The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Cross-Sectional and Longitudinal Associations of Creatinine-to-Cystatin C Ratio with Sarcopenia Parameters in Older Adults.

OBJECTIVES: Accumulating evidence from cross-sectional studies suggests that the serum creatinine-to-cystatin C ratio (CCR) may be a useful biomarker for sarcopenia. This study aimed to assess the cross-sectional and longitudinal associations of CCR with sarcopenia and its parameters in community-dwelling older adults. DESIGN: Cross-sectional and longitudinal study. SETTING AND PARTICIPANTS: This 6-year prospective cohort study included the repeated measurement data from 1,253 Japanese residents (662 males and 591 females) aged ≥65 years who underwent medical checkups in Kusatsu and Hatoyama, Japan. A total of 4,421 observations were collected. MEASUREMENTS: The CCR was grouped into quartiles by sex (Q1-Q4) using Q4 as the reference category. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019 algorithm. Skeletal muscle mass index (SMI) measured using segmental multifrequency bioelectrical impedance analysis, handgrip strength (HGS), usual gait speed (UGS), and maximal gait speed (MGS) were measured repeatedly as sarcopenia parameters. The association of the CCR with changes in sarcopenia, SMI, HGS, UGS, and MGS during the 6-year period were analyzed using a generalized linear mixed-effects model. RESULTS: The prevalence of sarcopenia at baseline was 13.1% (11.9% in males and 14.5% in females). In a cross-sectional analysis, the CCR quartile was inversely associated with sarcopenia and was positively associated with SMI, HGS, and MGS (P for trend < 0.001). In a longitudinal analysis during the 6 years, a significant increase in sarcopenia in Q2 (B = 1.1% point/year; P = 0.026 for group-by-time interaction) and significant declines in SMI (B = -0.01 kg/m2/year; P = 0.044 for group-by-time interaction) and MGS (B = -0.008 m/sec/year; P = 0.041 for group-by-time interaction) in Q1 were observed compared with Q4. However, the dose-response relationship was significant only for MGS (P = 0.033 for trend). No significant group-by-time interaction was observed for HGS. CCR was not significantly associated with UGS either cross-sectionally or longitudinally. CONCLUSIONS: CCR is a useful biomarker regarding the status of sarcopenia. It may be used for sarcopenia screening even in older adults whose physical function is difficult to assess. However, further longitudinal studies are needed to determine whether CCR can be a predictor of future sarcopenia.

Electrically driven europium-doped GaN microdisk.

For the practical implementation of microdisk resonators as active nanophotonic devices, it is essential that they can be electrically driven. However, it is difficult to inject current in such small-scale devices without severely degrading their optical properties. We demonstrate the successful fabrication of an electrically injected microdisk based on Eu-doped GaN, in which an SiO2 spacer is used to prevent the interaction of the metal contact with the optical resonances. The microdisk shows Eu-related emission upon electrical injection and from the observed resonance peak, a cavity quality (Q)-factor of 3400 is concluded.

Occupational Fall Risk Assessment Tool for older workers.

BACKGROUND: No easy-to-use fall risk assessment tools have been devised to assess occupational fall risk in older workers. AIMS: To develop an Occupational Fall Risk Assessment Tool (OFRAT) and report its predictive validity and reliability in older workers. METHODS: The baseline fall risk assessment was completed by 1113 participants aged ≥60 years who worked ≥4 days/month in Saitama, Japan. Participants were followed up for falls during occupational activities for 1 year, and 30 participants were assessed twice for test-retest reliability. The following assessment measures were summed to form the OFRAT risk score: older age, male sex, history of falls, physical work participation, diabetes, use of medications increasing fall risk, reduced vision, poor hearing, executive dysfunction and slow stepping. The scores were then classified into four grades (0-2 points: very low, 3 points: low, 4 points: moderate and ≥5 points: high). RESULTS: During follow-up, 112 participants fell 214 times during work. The negative binomial regression model showed that participants with higher grades had a higher incidence rate ratio [95% confidence interval] for falls than those with very low grades (low: 1.64 [1.08-2.47], moderate: 4.23 [2.82-6.34] and high: 6.12 [3.83-9.76]). The intraclass correlation coefficient for risk score was 0.86 [0.72-0.93], and the weighted kappa coefficient for grade assessment was 0.74 [0.52-0.95]. CONCLUSIONS: The OFRAT is a valid and reliable tool for estimating the occupational fall risk in older workers. It may assist occupational physicians implement strategies to prevent falls in this group.

Interaction of Eating Status and Dietary Variety on Incident Functional Disability among Older Japanese Adults.

OBJECTIVES: To examine whether eating status and dietary variety were associated with functional disability during a 5-year follow-up analysis of older adults living in a Japanese metropolitan area. DESIGN: A 5-year follow-up study. SETTING: Ota City, Tokyo, Japan. PARTICIPANTS: A total of 10,308 community-dwelling non-disabled adults aged 65-84 years. MEASUREMENTS: Eating status was assessed using a self-reported questionnaire. Dietary variety was assessed using the dietary variety score (DVS). Based on the responses, participants were classified according to eating alone or together and DVS categories (low: 0-3; high: 4-10). Functional disability incidence was prospectively identified using the long-term care insurance system's nationally unified database. Multilevel survival analyses calculated the adjusted hazard ratio (HR) and 95% confidence interval (CI) for incident functional disability. RESULTS: During a 5-year follow-up, 1,991 (19.3%) individuals had functional disabilities. Eating status or DVS were not independently associated with incident functional disability. However, interaction terms between eating status and DVS were associated with functional disability; HR (95% CI) for eating together and low DVS was 1.00 (0.90-1.11), eating alone and high DVS was 0.95 (0.77-1.17), and eating alone and low DVS was 1.20 (1.02-1.42), compared to those with eating together and high DVS. CONCLUSION: Older adults should avoid eating alone or increase dietary variety to prevent functional disability. This can be ensured by providing an environment of eating together or food provision services for eating a variety of foods in the community.

Difference between "Physical Fitness Age" Based on Physical Function and Chronological Age Is Associated with Obesity, Hyperglycemia, Depressive Symptoms, and Low Serum Albumin.

OBJECTIVES: This study aimed to (1) develop the physical fitness age, which is the biological age based on physical function, (2) evaluate the validity of the physical fitness age for the assessment of sarcopenia, and (3) examine the factors associated with the difference between physical fitness age and chronological age. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Community-dwelling older adults and outpatients. MEASUREMENTS: A formula for calculating the physical fitness age was created based on the usual walking speed, handgrip strength, one-leg standing time, and chronological age of 4,076 older adults from the pooled data of community-dwelling and outpatients using the principal component analysis. For the validation of the physical fitness age, we also used pooled data from community-dwelling older adults (n = 1929) and outpatients (n = 473). Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 consensus. The association of D-age (the difference between physical and chronological ages) with cardiovascular risk factors, renal function, and cardiac function was examined. RESULTS: The receiver operating characteristic analysis, with sarcopenia as the outcome, showed that the area under the curve (AUC) of physical fitness age was greater than that of chronological age (AUC 0.87 and 0.77, respectively, p < 0.001). Binomial logistic regression analysis revealed that the D-age was significantly associated with sarcopenia after adjustment for covariates (odds ratio 1.22, 95% confidence interval 1.19-1.26; p <0.001). In multivariate linear regression analysis with D-age as the dependent variable, D-age was independently associated with a history of diabetes mellitus (or hemoglobin A1c as a continuous variable), obesity, depression, and low serum albumin level. D-age was also correlated with estimated glomerular filtration rate derived from serum cystatin C, brain natriuretic peptide, and ankle-brachial index, reflecting some organ function and arteriosclerosis. CONCLUSIONS: Compared to chronological age, physical fitness age calculated from handgrip strength, one-leg standing time, and usual walking speed was a better scale for sarcopenia. D-age, which could be a simple indicator of physical function, was associated with modifiable factors, such as poor glycemic control, obesity, depressive symptoms, and malnutrition.

The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-Month, Multicenter, Randomized, Controlled Trial.

BACKGROUND/OBJECTIVES: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. DESIGN/SETTING: Eighteen-month, multi-centered, randomized controlled trial. PARTICIPANTS: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. INTERVENTION: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. MEASUREMENTS: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. CONCLUSIONS: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.

Outcome of neoadjuvant treatment for pancreatic cancer in elderly patients: comparative, observational cohort study.

BACKGROUND: Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. METHODS: This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70-74, 75 or more years) and respective treatment outcomes were compared. RESULTS: The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70-74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70-74 years, and 12 of 34 aged 75 years or more; P < 0.001). Resectability was similar among the three groups (60.0, 58.3, and 55.9 per cent respectively; P = 0.919). Trends towards shorter survival were observed in the elderly (median overall survival time 23.6, 18.0, and 17.6 months for patients aged less than 70, 70-74, and 75 or more years respectively; P = 0.090). After adjusting for co-variables, age was not a significant predictive factor. CONCLUSION: The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

Efficacy of Paclitaxel-based Chemotherapy After Progression on Nivolumab for Head and Neck Cancer.

BACKGROUND/AIM: In the CheckMate-141 trial regarding head and neck cancer (HNC), nivolumab conferred a survival benefit to patients. However, the best treatment sequence of chemotherapy and anti-PD-1/PD-L1 therapy in these cancers is unclear. PATIENTS AND METHODS: This was an observational study using data collected prospectively from 97 HNC patients treated with nivolumab at our institutions. Twenty-two HNC patients who received paclitaxel-based chemotherapy before (pre-PTX, n=12) and after (post-PTX, n=10) nivolumab were evaluated. RESULTS: The median follow-up time was 15.9 months (range=6.9-35.9 months). There was a significant difference in the overall response rate (ORR) between pre-PTX (17%) and post-PTX (70%) (p=0.027). Similarly, time to progression (TTP) was significantly longer after nivolumab than before nivolumab (post-PTX, 7.4 months; pre-PTX, 4.9 months, p=0.020). CONCLUSION: Paclitaxel-based chemotherapy had a better ORR and TTP after nivolumab than before nivolumab for HNC. The sequential administration of anti-PD-1 therapy followed by paclitaxel-based chemotherapy could be a better strategy for HNC.

Neutron-induced signal on the single crystal chemical vapor deposition diamond-based neutral particle analyzer.

A diamond-based neutral particle analyzer (DNPA) array composed of single-crystal chemical vapor deposition (sCVD) diamond detectors was installed on the Large Helical Device (LHD) for measuring the helically trapped energetic particles. In high neutron flux experiments, the unwanted neutron-induced pulse counting rate should be estimated using the neutron diagnostics because a diamond detector is sensitive to neutrons as well as energetic neutral particles. In order to evaluate the quantitative neutron-induced pulse counting rate on the DNPA, the response functions of the sCVD diamond detector for mono-energetic neutrons were obtained using accelerator-based D-D and D-7Li neutron sources in Fast Neutron Laboratory (FNL). As a result of the neutron flux estimation by the Monte Carlo N-Particle code at the NPA position in the LHD and the response function obtained in the FNL experiment, the counting rate of the neutron-induced signal was predicted to be 1.1 kcps for the source neutron emission rate of Sn = 1 × 1015 n/s. In the LHD experiment, the neutron-induced signals were observed by closing the gate valve during the plasma discharges. It is found that the counting rates of the neutron-induced signals proportional to Sn reached 1.1 kcps at Sn = 1 × 1015 n/s. As a result of the quantitative estimation of the neutron-induced signals on the DNPA using other neutron measurements, it has become possible to accurately measure energetic neutral particles in the high neutron flux experiment.

Performance of the newly installed vertical neutron cameras for low neutron yield discharges in the Large Helical Device.

Two new vertical neutron cameras characterized by high detection efficiency were developed on the Large Helical Device in order to observe poloidal structures of helically trapped beam ions created by the perpendicularly injected positive-ion based neutral beam (P-NB) and are newly operated since 2018. In this work, the neutron fields at the vertical neutron cameras are investigated using the Monte Carlo N-particle transport code to evaluate the performance of its collimators. The results indicate that neutrons are attenuated by the heavy concrete and are well collimated through the collimator to detectors. Neutron spectra at the detector position show over 99% of uncollided 2.45 MeV neutrons. Time evolution of neutron emission profiles during the short pulse of P-NB injection is measured by the vertical neutron cameras. Peaks on the neutron emission profiles corresponding to the helically trapped beam ion are successfully obtained, as designed. The decrease in line integrated neutron flux at the peak positions after the P-NB stops is consistent with the behavior of the total neutron emission rate measured by the neutron flux monitor.

Neutrophil-to-Lymphocyte Ratio as a Prognostic Marker for Anaplastic Thyroid Cancer Treated With Lenvatinib.

BACKGROUND/AIM: Lenvatinib is one of the few options for patients with anaplastic thyroid cancer (ATC). However, tumor markers for ATC treated with lenvatinib is lacking. The aim of this study was to explore whether the neutrophil-to-lymphocyte ratio (NLR) can be a tumor marker for ATC treated with lenvatinib. PATIENTS AND METHODS: We retrospectively analyzed the prognostic significance of the NLR in 13 ATC patients treated with lenvatinib. RESULTS: The disease control rate was better in patients with lower NLR (<8; 89%) than higher NLR (≥8; 25%) (p=0.05). Median progression-free survival and overall survival were longer in patients with lower NLR than higher NLR (4.0 vs. 1.6 months, p<0.05; and 10.2 vs. 3.8 months, p<0.05, respectively). Patients whose NLR on day 14 decreased compared to baseline had a slightly higher overall response rate than patients without NLR decrease (42.9% vs. 0%, p=0.19). CONCLUSION: The baseline NLR is a potential prognostic marker, and the change of NLR can be an early indicator of response for ATC patients treated with lenvatinib.

Size dependence of quantum efficiency of red emission from GaN:Eu structures for application in micro-LEDs.

GaN-based micro-LEDs typically suffer from a size-dependent efficiency due to the relatively long carrier lifetime and sidewall-related recombination effects. We demonstrate that for red-emitting Eu-doped GaN, sidewall-related recombination is hardly an issue for emission efficiency. We determine the photoluminescence quantum efficiency (PL QE) of Eu-related emission as a function of the size of square structures ranging from 3 to 192 µm. With the support of finite-difference time-domain simulations, we show that the light extraction efficiency and material losses are responsible for the decrease in PL QE for large sizes. For sizes smaller than 24 µm, there is an influence of the sidewall-related non-radiative recombination of carriers on the PL QE; however, it is only minor as a result of the limited carrier diffusion lengths in the Eu-doped material. These properties combined with the high efficiency of luminescence indicate the potential of this material for micro-LED applications.

Study of correlation between plasma parameter and beam optics.

Simultaneous measurement of negative ion source plasma and extracted beam is carried out in order to clarify a key plasma parameter governing the meniscus formation in negative ion sources for fusion. The plasma discharge is performed with various discharge powers at different bias voltages in order to vary the plasma parameters. It is shown that the beam width changes along the same curve with respect to the negative ion density at any bias voltage while it varies along different curves with other plasma parameters depending on the bias voltage. This implies that the mechanism of meniscus formation in negative ion sources could be described along the similar manner as positive ion sources.

Transition between Isotope-Mixing and Nonmixing States in Hydrogen-Deuterium Mixture Plasmas.

The transition between isotope-mixing and nonmixing states in hydrogen-deuterium mixture plasmas is observed in the isotope (hydrogen and deuterium) mixture plasma in the Large Helical Device. In the nonmixing state, the isotope density ratio profile is nonuniform when the beam fueling isotope species differs from the recycling isotope species and the profile varies significantly depending on the ratio of the recycling isotope species, although the electron density profile shape is unchanged. The fast transition from nonmixing state to isotope-mixing state (nearly uniform profile of isotope ion density ratio) is observed associated with the change of electron density profile from peaked to hollow profile by the pellet injection near the plasma periphery. The transition from nonmixing to isotope-mixing state strongly correlates with the increase of turbulence measurements and the transition of turbulence state from TEM to ion temperature gradient is predicted by gyrokinetic simulation.

Spatial distribution of negative ion density near the plasma grid.

Density distributions of negative hydrogen (H-) ions and negative deuterium (D-) ions were measured with the laser photodetachment method in the extraction region of the negative ion source. The distribution of H- ion density peaks at the center of the ion source, while that of the D- ion shows a flatter profile in the direction parallel to the plasma grid. The positive ion densities of hydrogen and deuterium estimated from the positive saturation current indicate similar profiles with different amounts close to the grid. The difference in the H- ion and D- ion distributions can be explained by the difference in the negative ion yield and the survival probability of the ions due to the isotope effect.

Extension of high power deuterium operation of negative ion based neutral beam injector in the large helical device.

Second deuterium operation of the negative ion based neutral beam injector was performed in 2018 in the large helical device. The electron and ion current ratio improves to Ie/Iacc(D) = 0.31 using the short extraction gap distance of 7 mm between the plasma grid (PG) and the extraction grid (EG). The strength of the magnetic field by the electron deflection magnet installed in the EG increases by 17% at the PG ingress surface, which effectively reduces the electron component in the negative ion rich plasma in the vicinity of PG apertures. The reduction of the electron current made it possible to operate at a high power arc discharge and beam extraction. Then, the deuterium negative ion current increases to 55.4 A with the averaged current density of 233 A/m2. The thermal load on the EG using 7 mm gap distance is 0.6 times smaller than the thermal load using a 8 mm gap caused by the reduction of coextracted electron current. The injection beam power increases to 2.9 MW in the beam line BL3, and the total beam injection power increases to 7 MW by three beam lines in the second deuterium campaign.

Measurements of radial profile of hydrogen and deuterium density in isotope mixture plasmas using bulk charge exchange spectroscopy.

A bulk charge exchange spectroscopy system has been applied to measure the radial profiles of the hydrogen (H) and deuterium (D) density ratio in the isotope mixture plasma in a large helical device. Charge exchange lines of Hα and Dα are fitted by 4 Gaussian of H and D cold components and H and D hot components with 5 parameters by combining the measurement of plasma toroidal rotation velocity with carbon charge exchange spectroscopy. The radial profiles of the relative density of hydrogen and deuterium ions are derived from H and D hot components measured and the beam density calculated from beam attenuation calculation. A proof-of-principle experiment is performed by the H pellet and the D pellet injections into the H-D mixture plasma.