BACKGROUNDPembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced ...solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODSEligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTSThree hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% 95% confidence interval (CI) 25.8% to 36.2%. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONSPembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.
Objectives
To identify the relationships between physical and/or cognitive frailty and instrumental activities of daily living (IADL) functioning in community living older persons.
Design
Cross ...sectional observation study.
Setting
Data extracted from the 2011–2013 of the National Center for Geriatrics and Gerontology–Study of Geriatric Syndromes (NCGG-SGS) database.
Participants
A total of 8,864 older adults aged ≥ 65 years who were enrolled in the NCGG-SGS.
Measurements
We characterized physical frailty as limitations in three or more of the following five domains: slow walking speed, muscle weakness, exhaustion, low activity and weight loss. To screen for cognitive impairment, we used the National Center for Geriatrics and Gerontology-Functional Assessment Tool (NCGG-FAT) which included tests of word list memory, attention and executive function (tablet version of the Trail Making Test, part A and B), and processing speed (tablet version of the Digit Symbol Substitution Test). Two or more cognitive impairments indicated by an ageadjusted score of at least 1.5 standard deviations below the reference threshold was characterized as cognitive impairment. Each participant reported on their IADL status (use of public transportation, shopping, management of finances, and housekeeping) and several potential confounders such as demographic characteristics.
Results
The overall prevalence of physical frailty, cognitive impairment, and cognitive frailty, i.e. co-occurrence of frailty and cognitive impairment, was 7.2%, 5.2%, and 1.2%, respectively. We found significant relationships between IADL limitations and physical frailty (Odds Ratio (OR) 1.24, 95% confidence interval (95% CI) 1.01 to 1.52), cognitive impairment (OR 1.71, 95% CI 1.39 to 2.11), and cognitive frailty (OR 2.63, 95% CI 1.74 to 3.97).
Conclusion
Using the NCGG-SGS frailty criteria, we found more participants with physical frailty than with cognitive frailty. The individuals with cognitive frailty had the highest risks of IADL limitations. Future investigation is necessary to determine whether this population is at increased risk for incidence of disability or mortality.
Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and ...safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.
Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.
From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months 95% confidence interval (CI) 1.6-2.9 months with pimitespib versus 1.4 months (0.9-1.8 months) with placebo hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo HR 0.42 (0.21-0.85), one-sided P = 0.007. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.
Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.
•Pimitespib improved PFS compared with placebo in patients with previously treated advanced GIST.•OS was improved with pimitespib compared with placebo using the RPSFT model.•Exploratory pharmacogenomic analysis showed a benefit of pimitespib irrespective of KIT mutation status.•The safety profile of pimitespib was acceptable, and quality of life was not deteriorated by pimitespib compared with placebo.
This paper proposes a new quantum cellular automaton (quantum CA) for simulating macroscopic electromagnetic fields. The final target is to simulate the macroscopic electromagnetic fields on a ...quantum computer. In the proposal approach, Maxwell's historical model, which was explained the nature of electromagnetic fields in 1861, has been modified for a quantum CA model to simulate the electromagnetic fields. Then, a state transition rule for CA is determined by a strategy based on the quantum mechanics and the quantum computation theories. One of originalities of the proposed approach is that a system using quantum gates is superstructed to simulate magneto-static fields from currents. First, a modified Maxwell model for applying to quantum CA was shown. Second, by using the quantum computation theory, a quantum gate system to simulate the magnetic fields from currents was described. Finally, the proposed approach was applied to an example of magnetostatic field simulation.
Experimental evidence exists that the Ξ-nucleus interaction is attractive. We search for NNΞ and NNNΞ bound systems on the basis of the AV8 NN potential combined with either a phenomenological ...Nijmegen ΞN potential or a first principles HAL QCD ΞN potential. The binding energies of the three-body and four-body systems (below the d+Ξ and ^{3}H/^{3}He+Ξ thresholds, respectively) are calculated by a high precision variational approach, the Gaussian expansion method. Although the two ΞN potentials have significantly different isospin (T) and spin (S) dependence, the NNNΞ system with quantum numbers (T=0, J^{π}=1^{+}) appears to be bound (one deep for Nijmegen and one shallow for HAL QCD) below the ^{3}H/^{3}He+Ξ threshold. Experimental implications for such a state are discussed.
Objective
The objective of this study was to investigate whether older adults who have a particularly long sleep duration are likely to exhibit physical frailty, similar to those with a particularly ...short sleep duration.
Design
Cross-sectional study.
Setting
The National Center for Geriatrics and Gerontology – Study of Geriatric Syndromes.
Participants
A total of 9,824 older adults (mean age: 73.6 ± 5.5 years, 4,812 men and 5,012 women) met the entry criteria for this study.
Measurements
We divided the participants into three groups according to self-reported sleep duration (Short: ≤ 6 h, Mid: 6.1–8.9 h (control), Long: ≥ 9 h). Physical frailty was characterized based on the criteria from the Cardiovascular Health Study. Multinomial logistic regression analysis was performed to evaluate the effect of sleep duration on physical frailty by sex.
Results
Among all participants, the prevalence of physical frailty was higher in the Short (10.5%) and Long (17.9%) groups than in the Mid (7.4%) group (p < 0.001). Multinomial logistic regression analysis showed that both Short and Long groups had a significantly higher odds ratio (OR) for physical frailty than the Mid group Short: OR 1.53, 95% confidence interval (CI) 1.26–1.87; Long: OR 2.39, 95% CI 1.90–3.00, even after adjusting for age, educational level, number of medications, body mass index, Mini Mental State Examination score, current smoking and alcohol habits, self-perceived health, and medical history.
Conclusion
Both long and short sleep durations were associated with physical frailty. Further studies are required to confirm the effect of sleep duration on the incidence or worsening of physical frailty in older adults.
Objectives
Association between cognitive frailty as identified by a new operational definition and incident disability in the community setting remains unclear. This will be the catalyst for ...preventive interventions designed to treat adverse health problems among elderlies.
Design
A 24-month follow-up longitudinal study on a community-based cohort.
Setting
Community-setting.
Participants
Participants included a total of 9,936 older adults aged 65 years or older.
Measurements
Frailty was characterized as slow walking speed or/and muscle weakness represented by grip strength. Cognitive function was assessed according to several tests. Cognitive impairment was defined below the age-education reference threshold. Participants were categorized into the four groups: robust, cognitive impairment alone, frailty alone, and cognitive frailty (both frail and cognitive impairment). Incident disability data was extracted from the Japanese Long-Term Care system.
Results
The prevalence of cognitive frailty was 11.2%. The cumulative incidence rates of incident disability in each group were also estimated (robust, 9.6/1,000 person-years (95% CI 7.9 to 11.7); cognitive impairment, 21.3/1,000 person years (95% CI 16.3 to 27.7); frailty, 45.4/1,000 person years (95% CI 39.5 to 52.3); and cognitive frailty, 79.9/1,000 person years (95% CI 68.6 to 93.1)). Adjusted Cox proportional hazard model revealed that the cognitive frailty group had the highest hazard ratio (HR 3.86, 95%CI 2.95–5.05, P < 0.001).
Conclusions
A proper operational definition was developed to determine cognitive frailty among elderlies. Cognitive frailty is more associated with incident disability in community-setting than cognitive impairment or physical frailty alone.
A long‐term data synthesis experiment was conducted for the period 1957–2011 using a modified quasi‐global four‐dimensional variational data assimilation system that was originally developed to ...improve the representation of the deep ocean, including a unique method for anomaly assimilation. The overall characteristics of the resulting ocean state estimate, which is dynamically consistent without any artificial sources or sinks for heat and salt, are evaluated in the Pacific Ocean. It is shown that the data set better represents the comprehensive ocean state: the mean state of the water mass distribution and volume transport and components of temporal variability from the sea surface to the bottom on interannual to multidecadal timescales. This suggests that the data set can be used to examine interactions between temporal variations throughout the entire depth range and is useful for understanding ocean physics and its role in the climate system.
Key Points
A 55 year ocean state estimation data set is obtained using a 4D‐VAR system
This better represents the comprehensive ocean state over the entire depth range
The data set is useful for understanding ocean's role in climate system
Objective
We examined whether skeletal muscle mass and lower extremity functioning are closely associated with multiple cognitive domains, including global cognition, memory, attention, executive ...functioning, and processing speed, in community-dwelling older Japanese adults.
Design
A cross-sectional, population-based community study.
Setting
This study was conducted among community-living older people enrolled in the Obu Study of Health Promotion for the Elderly.
Participants
Participants comprised 5,104 adults (≥ 65 years, mean age: 71 years).
Measurements
Data from 4273 participants were analyzed. Appendicular skeletal muscle mass was estimated from bioelectrical impedance analysis and expressed as appendicular skeletal muscle mass index (ASMI). Lower-extremity functioning was assessed by the Five-Times-Sit-to-Stand test (FTSS) and Timed Up and Go test (TUG). Cognitive functions were assessed by the Mini Mental State Examination, word list memory, Trail Making Test parts A and B, and Symbol Digit Substitution Task. Logistic regression analysis were performed to calculate odds ratios (ORs) of cognitive impairment in various domains among skeletal muscle mass, lower-extremity functioning levels adjusted for important demographic variables, and comorbidities.
Results
Participants with lower ASMI and slower FTSS and TUG groups had lower cognitive functioning scores than did participants with higher ASMI and faster FTSS and TUG. The slowest quartiles (Q4) of FTSS and TUG were significantly associated with impaired global functioning (MMSE score < 24) compared to the fastest quartile (Q1) after multivariate adjustment (FTSS, OR = 1.46, 95% confidence interval (CI) = 1.12–1.90; TUG, OR = 1.65, 95% CI = 1.25–2.17). In other dimensions of cognitive functioning, FTSS and TUG were significantly associated with all cognitive impairment in the full adjustment model.
Conclusion
Lower-extremity functioning, rather than skeletal muscle mass, is closely related to multiple cognitive domains. This study suggests that maintaining lower-extremity functioning, rather than skeletal muscle mass, may be required for detecting and preventing cognitive impairment.
The 2018 tropical cyclone (TC) season in the North Pacific was very active, with 39 tropical storms including eight typhoons/hurricanes. This activity was successfully predicted up to 5 months in ...advance by the Geophysical Fluid Dynamics Laboratory Forecast‐Oriented Low Ocean Resolution (FLOR) global coupled model. In this work, a suite of idealized experiments with three dynamical global models (FLOR, Nonhydrostatic Icosahedral Atmospheric Model, and Meteorological Research Institute Atmospheric General Circulation Model) was used to show that the active 2018 TC season was primarily caused by warming in the subtropical Pacific and secondarily by warming in the tropical Pacific. Furthermore, the potential effect of anthropogenic forcing on the active 2018 TC season was investigated using two of the global models (FLOR and Meteorological Research Institute Atmospheric General Circulation Model). The models projected opposite signs for the changes in TC frequency in the North Pacific by an increase in anthropogenic forcing, thereby highlighting the substantial uncertainty and model dependence in the possible impact of anthropogenic forcing on Pacific TC activity.
Plain Language Summary
The potential causes of the active 2018 tropical cyclone season in the North Pacific were explored with a series of high‐resolution climate model experiments, revealing that this active cyclone season was mainly induced by subtropical Pacific warming and secondarily by tropical Pacific warming. The possible effect of anthropogenic forcing on the active cyclone season was also investigated. However, diverse results were obtained regarding projected changes in storm frequency in the case of an increase in anthropogenic forcing, thereby highlighting the substantial uncertainty in the possible impact of anthropogenic forcing on the 2018 active cyclone season.
Key Points
The 2018 active tropical cyclone season in the North Pacific was successfully predicted 5 months in advance
The subtropical Pacific warming in 2018 mainly caused the active storm season in the North Pacific
The potential effect of anthropogenic forcing on the 2018 active storm season is uncertain
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