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Background Patients with advanced cancer have been reported to be more likely to receive goal-concordant care if they have accurate prognostic awareness. However, many patients do not have this awareness. This study aimed to examine the prognostic awareness among Japanese patients with advanced cancer. Methods This single-center, follow-up cohort study included Japanese patients with advanced cancer who received chemotherapy at Tohoku University Hospital between January 2015 and January 2016. Patients were surveyed at enrollment and followed up for clinical events for 5 years thereafter. We compared (i) the patients’ prognostic awareness with both actual survival time and physician’s prediction of survival and (ii) physician’s prediction of survival time with actual survival. Factors associated with accurate prognostic awareness were identified by univariate analysis. Results Of the 133 patients eligible for the study, 57 patients were analyzed. Only 10 (17.5%) patients had accurate prognostic awareness. Forty-three patients (75.4%) were optimistic about their prognosis; >80% of patients were more optimistic than their physicians about their prognosis. The physicians’ predictions were accurate in for patients (37.5%). Accurate prognostic awareness was associated with physician’s explanation of the prognosis and patients’ perception of a good death. Conclusions A majority of the patients with advanced cancer in this study had prognostic awareness that was more optimistic in comparison with their actual survival, and most were more optimistic than their physicians about their prognosis. Further research is needed to develop programs to facilitate the discussion of life expectancy with patients in a manner that is consistent with their preferences.

Several prognostic models such as the Palliative Performance Scale (PPS), Palliative Prognostic Index (PPI), Palliative Prognostic Score (PaP) have been developed to complement clinician's prediction of survival (CPS). However, few studies with large scales have been conducted to show which prognostic tool had better performance than CPS in patients with weeks of survival.We aimed to compare the prognostic performance of the PPS, PPI, PaP, and CPS in inpatients admitted to palliative care units (PCUs).This study was part of a multi-center prospective observational study involving patients admitted to PCUs in Japan. We computed their prognostic performance using the area under the receiver operating characteristics curve (AUROC) and calibration plots for seven, 14-, 30- and 60-day survival.We included 1896 patients with a median overall survival of 19 days. The AUROC was 73% to 84% for 60-day and 30-day survival, 75% to 84% for 14-day survival, and 80% to 87% for seven-day survival. The calibration plot demonstrated satisfactory agreement between the observational and predictive probability for the four indices in all timeframes. Therefore, all four prognostic indices showed good performance. CPS and PaP consistently had significantly better performance than the PPS and PPI from one-week to two-month timeframes.The PPS, PPI, PaP, and CPS had relatively good performance in patients admitted to PCUs with weeks of survival. CPS and PaP had significantly better performance than the PPS and PPI. CPS may be sufficient for experienced clinicians while PPS may help to improve prognostic confidence for inexperienced clinicians.

We aimed to compare the performance of established inflammation and nutrition-based prognostic indices with a relatively novel index 'mid-upper arm circumference (MUAC)' in outpatients with advanced cancer.This study was a secondary analysis of a prospective cohort study that enrolled 200 outpatients with advanced cancer visiting a medical oncology clinic at a tertiary hospital. All patients were followed until death, and the Glasgow Prognostic Score (GPS), modified GPS (mGPS), Prognostic Nutritional Index (PNI), neutrophil/lymphocyte ratio (NLR), C-reactive protein/albumin ratio (CAR), and MUAC were compared by calculating the area under the receiver operating characteristic curves (AUROCs).The mean age of the patients was 64.4 years, 64.0% were male, and the median overall survival was 32.4 weeks [95% confidence interval (CI): 5.6-142.7]. Overall, all indices showed similarly high AUROCs for estimating 12-week (0.68 to 0.75) and 24-week survival (0.67 to 0.74). When confined to the GPS, mGPS, and MUAC, the AUROCs for 12-week survival were 0.75 (95% CI: 0.66-0.82), 0.74 (95% CI: 0.65-0.82), and 0.72 (95% CI: 0.64-0.79), respectively. For 24-week survival, the AUROCs were 0.70 (95% CI: 0.62-0.76), 0.67 (95% CI: 0.60-0.74), and 0.72 (95% CI: 0.64-0.79), respectively. MUAC had the highest specificity for estimating 12-week survival (86.0%), while GPS showed the highest sensitivity for estimating 12-week survival (81.1%).Inflammation and nutrition-based prognostic indices showed similar acceptable accuracies in estimating the 12- and 24-week survival of oncology outpatients. Notably, a simple and non-invasive index MUAC, showed comparable performance with established indices including GPS and mGPS.

Purpose Mid-upper arm circumference (MUAC) has been used to assess malnutrition and health status across various disease groups. However, it is unclear whether MUAC is associated with quality of life (QOL) of patients with advanced cancer. Our goal was to investigate the relationship between MUAC and QOL in ambulatory out-patients with advanced cancer. Method This was a cross-sectional study conducted in a tertiary cancer center in South Korea. A total of 200 patients with advanced cancer at oncology clinics of Seoul National University Bundang Hospital from March 2016 to January 2019 were enrolled. Out-patients with advanced cancer whose survival was expected to be less than one year by their oncologists were enrolled. QOL of patients was evaluated using the European Organization for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ-C30). Associations of QOL with MUAC and nutritional parameters were examined with generalized linear models. Results The most common cancer sites were the lung, colon or rectum, and genitourinary tract. In univariate analyses, significant factors associated with higher summary score of EORTC QLQ-C30 were higher MUAC (≥ 26.5 cm, p < 0.001), higher body mass index (BMI) (≥ 22 kg/m2, p < 0.001), higher serum albumin (≥ 3.7 g/dL, p = 0.004), higher creatinine (≥ 0.8 mg/dL, p = 0.023), and higher uric acid (≥ 5 mg/dL, p = 0.001). In multivariate analysis, higher serum albumin (≥ 3.7 g/dL, p < 0.01) and higher MUAC (≥ 26.5 cm, p = 0.03) were independently associated with better summary score of EORTC QLQ-C-30. Conclusion MUAC was highly associated with QOL in terms of summary score and overall health status. Thus, MUAC, with its simplicity, can be a useful tool to reflect QOL in patients with advanced cancer.

Several prognostic tools have been developed to aid clinicians in survival prediction. However, changes in symptoms are rarely included in established prognostic systems. We aimed to investigate the influence of changes in symptoms and quality of life (QOL) on survival time in outpatients with advanced cancer.Study subjects included a subgroup of those with longitudinal symptom and QOL data within a larger, single-site parent study. We assessed patients' symptoms and QOL at enrollment and follow-up at an approximately 3-month interval. Patients' symptoms were evaluated by the Korean version of the Edmonton Symptom Assessment System (K-ESAS). QOL was checked by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Participants were categorized into three groups by changes in symptoms or QOL. These groups were: improved (having at least a one level of improvement in the response scale), stable (no change), or worsened (at least a one level of worsening in the scale). We compared survival time in the improved plus stable vs. worsened groups, using a log-rank test.We analyzed 60 patients, with a median survival time of 346 days. In the Worsened group, depression (P0.01) and sleep disturbance (P0.01) by K-ESAS, and dyspnea (P0.03) per the EORTC QLQ-C30, were statistically significantly related to shorter survival time compared to 'improved and stable' group. There was no relationship between changes in other symptoms, overall QOL, and survival.Longitudinal assessment of depression, sleep disturbance and dyspnea may be useful in prognostication of patients with advanced cancer. Further studies are needed to confirm our findings with more consecutive assessments in diverse populations.

ObjectivesIt has been suggested that psychosocial factors are related to survival time of inpatients with cancer. However, there are not many studies examining the relationship between spiritual well-being (SWB) and survival time among countries. This study investigated the relationship between SWB and survival time among three East Asian countries.MethodsThis international multicenter cohort study is a secondary analysis involving newly admitted inpatients with advanced cancer in palliative care units in Japan, South Korea, and Taiwan. SWB was measured using the Integrated Palliative Outcome Scale (IPOS) at admission. We performed multivariate analysis using the Cox proportional hazards model to identify independent prognostic factors.ResultsA total of 2,638 patients treated at 37 palliative care units from January 2017 to September 2018 were analyzed. The median survival time was 18.0 days (95% confidence interval [CI] 16.5–19.5) in Japan, 23.0 days (95% CI 19.9–26.1) in Korea, and 15.0 days (95% CI 13.0–17.0) in Taiwan. SWB was a significant factor correlated with survival in Taiwan (hazard ratio [HR] 1.27; 95% CI 1.01–1.59; p = 0.04), while it was insignificant in Japan (HR 1.10; 95% CI 1.00–1.22; p = 0.06), and Korea (HR 1.02; 95% CI 0.77–1.35; p = 0.89).Significance of resultsSWB on admission was associated with survival in patients with advanced cancer in Taiwan but not Japan or Korea. The findings suggest the possibility of a positive relationship between spiritual care and survival time in patients with far advanced cancer.

Purpose: Achieving “good death” is one of the important goals of palliative care. Providing goal-concordant care and an environment tailored to the patient's preferences can contribute to “good death.” However, the concordance rate between the preferred and actual places of death among advanced cancer patients in Japan is less explored. This study aimed to identify the concordance between patients’ preferred and actual places of death, and the associated factors among patients with advanced cancer in Japan. Methods: Patients with advanced cancer who underwent chemotherapy between January 2015 and January 2016 were enrolled and followed up for 5 years. The enrolled patients were asked about their preference for their place of death. The response options were: “Own home,” “General ward” and “Palliative care unit (PCU).” We compared the actual place of death with the patient’s preference through a follow-up review of the medical records. Results: A total of 157 patients with advanced cancer were enrolled between January 2015 and January 2016. Of these patients, 22.9% (11/48) died at home according to their preference, 64.0% (16/25) in the general ward, and 37.9% (11/29) in the PCU. Only thirty-seven (37.3%) patients died where they wanted, based on the comparison between patients' preferences and actual places of death. Conclusion: The concordance rate between the preferred and actual places of death is not high in Japan. Improving concordance between patients' preferences and actual places of death has the potential to improve end-of-life care.

Purpose Few large-scale studies have focused on the prevalence of symptoms and signs during the last days of patients diagnosed with advanced cancer. Identifying the patterns of specific symptoms according to cancer type is helpful to provide end-of-life care for patients with advanced cancer. We investigated the prevalence and severity of symptoms and signs associated with impending death in patients with advanced cancer. Methods In this secondary analysis of an international multicenter cohort study conducted in three East Asian countries, we compared the severity of symptoms and signs among dying patients 3 days before death according to the type of primary cancer using one-way analysis of variance (ANOVA). Post hoc analysis was conducted for multiple comparisons of each symptom according to the type of primary cancer. Results We analyzed 2131 patients from Japan, Korea and Taiwan. Fatigue, dry mouth, drowsiness and dyspnea were present in nearly half of the patients, and edema of lower extremities was the most common sign in all dying patients. According to cancer type, edema of lower extremities was the most common symptom and fatigue/ ascites were the most severe symptoms in digestive tract cancer. For lung cancer, respiratory secretion was the most prevalent and dyspnea/ respiratory secretion were the most severe symptoms. Conclusion We demonstrated the prevalence and severity of symptoms and signs associated with impending death of patients with advanced cancer in East Asia. Our study can enable clinicians to recognize the specific symptoms and signs at the very end of life.

Research on the association between circumstances of death in advanced cancer patients and depression in their bereaved caregivers is limited.A longitudinal study was performed on patients admitted to 21 inpatient hospices/palliative care units (PCUs) in Japan. Patient symptoms were assessed at admission and in the last 3 days of life. Data on distressing events (unexpected death, bleeding) and received treatments (morphine prescriptions, continuous deep sedation, cardiopulmonary resuscitation) were also obtained. Bereaved caregiver depression was assessed 6 months or more after patient death via mail survey using the Patient Health Questionnaire-9 (PHQ-9). A multivariable logistic regression analysis was used to explore variables predicting bereaved caregiver depression.Of 1324 deceased patient-bereaved caregiver dyads, data were finally analyzed for 711 dyads. The proportion of probable depression (PHQ-9 scores ≥10) in bereaved caregivers was 13.6% (91/671; 95% confidence interval: 11.0-16.2). The multivariable logistic regression analysis showed that patient hyperactive delirium at PCU admission was significantly associated with the development of bereaved caregiver depression (odds ratio: 2.2, 95% CI: 1.2-3.8). Bereaved caregiver perceived low social support (OR: 4.7, 95% CI: 2.2-10.0) and low preparedness for death (OR: 4.5, 95% CI: 2.6-7.8) were also significantly associated with the development of depression. Other patient and bereaved caregiver variables had no association with depression.Hyperactive delirium in terminally ill cancer patients was associated with bereaved caregiver depression. The development of effective strategies to reduce delirium-related agitation and to provide educational interventions for caregivers may be needed.

Artificial hydration (AH) is a challenging issue in terminally ill patients with cancer, because it influences patients' symptoms control, quality of life, and quality of dying (QOD). To date, it is not clear how much AH supply is proper for imminently dying patients. This study aimed to investigate the association between the amount of AH and QOD.This study is part of the East Asian Collaborative Cross-Cultural Study to Elucidate the Dying Process (EASED) conducted in Japan, Korea, and Taiwan from January 2017 to September 2018. Patients' demographics, symptoms, and managements on admission to palliative care units (PCUs) and before death were recorded. The AH amount was classified into different groups by 250-mL intervals to compare their difference. The Good Death Scale (GDS) was used to measure QOD, with patients classified into higher or lower QOD groups using GDS = 12 as the cutoff point. We used logistic regression analysis to assess the association between AH amount and QOD.In total, 1530 patients were included in the analysis. Country, religion, spiritual well-being, fatigue, delirium, dyspnea, AH, and antibiotics use before death were significantly associated with QOD. After conducting regression analysis, patients administered with 250 to 499 mL AH had significantly better QOD (odds ratio, 2.251; 95% confidence interval, 1.072-4.730; P = .032) than those without AH.AH use impacts the QOD of terminally ill patients with cancer admitted to PCUs. Communication with patients and their families on appropriate AH use has a positive effect on QOD.Our prospective cross-cultural multicenter study aims to investigate the relationship between artificial hydration (AH) amount and quality of dying among terminally ill patients with cancer. The findings reveal that country, religion, spiritual well-being, fatigue, delirium, dyspnea, AH, and antibiotics use before death were significantly associated with quality of death (QOD). After multivariable logistic regression, patients administered with AH amount 250 to 499 mL had significantly better QOD (odds ratio, 2.251; 95% confidence interval, 1.072-4.730; P = .032) than those without AH. Communication with patients and their families regarding AH is recommended as it may help them be better prepared for the end-of-life stage and achieve a good death.

Summary: Background & Aims: The prevalence of artificially administered nutrition and hydration (AANH) in different age groups among patients with advanced cancer remains unknown. The present study investigated the current utilization of AANH according to age groups in palliative care units. Methods: This was a secondary analysis of a prospective cohort study. We obtained information on primary nutritional administration routes during the first week of admission and data on the averaged calorie sufficiency rate or total calorie intake on the 7th day of admission. Patients were divided into five age groups (18–39, 40–59, 60–74, 75–89, and 90- years). Among patients receiving AANH, the proportions of higher-calorie AANH were compared between the five age groups. Results: A total of 1453 patients were included. The proportion of patients categorized as receiving nutrition and hydration via the parenteral route was the highest in the 18–39 and 40–59 groups (52.4 and 41.1%, respectively). Among patients receiving AANH (n = 534), the proportions of patients categorized into the

Purpose No study has been conducted to compare the clinicians' prediction of survival (CPS) with Palliative Prognostic Scores (PaP) across countries. We aimed to compare the performance of the CPS in PaP (PaP-CPS), the PaP without the CPS, and the PaP total scores in patients with advanced cancer in three East Asian countries. Methods We compared the discriminative accuracy of the three predictive models (the PaP-CPS [the score of the categorical CPS of PaP], the PaP without the CPS [sum of the scores of only the objective variables of PaP], and the PaP total score) in patients admitted to palliative care units (PCUs) in Japan, Korea, and Taiwan. We calculated the area under the receiver operating characteristic curve (AUROC) for 30-day survival to compare the discriminative accuracy of these three models. Results We analyzed 2,072 patients from three countries. The AUROC for the PaP total scores was 0.84 in patients in Japan, 0.76 in Korea, and 0.79 in Taiwan. The AUROC of the PaP-CPS was 0.82 in patients in Japan, 0.75 in Korea, and 0.78 in Taiwan. The AUROC of the PaP without the CPS was 0.75 in patients in Japan, 0.66 in Korea, and 0.67 in Taiwan. Conclusion The PaP total scores and the PaP-CPS consistently showed similar discriminative accuracy in predicting 30-day survival in patients admitted to PCUs in Japan, Korea, and Taiwan. It may be sufficient for experienced clinicians to use the CPS alone for estimating the short-term survival (less than one month) of patients with far-advanced cancer. The PaP may help to improve prognostic confidence and further reduce subjective variations.

BACKGROUND For cancer patients nearing death, the prediction of their prognosis by physicians is crucial. This study examined the usefulness of the 1-Day Surprise Question (1DSQ). METHODS This study was conducted as part of a multicenter prospective observational study. The physicians answered the 1DSQ "Would I be surprised if this patient died in the next 1 day?" when patients have palliative performance scale (PPS) ≤20. We calculated the sensitivity and specificity of the 1DSQ. Moreover, using multivariate analysis, we evaluated the characteristics of patients who died among those whose physicians answered the 1DSQ as "not surprised". RESULTS Overall, 1,896 patients were enrolled, and 1411 (74.4%) were analyzed between January and December 2017. Among these, 847 (60.0%) patients were placed in the "not surprised" group. The sensitivity, specificity, and positive and negative predictive values of the 1DSQ were 82.0% [95% confidence interval (CI): 77.5-85.8%], 45.5% (95% CI: 44.4-46.4%), 27.4% (95% CI: 25.9-28.7%), and 91.0% (95% CI: 88.9-92.9%), respectively. Multivariate analysis revealed that urine output over last 12 hours

Objective Accurate prognostication is important for patients and their families to prepare for the end of life. Objective Prognostic Score (OPS) is an easy-to-use tool that does not require the clinicians’ prediction of survival (CPS), whereas Palliative Prognostic Score (PaP) needs CPS. Thus, inexperienced clinicians may hesitate to use PaP. We aimed to evaluate the accuracy of OPS compared with PaP in inpatients in palliative care units (PCUs) in three East Asian countries. Method This study was a secondary analysis of a cross-cultural, multicenter cohort study. We enrolled inpatients with far-advanced cancer in PCUs in Japan, Korea, and Taiwan from 2017 to 2018. We calculated the area under the receiver operating characteristics (AUROC) curve to compare the accuracy of OPS and PaP. Results A total of 1,628 inpatients in 33 PCUs in Japan and Korea were analyzed. OPS and PaP were calculated in 71.7% of the Japanese patients and 80.0% of the Korean patients. In Taiwan, PaP was calculated for 81.6% of the patients. The AUROC for 3-week survival was 0.74 for OPS in Japan, 0.68 for OPS in Korea, 0.80 for PaP in Japan, and 0.73 for PaP in Korea. The AUROC for 30-day survival was 0.70 for OPS in Japan, 0.71 for OPS in Korea, 0.79 for PaP in Japan, and 0.74 for PaP in Korea. Significance of results Both OPS and PaP showed good performance in Japan and Korea. Compared with PaP, OPS could be more useful for inexperienced physicians who hesitate to estimate CPS.

Parenteral morphine is widely used for dyspnea of imminently dying cancer patients (terminal dyspnea). However, the efficacy of other opioids such as oxycodone remains largely unknown.To explore the efficacy of parenteral oxycodone vs. morphine by continuous infusion over 24 hours in cancer patients with terminal dyspnea.This was a pre-planned subgroup analysis of a multicenter prospective observational study. Inclusion criteria were advanced cancer patients admitted to palliative care units, Eastern Cooperative Oncology Group performance status = 3-4, and a dyspnea intensity ≥2 on the Integrated Palliative care Outcome Scale (IPOS) for which oxycodone or morphine was initiated by continuous infusion. We measured dyspnea IPOS scores over 24 hours.We analyzed 164 patients who received oxycodone (n = 26) and morphine (n = 138) for dyspnea (median survival = 5 days). The mean age was 70 years, 58 patients (35%) had lung cancer, and 97 (59%) had lung metastases. Complete case analysis revealed that mean dyspnea IPOS scores decreased from 3.0 (standard deviation = 0.7) to 1.5 (0.7) in the oxycodone group (difference in means = 1.5; P 0.001), and from 2.9 (0.7) to 1.6 (1.0) in the morphine group (difference in means = 1.3; P 0.001). No significant between-group differences existed in the IPOS scores at 24 hours (P = 0.753). Adverse events were seen in no and 5 patients in the oxycodone and morphine groups, respectively.Parenteral oxycodone may be equally effective and safe as morphine in the treatment of terminal dyspnea in cancer patients. Future randomized controlled trials should confirm the efficacy and safety of opioids other than morphine for terminal dyspnea.

Purpose:This study aimed to identify factors associated with specialized palliative care (SPC) use and aggressive care at the end of life (EOL) among Japanese patients with advanced cancer. Methods:This single-center, follow-up cohort study involved patients with advanced cancer who received chemotherapy at Tohoku University Hospital. Patients were surveyed at enrollment, and we followed clinical events for 5 years from enrollment in the study. We performed multivariate logistic regression analysis to identify independent factors related to SPC use and chemotherapy in the last month before death.Results:We analyzed a total of 135 patients enrolled between January 2015 and January 2016. No patients were admitted to the intensive care unit, and few received resuscitation or ventilation. We identified no factors significantly associated with SPC use. Meanwhile, younger age (20–59 years, odds ratio [OR] 4.10; 95% confidence interval [CI] 1.30–12.91; p=0.02) and no receipt of SPC (OR 4.32; 95% CI 1.07–17.37; p=0.04) were associated with chemotherapy in the last month before death.Conclusion:Younger age and a lack of SPC were associated with chemotherapy at the EOL in patients with advanced cancer in Japan. These findings suggest that Japanese patients with advanced cancer may benefit from access to SPC.

Background: Some factors associated with spiritual well-being in dying patients have previously been reported. However, there has been no cross-cultural study comparing factors related to spiritual well-being. The current investigation may shed light on this under-investigated area through a comparison of diverse factors. Aim: We aimed to (1) examine factors associated with spiritual well-being in the last days and (2) compare those factors across three East Asian countries. Design: This is an international multicenter prospective cohort study. Setting/participants: Newly admitted inpatients with far advanced cancer in palliative care units in Japan, Korea and Taiwan were enrolled. Each patient was classified into one of two groups based on spiritual well-being score in the last days of life. Univariate and multivariate analyses were performed to identify the factors related to better spiritual well-being score in each country. Results: A total of 1761 patients treated at 37 palliative care units from January 2017 to September 2018 were analyzed. Seven variables were significant in Japan, three in Korea, and five in Taiwan. “Good death scale [acceptance],” “fatigue” and “expressed wish for hastened death” were unique in Japan. “Visit from a pastoral care worker within 48 h of death” was unique in Korea. “Patient’s preferences for place of death,” “dyspnea” and “continuous deep sedation” were unique in Taiwan. Conclusions: This study found novel factors related to spiritual well-being in the last days of life, several of which differed according to country. Recognition of factors associated with spiritual well-being can improve the quality of palliative care.

Purpose: It is important for palliative care providers to identify what factors are associated with "good death" for patients with advanced cancer. We aimed to clarify factors associated with "good death" evaluated by the Good Death Scale (GDS) score among inpatients with advanced cancer in palliative care units (PCUs) in Japan. Methods: The study is a sub-analysis of a multicenter prospective cohort study conducted in Japan. All variables were recorded on a structured data collecting sheet designed for the study. We classified each patient into better GDS group or worse GDS group, and examined factors associated with better GDS using multivariate analysis. Results: Between January to December in 2017, 1896 patients were enrolled across 22 PCUs in Japan. Among them, a total of 1157 patients were evaluated. Five variables were significantly associated with a better GDS score in multivariate analysis: preferred place of death at PCU (odds ratio [OR] 2.85; 95% confidence interval [CI] 1.72–4.71; p p p p p = 0.03). Conclusions: We clarified factors associated with "good death" using GDS among advanced cancer patients in Japanese PCUs. Recognition of factors associated with GDS could improve the quality of end-of-life care.

ObjectivesTo clarify the relationship between Phase of Illness at the time of admission to palliative care units and symptoms of patients with advanced cancer.MethodsThis study was a secondary analysis of the East Asian collaborative cross-cultural Study to Elucidate the Dying process. Palliative physicians recorded data, including Phase of Illness, physical function and the Integrated Palliative care Outcome Scale. We used multinomial logistic regression to analyse ORs for factors associated with Phase of Illness. Twenty-three palliative care units in Japan participated from January 2017 to September 2018.ResultsIn total, 1894 patients were analysed—50.9% were male, mean age was 72.4 (SD±12.3) years, and Phase of Illness at the time of admission to the palliative care unit comprised 177 (8.9%) stable, 579 (29.2%) unstable, 921 (46.4%) deteriorating and 217 (10.9%) terminal phases. Symptoms were most distressing in the terminal phase for all items, followed by deteriorating, unstable and stable (pConclusionOur study is reflective of the situation in palliative care units in Japan. Future studies should consider the differences in patients’ medical conditions and routinely investigate patients’ Phase of Illness and symptoms.Trial registrarion numberUMIN000025457

Background The study aimed to clarify the efficacy of the “3‐Day Surprise Question (3DSQ)” in predicting the prognosis for advanced cancer patients with impending death. Patients and Methods This study was a part of multicenter prospective observational study which investigated the dying process in advanced cancer patients in Japan. For patients with a Palliative Performance Scale ≤20, the 3DSQ “Would I be surprised if this patient died in the next 3 days?” was answered by their physicians. In addition to the sensitivity and specificity of the 3DSQ, the characteristics of patients who survived longer than expected were examined via multivariate analysis. Results Among the 1896 patients enrolled, 1411 were evaluated. Among 1179 (83.6%) patients who were classified into the “Not surprised” group, 636 patients died within 3 days. Among 232 (16.4%) patients of “Yes surprised” group, 194 patients lived longer than 3 days. The sensitivity, specificity, positive predictive value, and negative predictive value of the 3DSQ were 94.3% (95% confidence interval [CI]: 92.7% to 95.8%), 26.3% (95% CI: 24.8% to 27.6%), 53.9% (95% CI: 53.0% to 54.7%), and 83.6% (95% CI: 78.7% to 87.7%), respectively. Multivariate analysis showed palpable radial artery, absent respiration with mandibular movement, SpO2 ≥ 90%, opioid administration, and no continuous deep sedation as characteristics of patients who lived longer than expected. Conclusions The 3‐Day Surprise Question can be a useful screening tool to identify advanced cancer patients with impending death., Survival prediction in cancer patients with impending death is important for patients, families, and physicians. The 3‐Day Surprise Question can be a useful screening tool to identify advanced cancer patients with impending death.

Spiritual well-being is very important in patients undergoing palliative care. Although psychosocial factors have been suggested to be associated with spiritual well-being, the relationship between physical signs and spiritual well-being has not been fully elucidated. The aim of this study was to explore diverse factors associated with spiritual well-being among palliative care patients in Japan. This study is a secondary analysis of a multicenter prospective cohort study involving patients admitted to palliative care units in Japan. Physicians recorded all data prospectively on a structured sheet designed for the study. The spiritual well-being score was measured using the Integrated Palliative Outcome Scale after patients’ death in regard to symptoms over the previous 3 days. We classified each patient into “better” score (0–1) and “worse” score (2–4) groups and examined diverse factors associated with spiritual well-being. Among the 1896 patients enrolled, 1313 were evaluated. In the multivariate analysis, seven variables were significantly associated with “worse” score: worse spiritual well-being on admission (2–4) (p < 0.0001), younger age (< 80) (p = 0.0001), hyperactive delirium over 3 days before death (mild/moderate/severe) (p = 0.0001), expressed wish for hastened death (yes) (p = 0.0006), worse communication among patients and families (Support Team Assessment Schedule score 2–4) (p = 0.0008), pleural effusion (present) (p = 0.037), and marital status (unmarried) (p = 0.0408). Recognizing factors associated with spiritual well-being is potentially useful for identifying high-risk groups with lower spiritual well-being at the end of life. Further study is required to investigate factors associated with patient-reported spiritual well-being.

Background Although adjuvant analgesics are used to treat opioid-refractory cancer pain, there is insufficient evidence to support this practice and limited data to guide the choice depending on cancer pain pathophysiology, dose titration and starting dose. This survey aimed to clarify the current use of adjuvant analgesics for treating opioid-refractory cancer pain. Methods In this cross-sectional study, we sent an online survey questionnaire to 208 certified palliative care specialists. Primary outcomes were (i) effective pathophysiological mechanism of cancer pain and (ii) initiating doses and time period to the first response to each adjuvant analgesic therapy. Results In total, 87 (42%) palliative care specialists responded. Of all patients with cancer pain, 40% of patients (median) with refractory cancer pain were prescribed adjuvant analgesics. Additionally, 94.3, 93.1 and 86.2% of palliative care specialists found dexamethasone/betamethasone effective for neuropathic pain caused by tumor-related spinal cord compression, pregabalin effective for malignant painful radiculopathy and dexamethasone/betamethasone effective for brain tumor or leptomeningeal metastases-related headache, respectively. The median starting dose of pregabalin, dexamethasone/betamethasone, lidocaine and ketamine were 75, 4, 200, and 50 mg/day, respectively, and the median time to the first response of those medications were 5, 3, 2 and 3 days, respectively. Conclusions Many palliative care specialists select adjuvant analgesics depending on the pathophysiological mechanism of cancer pain in each case. They used such adjuvant analgesics in low doses for cancer pain with short first-response periods.

Background: Continuous deep sedation is ethically controversial with respect to whether it shortens a patient’s life. Aim: To examine whether continuous deep sedation shortens patient survival from the day of Palliative Performance Scale decline to 20 (PPS20). Design: A part of a multicenter prospective cohort study (EASED study). Setting/participants: We recruited consecutive adult patients with advanced cancer admitted to 23 participating palliative care units in 2017 in Japan. We compared survival from PPS20 between those who did and did not receive continuous deep sedation. Continuous deep sedation was defined as the continuous administration of sedative medication with the intention to keep a patient continuously unconscious to alleviate otherwise uncontrollable symptoms, but the dose of sedatives was adjusted to achieve adequate symptom relief for each patient. The propensity score-weighting method was used to control for potential confounders, and five sensitivity analyses were performed. Results: A total of 1926 patients were enrolled. Patients discharged alive were excluded, and we analyzed 1625 patients of whom 156 (9.6%) received continuous deep sedation. Median survival from PPS20 of 1625 patients was 81 h (95% CI: 77–88). The RASS scores decreased to ⩽−4 was 66% at 24 h. Continuous deep sedation was not associated with a significant survival risk (adjusted hazard ratio: 1.06, 95% CI: 0.85–1.33). All sensitivity analyses, including continuous deep sedation defined as the RASS score was ⩽−4 achieved the essentially the same results. Conclusions: Continuous deep sedation with careful dose adjustment was not associated with shorter survival in the last days of life in patients with advanced cancer.

Background: Symptoms are not typically part of established various prognostic factors and scoring systems but are among the most frequently assessed issues in patient care. Objectives: To evaluate ...

Purpose:No study has been conducted to compare the clinicians’ prediction of survival (CPS) with Palliative Prognostic Scores (PaP) across countries. We aimed to compare the performance of the CPS in PaP (PaP-CPS), the PaP without the CPS, and the PaP total scores in patients with advanced cancer in three East Asian countries.Methods:We compared the discriminative accuracy of the three predictive models (the PaP-CPS [the score of the categorical CPS of PaP], the PaP without the CPS [sum of the scores of only the objective variables of PaP], and the PaP total score) in patients in Japan, Korea, and Taiwan. We calculated the area under the receiver operating characteristic curve (AUROC) for 30-day survival to compare the discriminative accuracy of these three models.Results:We analyzed 2,072 patients from three countries. The AUROC for the PaP total scores was 0.84 in patients in Japan, 0.76 in Korea, and 0.79 in Taiwan. The AUROC of the PaP-CPS was 0.82 in patients in Japan, 0.75 in Korea, and 0.78 in Taiwan. The AUROC of the PaP without the CPS was 0.75 in patients in Japan, 0.66 in Korea, and 0.67 in Taiwan.Conclusion:The PaP total scores and the PaP-CPS consistently showed similar discriminative accuracy in predicting 30-day survival in patients in Japan, Korea, and Taiwan. It may be sufficient for experienced clinicians to use the CPS alone for estimating the short-term survival (less than one month) of patients with far-advanced cancer. The PaP may help to improve prognostic confidence and further reduce subjective variations.

Management of nausea is an important dimension of palliative care. The first choice for treating nausea is antiemetics, but their efficacy is inadequate. Acupressure intervention for nausea in cancer patients has been studied as a non-pharmacological therapy, and appears to have had some effect. However, such a therapy has not been well reviewed in patients with terminal cancer. The purpose of this study was to clarify the feasibility of acupressure intervention and examine its safety and preliminary efficacy. We recruited cancer patients that fulfilled the eligibility criteria and were admitted to the palliative care unit, from August 2018 to February 2019, in Tohoku University Hospital, Japan. We conducted a longitudinal assessment of acupressure intervention in a single arm. We identified the patient's research accomplishments and evaluated possible fainting due to the vagal reflex and symptom severity. Descriptive statistics were used to calculate the completion rate for the feasibility and Wilcoxon signed-rank tests to compare the average of continuous variables for the safety and efficacy. Twelve patients participated in this study and completed the procedure. Their average age was 70 years (SD = 9.3), and the most common primary cancer sites were the rectum and pancreas. The blood pressure and pulse rate did not drop sharply. Four patients exhibited decreased nausea but there was no statistically significant difference (P = 0.5). We suggested that acupressure has high feasibility and safety, as an intervention for patients with terminal cancer. However, no significant differences were observed regarding its effect on nausea.

Few studies have investigated appropriate referral timing of specialized palliative care (SPC) from the perspective of cancer patients’ and families’ experiences. We aimed to clarify appropriate SPC referral timing for patients with advanced cancer and their families. We used data from a nationwide bereaved family survey in Japan. We sent a questionnaire to 999 bereaved families of cancer patients who died in 164 palliative care units (PCUs) and analyzed the first SPC referral timing and how patients evaluated it. We defined SPC as outpatient or inpatient palliative care service comprising certified palliative care physicians, advanced-practice nurses, and multidisciplinary practitioners. Finally, 51.6% (n = 515) of all responses were analyzed. The SPC referral timing was evaluated as appropriate (26.1%), late or too late (20.2%), early or too early (1.2%), and none of these (52.5%). Of these, 32.3% reported that they were referred to an SPC when diagnosed with advanced or incurable cancer or during anti-cancer treatment, and 62.6% reported they were referred after anti-cancer treatment. Patient-perceived appropriateness of SPC referral timing was associated with their good death process. After excluding “none of these” responses, a significantly higher proportion of respondents who reported being referred to SPC at diagnosis and during anti-cancer treatment evaluated the response timing as appropriate, compared to those who reported being referred after anti-cancer treatment. Appropriate timing for SPC referrals relates to quality of death; findings suggest that appropriate timing is at the time of diagnosis or during anti-cancer treatment.

Background We aimed to investigate the performance of clinician prediction of survival (CPS) and the association between CPS and the prognostic confidence of clinicians in ambulatory medical oncology outpatients. Methods Eight medical oncologists estimated the expected survival of their patients in a prospective cohort study. They were asked to provide a temporal type of CPS in weeks, together with their level of confidence for each prediction (0–100%). We analyzed the accuracy of CPS, the association between CPS and the prognostic confidence, and the characteristics of patients showing inaccurate CPS. Results A total of 200 advanced cancer patients were enrolled and the median overall survival was 7.6 months. CPS was accurate in 67 (33.5%) patients, underestimated in 87 (43.5%), and overestimated in 46 (23.0%). The overall accuracy of CPS for 12-week, 24-week, 36-week, and 48-week survival was 83.0%, 72.0%, 75.5%, and 74.0%, respectively. The specificity was highest for 12-week survival (90.2%) and the sensitivity was highest for 48-week survival (96.1%). The sensitivity of 12-week CPS was 51.4% and the area under the receiver operating characteristic (AUROC) curve was 0.79 (95% confidence interval [CI] 0.71–0.87). The prognostic confidence of clinicians was not significantly associated with the accuracy of prediction (P = 0.359). Patients with overestimated survival had significantly poorer global health status and physical/role/emotional functioning in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Additionally, they showed significantly higher levels of fatigue, nausea/vomiting, pain, dyspnea, and loss of appetite. Conclusion The overall accuracy of CPS in predicting 12-week to 48-week survival was high in medical oncology outpatients. However the sensitivity of 12-week CPS was low and prognostic confidence was not associated with the accuracy of CPS. Patients with overestimated CPS showed poorer quality of life and higher symptom burden.

12029 Background: Prognosis is said to worsen when systemic anti-cancer therapy (SACT) is administered until a patient’s end of life (EOL) and professional palliative care is delayed. However, the prognostic impact of SACT at EOL is unclear. Methods: In this pre-planned secondary analysis of a multicenter, prospective East Asian cross-cultural collaborative cohort study, consecutive patients with advanced cancer admitted to palliative care units between January and December 2017 were divided into four groups: patients who had and had not received SACT (SACT vs. non-SACT) and patients whose last administration of SACT was before or within 1 month of study enrolment (non-1M SACT vs. 1M SACT). The primary endpoint was difference in survival time from a palliative performance scale (PPS) of < 20 to death between the SACT and non-SACT groups, and the 1M SACT and non-1M SACT groups. The analysis was adjusted for age; sex; primary cancer site; metastatic site; comorbidity (Charlson comorbidity index); and history of radiotherapy, smoking, and psychiatric disorders. Weighting for inverse probability of treatment was applied. A secondary endpoint was to identify EOL symptom and care factors prognostic for survival time using a Cox proportional hazards model. Results: The 1396 study patients (712 men, 684 women; median age: 73 years) came from 21 institutions throughout Japan. Primary tumor sites were upper gastrointestinal (471 patients), lower gastrointestinal (193 patients), lung (241 patients), breast (93 patients), urologic (101 patients), gynecologic (82 patients), head and neck (56 patients), central nervous system (25 patients), and hematologic (39 patients). Metastatic sites were liver (554 patients), lung (522 patients), bone (373 patients), and brain (199 patients). The SACT, non-SACT, 1M SACT, and non-1M SACT groups consisted of 853, 539, 126, and 1270 patients, respectively. Survival time was significantly shorter in the SACT group (6.83 days, p = 0.03) than in the non-SACT group (9.01 days). No significant difference between the 1M SACT group (7.57 days) and the non-1M SACT group (7.36 days) was evident. Prognostic factors were use of opioids (HR 1.289), antipsychotics (HR 0.787), and anxiolytics (HR 0.867); infusion of more than 1 L daily (HR 0.727); and apnea (HR 0.874), dyspnea (HR 1.874), nausea (HR 0.612), fatigue (HR 1.284), and ascites (HR 1.236). Conclusions: Prognosis was shorter for patients with a history of SACT than for those without a history of SACT at EOL. However, SACT at EOL was not a prognostic factor. This information is useful in advance care planning for selecting and explaining treatment at EOL to patients and their families.

PurposeWe aimed to develop a prognostic model to assist palliative care referral at least 3 months before death in advanced cancer patients treated at an outpatient medical oncology clinic.Materials and MethodsIn this prospective cohort study, a total of 200 patients were enrolled at a tertiary cancer center in South Korea. The major eligibility criterion was an expected survival of less than a year as estimated by their oncologists. We analyzed the influences of known prognostic factors along with chemotherapy status, mid-arm circumference, and triceps skinfold thickness on survival time. ResultsThe mean age of the patients was 64.5 years, 36% were female, and the median survival time was 7.6 months. In the multivariate analysis, we found 6 significant factors related to poor survival: a poor Eastern Cooperative Oncology Group (ECOG) performance status (≥2), not undergoing chemotherapy, anorexia, a low lymphocyte level (

ObjectivesThe present study aims were (1) to identify the proportion of terminally ill cancer patients with desire for hastened death (DHD) receiving specialized palliative care, (2) to identify the reasons for DHD, and (3) to classify patients with DHD into some interpretable subgroups.MethodsAdvanced cancer patients admitted to 23 inpatients hospices/palliative care units in 2017 were enrolled. Data were prospectively obtained by the primarily responsible physicians. The presence/absence of DHD and reasons for DHD were recorded. A cluster analysis was performed to identify patterns of subgroups in patients with DHD.ResultsData from 971 patients, whose Richmond Agitation–Sedation Scale score at admission was zero and who died in palliative care units, were analyzed. The average age was 72 years, common primary cancer sites were the gastrointestinal tract (31%) and the liver/biliary ducts/pancreas (19%). A total of 174 patients (18%: 95% confidence interval, 16–20) expressed DHD. Common reasons for DHD were dependency (45%), burden to others (28%), meaninglessness (24%), and inability to engage in pleasant activities (24%). We identified five clusters of patients with DHD: cluster 1 (35%, 61/173): “physical distress,” cluster 2 (21%, 37/173): “dependent and burdensome,” cluster 3 (19%, 33/173): “hopelessness,” cluster 4 (17%, 30/173): “profound fatigue,” and cluster 5 (7%, 12/173): “extensive existential suffering.”ConclusionsA considerable number of patients expressed DHD and could be categorized into five subgroups. These findings may contribute to the development of therapeutic strategies.

Purpose To investigate the efficacy of two types of palliative sedation: proportional and deep sedation, defined by sedation protocols. Methods From a multicenter prospective observational study, we analyzed the data of those patients who received the continuous infusion of midazolam according to the sedation protocol. The primary endpoint was goal achievement at 4 hours: in proportional sedation, symptom relief (Integrated Palliative care Outcome Scale: IPOS ≤ 1) and absence of agitation (modified Richmond Agitation-Sedation Scale: RASS ≤ 0); in deep sedation, the achievement of deep sedation (RASS ≤ -4). Secondary endpoints included deep sedation as a result of proportional sedation, communication capacity (Communication Capacity Scale item 4 ≤ 2), IPOS and RASS scores, and adverse events. Results A total of 81 patients from 14 palliative care units were analyzed: proportional sedation (n = 64) and deep sedation (n = 17). At 4 hours, the goal was achieved in 77% (n = 49; 95% confidence interval: 66-87) with proportional sedation; and 88% (n = 15; 71-100) with deep sedation. Deep sedation was necessary in 45% of those who received proportional sedation. Communication capacity was maintained in 34% with proportional sedation and 10% with deep sedation. IPOS decreased from 3.5 to 0.9 with proportional sedation, and 3.5 to 0.4 with deep sedation; RASS decreased from +0.3 to -2.6, and +0.4 to -4.2, respectively. Fatal events related to the treatment occurred in 2% (n = 1) with proportional and none with deep sedation. Conclusion Proportional sedation achieved satisfactory symptom relief while maintaining some patients’ consciousness, and deep sedation achieved good symptom relief while the majority of patients lost consciousness.

The purpose of this study was to develop a simple prognostic model based on objective indicators alone, i.e., routine blood test data, without using any subjective variables such as patient’s symptoms and physician’s prediction. The subjects of this retrospective study were patients at the palliative care unit of Tohoku University Hospital, Japan. Eligible patients were over 20 years old and had advanced cancer (n = 225). The model for predicting survival was developed based on Cox proportional hazards regression models for univariable and multivariable analyses of 20 items selected from routine blood test data. All the analyses were performed according to the TRIPOD statement ( https://www.tripod-statement.org/ ). The univariable and multivariable regression analyses identified total bilirubin, creatinine, urea/creatinine ratio, aspartate aminotransferase, albumin, total leukocyte count, differential lymphocyte count, and platelet/lymphocyte ratio as significant risk factors for mortality. Based on the hazard ratios, the area under the curve for the new risk model was 0.87 for accuracy, 0.83 for sensitivity, and 0.74 for specificity. Diagnostic accuracy was higher than provided by the Palliative Prognostic Score and the Palliative Prognostic Index. The Kaplan–Meier analysis demonstrated a survival significance of classifying patients according to their score into low-, medium-, and high-mortality risk groups having median survival times of 67 days, 34 days, and 11 days, respectively (p

Providing spiritual care in light of a patient's religious and/or spiritual background can help improve the quality of end-of-life care. Rinsho-shukyo-shi is a Japanese interfaith chaplain who provides religious and spiritual care to patients. In this study, we qualitatively explore the impressions of patients in a palliative care unit of the activities of an interfaith chaplain in a hospital in Japan. The authors used semi-structured interviews carried out by a male nurse experienced in qualitative and quantitative research in palliative care. The male nurse asked only a few predetermined questions in the interviews, which were conducted from January 19 to December 26, 2018. The interviewees were 15 patients diagnosed with advanced cancer (five men and 10 women; aged 53-81 years), and they were admitted to the palliative care unit of Tohoku University Hospital (the hospital has no religious affiliation). Patients who had spoken to the interfaith chaplain at the hospital at least twice were included in the study. The interviews were digitally audio-recorded, transcribed verbatim, and analyzed. Three main themes were identified through thematic analysis. Resistance varied across patients; no patient felt resistance to the intervention by, or to the presence of, the interfaith chaplain once he/she had spoken with him. Opinions about the interfaith chaplain also varied, with 10 patients claiming that his role was necessary for end-of-life care and beneficial for the chaplain himself. Finally, the patients' religious beliefs varied widely. In conclusion, the interfaith chaplain is deemed helpful by the interviewed patients in relieving their anxieties.

The benefits of artificial nutrition and hydration in patients with advanced cancer remain unknown. Therefore, we conducted a prospective study to evaluate effects of enteral nutrition (EN) and parenteral nutrition and hydration (PNH) on survival in palliative care units.This study involved a secondary analysis of a multicenter cohort study. Data of primary nutritional administration routes during the first week after admission (oral intake, enteral tube feeding, parenteral nutrition, parenteral hydration, poor oral intake) were obtained. Data of averaged calorie sufficiency rate/total calorie intake [high (75% ≤ or 750 kcal/day ≤), moderate (50-75% or 500-750 kcal/day), low (25-50% or 250-500 kcal/day), very low (25% or250 kcal/day)] were also obtained. After investigating the implementation of artificial nutrition and hydration, participants were divided into three groups according to the nutritional administration route and calorie sufficiency rate/total calorie intake: EN, PNH, and control. We conducted time-to-event analyses using the Kaplan-Meier method, log-rank test, and univariate and multivariate Cox regression analyses.Patients were divided into the EN group (n = 730), PNH group (n = 190), and control group (n = 533). Differences in survival rates among the three groups were significant (Log-rank P 0.001). Median survival times were 43.0 (95% CI 40-46), 33.0 (95% CI 29-37), and 15.0 (95% CI 14-16) days, respectively (P 0.001). In the multivariate-adjusted model, a significantly lower risk of mortality was observed in Cox's proportional hazard model in the EN group and PNH groups (HR 0.43 [95% CI 0.37-0.49], P 0.001; and HR 0.52 [95% CI 0.44-0.62], P 0.001, respectively) than in the control group.This study indicated the clinical benefits of EN and PNH for patients with advanced cancer. Nevertheless, managing symptoms to improve oral intake is essential before initiation of PNH, because EN was superior to PNH.

Background: Continuous deep sedation (CDS) is ethically controversial with respect to whether it shortens a patient’s life. Previous studies reported no significant difference in survival from admission or enrolment into a palliative care program to death between patients treated with and without CDS. However, these baselines are too distant from the initiation of CDS to detect the effect of CDS on survival. We aimed to examine whether CDS shortens patient survival from the day of Palliative Performance Scale decline to 20 (PPS20). Methods: This study was a part of a multicenter prospective cohort study that recruited patients between Jan. and Dec. 2017 in Japan (EASED study). Consecutive Adult patients with advanced cancer admitted to 23 participating inpatient palliative care units were eligible for this analysis. We compared survival from PPS20 between those who did and did not receive CDS. We used the inverse probability of treatment weighting method to control for potential confounders of patient characteristics, complications and laboratory data at admission, and symptoms at PPS20. Findings: A total of 1926 patients were enrolled. Of these, patients discharged alive were excluded, and finally we analyzed 1625 patients of whom 156 (9.6%) received CDS. Median survival from PPS20 of 1625 patients was 3.4 days (95% CI: 3.2-3.7). CDS was not associated with a significant survival risk from PPS20 (adjusted hazard ratio: 1.06, 95% CI:0.85–1.33; p = 0.595). In exploratory subgroup analyses, a significant survival risk was not observed in any subgroup except for those with primary lung cancer and agitated delirium. Interpretation: CDS was not associated with shorter survival in the last days of life in patients with advanced cancer, and CDS had no measurable effects on survival. Our findings may relieve the concern of patients, families, and physicians that CDS might shorten survival. Funding Statement: This work was supported by Grant-in-Aid from the Japanese Hospice Palliative Care Foundation and in part by JSPS KAKENHI Grant number JP19H03869. Declaration of Interests: No relevant conflict of interest to declare. Ethics Approval Statement: This study was conducted in accordance with the ethical standards of the Helsinki Declaration and the ethical guidelines for epidemiologic research of the Ministry of Health, Labour and Welfare of Japan. The local institutional review boards of all participating institutions approved this study. Japanese law does not require individual informed consent from participants in a non-invasive observational trial such as this. Therefore, we used an opt-out method rather than acquiring written or oral informed consent.