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ObjectiveTo evaluate the influence of comorbid cardiovascular disease severity on health-related quality of life (HRQL) in men treated with radical prostatectomy (RP) or radiotherapy (RT) for early stage prostate cancer.MethodsSubjects (n=830) with non-metastatic disease who had been diagnosed in 2000-2002 were drawn from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). We evaluated the influence of cardiovascular disease (CVD) severity on generic and disease-specific HRQL before and 6, 12, 18, and 24 months after treatment with RP or RT. HRQL was measured with the SF-36 and the UCLA Prostate Cancer Index.ResultsMen with moderate (n=193) or severe (n=51) cardiovascular disease had worse pre-treatment HRQL than did men without CVD (n=293) (P

Background: Palliative systemic therapy can prolong life and reduce tumor-related symptoms for patients with advanced esophagogastric cancer. However, side effects of treatment could negatively affect health-related quality of life (HRQoL). Our aim was to review the literature and conduct a meta-analysis to examine the effect of palliative systemic therapy on HRQoL.Methods: EMBASE, Medline, and Central were searched for phase II/III randomized controlled trials until April 2018 investigating palliative systemic therapy and HRQoL. Meta-analysis was performed on baseline and follow-up summary values of global health status (GHS) and other European Organisation for Research and Treatment of Cancer scales. A clinically relevant change and difference of 10 points (scale 0-100) was set to assess the course of HRQoL over time within treatment arms as well as between arms.Results: We included 43 randomized controlled trials (N = 13 727 patients). In the first-line and beyond first-line treatment setting, pooled baseline GHS mean estimates were 54.6 (95% confidence interval = 51.9 to 57.3) and 57.9 (95% confidence interval = 55.7 to 60.1), respectively. Thirty-nine (81.3%) treatment arms showed a stable GHS over the course of time. Anthracycline-based triplets, fluoropyrimidine-based doublets without cisplatin, and the addition of trastuzumab to chemotherapy were found to have favorable HRQoL outcomes. HRQoL benefit was observed for taxane monotherapy and several targeted agents over best supportive care beyond first line.Conclusions: Patients reported impaired GHS at baseline and generally remained stable over time. Anthracycline-based triplets and fluoropyrimidine-based doublets without cisplatin may be preferable first-line treatment options regarding HRQoL for HER2-negative disease. Taxanes and targeted agents could provide HRQoL benefit beyond first line compared with best supportive care. [ABSTRACT FROM AUTHOR]

Albeit treatable, metastatic breast cancer (MBC) remains incurable. To achieve remaining life years lived well, extended survival should be balanced with optimal health-related quality of life (HRQoL) and timely initiated supportive, palliative, and end-of-life care. The Advanced Breast Cancer (ABC) Global Alliance identified 10 urgent and actionable goals for the decade between 2015 and 2025 to achieve substantial improvement in the lives of patients living with ABC, including MBC. Enhancements are needed for HRQoL, research, quality of care, and survival. We explore the potential of patient-reported outcome measures (PROMs) in addressing these gaps and aim to describe opportunities and current initiatives for improving the MBC care continuum through PROMs. Narrative description of recent literature on MBC and PROMs. We believe PROMs can make valuable contributions to seven of the 10 goals described: 1) enhancing the understanding of MBC through high-quality data collection, 2) improving HRQoL and raising consideration of survival versus HRQoL, 2) prolonging survival, 4) increasing referral to nonclinical support services, 5) supporting patient–healthcare provider communication, 6) encouraging improvements in healthcare access, and 7) supporting meeting patients' informational needs. Maximizing the benefits of PROMs requires effective implementation. Because nurses and nurse practitioners are at the forefront of care, they can offer a comprehensive understanding of patients' needs and play a crucial role in facilitating the integration of PROMs into routine care for MBC patients and ultimately optimizing patients' outcomes and life years and months left. [ABSTRACT FROM AUTHOR]

Introduction: The EORTC QLQ-CR29 is a patient-reported outcome measure to evaluate health-related quality of life among colorectal cancer patients in research and clinical practice. The aim of this systematic review was to investigate whether the initial positive results regarding the measurement properties of the QLQ-CR29 are confirmed in subsequent studies.Methods: A systematic search of Embase, Medline, PsycINFO, and Web of Science was conducted to identify studies investigating the measurement properties of the QLQ-CR29 published up to January 2019. For the 11 included studies, data were extracted, methodological quality was assessed, results were synthesized, and evidence was graded according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology on the measurement properties: structural validity, internal consistency, reliability, measurement error, construct validity (hypothesis testing, including known-group comparison, convergent and divergent validity), cross-cultural validity, and responsiveness.Results: Internal consistency was rated as "sufficient," with low evidence. Reliability was rated as "insufficient," with moderate evidence. Construct validity (hypothesis testing; known-group comparison, convergent and divergent validity) was rated as "inconsistent," with moderate evidence. Structural validity, measurement error, and responsiveness were rated as "indeterminate" and could therefore not be graded.Conclusion: This review indicates that current evidence supporting the measurement properties of the QLQ-CR29 is limited. Additionally, better quality research is needed, taking into account the COSMIN methodology. [ABSTRACT FROM AUTHOR]

Health-related quality of life (HRQoL) is important in the management of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Disease-specific questionnaires exist, but with important shortcomings. The aim of this study was to develop and validate a questionnaire suitable for use in all patients with BCC and those with SCC. In a 4-phase trajectory, a preliminary questionnaire was created and population-based testing (1,173 patients) carried out. The questionnaire was reduced using exploratory factor analysis and item response theory. Individual item performance was assessed using classical test theory. A total of 721 patients completed the questionnaire. The number of items was reduced to 16, covering 5 scales. Confirmatory factor analysis showed a good fit. Cronbach's as (range 0.67-0.82) were reasonable to high with good internal consistency. In conclusion, the Basal and Squamous Cell Carcinoma Quality of Life questionnaire has good face, content and construct validity. It is useful in the wide range of BCC and SCC patients and captures HRQoL impact over different time-frames. [ABSTRACT FROM AUTHOR]

BACKGROUND With the increasing number and diversity of cancer survivors, studies of survivors' physical, emotional, and social health and well being are of growing importance. Population-based cancer registries, which collect data on incident cases, can play an important role in quality-of-life (QoL) studies. In this review, the authors provide an overview of QoL studies that have used cancer registry data in this emerging area of research. METHODS Publication databases were searched for relevant peer-reviewed original articles published between 2001 and mid-2011. Inclusion criteria were articles published in English that used cancer registries as the sampling frame and/or that used registry data in analyses with QoL data. All included articles were assessed on the quality of information provided, cancer registry procedures, and study design. RESULTS In total, 173 articles from 13 countries were reviewed, and a large proportion were from the United States (n = 72) and Europe (n = 70). Fourteen different malignancies were studied, and the most frequent were breast cancer. Most studies focused on adult survivors, and only 4 focused on the elderly (aged >70 years). Of the reviewed articles, 110 (64%) provided a good amount of information on the cancer registry. Information less frequently reported included mainly follow-up of vital status and characteristics of respondents/nonrespondents. CONCLUSIONS QoL studies increasingly use population-based registries, which provide important clinical variables and an excellent sampling frame for identifying subgroups. Until now, most studies have tended to focus on more prevalent cancers, and surprisingly few studies have focused on QoL of elderly survivors, who remain understudied in clinical trials. Cancer 2013;119(11 suppl):2109-23. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: ‘Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship (PROFILES)’ is a registry for the study of the physical and psychosocial impact of cancer and its treatment from a dynamic, growing population-based cohort of both short and long-term cancer survivors. PROFILES contains a large web-based component and are linked directly to clinical data from the population-based Eindhoven cancer registry. This paper describes the rationale and design of PROFILES. The primary aims of studies that use the PROFILES registry are: (1) psychosocial risk and outcome assessment to identify patients at high risk for poor physical and mental health outcomes, (2) to analyse mediating mechanisms to better understand the biological and behavioural factors associated with cancer treatment outcomes, and (3) to evaluate physical and psychosocial care needs of cancer survivors. PROFILES is a tool that enables data collection management; from inviting patients to participation in studies, to collecting patient-reported outcomes data via web-based or mailed questionnaires and linking these data with clinical data. The availability of a control cohort of approximately 2000 persons from the general population who complete the same basic questionnaire annually will provide the opportunity to estimate the unique impact of cancer, beyond that of normal ageing and comorbidities. Raw data from the PROFILES registry will be available for non-commercial scientific research, subject to study question, privacy and confidentiality restrictions, and registration (www.profilesregistry.nl). [Copyright &y& Elsevier]

Study Type – Therapy (outcomes research) Level of Evidence 2c OBJECTIVE To assess and identify factors associated with the long-term health-related quality of life (HRQL) of prostate cancer survivors managed expectantly, as patients with low-risk prostate cancer can be managed with active surveillance (AS), but research on associated long-term HRQL is scarce. PATIENTS AND METHODS From the population-based Eindhoven Cancer Registry, 71 men managed with AS were matched with 71 survivors who had similar demographic and clinical characteristics but treated with external beam radiotherapy (RT). All were diagnosed between 1994 and 1998. HRQL data were collected 5–10 years after diagnosis. Patients completed generic- (Short Form-36) and cancer-specific (Quality of Life – Cancer Survivors) HRQL instruments, and symptom burden (Expanded Prostate Cancer Index, Sexual Activity) questionnaires. RESULTS Patients on AS were comparable to those treated with RT for most generic- and disease-specific HRQL dimensions. Patients treated with RT had poorer mean (sd) bowel function scores, of 87.1 (13.1) vs 92.8 (10.7) ( P < 0.001), more bother with bowel function, at 85.0 (16.4) vs 93.7 (10.1) ( P < 0.001), and more problems with getting an erection (68% vs 47%, P = 0.005). Multivariate regression analyses (corrected for comorbidity and clinical disease progression) indicated that the management strategy independently predicted differences in physical functioning, bodily pain, spiritual and total well-being, and bowel function and bowel bother. CONCLUSIONS Patients managed expectantly at initial diagnosis (AS) have comparable HRQL and a lower symptom burden than patients treated with RT up to 10 years after the diagnosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE To assess the health-related quality of life (HRQoL) of long-term, disease-free prostate cancer survivors and compare it with that of prostate cancer survivors with diabetes mellitus (DM), and a Dutch normative population, as comorbidity can have a major impact on HRQoL in cancer survivors. PATIENTS AND METHODS The Eindhoven Cancer Registry was used to select all men diagnosed with prostate cancer from 1994 to 1998. Questionnaires on HRQoL (Short Form 36) and prostate specific problems (University of California, Los Angeles Expanded Prostate Cancer Index) were sent to 964 patients, and 780 (81%) responded. Excluding patients with disease progression, the sample comprised 525 with prostate cancer and 65 with both prostate cancer and DM. Survivors with DM were more likely to have other comorbid conditions at the time of survey besides DM than were those without DM (74% vs 60%, P = 0.05). At 5–10 years after diagnosis, patients with DM reported worse General Health Perceptions than patients without DM or the normative population (means 52, 61 and 63; P < 0.001). Patients with DM also reported worse Vitality scores (59 vs 63; P < 0.001) than the normative population. Regression analysis indicated that DM was negatively associated with General Health Perceptions (β = −0.13; P < 0.01) and Vitality (β = −0.12; P < 0.01). Survivors with DM did not report worse urinary and bowel function or bother, nor more sexual problems than those without DM. CONCLUSIONS Except for general health perceptions and vitality, the HRQoL of prostate cancer survivors with or without DM was comparable to a normative population. Survivorship selection can possibly explain, in part, why patients with DM did not report worse generic or disease-specific HRQoL than those without DM, as had been expected. [ABSTRACT FROM AUTHOR]

Simple Summary: Adolescents and young adults (AYA), aged 18–39 years at first cancer diagnosis, are recognized as a distinct population within the oncology community due to the unique challenges they encounter including recognition, diagnosis, treatment, and monitoring of their disease. It is imperative for advances in the field of AYA oncology to pool data sources (patient-reported outcomes, clinical, treatment, genetic, and biological data) across institutions and countries and create large cohorts that include the full range of AYA ages and diagnoses to be able to address the many pressing questions that remain unanswered in this vulnerable population. The Dutch COMPRAYA study aims to examine the incidence, risk factors, and mechanisms of impaired health outcomes (short- and long-term medical and psychosocial effects) over time among AYA cancer patients. The overarching aim is to provide a research infrastructure for (future) data analyses and observational retrospective/prospective ancillary studies and to expand data collection to other countries. Adolescent and young adult (AYA) cancer patients suffer from delay in diagnosis, and lack of centralized cancer care, age-adjusted expertise, and follow-up care. This group presents with a unique spectrum of cancers, distinct tumor biology, cancer risk factors, developmental challenges, and treatment regimens that differ from children and older adults. It is imperative for advances in the field of AYA oncology to pool data sources across institutions and create large cohorts to address the many pressing questions that remain unanswered in this vulnerable population. We will create a nationwide infrastructure (COMPRAYA) for research into the incidence, predictive/prognostic markers, and underlying mechanisms of medical and psychosocial outcomes for AYA between 18–39 years diagnosed with cancer. A prospective, observational cohort of (n = 4000), will be established. Patients will be asked to (1) complete patient-reported outcome measures; (2) donate a blood, hair, and stool samples (to obtain biochemical, hormonal, and inflammation parameters, and germline DNA); (3) give consent for use of routinely archived tumor tissue and clinical data extraction from medical records and registries; (4) have a clinic visit to assess vital parameters. Systematic and comprehensive collection of patient and tumor characteristics of AYA will support the development of evidence-based AYA care programs and guidelines. [ABSTRACT FROM AUTHOR]

Background: Sarcoma patients often experience a long time to diagnosis, known as the total interval. This interval can be divided into the patient (time from symptoms to doctor consultation) and diagnostic intervals (time from first consultation to diagnosis). In other cancers, a long total interval has been associated with worse outcomes, but its effect on health-related quality of life (HRQoL) has never been investigated among sarcoma patients. This study investigates the association between (1) the actual time to diagnosis and HRQoL; (2) the perceived impact of the diagnostic interval length and HRQoL; (3) the actual length and perceived impact of the length and the HRQoL of sarcoma survivors. Methods: A cross-sectional study was performed among sarcoma patients aged ≥18, diagnosed 2–10 years ago in the Netherlands. The participants completed a questionnaire on HRQoL, the time to diagnosis, the perceived impact of the diagnostic interval on HRQoL, and coping. Results: 1099 participants were included (response rate, 58%). The mean time since diagnosis was 67.4 months. More than half reported a patient (60%) or diagnostic interval (55%) ≥1 month. A third (31%) perceived a negative impact of the diagnostic interval length on HRQoL. Patient or diagnostic interval length was not associated with HRQoL. By contrast, participants perceiving a negative impact (32%) had lower HRQoL scores than those perceiving a positive (11%) or no impact (58%) (p = 0.000). This association remained significant in a multivariable model, in which maladaptive coping strategies and tumour characteristics were also found to be associated with HRQoL. Participants perceiving a negative impact of the length of the diagnostic interval related this to high psychological distress levels, more physical disabilities, and worse prognosis. Conclusion: The perceived impact of the diagnostic interval length was associated with the HRQoL of sarcoma survivors, whereas the actual length was not associated with HRQoL. Maladaptive coping strategies were independently associated with HRQoL. This offers opportunities for early intervention to improve HRQoL. [ABSTRACT FROM AUTHOR]

Abstract: Background: The consequences of cancer and its treatment on health-related quality of life (HRQL) and health care utilisation among elderly long-term cancer survivors have rarely been studied. However, the impact can be different for older compared to younger patients due to the higher prevalence of comorbid diseases, a higher risk of treatment-related complications and because they often receive different therapies compared to younger patients. Therefore, this study addressed the following questions; do HRQL and health care utilisation differ between younger and elderly cancer survivors, and are those differences age or disease related. Methods: A population-based, cross-sectional survey among 1893 long-term survivors of endometrial cancer, prostate cancer and non-Hodgkin’s lymphoma was conducted using a cancer registry. HRQL was measured by the SF-36 and health care utilisation was measured with a self-reported questionnaire. Results were compared to a normative population. Patients with disease progression were excluded resulting in a total number of 1112 patients to be analysed. Results: Young non-Hodgkin lymphoma survivors (<70 years) reported lower vitality, bodily pain and general health compared to the normative population while older (⩾70 years) survivors did not differ from the norm. Young lymphoma survivors experienced better physical functioning compared to older survivors. Young endometrial cancer survivors experienced less bodily pain compared to the normative population while older survivors did not differ from the norm. Young endometrial cancer survivors experienced better physical and role functioning compared to older survivors. Young prostate cancer survivors reported less bodily pain compared to the norm while older survivors did not. Young prostate cancer survivors reported higher scores on physical functioning compared to older survivors. Age, comorbid diseases, educational level and current occupation influenced HRQL significantly. Both younger and older cancer survivors visited their medical specialist, but not their GP, significantly more often compared to the age-matched general Dutch population. Both younger and older cancer survivors only sporadically used additional care services after cancer treatment. Discussion: HRQL of older and younger survivors is comparable, with the exception of physical functioning which is lower in older survivors. This difference in physical functioning was probably not caused by cancer because physical functioning among cancer survivors did not differ much compared to an age-matched normative population. Both younger and older long-term cancer survivors visited their medical specialist often but only sporadically used additional care services after cancer treatment. [Copyright &y& Elsevier]

Objective This study assessed the prevalence and risk factors of chemotherapy-induced peripheral neuropathy, and its impact on health-related quality of life among ovarian cancer survivors, 2-12 years after diagnosis. Methods Women (n = 348) diagnosed with ovarian cancer between 2000 and 2010, as registered by the Dutch population-based Eindhoven Cancer Registry, were eligible for participation. A questionnaire, including the EORTC QLQ-C30 and EORTC QLQ-OV28 measures, containing 3 items about neuropathy, was returned by 191 women (55%). Recurrence and chemotherapy data were obtained from medical records. Results Of all 191 women, the 129 women who received chemotherapy more often reported having tingling hands/feet and feeling numbness in fingers/toes, specifically 51% reported "a little" to "very much" of these symptoms vs. about 27% who did not receive chemotherapy. Women reporting more neuropathy symptoms reported lower levels of functioning and overall quality of life. They also reported more symptoms of fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, and financial problems. Moreover, women reporting more neuropathy symptoms had experienced the disease and treatment more often as being a burden and were more worried about their health, had more gastrointestinal and hormonal symptoms, hair loss and more other chemotherapy side effects. Linear regression analyses showed that more cycles of chemotherapy, more recurrences and a shorter period since last treatment were associated with a higher neuropathy score. Conclusion Neuropathy symptoms were experienced by 51% of women with ovarian cancer who received chemotherapy even up to 12 years after the end of treatment, and this seriously affected their HRQoL. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To examine to what extent endometrial cancer survivors experienced follow-up according to the Dutch national guidelines, and to identify associations between follow-up care consumption and socio-demographic and clinical characteristics, Health-Related Quality of Life (HRQL), and worry (including fear of recurrence). Patients' preferences with the received follow-up care were also evaluated. Methods: All patients diagnosed with endometrial cancer FIGO stages I–II between 1999 and 2007, registered in the Eindhoven Cancer Registry (ECR), received a questionnaire including patients' follow-up care consumption, preferences regarding the follow-up schedule, HRQL (SF36 and EORTC-QLQ-EN24), and worry (IOCv2). Results: 742 (77%) endometrial cancer survivors returned a completed questionnaire. Overall, 19% reported receiving more follow-up visits than recommended by the guidelines. Overconsumption of follow-up care was lowest in follow-up year 1 (13%), and highest in follow-up years 6–10 (27%). In addition, overconsumption was associated with having a comorbid condition, a higher score on the worry subscale, and hospital of treatment. Most patients (83%) felt comfortable with their follow-up schedule. Patients in follow-up years 6–10 felt least comfortable (69%). Conclusion: Follow-up frequency was higher than recommended in a large group of endometrial cancer survivors, mainly in follow-up years 6–10. Moreover, a substantial variation in follow-up practice was observed between the different hospitals. Despite limited evidence to support the use of intensive follow-up schedules, the current study suggests that intensive routine follow-up after endometrial cancer continues to be standard practice. Possibly, patients should be better informed in order to reduce overconsumption and worry. [Copyright &y& Elsevier]

Abstract: Background: This population-based study assessed the impact of chemotherapy on general and disease-specific health status of resected colon cancer survivors up to 10years post-diagnosis. Patients and methods: Colon cancer survivors diagnosed between 1998 and 2007 were selected from the Eindhoven Cancer Registry. Survivors completed the SF-36 and the EORTC colorectal module (EORTC-QLQ-CR38). Comparisons to a normative population were conducted. Multiple linear regression analyses investigated the association between treatment and health status. Results: Eight hundred and forty eight survivors were evaluated: 29% had chemotherapy (CT); 71% without chemotherapy (nCT). Survivors had similar SF-36 scores and scored better than the normative population on several domains. On the EORTC-QLQ-CR38, male nCT survivors had more sexual problems than CT survivors (p =0.01). Among the sexually active respondents, the survivors reported sex to be less enjoyable than the normative population (p =0.02). In multivariate analyses, CT predicted better physical function, and less male sexual dysfunction and weight loss problems than nCT. Conclusions: Overall, CT survivors have general health status scores comparable to nCT survivors and the normative population up to 10years since initial diagnosis. Sex-related problems among survivors suggest more attention on this often sensitive issue is required in clinical management. [Copyright &y& Elsevier]

Abstract: Objective: We aimed to investigate the prevalence of Type D personality (the conjoint effects of negative affectivity and social inhibition) among melanoma survivors and to obtain insight into its effects on health status, impact of cancer and health care utilisation. Methods: We selected all patients diagnosed with melanoma between 1998 and 2007 from three large regional hospitals in the Netherlands. In total, 699 survivors, alive in January 2008, received a questionnaire including Type D personality scale (DS14), impact of cancer questionnaire (IOC) and SF-36 and 80% responded (n =562). Results: Twenty-two percent of survivors (n =125) were classified as Type D. They reported a clinically and statistically significant worse general health (57.8 versus 75.6), social functioning (73.1 versus 88.7), mental health (61.7 versus 80.6), more emotional role limitations (67.8 versus 89.4) and less vitality (54.5 versus 72.8) than non-Type D patients. Additionally, they reported a statistically and clinically relevant higher impact of cancer on body changes, negative self-evaluation, negative outlook on life, life interferences and health worry. Furthermore, they were more worried about the influence of the sun on their skin and acted accordingly. No differences were found in health care utilisation. Conclusions: Type D personality has a distinct negative impact on health status in melanoma survivors and is an important factor to screen for in clinical practice. Giving special attention to these patients is important while they are more likely to experience a strong impact of cancer which cannot be explained by socio-demographical or clinical characteristics. [Copyright &y& Elsevier]

Purpose: To date, few studies have evaluated the impact of preoperative radiotherapy (pRT) on long-term health status of rectal cancer survivors. Using a population-based sample, we assessed the impact of pRT on general and disease-specific health status of rectal cancer survivors up to 10 years postdiagnosis. The health status of older (≥75 years old at diagnosis) pRT survivors was also compared with that of younger survivors. Methods and Materials: Survivors identified from the Eindhoven Cancer Registry treated with surgery only (SU) or with pRT between 1998 and 2007 were included. Survivors completed the Short Form-36 (SF-36) health survey questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Colorectal 38 (EORTC QLQ-CR38) questionnaire. The SF-36 and EORTC QLQ-CR38 (sexuality subscale) scores of the survivors were compared to an age- and sex-matched Dutch normal population. Results: A total of 340 survivors (response, 85%; pRT survivors, 71%) were analyzed. Overall, survivors had similar general health status. Both short-term (<5 years) and long-term (≥5 years) pRT survivors had significantly poorer body image and more problems with gastrointestinal function, male sexual dysfunction, and defecation than SU survivors. Survivors had comparable general health status but greater sexual dysfunction than the normal population. Older pRT survivors had general and disease-specific health status comparable to that of younger pRT survivors. Conclusions: For better survivorship care, rectal cancer survivors could benefit from increased clinical and psychological focus on the possible long-term morbidity of treatment and its effects on health status. [ABSTRACT FROM AUTHOR]