Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma.

BACKGROUND & AIMS: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA). METHODS: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance mutations in the mitogen-activated protein kinase (MAPK) pathway were introduced to assess their effect on sensitivity to FGFRi in vitro. RESULTS: On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, new FGFR2 mutations were detected in 11 (64.7%) and new alterations in MAPK pathway genes in nine (52.9%) patients, with seven (41.2%) patients developing new alterations in both the FGFR2 and MAPK pathways. In serially collected plasma samples, a patient treated with an irreversible FGFRi tested positive for previously undetected BRAF V600E, NRAS Q61K, NRAS G12C, NRAS G13D and KRAS G12K mutations upon progression. Introduction of a FGFR2-BICC1 fusion into biliary tract cells in vitro sensitized the cells to FGFRi, while concomitant KRAS G12D or BRAF V600E conferred resistance. MEK inhibition was synergistic with FGFRi in vitro. In an in vivo animal model, the combination had antitumor activity in FGFR2 fusions but was not able to overcome KRAS-mediated FGFRi resistance. CONCLUSIONS: These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi. CLINICAL TRIAL NUMBER: NCT02052778. IMPACT AND IMPLICATIONS: We evaluated tumors and plasma from patients who previously received inhibitors of fibroblast growth factor receptor (FGFR), an important receptor that plays a role in cancer cell growth, especially in tumors with abnormalities in this gene, such as FGFR fusions, where the FGFR gene is fused to another gene, leading to activation of cancer cell growth. We found that patients treated with FGFR inhibitors may develop mutations in other genes such as KRAS, and this can confer resistance to FGFR inhibitors. These findings have several implications for patients with FGFR2 fusion-positive tumors and provide mechanistic insight into emerging MAPK pathway alterations which may serve as a therapeutic vulnerability in the setting of acquired resistance to FGFRi.

Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment. Here, we show that futibatinib, an irreversible pan-FGFR inhibitor, inhibits the growth of RMS cell lines in vitro by inhibiting phosphorylation of FGFR4 and its downstream targets. Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. However, in RMS xenograft models, futibatinib monotherapy and combination treatment have limited efficacy in delaying tumor growth and prolonging survival. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.

Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1-4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I-III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.

Phase I study of the irreversible fibroblast growth factor receptor 1-4 inhibitor futibatinib in Japanese patients with advanced solid tumors.

This phase I study was designed to: (1) determine the maximum tolerated dose (MTD) and recommended dose (RD) of the fibroblast growth factor receptor (FGFR) inhibitor futibatinib in Japanese patients with advanced solid tumors, and (2) examine the antitumor activity of the RD in patients with gastric cancer (GC) or other advanced solid tumors who have FGFR or FGF/FGFR abnormalities, respectively. In the dose-escalation phase, patients were assigned to 21-day cycles of oral futibatinib 8-160 mg three times a week (TIW) or 16 or 20 mg once daily (QD). In the expansion phase, patients received oral futibatinib 56, 80, or 120 mg TIW, or 16 or 20 mg QD. Eighty-three patients received futibatinib TIW (n = 40) or QD (n = 43). No dose-limiting toxicities were observed according to the final study protocol definition, and the MTD was not reached. The most common adverse events with both regimens were hyperphosphatemia (TIW, 82.5%; QD, 100.0%) and decreased appetite (TIW, 40.0%; QD, 58.1%). Hyperphosphatemia was asymptomatic, not leading to futibatinib discontinuation. The overall response rate (ORR) was 11.5% in patients with FGF/FGFR abnormalities. Notably, in GC patients harboring FGFR2 copy number (CN) ≥10, the ORR was 36.4% versus 0 in patients with CN <10. Therefore, futibatinib had a generally predictable and manageable safety profile in patients with advanced solid tumors. Antitumor activity was seen in patients with FGF/FGFR abnormalities, particularly those with GC and high FGFR2 CNs. Thus, futibatinib 20 mg QD was chosen as the RD for phase II studies.

Neighbourhood transportation, elapsed years, and well-being after surrendering the driver's licence in older Japanese adults: The JAGES longitudinal study.

This study aimed to examine how the associations between surrendering driving licence and changes in self-rated health and social interactions among older adults differ by the years elapsed since surrendering and the number of public transportation systems (PTS) in the neighbourhood. We used the 2013 and 2016 survey data from the Japan Gerontological Evaluation Study targeting residents aged ≥65 years in 30 municipalities in Japan. Two-waves longitudinal data from 4894 older adults were evaluated. Based on the difference-in-differences method, the interaction terms of respondents' driving status, which was the categorical exposure variable representing respondents' driving status for three years during the study period, and a dummy variable of year (2016) were used as explanatory variables in logistic regression analyses to examine changes in outcomes (poor self-rated health and infrequent meeting with friends) between 2013 and 2016 by driving status during this period. Analyses were stratified based on neighbourhood PTS ('more PTS' and 'fewer PTS' groups). We found that, while surrendering licence within three years was associated with increased probability of poor self-rated health in more PTS group, the confidence interval was large. Although surrendering licence within three years was associated with decreased social interactions, this association weakened if licence was surrendered more than three years ago. These associations were not markedly affected by neighbourhood PTS. Our findings suggested that, regardless of neighbourhood PTS, support and care to promote social interactions at or shortly after surrendering licence may be beneficial to the well-being of older adults who lost their driving licence.

[Differences in risk of requiring care between screening using queries with and without definitions when determining frequency of going out].

Objectives　This study elucidates the differences in risk for a functional decline in general housebound screening using queries with and without definitions.Methods　This study involved 10,802 community-dwelling older people who lived in four municipalities in Aichi Prefecture. The participants were asked about their frequency of going out in general and for five specific purposes: shopping, hospital visitation, strolling, leisure, and work. A person was defined as being "generally housebound" if he/she answered "less than once per week." However, a query with the definition of "going out" was used in only one of the four municipalities. Furthermore, we defined a person who goes out once a week, for any of the purposes, as "by-purpose non-housebound." If the response to the general and purpose-specific queries were inconsistent, we regarded it as an "inconsistent answer." Additionally, we compared the occurrence rate and hazard ratio for the onset of long-term care insurance certification of general housebound screening using queries with and without definition. We also calculated the occurrence rate and related risk factors for inconsistent answers.Results　The occurrence rate of general housebound screening using query with and without definition was 2.8% and 11.7%, respectively. Additionally, the hazard ratio for the onset of long-term care insurance certification of general housebound screening using the query with definition was 1.56 times more than that of general housebound screening using query without definition. The rate of inconsistent answers in by-purpose non-housebound using query with and without definition was 2.2% and 10.2%, respectively. However, sex, age, living with spouse and child(ren), years of schooling, self-rated health, depression, habitation in islands, and indicating definition of "going out" were related to inconsistent answers. The prevalence ratio of inconsistent answers in respondents using query with definition was significantly lower than among respondents using query without definition (PR=0.29).Conclusion　Query with definition reduced the occurrence rate of general housebound and increased the hazard ratio for the onset of long-term care insurance certification. Therefore, a definition should be added to queries asking for the frequency of going out to screen for housebound.

Physical Activity and Cumulative Long-Term Care Cost among Older Japanese Adults: A Prospective Study in JAGES.

This study aimed to determine the impact of physical activity on the cumulative cost of long-term care insurance (LTCI) services in a cohort of community-dwelling people (65 years and older) in Japan. Using cohort data from the Japan Gerontological Evaluation Study (JAGES) on those who were functionally independent as of 2010/11, we examined differences in the cumulative cost of LTCI services by physical activity. We followed 38,875 participants with LTCI service costs for 59 months. Physical activity was assessed by the frequency of going out and time spent walking. We adopted a generalized linear model with gamma distribution and log-link function, and a classical linear regression with multiple imputation. The cumulative LTCI costs significantly decreased with the frequency of going out and the time spent walking after adjustment for baseline covariates. LTCI's cumulative cost for those who went out once a week or less was USD 600 higher than those who went out almost daily. Furthermore, costs for those who walked for less than 30 min were USD 900 higher than those who walked for more than 60 min. Physical activity among older individuals can reduce LTCI costs, which could provide a rationale for expenditure intervention programs that promote physical activity.

TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, ß-Catenin, and TRK pathways.

Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC50 value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC50 value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.

Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors.

FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing. SIGNIFICANCE: Preclinical characterization of futibatinib, an irreversible FGFR1-4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.

Aurora A Inhibitor TAS-119 Enhances Antitumor Efficacy of Taxanes In Vitro and In Vivo: Preclinical Studies as Guidance for Clinical Development and Trial Design.

TAS-119 is a novel orally active, selective inhibitor of Aurora kinase A identified as a clinical candidate for efficacy testing in combination with taxanes. In vitro, TAS-119 enhanced cell growth inhibition of paclitaxel in multiple human cancer cell lines derived from various tissues, including paclitaxel-resistant cell lines. Interestingly, TAS-119 did not enhance paclitaxel antitumor activity in normal lung diploid fibroblast cell lines WI-38 and MRC5. In vivo, TAS-119 enhanced the antitumor efficacy of paclitaxel and docetaxel in multiple models at doses inhibitory to Aurora A in tumors. Moreover, the drug combination was well tolerated, and TAS-119 did not exaggerate clinically documented side effects of taxanes, neutropenia and neurotoxicity, in rats. The same TAS-119 concentration enhanced the cell growth inhibitory activity of three clinically approved taxanes, paclitaxel, docetaxel, and cabazitaxel. The degree of enhancement calculated as fold of change of the IC50 value for each taxane was almost the same among the three taxanes. We conducted in vitro and in vivo experiments to develop an optimized combination therapy regimen for TAS-119 with paclitaxel/docetaxel. Using in vitro and in vivo models, we tested the drug administration order for TAS-119 combined with paclitaxel and the TAS-119 treatment duration. The best regimen in preclinical models was combining paclitaxel or docetaxel treatment with 4 days of TAS-119 dosing, which was initiated on the same day as the paclitaxel or docetaxel administration or one day later. This information provided guidance for the design of a clinical trial of TAS-119 and paclitaxel or docetaxel combination.

The Risk of Functional Limitations After Driving Cessation Among Older Japanese Adults: The JAGES Cohort Study.

BACKGROUND: Population ageing and stringent licensing policies will increase the number of older drivers who stop driving. Adverse health outcomes owing to driving cessation and their prevention are emerging concerns. Therefore, we longitudinally examined the impact of driving cessation and alternative transportation use after cessation on the risk of functional limitations in a cohort of community-dwelling people (65 years and older) in Japan. METHODS: Using cohort data of those who drove as of 2006/07, we compared the risk of functional limitations between 2,704 current drivers and 140 former drivers (who stopped driving by 2010). Of the former drivers, 77 did not use public transportation or bicycles after driving cessation (thus losing independent mobility). We calculated the hazard ratios (HRs) for the incidence of functional limitations with 95% confidence intervals (CIs) based on the Cox proportional hazards model with the covariates influencing the functional limitations. RESULTS: From 2010 through 2016, 645 people had functional limitations, which included 38, 82, and 119 per 1,000 person-years among current drivers, former drivers who used public transportation or bicycles, and former drivers who were only driven by others, respectively (HR 1.69; 95% CI, 1.15-2.49 and HR 2.16; 95% CI, 1.51-3.10, relative to current drivers). CONCLUSION: Driving cessation is associated with an increased risk of functional limitations among older adults, but this risk might be alleviated if they are able to maintain independent mobility using public transportation or bicycles after driving cessation.

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma.

ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.

Giving social support to outside family may be a desirable buffer against depressive symptoms in community-dwelling older adults: Japan gerontological evaluation study.

BACKGROUND: Depression is the leading cause of impaired quality of life and burden upon societies. Social supports can buffer against depressive symptoms effectively. The aim of this study is to determine the type of social support to have a positive relationship with depressive symptoms in healthy population. METHODS: 11,869 male and 12,763 female residents within the age range of 65-100 were analyzed cross-sectionally with regard to depressive symptoms (evaluated by the Japanese version of the 15-item Geriatric Depression Scale), social supports (four dimensions: giving or receiving, emotional or instrumental), and covariates utilizing data collected by the Japan Gerontological Evaluation Study. Analyzed　participants were GDS scores ≤ 10 and independence in ADL, who could give and receive supports well. Multiple linear models were applied for the analysis. RESULTS: All supports between husband and wife were significantly associated with lower depressive degrees. In comparison with the differences between receiving and giving supports in predictive effects on depressive degrees, giving social supports to outside family, emotional or instrumental, were associated with fewer depressive symptoms. CONCLUSIONS: There is a possibility that not only supports between husband and wife but giving social supports to outside family accounts for psychological benefits against depression, in addition to supports between husband and wife.

Evaluating Chemical CDK Inhibitors as Cell Death Inducers.

The cell cycle of eukaryotic cells is regulated by a family of protein kinases called cyclin-dependent kinases (Cdks). We have reported the identification and biological characterization of a highly potent, small-molecule pan-Cdk inhibitor, which inhibited Cdk1, 2, 4, 5, 6, and 9 with equal potency in the nM range. This compound inhibited multiple events in the cell cycle and induced cell death in human cancer cell lines as well as in peripheral blood or purified resting lymphocytes ex vivo. We describe the materials and methods to determine antitumor efficacy in vivo xenograft models. Pharmacodynamic marker assays that have been performed using tumors and normal tissues are explained. Moreover, we briefly describe methods for determining the effects of chemical Cdk inhibitors on peripheral blood cells or lymphocytes ex vivo.

[Criteria for social isolation based on associations with health indicators among older people. A 10-year follow-up of the Aichi Gerontological Evaluation Study].

OBJECTIVES: No clear evidence for a cut-off point for social isolation has been established so far. The purpose of this study was to evaluate the criteria for social isolation based on associations with objective health outcomes in a 10-year follow-up study. METHODS: We performed a prospective study of functionally independent residents aged 65 years or older who lived in six municipalities as part of the Aichi Gerontological Evaluation Study (response rate: 50.4%) that began in 2003. Data on the onset of functional disability, dementia, and death were obtained from municipal databases of the public long-term care insurance system. A total of 12,085 participants were followed up for up to 10 years. We used frequencies of face-to-face and non-face-to-face contact with non-resident children, relatives and friends, or neighbors as indicators of social isolation. The overall frequency of contact with others was categorized from "less than once a month" to "frequently, every day." RESULTS: Cox's proportional hazard model revealed that, after controlling for sex, age, education level, marital status, equivalent household income, need for medical care, self-recognition of forgetfulness, and residential area, the hazard ratios for functional disability (over long-term care level 2), dementia, and premature death increase in those with contact frequency of "less than once a month" were 1.37 (95% confidence interval [CI]: 1.16-1.61), 1.45 (95% CI: 1.21-1.74), and 1.34 (95% CI: 1.16-1.55), respectively. The "from once a month to once a week" frequency was also associated with these health indicators, although the "more than once a week" frequency was not significantly associated with any measured outcome. The prevalence of "less than once a month" contact was 7.4% (men=10.2%, women=4.7%), and this was 15.8% (men=21.2%, women=10.6%) when including those with "less than once a week" contact. CONCLUSION: These findings suggest that "less than once a week" or "less than once a month" contact with non-cohabitant others are valid operational definitions of social isolation that are closely associated with premature death and other health indicators.

Influence of socioeconomic status on the association between body mass index and cause-specific mortality among older Japanese adults: The AGES Cohort Study.

OBJECTIVE: Many studies have suggested a U-shaped curve for the association between body size and mortality risks, i.e., mortality risks increase in those who are both overweight and underweight. The strength of the associations may vary according to socioeconomic statuses (SES), as they determine levels of access to healthcare and psychosocial stresses. We investigated the modifying effects of SES on the relationship between body mass index (BMI) and mortality. METHOD: We used prospective cohort data of participants in the Aichi Gerontological Evaluation Study in 2003 (n=14,931), who were 65years or older and physically and cognitively independent at baseline, and residing in eight municipalities in Japan. Data on all-causes mortality and mortality from cancer, cardiovascular disease, and respiratory disease was obtained from municipal government registries. RESULTS: Proportional hazard regression analyses showed that, among men, the associations between overweight (BMI≥25kg/m(2)) and higher mortality risks by any cause were stronger among lower income groups. Even adjusting for multiple confounding factors, hazard ratios (95% confidence intervals) for mortality by all causes among low income group (household income<1.5 million yen) were 1.96 (1.02-3.73) for overweight compared with BMIs between 23.0 and 24.9, whereas they were 0.94 (0.57-1.38) among men in high income group (income>3 million yen). The modifying effects of income were not marked among women. CONCLUSION: Household income, which may directly reflect accessibility to healthcare and psychosocial stress among older Japanese men, may be an important modifying factor in the health risks attributable to overweight.

Access disparity and health inequality of the elderly: unmet needs and delayed healthcare.

The purpose of this study is to investigate healthcare access disparity that will cause delayed and unmet healthcare needs for the elderly, and to examine health inequality and healthcare cost burden for the elderly. To produce clear policy applications, this study adapts a modified PRECEDE-PROCEED model for framing theoretical and experimental approaches. Data were collected from a large collection of the Community Tracking Study Household Survey 2003-2004 of the USA. Reliability and construct validity are examined for internal consistency and estimation of disparity and inequality are analyzed by using probit/ols regressions. The results show that predisposing factors (e.g., attitude, beliefs, and perception by socio-demographic differences) are negatively associated with delayed healthcare. A 10% increase in enabling factors (e.g., availability of health insurance coverage, and usual sources of healthcare providers) are significantly associated with a 1% increase in healthcare financing factors. In addition, information through a socio-economic network and support system has a 5% impact on an access disparity. Income, health status, and health inequality are exogenously determined. Designing and implementing easy healthcare accessibility (healthcare system) and healthcare financing methods, and developing a socio-economic support network (including public health information) are essential in reducing delayed healthcare and health inequality.

Distance to retail stores and risk of being homebound among older adults in a city severely affected by the 2011 Great East Japan Earthquake.

BACKGROUND: after the Great East Japan Earthquake in 2011, inactivity and the homebound status of older victims in affected areas have been a serious public health concern owing to the victims' prolonged existence as evacuees in mountainous areas. OBJECTIVE: to evaluate the association between distances to retail stores and risks of being homebound. DESIGN: secondary analysis of cross-sectional interview survey data with a geographical information analysis. SETTING: Rikuzentakata, Iwate, a municipality seriously damaged by the 2011 earthquake and tsunami. SUBJECTS: all Rikuzentakata residents aged 65 or older except for those living in temporary housing (n = 2,327). METHODS: we calculated road distances between each residential address and retail stores, hawker sites and shopping bus stops, accounting for the extra load caused by walking on slopes. The prevalence ratio of being homebound adjusted for age, source of income and morbidity by road distance was estimated using Poisson regression with a generalised estimating equation. RESULTS: those living at distances of 1,200 m or more were 1.78 (95% confidence intervals, 1.03-3.08) times more likely to be homebound (going out only every 4 or more days a week) among men and 1.85 (1.13-3.02) among women, compared with those residing in places <400 m from retail stores or shopping bus stops. The distances were reduced by new hawker and shopping bus services, but the improvements varied greatly across the districts. CONCLUSIONS: access to daily needs is essential to prevent homebound status. Post-disaster community diagnosis in terms of the built environment is important for strategic community restoration.

Social participation and the prevention of functional disability in older Japanese: the JAGES cohort study.

BACKGROUND: We examined the relationship between incident functional disability and social participation from the perspective of number of types of organizations participated in and type of social participation in a prospective cohort study. METHOD: The study was based on the Aichi Gerontological Evaluation Study (AGES) Cohort Study data. We followed 13,310 individuals aged 65 years or older for 4 years. Analysis was carried out on 12,951 subjects, excluding 359 people whose information on age or sex was missing. Social participation was categorized into 8 types. RESULTS: Compared to those that did not participate in any organizations, the hazard ratio (HR) was 0.83 (95% CI: 0.73-0.95) for participation in one, 0.72 (0.61-0.85) for participation in two, and 0.57 (0.46-0.70) for participation in three or more different types of organizations. In multivariable adjusted models, participation in the following types of organization was protective for incident disability: local community organizations (HR = 0.85, 95% CI: 0.76-0.96), hobby organizations (HR = 0.75, 95% CI: 0.64-0.87), and sports organizations (HR = 0.64, 95% CI: 0.54-0.81). CONCLUSION: Social participation may decrease the risk of incident functional disability in older people in Japan. This effect may be strengthened by participation in a variety of different types of organizations. Participating in a local community, hobby, or sports group or organization may be especially effective for decreasing the risk of disability.

Does social participation improve self-rated health in the older population? A quasi-experimental intervention study.

Social participation has been linked to healthy aging and the maintenance of functional independence in older individuals. However, causality remains tenuous because of the strong possibility of reverse causation (healthy individuals selectively participate in social activities). We describe a quasi-experimental intervention in one municipality of Japan designed to boost social participation as a way of preventing long-term disability in senior citizens through the creation of 'salons' (or community centers). In this quasi-experimental intervention study, we compared 158 participants with 1391 non-participants in salon programs, and examined the effect of participation in the salon programs on self-rated health. We conducted surveys of community residents both before (in 2006) and after (in 2008) the opening of the salons. Even with a pre/post survey design, our study could be subject to reverse causation and confounding bias. We therefore utilized an instrumental variable estimation strategy, using the inverse of the distance between each resident's dwelling and the nearest salon as the instrument. After controlling for self-rated health, age, sex, equivalized income in 2006, and reverse causation, we observed significant correlations between participation in the salon programs and self-rated health in 2008. Our analyses suggest that participation in the newly-opened community salon was associated with a significant improvement in self-rated health over time. The odds ratio of participation in the salon programs for reporting excellent or good self-rated health in 2008 was 2.52 (95% CI 2.27-2.79). Our study provides novel empirical support for the notion that investing in community infrastructure to boost the social participation of communities may help promote healthy aging.