Relationship between dyspnoea and related factors in patients with cancer: a cross-sectional study.

OBJECTIVES: Dyspnoea is a common and distressing symptom in patients with cancer. We aimed to analyse the association between dyspnoea and related factors and to estimate their causal relationship. METHODS: A cross-sectional study was conducted. Patients with cancer with dyspnoea and a mean Numerical Rating Scale (NRS) of ≥3 over 24 hours were enrolled at 10 institutions in Japan from December 2019 to February 2021. The outcomes included dyspnoea, cough and pain NRS over 24 hours, Eastern Cooperative Oncology Group Performance Status, Hospital Anxiety and Depression Scale, Somatosensory Amplification Scale, opioids for dyspnoea and respiratory failure. Path analyses were conducted to estimate the direct and indirect paths with reference to dyspnoea and related factors. RESULTS: A total of 209 patients were enrolled and 208 patients were included in the analysis. Cough worsened dyspnoea (ß=0.136), dyspnoea increased emotional distress (ß=1.104), emotional distress increased somatosensory amplification (ß=0.249) and somatosensory amplification worsened cough (ß=0.053) according to path analysis. CONCLUSION: There may be a vicious circle among dyspnoea and related factors: cough worsened dyspnoea, dyspnoea increased emotional distress, emotional distress increased somatosensory amplification and somatosensory amplification worsened cough. When treating dyspnoea in patients with cancer, managing these factors aimed at interrupting this vicious circle may be useful. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000038820).

Psychological symptom burden associated with malignant wounds: Secondary analysis of a prospective cohort study.

OBJECTIVES: Patients with malignant wounds suffer from physical and psychological symptom burden. Despite psychological support being required, the impact of malignant wounds on patients' psychological distress is poorly investigated. We evaluated psychological distress associated with malignant wounds for patients at their end of life. METHODS: This study used the secondary analysis of the results of a large prospective cohort study, which investigated the dying process among patients with advanced cancer in 23 palliative care units in Japan. The primary outcome of this study was the prevalence of moderate to severe psychological symptom burden, evaluated by the Integrated Palliative Care Outcome Scale (IPOS)-feeling at peace scores of 2-4. In addition, the factors affecting psychological symptoms were investigated. The quality of death was also evaluated upon death using the Good Death Scale score. RESULTS: Out of the total 1896 patients, 156 had malignant wounds (8.2%). Malignant wounds were more common in female and young people. The breast, head, and neck were the most prevalent primary sites. More patients with malignant wounds had IPOS-feeling at peace scores of 2-4 than patients without malignant wounds (41.0% vs. 31.3%, p = 0.024). Furthermore, psychological distress was associated with moderate to severe IPOS-pain and the frequency of dressing changes. The presence of malignant wounds did not affect the quality of death. SIGNIFICANCE OF RESULTS: This study showed increased psychological distress due to malignant wounds. Patients with malignant wounds require psychological support in addition to the treatment of physical symptoms for maintaining their quality of life.

Visualizing How to Use Antipsychotics for Agitated Delirium in the Last Days of Life.

CONTEXT: How physicians use antipsychotics for agitated delirium in the last days of life varies markedly, which could hamper the quality of care. OBJECTIVES: To examine adherence to an algorithm-based treatment for terminal agitated delirium, and explore its effectiveness and safety. METHODS: A single-center, prospective, observational study was conducted in a 27-bed palliative care unit in Japan. All adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS) of +1 or more were included; the palliative care specialists determined that the etiology was irreversible, the estimated survival was three weeks or less, and the Eastern Cooperative Oncology Group (ECOG) performance status was three or four. Patients were treated with an algorithm to visualize how to use antipsychotics, with the treatment goal defined as no agitation (RASS≤0) or acceptable agitation for patients and families. We provided all patients nonpharmacological management to alleviate the symptoms of delirium and administered antipsychotic medications when the nonpharmacological approach was insufficient. We measured the adherence rate, RASS, Nursing Delirium Screening Scale items 2, 3, 4 (Nu-DESC), and Agitation Distress Scale item 2 (ADS) on days 0, 1, 3, 7, 14, 21, and 24 hours before death. RESULTS: A total of 164 patients were enrolled. Adherence rates were 99, 94, and 89%, and treatment goals were achieved in 66, 83, and 93% on days one, three, and seven, respectively. The mean RASS decreased from +1.41 to -0.84 on day three; Nu-DESC decreased from 4.19 to 1.83, and ADS decreased from 1.54 to 0.38. There were seven severe adverse events (Common Terminology Criteria for Adverse Events (CTCAE) of 3), including aspiration (n = 3), apnea (n = 2), tremor (n = 1), and muscle rigidity (n = 1) on day three. CONCLUSION: The algorithm-based treatment could be feasible, effective, and safe. Visualizing how palliative care specialists provide pharmacological management could be beneficial for nonspecialist clinicians, and clinical, educational, and research implications warrant further empirical testing.

Systemic Opioids for Dyspnea in Cancer Patients: A Real-world Observational Study.

CONTEXT: Although Systemic opioids are recommended as a pharmacological treatment for cancer-related dyspnea, their effectiveness and safety needs to be investigated in a real-world context OBJECTIVES: To evaluate the effectiveness and safety of systemic regular opioids for dyspnea in cancer patients, in the real-world palliative care practice. METHODS: This was a multicenter prospective observational study. We consecutively enrolled adult cancer patients starting regular opioids (morphine, oxycodone, hydromorphone, or fentanyl) for dyspnea from 12 palliative care services across Japan. We evaluated dyspnea intensity using the Numerical Rating Scale (NRS) and Integrated Palliative Outcome Scale (IPOS) every 24 hours until 72 hours after starting opioids (T1-T3). We also evaluated common opioid-related adverse events (AEs) and other severe AEs. RESULTS: We enrolled 402 cancer patients. The proportion of responders was 68.8% (95%confidence intervals (CI): 0.63-0.74) at T1, 75.7% (95%CI: 0.70-0.81) at T2, and 82.1% (95%CI: 0.76-0.87) at T3. The mean differences in dyspnea NRS from baseline were 1.73 (95%CI: 1.46-1.99) at T1, 1.99 (95%CI: 1.71-2.28) at T2, and 2.47 (95%CI:2.13-2.82) at T3. The most common treatment-emergent AE was somnolence with an incidence of the severe form of approximately 10% throughout the study period. In the multivariate analysis, baseline dyspnea NRS ≥6 had a positive correlation with dyspnea relief by systemic regular opioids, while liver metastasis, clinician-predicted survival days, and opioid tolerance had a negative correlation. CONCLUSION: Regular systemic opioids were effective for dyspnea in real-world cancer patients.

Beliefs and Perceptions About Parenteral Nutrition and Hydration by Advanced Cancer Patients.

Background: The beliefs and perceptions of parenteral nutrition and hydration (PNH) by advanced cancer patients have not been elucidated. Objectives: To clarify their beliefs and perceptions and to explore the relationships between their beliefs and perceptions and cachexia stages. Design/setting/subjects: A questionnaire survey of advanced cancer patients receiving palliative care across Japan. Measurements: We asked patients to answer 15 items regarding their beliefs and perceptions of PNH. Frequencies were calculated for the patient characteristics and survey parameters. Comparisons were performed using the Mann-Whitney U test. We conducted a factor analysis and a multiple logistic regression analysis to identify the independent factors affecting cancer cachexia stages. Results: Among 495 patients, 378 responded. Due to missing data, 357 remained in the frequency distribution analysis, and 344 were classified into the noncachexia group (n = 174) and cachexia group (n = 170). Approximately 60% thought that PNH were beneficial. Approximately 70% considered PNH a standard medical practice. Approximately 70% did not feel that they received a sufficient explanation. There were no significant differences in any items between the two groups. We extracted four conceptual groups. The concept of "Belief that PNH are harmful" was identified as an independent factor [odds ratio 2.57 (95% confidence intervals 1.10-6.01), p = 0.030]. Conclusion: More than half of the patients thought that PNH were beneficial and standard medical practices with or without cancer cachexia. The negative perception of PNH decreased in patients with cancer cachexia.

Clinical role and safety of tapentadol in patients with cancer: A single-center experience.

OBJECTIVE: To evaluate real-world data on the use of tapentadol (TAP) in cancer patients. DESIGN: Single-center retrospective study. SETTING: Curative/palliative. PATIENTS, PARTICIPANTS: Patients who started TAP between October 2014 and December 2018 at our institution. MAIN OUTCOME MEASURE(S): The primary outcome was the reason for TAP initiation. Secondary outcomes included prescription duration, TAP cessation rate, reason for cessation, and adverse events (AEs). Since the palliative care team (PCT) tended to prescribe to cancer patients with intractable pain more often than patients in usual care, and also tended to prescribe opioids based on their characteristics, we decided to compare patients with and without PCT intervention. RESULTS: There were 175 patients who first received TAP during the study period, of whom 81 patients (46.3 percent) were male. The median age was 60 years. TAP was prescribed for opioid-naive patients in 45 (26 percent) cases and opioid switch in 130 (74 percent) cases. When comparing the PCT group (n = 121) and the non-PCT group (n = 54) using univariate analysis, the PCT group had a higher opioid switch rate (81.8 percent vs 57.4 percent, p < .001), higher proportion of patients with neuropathic pain (NP) (65.3 percent vs 16.7 percent, p < .001), and a higher proportion of patients with a history of nausea (41.3 percent vs 18.5 percent, p < .01). The cessation rate due to AEs was 8 percent overall. CONCLUSIONS: Palliative care physicians prescribed TAP for patients with NP or a history of nausea. Opioid-naive patients were preferred by oncologists. TAP has good tolerability in both groups, with a low dropout rate due to AEs.

Effectiveness and safety of opioids for dyspnea in patients with lung cancer: secondary analysis of multicenter prospective observational study.

Background: Patients with lung cancer are more likely to have comorbidities [e.g., interstitial lung disease (ILD)], chronic obstructive pulmonary disease) and metastases that may affect dyspnea and the effectiveness and safety of opioids for dyspnea than other cancer types. Therefore, this study examined the effectiveness and safety of opioids for dyspnea, among the patients with lung cancer. Methods: The present study is a secondary analysis of a multicenter prospective observational study examining the effectiveness and safety of opioids for dyspnea in patients with cancer in Japan. For this secondary analysis, patients with lung cancer with a documented dyspnea Numerical Rating Scale (NRS) at baseline were included. The primary outcome was dyspnea NRS, and Integrated Palliative care Outcome Scale/Support Team Assessment Schedule (IPOS/STAS) scores change between baseline and 24 hours after baseline. As secondary outcomes, we investigated the predictors of opioid effectiveness for dyspnea improvement and adverse events (nausea, somnolence, and delirium). Results: This study analyzed 124 patients with lung cancer with known dyspnea NRS at baseline. The median age was 74, and the Eastern Cooperative Oncology Group performance status of 107 patients were 3-4. Both NRS and IPOS/STAS score of dyspnea significantly improved 24 hours after opioid initiation [-1.64, 95% confidence interval (CI): -2.12 to -1.17, P<0.001; -1.03; 95% CI: -1.21 to -0.85, P<0.001; respectively]. Moreover, the improvement of NRS score was greater than the minimal clinically important difference of 1 point. In the multivariate logistic regression analysis, ILD was significantly associated with a better improvement [(hazard ratio (HR): 3.39, 95% CI: 1.34-11.09, P=0.043]. Somnolence was the most common grade 3-4 adverse event (n=16), followed by delirium (n=9). Conclusions: Opioids were effective and safe for treating dyspnea in patients with lung cancer. Furthermore, lung cancer patients with ILD may benefit more from opioids.

Patient-perceived symptomatic benefits of olanzapine treatment for nausea and vomiting in patients with advanced cancer who received palliative care through consultation teams: a multicenter prospective observational study.

PURPOSE: To examine the safety, effectiveness, and patient-perceived benefit of treatment with olanzapine for nausea and vomiting (N/V) in patients with advanced cancer. METHODS: We conducted a multicenter prospective observational study in a tertiary care setting (Trial registration number: UMIN000020493, date of registration: 2016/1/12). We measured the following: average nausea in the last 24 h using a Numeric Rating Scale (NRS: range 0-10) at baseline and day 2, patient-perceived treatment benefit (based on a 5-point verbal scale), and adverse events (AEs; using the Common Terminology Criteria for Adverse Events version 4). RESULTS: The 85 participants (45% men) had a mean age of 58.7±15.8 years. Major causes of N/V were opioids (44%) and chemotherapy (34%). All patients received a daily dose of olanzapine of 5 mg or less as first-line treatment (N=35) or second- or later-line treatment (N=50). Nausea NRS decreased from 6.1±2.2 to 1.8±2.0 (differences: -4.3, 95% CI -3.7 to -4.9, p<0.001). The proportion of patients who did not experience vomiting episodes in the last 24 h increased from 40-89%. Mean decrease in nausea NRS by patient-perceived treatment benefit were as follows: -0.8 for "none" (n=4, 5%); -2.8 for "slight" (n=17, 20%); -3.3 for "moderate" (n=14, 16%); -4.7 for "lots" (n=25, 29%); and -6.1 for "complete" (n=25, 29%; p-for-trend<0.001). The most prevalent AE was somnolence (n=15, 18%). CONCLUSION: Short-term and relatively low-dose olanzapine treatment was effective for multifactorial N/V. Confirmatory studies with longer observation periods are needed to clarify the duration of the effect and adverse events.

[Hydromorphone in Cancer Patients-A Retrospective Study].

We retrospectively investigated the use of oral hydromorphone for cancer pain. Nineteen patients treated for cancer pain with oral hydromorphone were reviewed in this study. Cancers had occurred in the gastrointestinal (n=4), lung(n=3), breast(n=2), bone and soft tissue(n=2), hematological(n=2), and others(n=6). The administered opioids before switching to hydromorphone were morphine, oxycodone, and tapentadol. The mean oral morphine equivalent daily dose (OMEDD)was 89.3 mg. The average dose of hydromorphone administered was 16.4 mg/day, and average NRS 10(numerical rating scale: 0-10)scores of cancer pain before and after switching were 4.1 and 3.8, respectively, showing no significant differences. In this study, switching from other opioids to oral hydromorphone was feasible with an approved conversion ratio, ie, an oral hydromorphone-to-oral morphine ratio of 1:5. No severe adverse effects were observed. The oral hydromorphone extended-release formulation was administered every 24 h, as a tiny tablet formulation that is preferable owing to easy administration and adherence.

[A Case of Methadone Induced Drowsiness Following Trabectedin Induced Liver Injury].

A 66-year-old man with malignant fibrous histiocytoma suffered from severe right arm and shoulder pain. Methadone 45 mg per day was effective in alleviating his pain, but he experienced severe drowsiness following trabectedin induced liver injury. We suspected that impaired methadone metabolism was responsible for the drowsiness. Reduction in methadone dosage and liver supporting therapy was effective in reducing the drowsiness.

Japanese physicians' experiences of terminally ill patients voluntarily stopping eating and drinking: a national survey.

OBJECTIVES: Voluntarily stopping eating and drinking (VSED) could be regarded as a patients' own non-treatment decision that hastens death, which involves patients voluntarily forgoing food and liquid until death. The aims of this study were to investigate the experience of home hospice physicians and palliative care specialists who care for patients during VSED in Japan, and their opinions on continuous deep sedation (CDS) as a means to relieve patient symptoms during VSED. METHODS: 219 home hospice physicians and 695 palliative care specialists across Japan were surveyed by mail questionnaire in 2016. RESULTS: A total of 571 (62%) responses were analysed. A total of 185 (32%) had experience of patients who selected VSED. In response to questions about CDS to provide relief to patients during VSED, the number of physicians who replied that CDS was acceptable was 88 (15%). CONCLUSIONS: In Japan, 32% of physicians surveyed replied that they had experience of caring for patients during VSED in a clinical setting and 15% considered CDS acceptable.

Pneumocystis pneumonia in patients treated with long-term steroid therapy for symptom palliation: a neglected infection in palliative care.

We report 3 cases of pneumocystis pneumonia (PCP) in patients with advanced cancer who received palliative care. All patients received long-term steroid therapy for symptom management. A diagnosis of PCP was based on clinical symptoms and a positive Pneumocystis jiroveci polymerase chain reaction test from induced sputum specimens. Despite appropriate treatment, only 1 patient recovered from PCP. Long-term steroid, often prescribed in palliative care settings, is the most common risk factor for PCP in non-HIV patients. Pneumocystis pneumonia may cause distressing symptoms such as severe dyspnea, and the mortality rate is high. Therefore, it is important to consider PCP prophylaxis for high-risk patients and to diagnose PCP early and provide appropriate treatment to alleviate PCP-related symptoms and avert unnecessary shortening of a patient's life expectancy.

Regulation of multiple functions of SHPS-1, a transmembrane glycoprotein, by its cytoplasmic region.

SHPS-1 is a receptor-type transmembrane glycoprotein, which contains four tyrosine residues in its cytoplasmic region, and the phosphorylation of these tyrosine residues serves the binding sites for SHP-2 protein-tyrosine phosphatase. Its extracellular region interacts with another membrane protein, CD47, thereby constituting a cell-cell communication system. We analyzed this ligand-receptor interaction using Chinese hamster ovary (CHO) cells expressing wild-type (WT) or mutant SHPS-1. The binding affinity of an SHPS-1 mutant such as deltaCyto, that lacked most of cytoplasmic region, or 4F, in which all four tyrosine residues in cytoplasmic region were substituted with phenylalanine, for a recombinant CD47-Fc was greater than that of WT. In addition, oligomerization of deltaCyto or 4F mutant by binding of CD47-Fc was greater than WT. Chemical cross-linking of SHPS-1 indicated that SHPS-1 formed a cis-dimer. Furthermore, WT cells exhibited a less polarized cell shape with decreased formation of actin stress fibers, compared with parental CHO cells and mutant SHPS-1 expressing cells. Prominent lamellipodium formation and membrane ruffling were also observed at leading edges of migrating WT cells but not at those of other mutant SHPS-1 expressing cells. These results suggest that the binding affinity of SHPS-1 to CD47, clustering ability of SHPS-1, and cytoskeletal reorganization are regulated by the cytoplasmic region of SHPS-1.