D features of blood vessels in the palm and noninvasive analysis of arterial tortuousness.

The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury.

Ischemia/reperfusion injury associated with organ retrieval and storage influences the development of chronic graft dysfunction, the major clinical problem in solid organ transplantation. The potential role of mononuclear cells (T cells and monocyte/macrophages) in this type of injury is unknown. Inbred male Lewis rats were uninephrectomized and the left kidney perfused in situ with 10 ml of iced University of Wisconsin solution. Immunohistological studies showed mononuclear cell infiltration of the ischemic organs associated with the upregulation of MHC class II antigen expression. Reverse transcriptase-PCR indicated that T cell associated cytokines and monocyte/macrophage activation markers/products are upregulated early after the ischemic insult. B7 expression occurred within 24 h and peaked at 3 d. Plasma creatinine levels rose transiently with complete recovery of renal function by 5 d. Animals began to develop progressive proteinuria after 8-12 wk, indicative of the long-term functional consequences of early ischemia/reperfusion injury. Blockade of T cell CD28-B7 costimulation with CTLA4Ig resulted in significant inhibition of T cell and macrophage infiltration and activation in situ. Treated animals did not exhibit transient renal dysfunction, nor developed proteinuria over time. This is the first demonstration that blocking T cell costimulatory activation in the absence of alloantigen can prevent the early and late consequences of ischemia/reperfusion injury.

The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand.

Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes. The initial (

Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates.

Recombinant adeno-associated viral (rAAV) vector-mediated overexpression of alpha-synuclein (alphaSyn) protein has been shown to cause neurodegeneration of the nigrostriatal dopaminergic pathway in rodents and primates. Using serotype-2 rAAV vectors, we recently reported the protective effect of Parkin on alphaSyn-induced nigral dopaminergic neurodegeneration in a rat model. Here we investigated the neuronal specificity of alphaSyn toxicity and the effect of Parkin co-expression in a primate model. We used another serotype (type-1) of AAV vector that was confirmed to deliver genes of interest anterogradely and retrogradely to neurons in rats. The serotype-1 rAAV (rAAV1) carrying alphaSyn cDNA (rAAV1-alphaSyn), and a cocktail of rAAV1-alphaSyn and rAAV1 carrying parkin cDNA (rAAV1-parkin) were unilaterally injected into the striatum of macaque monkeys, resulting in protein expression in striatonigral GABAergic and nigrostriatal dopaminergic neurons. Injection of rAAV1-alphaSyn alone decreased tyrosine hydroxylase immunoreactivity in the striatum compared with the contralateral side injected with a cocktail of rAAV1-alphaSyn and rAAV1-parkin. Immunostaining of striatonigral GABAergic neurons was similar on both sides. Overexpression of Parkin in GABAergic neurons was associated with less accumulation of alphaSyn protein and/or phosphorylation at Ser129 residue. Our results suggest that the toxicity of accumulated alphaSyn is not induced in non-dopaminergic neurons and that the alphaSyn-ablating effect of Parkin is exerted in virtually all neurons in primates.

Drug interactions between tacrolimus and phenytoin in Japanese heart transplant recipients: 2 case reports.

OBJECTIVE: The purpose of the study was to demonstrate how the interaction between phenytoin and tacrolimus (FK 506) can be managed clinically and to characterize the change in FK 506 levels after discontinuation of phenytoin in two Japanese heart transplant recipients with different dosing periods ofphenytoin. METHODS: A drug interaction between phenytoin and FK 506 was investigated in 2 patients. The concentration-dose ratios (CDR: trough blood FK 506 level (ng/ml)/FK 506 dose (mg/day) on the previous day) were calculated as an index of the induction of the CYP3A4 enzyme during and after phenytoin therapy. RESULTS: About 2- to 3-fold dosages of FK 506 were required to maintain the required blood level when phenytoin was used concomitantly in the two cases examined. The FK 506 dose was constant within 21 days after discontinuing phenytoin in Patient 1 who had 36 days of phenytoin therapy. In Patient 2 with 21-day phenytoin therapy, the FK 506 doses and CDR varied for 10 days after discontinuing phenytoin, and expected FK 506 C0 levels were achieved within 11 days. CONCLUSIONS: The persistence of CYP induction after discontinuing phenytoin is dependent on the history of administration and, perhaps, on the dosing period in particular.

A phoswich detector for high-energy neutrons.

A phoswich detector was developed to measure neutron energy spectra from a few MeV to a few hundreds MeV in aircrafts and space crafts. Radiation fields, which both crafts are exposured, consist of neutrons, gamma rays, protons, etc. The phoswich detector can measure neutrons separately from gamma rays and protons. The capability of particle discrimination was tested at HIMAC and was found to be excellent. Detector response functions to neutrons were simulated with the MCNPX code using the measured light outputs of charged particles and were measured with quasi-mono-energetic neutrons produced by the p-Li reaction at the NIRS cyclotron. Test flight measurements at high altitudes, 6.5 and 8.5 km, were performed above the middle part of Japan (cut-off rigidity, 12 GV).

Extension of applicable neutron energy of DARWIN up to 1 GeV.

The radiation-dose monitor, DARWIN, needs a set of response functions of the liquid organic scintillator to assess a neutron dose. SCINFUL-QMD is a Monte Carlo based computer code to evaluate the response functions. In order to improve the accuracy of the code, a new light-output function based on the experimental data was developed for the production and transport of protons deuterons, tritons, (3)He nuclei and alpha particles, and incorporated into the code. The applicable energy of DARWIN was extended to 1 GeV using the response functions calculated by the modified SCINFUL-QMD code.