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Dyspnea is one of the most common and distressing symptoms in patients with cancer and noncancer advanced diseases. The Japanese Society for Palliative Medicine revised previous guidelines for the management of respiratory symptoms in patients with cancer and newly developed clinical guidelines for managing dyspnea in patients with advanced disease, based on the result of systematic reviews for each clinical question and consensus among experts. We describe the recommendations of the guidelines as well as provide insights into the reasoning behind the recommendations and their development process. There has been a paucity of evidence regarding the interventions for dyspnea in patients with advanced disease. Thus, more clinical research that includes not only randomized controlled trials but also real-world observational studies is warranted.

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Dyspnea is a prevalent symptom that significantly reduces quality of life of cancer patients. Palliative treatment is necessary when the symptoms do not respond to treatment for their cause. Opioids are widely used as pharmacological therapy, but evidence for individual agents is inconsistent. The purpose of this study was to evaluate the efficacy and safety of opioids for dyspnea in cancer patients. We searched the CENTRAL, MEDLINE, EMBASE, and ICHUSHI for studies using opioids for dyspnea in adult cancer patients reported by September 2019. Screening of the retrieved literature and assessment of risk of bias and outcomes were performed by two independent authors. A meta-analysis was performed on the primary endpoint, relief of dyspnea, and secondary endpoints including quality of life, somnolence as a side effect, and serious adverse events. Twelve randomized controlled trials were evaluated regarding relief of dyspnea. Somnolence and serious adverse events were evaluated in seven and four randomized controlled trials, respectively, but no randomized controlled trials were evaluable for quality of life. Overall, opioids were more effective than placebo for dyspnea (standardized mean difference - 0.43, 95% confidence interval [CI] - 0.75 to - 0.12). Although significant difference was found between systemic morphine and placebo in the drug-specific analysis, no significant difference could be detected in the other analyses. Systemic administration of opioids is more effective than placebo in relieving dyspnea in cancer patients. Robust evidence on the efficacy and safety of opioids on dyspnea in cancer patients is lacking, and further studies are needed.

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BACKGROUND: Supplemental oxygen is widely used for dyspnea relief; however, its efficacy is yet to be verified. This study aimed to determine the efficacy of supplemental oxygen for dyspnea relief in patients with advanced progressive illness. METHODS: In this systematic review, several databases, including MEDLINE and EMBASE, were searched to identify eligible randomized controlled trials (RCTs) on the topic published up to September 23, 2019. The search criteria included RCTs investigating patients with advanced progressive illness (advanced cancer, chronic obstructive pulmonary disease, and chronic heart failure). The study protocol was registered with PROSPERO (No. CRD42020161838). Separate analyses were pre-planned regarding the presence or absence of resting hypoxemia. RESULTS: RCTs investigating supplemental oxygen for dyspnea relief in participants with and without resting hypoxemia (39 and five, respectively) were included in the study. Heterogeneity of supplemental oxygen for dyspnea in RCTs, including participants without resting hypoxemia was evident; hence, post-hoc analyses in four subgroups (supplemental oxygen during exercise or daily activities, short-burst oxygen, continuous supplemental oxygen, and supplemental oxygen during rehabilitation intervention) were conducted. In the meta-analysis, supplemental oxygen during exercise was found to improve dyspnea in patients without resting hypoxemia compared with that in the control (standardized mean difference = -0.57, 95% confidence interval = -0.77 to -0.38). However, supplemental oxygen for the other subgroups failed to improve patients' dyspnea. CONCLUSION: The results of this systematic review do not support supplemental oxygen therapy for dyspnea relief in patients with advanced progressive illness, except during exercise.

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OBJECTIVE: the role of benzodiazepines in relieving dyspnea in patients with cancer has not yet been established. This systematic review and meta-analysis aimed to determine the efficacy and safety of benzodiazepines alone or in combination with opioids for dyspnea in patients with cancer. METHODS: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Ichushi-Web were searched for articles published from database inception to 23 September 2019. Studies of benzodiazepines alone or in combination with opioids for dyspnea were included. The primary outcome measure was the relief of dyspnea. The secondary outcome measures were anxiety, somnolence and severe adverse events. RESULTS: of 505 publications initially identified, two trials and one trial were included in the meta-analysis of midazolam alone and in combination with morphine, respectively. With regard to the relief of dyspnea, midazolam alone showed no significant difference compared with morphine alone, with a relative risk of 0.95 (95% confidence interval: 0.47-1.89). Meanwhile, midazolam plus morphine was significantly more effective than morphine alone, with a relative risk of 1.33 (95% confidence interval: 1.02-1.75). For anxiety relief, a meta-analysis could not be performed because of insufficient data. The incidence of somnolence and severe adverse events was not significantly different between the experimental and control groups for either midazolam alone or in combination with morphine. CONCLUSIONS: benzodiazepines alone do not significantly improve dyspnea compared with opioids alone, but a combination of benzodiazepines and opioids may be more effective. Evidence from randomized controlled trials focusing on patients with cancer has not been generated in recent years. Further appropriately designed randomized controlled trials are required.

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Pain control becomes poor in some cases after opioid switching from oxycodone tablet (OXC) to fentanyl patch (FP). However, fewer studies on risk factors have been reported. In this study, we surveyed the states of pain control (PC) and opioid administration, patient background, laboratory test values, and concomitant drugs retrospectively in 86 patients switching from OXC to FP between June 2010 and April 2018 in Mazda Hospital and Hiroshima Prefectural Hospital. The subjects were divided into 2 groups based on the median number of days to the initial dose increase after switching to FP. Between the early (<7.5 d) and late (≥7.5 d) increase groups, a significant difference was noted in the presence or absence of liver metastasis (LM), concomitant drugs with a high protein binding rate (CDHPBR), and the state of PC before and after switching to FP (p < 0.05). Binary logistic regression analysis showed the presence of CDHPBR, absence of LM, and poor PC after switching were risk factors for early dose increase (presence of CDHPBR: odds ratios (OR), 3.30, 95% confidence interval (CI), 1.09-9.98; presence of LM: OR, 0.31, 95% CI, 0.10-0.93; good PC: OR, 0.23, 95% CI, 0.07-0.79, respectively). The initial dose increase after switching to FP was earlier in patients with CDHPBR and/or without LM than those without CDHPBR and with LM (p < 0.05, log-rank test). It was suggested that the analgesic effect of FP after switching from OXC is likely to be insufficient in patients treated with CDHPBR and patients without LM.

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Wistar Hannover rats, which are maintained by three animal breeders in Japan, were examined to obtain basic data on reproductive and developmental parameters. Untreated pregnant females were terminated on gestational day 20, and the fetuses were removed by cesarian section. The fetuses were counted, weighed and examined for morphological abnormalities. There were few differences among the three stocks of Wistar Hannover rats on the numbers of implantations and live fetuses, sex ratio and fetal weights. The most common fetal abnormalities were the presence of left-sided umbilical arteries, supernumerary ribs and wavy ribs. The incidences of these abnormalities were different among the three stocks of Wistar Hannover rats. Our results provide important data which should be considered in the determination of which stock of rat is used in developmental studies.

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The volatile components of both peel and juice of Japanese citrus, Kabosu (Citrus sphaerocarpa Hort. ex Tanaka) were investigated using SAFE (Solvent Assisted Flavor Evaporation) technique after solvent extraction. In this study, wine lactone, rose oxide, (2E)-4,5-epoxy-2-decenal, mintsulfide, and indole were newly identified from Kabosu. AEDA (Aroma Extract Dilution Analysis) of the oxygenated fraction of the peel extract showed high FD (Flavor Dilution) factors for linalool, (2E)-4,5-epoxy-2-decenal, octanal, (4Z)-decenal, beta-citronellol, geraniol, and wine lactone, while wine lactone, linalool, eugenol, geraniol, and (2E)-4,5-epoxy-2-decenal from the juice extract. The enantiomeric distribution of linalool, cis-rose oxide, beta-citronellol, and wine lactone were also determined using a multidimensional chiral GC/MS.

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