Combined Social Frailty and Life-Space Activities Associated with Risk of Disability: A Prospective Cohort Study.

OBJECTIVES: To examine the association between social frailty and life-space activities, and determine whether a combined status of life-space activities and social frailty is associated with risk of disability among older adults. DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: The participants were 8,301 older adults (mean age 72.9 ± 5.6 years, women [53.3%]) from a community setting. METHODS: Life-space activities were evaluated using the Active Mobility Index (AMI) to assess activities in each life-space (distance from the respondent's home: up to 1 km, 1-10 km, or greater than 10 km) during the past 1 month. Activities were also assessed according to physical or social activity. Social frailty and characteristics were measured at the baseline. Incident disability was assessed according to long term care insurance. RESULTS: The lowest scoring group was based on the quartile in each of the AMI scores (Q1), with reference to the highest scoring group, which had a higher odds ratios for social frailty (AMI total score Q1: OR 4.32, 95% CI 3.43-5.45, AMI physical score Q1: 2.19, 95% CI 1.79-2.69, AMI social score Q1: 5.04, 95% CI 3.94-6.44). During the follow-up (mean 23.5 months), 330 participants had incident disability. Incident disability was associated with social frailty. Combined status of social frailty and low AMI increased the risk of disability (HR 2.15, 95% CI 1.52-3.03), with reference to non-frailty and higher AMI scores. CONCLUSIONS AND IMPLICATIONS: Social frailty or reduced activity in life-space assessment were identified as risk factors for incident disability. To decrease the risk of disability, the development of an intervention program to enhance activities and cope with social frailty is required.

Predictive Validity of Different Walking Measures to Identify the Incident Long-Term Care Needs in Older Adults.

OBJECTIVES: A comfortable walking speed is a suitable measurement of functional status in older adults. In addition to assessing their comfortable walking speed, two complex walking tests were administered to a cohort of older people, assuming that these tests would be a more sensitive predictor of the incident long-term care needs than comfortable walking speed. DESIGN: A prospective observational study was conducted to collect data. SETTING AND PARTICIPANTS: Among the initial 5,563 community-dwelling independent older adults (aged ≥ 65 years), 935 were excluded and the data of 4,628 (mean age, 73.9 ± 5.5 years, 65-94 years; 2,052 men, 2,576 women) older adults were finally analyzed. METHODS: Three walking tasks were administered: comfortable, complicated balance, and Go-stop walking. Complicated balance walking was measured under comfortable walking conditions, with participants having to walk with their hands crossed at the shoulder joint at 90°. For the Go-stop walking test, the time taken to walk 2 meters was measured using a stopwatch. For two years following baseline assessments, participants received monthly follow-ups for incident certification of the need for care under the long-term care insurance (LTCI) system. RESULTS: Low performance in comfortable, complicated balance, and Go-stop walking were 29.8%, 37.7%, and 35.1%, respectively. During the 24-month follow-up period, 246 participants (5.3%) required LTCI certification. The Youden Index was used to determine the cut-points of the incident long-term care needs in the comfortable, complicated balance, and Go-stop walking conditions, which were 1.055 m/s, 0.936 m/s, and 3.205 seconds, respectively. Participants classified as exhibiting low performance included 1,381 (29.8%) under comfortable walking, 1,746 (37.7%) under complicated balance walking, and 1,623 (35.1%) under the Go-stop walking tests. The C-indices of the comfortable, complicated balance, and Go-stop walking tests were 0.72 (95% confidence interval (CI) 0.69-0.76), 0.71 (95% CI 0.67-0.74), and 0.65 (95% CI 0.61-0.69), respectively. Cox proportional hazards regression model revealed significant relationships between the incident long-term care needs and the comfortable (hazard ratio (HR) 2.14, 95% CI 1.62-2.84), complicated balance (1.81, 1.36-2.41), and Go-stop (1.46, 1.12-1.91) walking conditions. CONCLUSIONS AND IMPLICATIONS: The findings suggest that slow walking speed has a considerably greater impact on the incident long-term care needs in older adults. However, the complex walking task did not improve the predictive performance. Comfortable walking speed tests, which can easily be measured to predict the future incident long-term care needs, are effective tools in community health promotion and primary care.

Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer.

BACKGROUND: We conducted comprehensive clinical and molecular characterization of claudin 18.2 expression (CLDN18.2) in advanced gastric or gastroesophageal junction cancer (GC/GEJC). PATIENTS AND METHODS: Patients with advanced GC/GEJC who received systemic chemotherapy from October 2015 to December 2019 with available tumor specimens were analyzed. We evaluated clinicopathological features of CLDN18.2 expression with four molecular subtypes: mismatch repair deficient, Epstein-Barr virus-positive, human epidermal growth factor receptor 2-positive, and others. In addition, programmed death-ligand 1 (PD-L1) combined positive score (CPS), genomic alterations, and the expression of immune cell markers were assessed. Clinical outcomes of standard first- or second-line chemotherapy and subsequent anti-programmed cell death protein 1 (anti-PD-1) therapy were also investigated according to CLDN18.2 expression. RESULTS: Among 408 patients, CLDN18.2-positive (moderate-to-strong expression in ≥75%) was identified in 98 patients (24.0%) with almost equal distribution in the four molecular subtypes or CPS subgroups. CLDN18.2-positive was associated with Borrmann type 4, KRAS amplification, low CD16, and high CD68 expression. Overall survival with first-line chemotherapy was not significantly different between CLDN18.2-positive and -negative groups [median 18.4 versus 20.1 months; hazard ratio 1.26 (95% confidence interval 0.89-1.78); P = 0.191] regardless of stratification by PD-L1 CPS ≥5. Progression-free survival and objective response rates of first- and second-line chemotherapy, and anti-PD-1 therapy also showed no significant differences according to CLDN18.2 status. CONCLUSIONS: CLDN18.2 expression in advanced GC/GEJC was associated with some clinical and molecular features but had no impact on treatment outcomes with chemotherapy or checkpoint inhibition. CLDN18.2-positive also had no impact on overall survival. This information could be useful to interpret the results from currently ongoing clinical trials of CLDN18.2-targeted therapies for advanced GC/GEJC and to consider a treatment strategy for CLDN18.2-positive GC/GEJC.

Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. PATIENTS AND METHODS: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. RESULTS: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. CONCLUSIONS: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.

Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study.

BACKGROUND: Pembrolizumab 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 METHODS: Eligible 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. RESULTS: Three 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). CONCLUSIONS: Pembrolizumab 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.

Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia.

BACKGROUND: In the randomized phase III KEYNOTE-181 study, pembrolizumab prolonged overall survival (OS) compared with chemotherapy as second-line therapy in patients with advanced esophageal cancer and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10. We report a post hoc subgroup analysis of patients with esophageal squamous cell carcinoma (ESCC) enrolled in KEYNOTE-181 in Asia, including patients from the KEYNOTE-181 China extension study. PATIENTS AND METHODS: Three hundred and forty Asian patients with advanced/metastatic ESCC were enrolled in KEYNOTE-181, including the China cohort. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200 mg every 3 weeks for ≤2 years or investigator's choice of paclitaxel, docetaxel, or irinotecan. OS, progression-free survival, response, and safety were analyzed without formal comparisons. OS was evaluated based on PD-L1 CPS expression level. RESULTS: In Asian patients with ESCC, median OS was 10.0 months with pembrolizumab and 6.5 months with chemotherapy [hazard ratio (HR), 0.63; 95% CI 0.50-0.80; nominal P < 0.0001]. Median progression-free survival was 2.3 months with pembrolizumab and 3.1 months with chemotherapy (HR, 0.79; 95% CI 0.63-0.99; nominal P = 0.020). Objective response rate was 17.1% with pembrolizumab and 7.1% with chemotherapy; median duration of response was 10.5 months and 7.7 months, respectively. In patients with PD-L1 CPS <1 tumors (pembrolizumab versus chemotherapy), the HR was 0.99 (95% CI 0.56-1.72); the HR (95% CI) for death was better for patients with PD-L1 CPS cut-offs >1 [CPS ≥1, 0.57 (0.44-0.75); CPS ≥5, 0.56 (0.41-0.76); CPS ≥10, 0.53 (0.37-0.75)]. Treatment-related adverse events were reported in 71.8% of patients in the pembrolizumab group and 89.8% in the chemotherapy group; grade 3-5 events were reported in 20.0% and 44.6%, respectively. CONCLUSIONS: Pembrolizumab monotherapy demonstrated promising efficacy in Asian patients with ESCC, with fewer treatment-related adverse events than chemotherapy. PD-L1 CPS ≥1 is an appropriate cut-off and a predictive marker of pembrolizumab efficacy in Asian patients with ESCC.

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.

Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study.

BACKGROUND: Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment. PATIENTS AND METHODS: Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety. RESULTS: Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups. CONCLUSIONS: This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.

Association between Sarcopenia, Its Defining Indices, and Driving Cessation in Older Adults.

OBJECTIVES: Driving a car is essential for older adults to support their activities of daily living and maintain their quality of life. However, physical function - which often declines with age - is a key factor to determine whether older adults can continue driving safely. As such, we sought to examine the association between sarcopenia and driving cessation in older adults. DESIGN: A prospective study. SETTING: A community setting. PARTICIPANTS: We conducted a study including 2,874 older adult participants from the community (mean age: 71.0 ± 4.7 years [range: 65-93 years], women: 36.3%). MEASUREMENTS: We assessed whether they were still driving at baseline examination as well as their degree of sarcopenia. Sarcopenia was assessed according to the clinical definition provided by the EWGSOP2 by measuring muscle mass, muscle strength, and physical performance represented by gait speed. Driving cessation was determined based on driving status at the initial visit and at a follow-up examination approximately 15 months later. RESULTS: At the baseline assessment, there were 62 participants (2.2%) with confirmed sarcopenia and 23 participants (0.8%) with severe sarcopenia. Participants were classified into either the ongoing driving (n = 2816) or driving cessation (n = 58) group. Low muscle strength and low muscle mass were associated with driving cessation (low muscle strength: odds ratio [OR] 2.09, 95% confidence interval [CI] 1.13-3.87; low muscle mass: OR 2.00, 95% CI 1.04-3.85). Slow gait was not associated with driving cessation (OR 1.35, 95% CI 0.68-2.69). Significantly, sarcopenia was associated with driving cessation (confirmed sarcopenia: OR 4.48, 95% CI 1.63-12.29; severe sarcopenia: OR 4.46, 95% CI 1.21-16.41). CONCLUSIONS: Sarcopenia is associated with an increased likelihood of driving cessation in community-dwelling older adults. Evaluation of physical function related to sarcopenia would be useful for judgment of the ability to drive safely among older adults.

Cognitive Frailty as a Risk Factor for Incident Disability During Late Life: A 24-Month Follow-Up Longitudinal Study.

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.

Possible Lightest Ξ Hypernucleus with Modern ΞN Interactions.

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.

Bone strength of the proximal femur in healthy subjects with ossification of the posterior longitudinal ligament.

We compared the bone strength measured via quantitative computed tomography-based finite element method (QCT/FEM) between healthy adults with and without ossification of the posterior longitudinal ligament (OPLL). No statistically significant difference was observed in the bone strength between healthy adults with and without OPLL. Hyperostosis of the posterior longitudinal ligament in OPLL may not be associated with the systemic bone strength. INTRODUCTION: Although patients with OPLL have been reportedly associated with increased level of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA), little is known about the bone strength in OPLL subjects. The aim of this study is to investigate the bone strength measured via QCT/FEM in healthy subjects with OPLL using the medical check-up data, including whole-body CT scans. METHODS: We examined 796 participants (529 men and 267 women) who underwent CT scans in a single health center between January 2008 and May 2009. We identified OPLL in whole spine and divided the subjects into two groups: non-OPLL and OPLL groups. We calculated the predicted bone strength (PBS) of the proximal femur using QCT/FEM and examined the bone mineral status of the calcaneus using quantitative ultrasound (QUS). We compared the PBS and the QUS parameters between the non-OPLL and OPLL groups. RESULTS: Seventy-four subjects (9.3%; 57 men and 17 women) were diagnosed with OPLL in the whole spine. The OPLL group was significantly older than the non-OPLL group. No statistically significant difference was observed in the PBS and the QUS parameters between the non-OPLL and OPLL groups in both sexes. Furthermore, no statistically significant difference was noted in the PBS and the QUS parameters between two groups in age- and gender-matched analysis. CONCLUSIONS: Our results suggest that hyperostosis of the posterior longitudinal ligament in OPLL may not be associated with bone strength and bone mineral status at the extremities.

Phase I trial of pimasertib monotherapy in Japanese patients with solid tumors and those with hepatocellular carcinoma.

PURPOSE: This study aimed to confirm the recommended phase II dose (RP2D) of pimasertib in Japanese patients. METHODS: This two-part, phase I dose-escalation and expansion study was conducted in Japanese patients (≥ 18 years old) with advanced solid tumors (ST) including hepatocellular carcinoma (HCC). In Part 1, patients with ST (Arm A) and HCC (Arm B) received escalating doses (3 + 3 design) of oral pimasertib [starting at 45 mg twice daily (BID)] in 21-day cycles, until disease progression or unacceptable toxicity. Dose levels could be escalated/de-escalated depending on tolerance. The primary outcome was the number of patients who experienced ≥ 1 dose-limiting toxicity (DLT). Safety and efficacy were also studied. Part 2 aimed to confirm observations in Part 1. RESULTS: In total, 26 patients (ST, n = 19; HCC, n = 7) were treated with pimasertib in Part 1: 30 mg (ST, n = 4; HCC, n = 5), 45 mg (ST, n = 9; HCC, n = 2), and 60 mg (ST, n = 6). Four patients reported DLTs [ST: hypokalemia (60 mg), and both stomatitis and muscle weakness (60 mg); HCC: retinal detachment (30 mg) and diarrhea (45 mg)]. All patients had ≥ 1 treatment-related adverse event. Partial response (n = 3) and stable disease (n = 1) were seen in patients with ST (pimasertib 45 mg). CONCLUSION: A maximum tolerated dose of pimasertib 45 mg BID was established in Japanese patients with ST, but not established in patients with HCC. The global RP2D of 60 mg BID was not confirmed in Japanese patients. Pimasertib monotherapy in unselected patients with ST may not warrant further investigation; Part 2 was not conducted.

Whitening Efficacy of Chewing Gum Containing Sodium Metaphosphate on Coffee Stain: Placebo-controlled, Double-blind In Situ Examination.

This study aimed to evaluate the ability of chewing gum containing sodium metaphosphate (SMP) to remove coffee stains from enamel in situ. This was a double-blind (subjects, evaluators), parallel-group, crossover, randomized clinical trial with 30 healthy adult volunteers. Each participant held an appliance with a hydroxyapatite (HA) pellet on the lower lingual side of his or her mouth for two hours to allow pellicle formation. The appliances were subsequently immersed in coffee solution at 37°C for 48 hours. The color of the HA pellet before and after coffee immersion was measured using a spectrophotometer. The participant set the appliance and chewed two pieces of test gum, which contained 7.5 mg of SMP per piece, or control gum without SMP. Each cycle included five minutes of exposure to chewing gum, after which the appliances were placed in 100% relative humidity at room temperature for a 30-minute incubation. This cycle was repeated five times for each gum type. The color of the HA pellet was measured after each chewing cycle using the spectrophotometer. In addition, ΔE* values, which indicate the change in pellet color after each chewing cycle compared with after coffee immersion, were calculated. Data were analyzed using the paired t-test with Bonferroni adjustment to compare ΔE* values of control and test gum after each chewing cycle. The ΔE* values of test gum were significantly higher than those of control gum after all chewing cycles, excluding the first cycle (p<0.05). This finding indicates that test gum containing SMP was more effective at removing coffee stains from the HA pellet than control gum. We conclude that chewing gum containing SMP can effectively remove coffee stains from HA pellets. Thus, SMP is a promising agent to be further explored in tooth-cleaning studies.

Associations of Skeletal Muscle Mass, Lower-Extremity Functioning, and Cognitive Impairment in Community-Dwelling Older People in Japan.

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.

Cognitive Frailty is Associated with Fall-Related Fracture among Older People.

OBJECTIVE: Cognitive frailty refers to cognitive impairment and physical frailty. Both cognitive impairment and physical frailty include risks of falling. The purpose of the study is to examine cognitive frailty and falling with/without a fracture. DESIGN: Cross-sectional observation study. SETTING: General communities in Japan. PARTICIPANTS: Data of 10,202 older adults aged ≥ 65 years were collected. MEASUREMENTS: Physical frailty was characterized as slow walking speed and/or muscle weakness. Assessment of cognitive function included word lists memory, attention, executive function, and processing speed. Cognitive impairment refers to one or more cognitive decline indicated by at least 1.5 standard deviations below the threshold after adjusting for age and education. We operationally defined cognitive frailty as having both cognitive impairment and physical frailty. Participants were interviewed about their falling, history of fall-related fractures, and several potentially confounding factors such as demographic characteristics. RESULTS: Multinomial logistic regression analysis revealed that functional decline in all groups, as compared to the robust group, was significantly associated with falling without fractures, after adjusting for the covariates; cognitive impairment group (P = .017), physical frailty group (P = .002), and cognitive frailty group (P < .001). Only the cognitive frailty group had a significant association with fall-related fracture after adjusting for the covariates (OR 1.92, 95% CI: 1.20-3.08, P = .007). CONCLUSION: Cognitive frailty is associated with not only falling but also fall-related fractures. Cognitive frailty may have a greater risk for fall-related fractures than cognitive impairment or physical frailty alone. Future research should examine causal the relationship between fall-related fractures and cognitive frailty.

Long and Short Sleep Duration and Physical Frailty in Community-Dwelling Older Adults.

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.