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Purpose: Adolescents and young adults (AYA) with cancer require highly individualized, age-specific end-of-life care. This study identified the characteristics of AYA patients with cancer receiving home-based palliative care and explored their unique needs and challenges compared with other age groups., Methods: This retrospective cohort study analyzed the medical records of AYA patients with cancer to compare home-based palliative care characteristics with those of older age groups. The study included 81 AYA patients with cancer aged 16-39 years who had received home palliative care at a single institution from 2013 to 2023. They were compared with 5,017 patients with cancer aged 40 years and older. Patient background, duration of home end-of-life care, sedation, and association with social factors were examined retrospectively from medical records., Results: The median age of AYA patients with cancer was 34 years; 65.4% were female. The primary cancer sites were gastrointestinal (34.6%) and thoracic (23.5%), with 80.0% at Stage IV. The median home care duration was 28.5 days, shorter than that for older patients (40 days) (p < 0.0001). Home care rates were similar between AYA and older patients (82.4% vs. 79.9%, p = 0.16). Sedation was more common in the 30-39 age group than in the 16-29 group (33.3% vs. 6.3%, p = 0.049)., Conclusion: AYA patients with cancer achieved a high rate of end-of-life care at home, although their duration of home care was shorter. The characteristics of home care varied depending on the primary site and age, highlighting the importance of creating highly individualized care plans., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Myoclonus is a relatively rare involuntary movement that is often observed in palliative care settings and that can cause patient distress. The purpose of this study is to investigate the occurrence of myoclonus and countermeasures against it in terminally ill patients with cancer diagnosed by palliative care specialists at Komaki City Hospital, Japan. We retrospectively reviewed patients with terminal cancer who received palliative care consultations between January 2018 and May 2019 and who were diagnosed with myoclonus by palliative care specialists, using electronic medical records. Patient demographics, time from onset of myoclonus to death, daily opioid use, countermeasures, and outcome of myoclonus were assessed. Of 360 patients examined during this period, 45 (12.5%) were diagnosed with myoclonus. Median age was 71 (range, 43-88) years; median time from onset of myoclonus to death was 8 days (range, 0-56); opioid usage was present in 39 patients (morphine, oxycodone, and fentanyl: n  = 6, 21, and 12, respectively); and median oral morphine equivalent at onset of myoclonus was 60 mg (range, 12-336 mg). Myoclonus treatment was administered to 21 patients (opioid dose reduction, opioid switching, and others: n  = 14, 3, and 4, respectively). Myoclonus is a common complication in patients with terminal cancer.

Objectives: The clinical outcomes of transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis (AS) and concomitant active cancer remain insufficiently explored. This study aimed to assess the midterm outcomes of TAVR in patients diagnosed with AS and active cancer., Methods: Data from the OCEAN-TAVI, a prospective Japanese registry of TAVR procedures, was analysed to compare prognoses and clinical outcomes in patients with and without active cancer at the time of TAVR., Results: Of the 2336 patients who underwent TAVR from October 2013 to July 2017, 89 patients (3.8%) had active cancer, whereas 2247 did not. Among patients with active cancer, 49 had limited-stage cancer (stage 1 or 2). The prevalent cancers identified before TAVR were colon (21%), prostate (18%), lung (15%), liver (11%) and breast (9%). Although the periprocedural complications and 30-day mortality rates were comparable between the groups, the 3-year survival rate after TAVR was notably lower in patients with active cancer (64.7%) than in those without active cancer (74.7%; p=0.016). Nevertheless, the 3-year survival rate of patients with limited-stage cancer (stage 1 or 2) did not significantly differ from those without cancer (70.6% vs 74.7%, p=0.50)., Conclusions: The patients with active cancer exhibited significantly reduced midterm survival rates. However, no distinct disparity existed in those with limited-stage cancer (stage 1 or 2). Although TAVR is a viable treatment in patients with AS with active cancer, the type and stage of cancer and prognosis should be carefully weighed in the decision-making process., Competing Interests: Competing interests: MT, TN and HU are clinical proctors at Edwards Lifesciences and Medtronic. MY, SS, NT, HW and KH are clinical proctors at Edwards Lifesciences, Abbott Medical and Medtronic. FY is a clinical proctor at Medtronic., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Current therapeutic approaches to cancer are not fully effective, and so development of more effective treatment is needed. Auger-electron therapy and photodynamic therapy have attracted marked attentions as a promising strategy in cancer treatment. In this study, we synthesized [ 125 I]BH-2/BH-2, which comprised Hoechst and 2,6-diiodo-substituted BODIPY, and evaluated its usefulness as a bi-modal agent for Auger-electron/photodynamic therapy by comparison with the previously reported compound [ 125 I]BH/BH. [ 125 I]BH-2 was obtained at a 13% radiochemical yield. [ 125 I]BH-2 showed similar uptake into the nucleus to [ 125 I]BH, suggesting that Hoechst can function as a nuclear localization tag. HeLa cell viabilities were reduced in both cells exposed to [ 125 I]BH-2 and [ 125 I]BH. γ-H2AX foci in HeLa cells exposed to [ 125 I]BH-2 or [ 125 I]BH were increased in a dose-dependent manner, indicating that DNA double-strand breaks may have occurred. No significant difference was observed between [ 125 I]BH-2 and [ 125 I]BH at these investigations. For PDT application, BH-2 showed a higher singlet oxygen quantum yield (Φ Δ ) and caused superior photo-induced cytotoxicity in HeLa cells compared with BH. These results suggest that bi-modal [ 125 I]BH-2/BH-2 can cause anti-tumor effects with Auger-electron and photodynamic therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PDRadiopharm/Inc., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Tumors contain various stromal cells, such as immune cells, endothelial cells, and fibroblasts, which contribute to the development of a tumor-specific microenvironment characterized by hypoxia and inflammation, and are associated with malignant progression. In this study, we investigated the activity of intratumoral hypoxia-inducible factor (HIF), which functions as a master regulator of the cellular response to hypoxia and inflammation. We constructed the HIF activity-monitoring reporter gene hypoxia-response element-Venus-Akaluc (HVA) that expresses the green fluorescent protein Venus and modified firefly luciferase Akaluc in a HIF activity-dependent manner, and created transgenic mice harboring HVA transgene (HVA-Tg). In HVA-Tg, HIF-active cells can be visualized using AkaBLI, an ultra-sensitive in vivo bioluminescence imaging technology that produces an intense near-infrared light upon reaction of Akaluc with the D-luciferin analog AkaLumine-HCl. By orthotopic transplantation of E0771, a mouse triple negative breast cancer cell line without a reporter gene, into HVA-Tg, we succeeded in noninvasively monitoring bioluminescence signals from HIF-active stromal cells as early as 8 days after transplantation. The HIF-active stromal cells initially clustered locally and then spread throughout the tumors with growth. Immunohistochemistry and flow cytometry analyses revealed that CD11b + F4/80 + macrophages were the predominant HIF-active stromal cells in E0771 tumors. These results indicate that HVA-Tg is a useful tool for spatiotemporal analysis of HIF-active tumor stromal cells, facilitating investigation of the roles of HIF-active tumor stromal cells in tumor growth and malignant progression., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Chelator-containing radioimmunoconjugates (RICs) composed of monoclonal antibodies, chelators, and radiometals exhibit broad potential for cancer diagnosis or therapy. In this study, we developed novel trifunctional chelating agents that enhance the tumor retention of RICs, MDPEI2, and MDPEI4, which contain the metal chelator DOTA, a maleimide moiety, and diethylenetriamine (PEI2) or tetraethylenepentamine (PEI4), respectively, as a poly(ethylenimine) (PEI) scaffold for the addition of positive charges to the radiometabolites of RICs to reduce their release from tumor cells. Trastuzumab radiolabeled by [ 111 In]In-MDPEI2 ([ 111 In]In-TMDPEI2) or [ 111 In]In-MDPEI4 ([ 111 In]In-TMDPEI4) showed high immunoreactivity and lower rates of exportations of their radiometabolites from tumor cells than RICs without PEI scaffolds. The tumor uptake of [ 111 In]In-TMDPEI2 and [ 111 In]In-TMDPEI4 was enhanced compared with RICs without PEI scaffolds, and [ 111 In]In-TMDPEI2 exhibited the highest tumor/blood ratio. These results indicate the utility of MDPEI2 to synthesize RICs with favorable tumor-targeting properties in vivo by controlling the radioactivity distribution in tumor cells.

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., (© 2023. The Author(s).)

Granzyme B is an attractive target as a biomarker for contributing to improve the treatment with immune checkpoint inhibitor (ICI). In this study, we designed novel 111 In-labeled granzyme B-targeting single-photon emission computed tomography (SPECT) imaging probes, [ 111 In]IDT and [ 111 In]IDAT. Nonradioactive In-labeled granzyme B-targeting compounds ([ nat In]IDT, [ nat In]IDAT) showed the affinity for recombinant mouse granzyme B. [ 111 In]IDT and [ 111 In]IDAT were obtained with moderate radiochemical yield and high stability in mouse plasma (>95%). In a biodistribution experiment using tumor-bearing mice, [ 111 In]IDT and [ 111 In]IDAT showed moderate accumulation in tumor. Ex vivo autoradiography (ARG) indicated that the accumulation of radioactivity in tumor was correlated to expression of granzyme B confirmed by the immunohistochemical staining. These results indicated that [ 111 In]IDT and [ 111 In]IDAT showed the basic properties as granzyme B-targeting SPECT probes., (© 2023 John Wiley & Sons Ltd.)

Context: Dyspnea is among the most distressing symptoms in the last weeks to days of life (terminal dyspnea). While physicians frequently use parenteral opioids other than morphine for terminal dyspnea, little is known about their effects in cancer patients., Objectives: To explore the effectiveness and safety of parenteral morphine, oxycodone, and hydromorphone for cancer patients with terminal dyspnea., Methods: This was a secondary analysis of a multicenter cohort study that consecutively enrolled advanced cancer patients with moderate/severe terminal dyspnea. Participating palliative care physicians initiated parenteral opioids (morphine/oxycodone/hydromorphone), utilizing a standardized treatment algorithm. We examined the dyspnea intensity (Integrated Palliative care Outcome Scale [IPOS]) at 24 and 48 hours., Results: Of 108 patients (mean age = 72), 66 (61%), 34 (32%), and 8 (7.4%) received morphine, oxycodone, and hydromorphone, respectively. At 24 hours, mean dyspnea IPOS scores significantly decreased from 3.0 (standard error (SE) = 0.1) at the baseline to 1.6 (0.1), 2.9 (0.1) to 2.0 (0.2), and 3.5 (0.2) to 1.2 (0.4) in the morphine (P < 0.001), oxycodone (P < 0.001), and hydromorphone (P = 0.011) groups, respectively. At 48 hours, the IPOS scores significantly reduced from 2.9 (0.1) at the baseline to 1.4 (0.1), 2.9 (0.1) to 1.6 (0.2), and 3.5 (0.2) to 1.2 (0.2) in the morphine (P < 0.001), oxycodone (P < 0.001), and hydromorphone (P = 0.004) groups, respectively. No significant differences in mean scores were found among the three groups at 24 (P = 0.080) and 48 hours (P = 0.322). Adverse events were rare., Conclusion: Parenteral morphine, oxycodone, and hydromorphone may be similarly effective and safe for cancer patients with terminal dyspnea., (Copyright © 2023 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Recent advances in immune-checkpoint inhibitors (ICIs) have highlighted the need for effective management of immune-related adverse events (irAEs). This study aimed to conduct a systematic surveillance of real-world development of irAEs for understanding their characteristics and examine the prognostic impact of steroid use for these events., Methods: We retrospectively investigated cancer patients treated with ICIs between 2014 and 2021 and collected information about irAEs throughout their development, management, and clinical outcomes., Results: Overall, 458 patients (45.4%) developed 670 irAEs. The prevalence of irAEs varied by cancer type, but it was increased in regimens with longer treatment durations. Severe irAEs were more common in the nivolumab + ipilimumab and pembrolizumab + axitinib regimens. Patients who received steroids for irAEs at a dosage of < 2 mg/kg had comparable prognosis to those who did not receive steroids; however, patients who received methylprednisolone pulse therapy, primarily for severe pneumonitis and hepatitis, had shorter overall survival than those who did not receive steroids (7.8 versus 23.4 months, p = 0.016). Furthermore, methylprednisolone pulse therapy for irAEs was a poor prognostic factor in multivariate analysis (hazard ratio: 2.19, 95% confidence interval: 1.34-2.86, p < 0.001)., Conclusion: Steroid treatment for irAE does not affect prognosis and should thus be used promptly to control inflammation. However, pulse therapy for severe cases is a poor prognostic factor, and early detection remains the key to managing such irAEs. The irAE characteristics in each regimen should be clarified to establish and provide more sophisticated irAE management, and the current findings will be beneficial to this goal., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Opinion Statement: Dyspnea is one of the most frequent and distressing symptoms in patients with advanced cancer. As dyspnea deteriorates patients' quality of life markedly and tends to worsen as the disease progresses, comprehensive assessment and timely treatment of the underlying etiologies are essential. International guidelines recommend various non-pharmacological and pharmacological management options. However, there is a scarcity of confirmatory clinical trials on cancer dyspnea, and the overall level of evidence is weak. Recently, observational and survey studies indicated a wide range of practice patterns of palliative care specialists, providing important insight into the real-world management of dyspnea. In this paper, we summarize current management options for dyspnea in cancer patients, highlight major controversies in the literature, and propose future research directions toward quality care for patients with dyspnea and their families., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Clinical guidelines recommend antipsychotics for the treatment of delirium; however, there has been no confirmed recommendation regarding their administrating patterns. This study aims to investigate whether different dosing patterns of antipsychotics (single or multiple administrations) influence the outcomes of delirium treatment., Methods: This is a secondary analysis of a prospective observational study involving patients with advanced cancer and delirium receiving antipsychotics. The Delirium Rating Scale Revised-98 was administered at baseline and after 72 h of starting pharmacotherapy. Patients were classified into single administration group (received a single dosage within 24 h before the assessment) and multiple administration group (received more than one dosage)., Results: A total of 555 patients (single administration 492 (88.6%); multiple administration 63 (11.4%)) were subjected to analyses. The patients in the multiple administration group were more likely to be male, in psycho-oncology consulting settings, with lower performance status, with hyperactive delirium and with severer delirium symptoms. In the multivariate analysis, single administration was significantly associated with better improvement of delirium (p < 0.01, 95% confidence interval: 1.83-5.87) even after controlling covariates. There were no significant differences in the mean dosages of antipsychotics per day in chlorpromazine equivalent (single administration 116.8 mg/day, multiple administration 123.5 mg/day) and the incidence of adverse events between the two groups., Conclusions: In this observational study sample, Delirium Rating Scale severity score improvement in single administration was higher than that seen in multiple administration. There was no difference in adverse events between the two groups., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: How clinicians treat patients with terminal dyspnea widely varies, which could hamper quality care. We visualized comprehensive pharmacological treatment delivered by palliative care physicians., Aim: To examine adherence to a comprehensive pharmacological treatment algorithm for patients with terminal dyspnea, and to explore its outcomes during 48 h., Design: A multicenter cohort study at five sites (February 2020 to June 2021)., Setting/participants: We prospectively enrolled consecutive patients with advanced cancer, Eastern Cooperative Oncology Group performance status 3-4, and moderate/severe dyspnea. Participating palliative care physicians initiated algorithm-based treatment. The primary outcome was the proportion of adherence to the treatment algorithm over 24 h (predefined goal, 70%). We evaluated the adherence, goal achievement, and dyspnea level with a numerical rating scale (NRS), as well as adverse events over 48 h., Results: All 108 patients received algorithm-based pharmacological treatment. Among 96 and 87 patients who were alive at 24 and 48 h, respectively, 96 (100%; 95% confidence interval [CI] = 96%-100%) and 82 (94%; 95%CI = 87%-98%) continued to receive the algorithm treatment, respectively, and 66 (69%; 95%CI = 59%-77%) and 64 (74%; 95%CI = 63%-82%) achieved the treatment goals, respectively. Using a complete case analysis with paired t-tests, mean dyspnea NRS scores significantly reduced from 7.3 (standard error, 0.2) at the baseline to 4.9 (0.3) at 24 h (n = 72; p < 0.001), and 7.2 (0.3) at the baseline to 4.6 (0.4) at 48 h (n = 55; p < 0.001). Most adverse events were mild to moderate., Conclusions: The comprehensive pharmacological treatment algorithm was feasible, and the study data supports its preliminary efficacy and safety. The use of this algorithm may help clinicians improve care for patients with terminal dyspnea., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Cancer cachexia demonstrates the same pathology as cachexia found in patients with disease-associated malnutrition presenting with inflammation. In advanced cancer, a decrease in skeletal muscle mass progresses with an increase in cancer cell mass. Moreover, cancer cachexia causes systemic edema and cachexia, reduces the efficacy of chemotherapy, and negatively affects cancer prognosis. Early nutritional intervention and multidisciplinary care are essential to ensure sufficient nutritional requirements and minimize anabolic resistance factors. In addition, preventive care that minimizes deterioration of nutritional status and loss of skeletal muscle mass is required for the effective treatment of cachexia. Therefore, the current review sought to comprehensively describe the available evidence for the effective pharmaceutical treatment of cancer-associated cachexia. Steroids have traditionally been used for cachexia drug therapy. However, their effects are limited, and it is difficult to radically restore the highly reduced muscle mass inherent to cancer-associated cachexia. Recently, anamorelin hydrochloride, an endogenous ligand for the growth hormone release-promoting factor receptor, which has a similar pharmacological action to that of ghrelin, was developed to treat weight loss accompanied by anorexia. This medication also treats cachexia and was the first drug to be approved for this purpose. Anamorelin hydrochloride is expected to bring new advancements into the field of clinical oncology as an effective therapeutic drug for cancer cachexia, a devastating complication that, so far, has no definitive and effective treatment., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Targeted radionuclide therapy using Auger electrons is a promising strategy in cancer treatment. A DNA-binding Hoechst-tagged radioiodinated BODIPY derivative ([ 125 I]BH) has been prepared as an Auger therapeutic agent. [ 125 I]BH showed high accumulation in the nucleus of HeLa cells and cytotoxicity caused by DNA double-strand breaks.

Weight loss during cancer chemotherapy affects the continuation of treatment; therefore, it is important to maintain and improve nutritional status. Additionally, appropriate fluid and electrolyte replacement is essential for maintaining life. This study included 100 patients who underwent outpatient chemotherapy in April 2021. The degree of dehydration was assessed based on serum osmolality, and the possibility of screening was examined by a hidden dehydration check sheet. Hidden dehydration was noted in 38 patients and dehydration in 6 patients. The incidence of pancreatic cancer was significantly lower than that of lung cancer. In the hidden dehydration check sheet, 51 patients were found to present with high possibility of hidden dehydration and required consultation to a medical professional. The serum osmolality of the results was not significantly different. During outpatient cancer chemotherapy, a certain percentage of patients present with hidden dehydration. To detect dehydration at an early stage, serum osmolality should be actively measured and continuous diet counseling, including confirmation of food and fluid intake, is required.

Purpose: Investigate the frequency and prognostic factors of severe drug-induced interstitial lung disease (DILD) caused by antineoplastic drugs regardless of cancer types or type of drugs., Methods: From 2014 to 2018, we reviewed patients with a history of antineoplastic agents administration in the real-world database of our hospital's electronic medical record and extracted patients who experienced "severe" DILD, requiring hospitalization with treatment or developed during hospitalization and required treatment. We collected patients' backgrounds, clinical and radiological features, laboratory data, treatment, and survival outcomes., Results: 19,132 cancer patients received antineoplastic drug therapy during the study period, and 120 (0.62%) experienced severe DILD. The incidence of severe DILD in patients with thoracic cancer was highest among the patients included in this analysis (2.52% vs. 0.34% other cancers). Diffuse alveolar damage (DAD) pattern on CT was associated with higher mortality in patients with severe DILD compared with non-DAD pattern (hazard ratio [HR], 11.24; 95% CI, 4.82-26.2). Multivariate analysis revealed that the DAD pattern at diagnosis as severe DILD (HR, 3.59; 95% CI, 1.17-11.03), concurrent/previous interstitial lung disease (HR, 3.20; 95% CI, 1.27-8.10), and ECOG performance status of 2-4 (HR, 3.81; 95% CI, 1.10-13.17) were independent risk factors for mortality in patients with severe DILD., Conclusions: The frequency of severe DILD was highest in patients with thoracic cancer. The DAD pattern was associated with a poor outcome. From the perspective of DILD, special attention should be paid when administering antineoplastic agents to patients with thoracic cancer., (© 2022. The Author(s).)

Myositis-specific autoantibodies are relevant factors that define the disease phenotype of dermatomyositis (DM). Anti-Mi-2 antibody-positive DM patients may present with the typical skin lesions and prominent myositis. On the other hand, adult DM patients with anti-TIF-γ antibody seem to be associated with internal malignancy. Here, we report a rare case of juvenile dermatomyositis (JDM) exhibiting anti-Mi-2 and anti-transcriptional intermediary factor-1 gamma (TIF1-γ) antibodies, with no internal malignancy. A 16-year-old female Japanese patient under treatment with a 2-year history of chronic eczematous lesions was admitted to our department with elevated levels of muscle enzymes. Characteristic skin changes, such as Gottron's papules of the hand, heliotrope rash of the eyelids, and poikiloderma-like legions and diffuse pigmentation on the back, were observed. Histologically, the patient's skin was characterized by the presence of lymphocytic vascular inflammation and endothelial swelling, which are consistent with DM. Severe symmetric proximal muscle weakness, elevated serum muscle enzymes and the presence of anti-TIF1-γ and Mi-2 antibodies were noted. The diagnosis of JDM was made according to the European League Against Rheumatism (EULAR) diagnostic criteria. A high dose of corticosteroids and following intravenous cyclophosphamide treatment (750 mg three times) resulted in an improvement in clinical manifestations and functional outcomes, and recurrence did not occur. Estimation of autoantibodies may serve as an ancillary tool in delineating and defining distinct clinical phenotypes in JDM.

Background: Predictive factors for the development of dyspnea have not been reported among terminally ill cancer patients., Objective: This current study aimed to identify the predictive factors attributed to the development of dyspnea within 7 days after admission among patients with cancer., Methods: This was a secondary analysis of a multicenter prospective observational study on the dying process among patients admitted in inpatient hospices/palliative care units. Patients were divided into 2 groups: those who developed dyspnea (development group) and those who did not (non-development group). To determine independent predictive factors, univariate and multivariate analyses using the logistic regression model were performed., Results: From January 2017 to December 2017, 1159 patients were included in this analysis. Univariate analysis showed that male participants, those with primary lung cancer, ascites, and Karnofsky Performance Status score (KPS) of ≤40, smokers, and benzodiazepine users were significantly higher in the development group. Multivariate analysis revealed that primary lung cancer (odds ratio [OR]: 2.80, 95% confidence interval [95% CI]: 1.47-5.31; p = 0.002), KPS score (≤40) (OR: 1.84, 95% CI: 1.02-3.31; p = 0.044), and presence of ascites (OR: 2.34, 95% CI: 1.36-4.02; p = 0.002) were independent predictive factors for the development of dyspnea., Conclusions: Lung cancer, poor performance status, and ascites may be predictive factors for the development of dyspnea among terminally ill cancer patients. However, further studies should be performed to validate these findings.

Background: Dyspnea is a common and distressing symptom in patients with cancer. To improve its management, multicenter confirmatory studies are necessary. Research policy would be useful in conducting these studies. Here, we propose a new research policy for the management of dyspnea in patients with cancer., Methods: The first draft was developed by a policy working group of 11 specialists in the field of supportive care or palliative care for dyspnea. Then, a provisional draft was developed after review by a research support group (the Japanese Supportive, Palliative and Psychosocial Care Study Group) and five Japanese scientific societies (Japanese Association of Supportive Care in Cancer, Japanese Society of Medical Oncology, Japanese Society of Palliative Medicine, Japanese Association of Rehabilitation Medicine and Japanese Society of Clinical Oncology), and receipt of public comments., Results: The policy includes the following components of research policy on dyspnea: (i) definition of dyspnea, (ii) scale for assessment of dyspnea, (iii) reason for dyspnea or factors associated with dyspnea and (iv) treatment effectiveness outcomes/adverse events. The final policy (Ver1.0) was completed on 1 March 2021., Conclusions: This policy could help researchers plan and conduct studies on the management of cancer dyspnea., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Parathyroid hormone-related protein (PTHrP), which is secreted from a tumor, contributes to the progression of cachexia, a condition that is observed in half of all cancer patients. Although drug clearance was reported to decrease in patients with cancer cachexia, the details have not been clarified. The present study reports on an investigation of whether PTHrP is involved in the alternation of drug metabolism in cases of cancer cachexia. Cancer cachexia model rats with elevated serum PTHrP levels showed a significant decrease in hepatic and intestinal CYP3A2 protein expression. When midazolam, a CYP3A substrate drug, was administered intravenously or orally to the cancer cachexia rats, its area under the curve (AUC) was increased by about 2 and 5 times, as compared to the control group. Accordingly, the bioavailability of midazolam was increased by about 3 times, thus enhancing its pharmacological effect. In vitro experiments using HepG2 cells and Caco-2 cells showed that the addition of serum from cancer cachexia rats or active PTHrP (1-34) to each cell resulted in a significant decrease in the expression of CYP3A4 mRNA. Treatment with a cell-permeable cAMP analog also resulted in a decreased CYP3A4 expression. Pretreatment with protein kinase A (PKA), protein kinase C (PKC), and nuclear factor-kappa B (NF-κB) inhibitors recovered the decrease in CYP3A4 expression that was induced by PTHrP (1-34). These results suggest that PTHrP suppresses CYP3A expression via the cAMP/PKA/PKC/NF-κB pathway. Therefore, it is likely that PTHrP would be involved in the changes in drug metabolism observed in cancer cachexia.

Context: Conducting randomized controlled trials on palliative care is difficult owing to barriers like fragility of the patients' health status and health care providers' concerns for patients. However, quality randomized controlled trials are required for care improvement., Objectives: To investigate the willingness of cancer patients and their relatives to participate in a clinical study on cancer dyspnea and identify feasible clinical study designs for this condition., Methods: A nationwide, cross-sectional, web-based survey was conducted with 206 cancer patients and 206 relatives of cancer patients. Their willingness to participate in clinical studies on cancer dyspnea and factors influencing this willingness were assessed in two scenarios: outpatients receiving anticancer treatment and terminally ill inpatients., Results: About 23% patients and 23% relatives were willing to participate in clinical trials while 40% and 32%, respectively, were unwilling. Factors related to patient participation were quick and easy trials (outpatient 57%, terminally ill 53%) and oral medication with minimal potential side effects (outpatient 48%). Factors related to unwillingness to participate were placebo-controlled trials (outpatient 51%, terminally ill 50%), disagreements about participation between patients and families (outpatient 49%, terminally ill 49%), and continuous injections (outpatient 61%, terminally ill 47%). Compared to patients, relatives responded more reluctantly, especially for patients in terminal care. Conversely, patients were less reluctant in the terminal setting than the outpatient setting., Conclusion: Some patients and relatives were reluctant to participate in clinical trials on cancer dyspnea. Thus, trials need to be minimally invasive, quick, and fully explained to and understood by patients and families., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Human serum albumin (HSA), which is distributed throughout the blood, is used as a carrier for transporting drugs to tumors based on the enhanced permeability and retention (EPR) effect. To develop an agent for the in vivo radiolabeling of endogenous albumin, we designed and synthesized novel hydroxamamide (Ham)-based technetium-99m ( 99m Tc) complexes, which contained a monovalent or bivalent 4-(4-iodophenyl)butyric acid (IA) derivative as an albumin binder (ALB) moiety ([ 99m Tc]AB2 and [ 99m Tc]ALB2, respectively), and evaluated their utility for in vivo tumor imaging. In an in vitro HSA-binding assay, [ 99m Tc]AB2 and [ 99m Tc]ALB2 showed greater binding to HSA than [ 99m Tc]BHam, a 99m Tc-Ham complex without an ALB moiety. In an in vivo biodistribution assay, [ 99m Tc]ALB2 showed marked blood and tumor retention (25.13 and 4.61% injected dose (ID)/g, respectively, at 1 h postinjection), suggesting that the EPR effect had been induced. However, [ 99m Tc]AB2 showed no marked blood or tumor retention (4.16 and 0.75% ID/g, respectively, at 1 h postinjection), probably because the affinity of the monovalent IA derivative for albumin was insufficient to induce the EPR effect. These findings indicated that the multivalent interactions of [ 99m Tc]ALB2 had enhanced its affinity for albumin. 99m Tc-complexes containing multivalent ALB moieties may be useful for tumor imaging., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The mammalian HSP105/110 family consists of four members, including Hsp105 and Apg-1, which function as molecular chaperones. Recently, we reported that Hsp105 knockdown increases sensitivity to the DNA-damaging agent Adriamycin but decreases sensitivity to the microtubule-targeting agent paclitaxel. However, whether the other Hsp105/110 family proteins have the same functional property is unknown. Here, we show that Apg-1 has different roles from Hsp105 in cell proliferation, cell division, and drug sensitivity. We generated the Apg-1-knockdown HeLa S3 cells by lentiviral expression of Apg-1-targeting short hairpin RNA. Knockdown of Apg-1 but not Hsp105 decreased cell proliferation. Apg-1 knockdown increased cell death upon Adriamycin treatment without affecting paclitaxel sensitivity. The cell synchronization experiment suggests that Apg-1 functions in mitotic progression at a different mitotic subphase from Hsp105, which cause difference in paclitaxel sensitivity. Since Apg-1 is overexpressed in certain types of tumors, Apg-1 may become a potential therapeutic target for cancer treatment without causing resistance to the microtubule-targeting agents., (© 2021 Wiley Periodicals LLC.)

Context: How physicians use opioids for dyspnea in imminently dying cancer patients (terminal dyspnea) varies markedly, which could hamper quality care., Objectives: To examine the adherence to an algorithm-based treatment for terminal dyspnea, and explore its outcomes over 24 hours., Methods: This was a pre-planned subgroup analysis of a multicenter prospective observational study. Inclusion criteria were: advanced cancer patients admitted to palliative care units, ECOG performance status = 3-4, and a dyspnea intensity ≥2 on the Integrated Palliative care Outcome Scale (IPOS). We developed an algorithm to visualize how palliative care physicians would use parenteral opioids. Participating physicians (palliative care specialists) initiated parenteral opioids, choosing whether to use the algorithm based on their preference. We measured the adherence rate to the algorithm over 24 hours (predefined goal = 70%), and compared dyspnea IPOS scores and adverse events between patients with and without algorithm-based treatment., Results: Of 164 patients (median survival = 5 days), 71 (43%) received algorithm-based treatment, and 70 (99%; 95% confidence interval = 92%-100%) adhered to it over 24 hours. In a complete case analysis, mean dyspnea IPOS scores significantly decreased from 2.9 (standard error = 0.1) to 1.5 (0.1) in the algorithm group (n = 54; P < 0.001), and 2.9 (0.1) to 1.6 (0.1) in the non-algorithm group (n = 72; P < 0.001). There was no significant between-group difference in changes in dyspnea IPOS scores (P = 0.65). Adverse events were rare (n = 5)., Conclusion: The algorithm-based treatment was feasible, and might be as effective and safe as the usual care by palliative care specialists. Its implementation may help physicians provide quality care for terminal dyspnea., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: We evaluated malignancy according to the characteristics of pericardial fluid in symptomatic Japanese patients undergoing pericardiocentesis and computed tomography (CT)., Methods: This was a retrospective, single-center, observational study of 125 symptomatic patients undergoing pericardiocentesis. The patients were classified into two groups: a malignancy group and a non-malignancy group, according to the primary disease and cytology of the pericardial effusion (PE). We compared the pericardial fluid sample and CT measurements between both groups., Results: All patients were diagnosed as having exudative PE by Light's criteria. PE with malignant cells was demonstrated in 76.8% of the malignancy group patients. Pericardial to serum lactate dehydrogenase (LDH) ratio > 0.6, as one of Light's criteria, was associated with malignancy (p = 0.017). Lower serum brain natriuretic peptide (BNP) concentration was also associated with malignancy (BNP: 126.9 ± 89.8 pg/ml vs 409.2 ± 97.7 pg/ml, malignancy vs non-malignancy groups, respectively; p = 0.037). A significant difference was observed in pericardial fluid glucose level between the malignancy and non-malignancy groups (pericardial fluid glucose: 78.24 ± 48.29 mg/dl vs 98.41 ± 44.85, respectively; p = 0.048). Moreover, CT attenuation values (Hounsfield units (HU)) tended to be higher in the malignancy group vs the non-malignancy group (22.7 [interquartile range (IQR), 17.4-26.0] vs 17.4 [IQR, 13.7-26.4], respectively; p = 0.08). The sensitivity and specificity of pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were 40.9% and 89.6%, respectively, in the malignancy group. The positive- and negative predictive values of pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were 85.7% and 50.0%, respectively, in the malignancy group. Pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were cutoff values associated with malignancy (p = 0.012)., Conclusions: Lower pericardial fluid glucose level with higher CT attenuation values may suggest malignancy-related PE.

Context: Previous studies suggest that clinicians' prediction of survival (CPS) may have reduced the accuracy of objective indicators for prognostication in palliative care., Objectives: We aimed to examine the accuracy of CPS alone, compared to the original Palliative Prognostic Score (PaP), and five clinical/laboratory variables of the PaP in patients with far advanced cancer., Methods: We compared the discriminative accuracy of three prediction models (the PaP-CPS [the score of the categorical CPS of PaP], PaP without CPS [sum of the scores of only the objective variables of PaP], and PaP total score) across 3 settings: inpatient palliative care consultation team, palliative care unit, and home palliative care. We computed the area under receiver operating characteristic curve (AUROC) for 30-day survival and concordance index (C-index) to compare the discriminative accuracy of these three models., Results: We included a total of 1534 subjects with median survival of 34.0 days. The AUROC and C-index in the three settings were 0.816-0.896 and 0.732-0.799 for the PaP total score, 0.808-0.884 and 0.713-0.782 for the PaP-CPS, and 0.726-0.815 and 0.672-0.728 for the PaP without CPS, respectively. The PaP total score and PaP-CPS showed similar AUROCs and C-indices across the three settings. The PaP total score had significantly higher AUROCs and C-indices than the PaP without CPS across the three settings., Conclusion: Overall, the PaP total score, PaP-CPS, and PaP without CPS showed good discriminative performances. However, the PaP total score and PaP-CPS were significantly more accurate than the PaP without CPS., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10-1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06-0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.

Background: There is a paucity of data comparing the long-term outcomes after inferior vena cava (IVC) filters placement for patients with acute venous thromboembolism (VTE) between those with and without active cancer., Methods: In the COMMAND VTE Registry, we evaluated the effects of IVC filter use on the long-term clinical outcomes stratified by the presence and absence of active cancer., Results: Among 2,626 patients with acute symptomatic VTE, there were 604 patients with active cancer, and 2022 patients without active cancer. IVC filters were placed and not retrieved in 455 patients (17%) in the entire cohort, in 150 patients (24.8%) in the active cancer stratum, and in 305 patients (15.1%) in the non-cancer stratum. In the entire cohort, non-retrieved IVC filter placement was not associated with a lower adjusted risk for PE recurrence (HR 0.59, 95% CI 0.30-1.15, P = 0.122), but with an increased adjusted risk for DVT recurrence (HR 2.27, 95% CI 1.43-3.60, P<0.001). In the non-cancer stratum, the non-retrieved IVC filter placement was associated with a decreased risk for PE (HR 0.29, 95% CI 0.09-0.93, P = 0.037), but not with an increased risk for DVT (HR 1.73, 95% CI 0.89-3.38, P = 0.108), while in the active cancer stratum, it was associated with an increased risk for DVT (HR 2.47, 95% CI 1.24-4.91, P = 0.010), but not with a decreased risk for PE (HR 0.82, 95% CI 0.34--1.96, P = 0.650)., Conclusions: There were some differences in the risk-benefit balance between VTE patients with and without active cancer., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan belonging to the aggrecan/lectican family. In adults, this proteoglycan serves as a structural macromolecule of the extracellular matrix in the brain and large blood vessels. In contrast, versican is transiently expressed at high levels during development and under pathological conditions when the extracellular matrix dramatically changes, including in the inflammation and repair process. There are many reports showing the upregulation of versican in cancer, which correlates with cancer aggressiveness. Versican has four classical splice variants, and all the variants contain G1 and G3 domains at N- and C-termini, respectively. There are two glycosaminoglycan attachment domains CSα and CSβ. The largest V0 variant contains both CSα and CSβ, V1 contains CSβ, V2 contains CSα, and the shortest G3 variant has neither of them. Versican degradation is initiated by cleavage at a site in the CSβ domain by ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases. The N-terminal fragment containing the G1 domain has been reported to exert various biological functions, although its mechanisms of action have not yet been elucidated. In this review, we describe the role of versican in inflammation and cancer and also address the biological function of versikine.

Death rattle occurs during the last days of life, and relatives of those afflicted frequently report that it is very distressful. However, there is no effective treatment for it. The purpose of this study was to investigate the perceptions of Japanese palliative care physicians in clinical practice in Japan. We conducted a nationwide survey of 268 physicians via an anonymous, self-report questionnaire. We assessed pharmacological and non-pharmacological management and anticholinergic agent choice. One hundred eighty-nine physicians (70.5%) returned the questionnaires. Fifty-five participants (29.1%) treating patients with Type-1 (real death rattle) and 36 participants (19%) treating patients with Type-2 (pseudo-death rattle) death rattle reported that they would frequently administer an anticholinergic agent. One-fourth would administer scopolamine butylbromide or scopolamine hydrobromide. In conclusion, more Japanese palliative care physicians thought that anticholinergic agents might be effective for treating Type-1 death rattle rather than Type-2. Further clinical trials of these agents are needed., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Parenteral morphine is widely used for dyspnea of imminently dying cancer patients, but the outcomes to expect over time remain largely unknown. We examined outcomes after the administration of parenteral morphine infusion over 48 h in cancer patients with a poor performance status., Methods: This was a multicenter prospective observational study. Inclusion criteria were metastatic/locally advanced cancer, ECOG performance status = 3-4, a dyspnea intensity ≥ 2 on a Support Team Assessment Schedule, Japanese version (STAS-J), and receiving specialized palliative care. After initiating parenteral morphine infusion, we measured dyspnea STAS-J as well as Memorial Delirium Assessment Scale (MDAS), item 9, and Communication Capacity Scale (CCS), item 4, every 6 h over 48 h., Results: We enrolled 167 patients (median survival = 4 days). The mean age was 70 years, 80 patients (48%) had lung cancer, and 109 (65%) had lung metastases. The mean STAS-J scores decreased from 3.1 (95% confidence interval (CI) = 3.0-3.2) at the baseline to 2.1 (95%CI = 1.9-2.2) at 6 h, and remained 1.6-1.8 over 12-48 h. The proportion of patients with dyspnea relief (STAS-J ≤ 1) increased to 39% at 6 h, and ranged between 49 and 61% over 12-48 h. In contrast, up to 6.6 and 20% of patients showed hyperactive delirium (MDAS item 9 ≥ 2) and an inability to communicate (CCS item 4 = 3), respectively, over 48 h., Conclusions: Overall, terminal dyspnea was relatively well controlled with parenteral morphine, though a significant number of patients continued to suffer from dyspnea. Future efforts are needed to improve outcomes following standardized dyspnea treatment using patient-reported outcomes for imminently dying patients.

Context: Dyspnea is one of the most distressing symptoms for terminally ill cancer patients and a predictor of poor prognosis. Identification of simple clinical signs, such as heart rate, indicating clinical course of each patient is of value., Objectives: To explore the potential association between heart rate and reversibility of the symptom, treatment response to palliative intervention, and survival in terminally ill cancer patients with dyspnea at rest., Methods: This is a secondary analysis of a multicenter prospective cohort study of patients with advanced cancer to validate multiple prognostic tools. In the patients with dyspnea at rest at the baseline, we examined a potential association between heart rate and the reversibility of dyspnea and refractoriness to palliative treatment using logistic regression analysis. Survivals were compared using the Cox proportional hazards model among four groups with different levels of the heart rate (≤74, 75-84, 85-97, and ≥98)., Results: A total of 2298 patients were enrolled, and 418 patients (18%) had dyspnea at rest. Reversibility of dyspnea was significantly higher in the patients with lower heart rate (P for trend = 0.008), and the refractoriness to palliative treatment tended to be higher in the patients with higher heart rate (P for trend = 0.101). The median survival for each heart rate quartile groups was significantly higher in the lower heart rate group (24 vs. 21 vs. 14 vs. 9 days; heart rate ≤74, 75-84, 85-97, and ≥98, respectively; log-rank P < 0.001)., Conclusion: Heart rate may help clinicians to make the prediction of the patient's clinical course more accurate., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: It is unclear whether patients with non-specific dyspnoea are suitable candidates for studies investigating the effectiveness of benzodiazepines against dyspnoea. The objective of this survey was to investigate suitable subjects for studies of benzodiazepines for cancer dyspnoea., Methods: A nationwide questionnaire survey was conducted among 536 Japanese-certified palliative care physicians. We randomly selected 268 physicians and inquired about their approach to dyspnoea management in patients with cancer, with and without anxiety, as follows: (1) Administration of a benzodiazepine. (2) Administration or titration of an opioid. We also asked them to consider their approach in the following situations: (1) Opioid-naïve. (2) Low-to-moderate baseline opioid dose. (3) High baseline opioid dose. We assessed the use of specific benzodiazepines separately., Results: Overall, 192 physicians responded to the questionnaire (71.6%). For patients without anxiety, the proportion of participants reporting that they frequently or very frequently 'administer a benzodiazepine' increased with baseline opioid dose (opioid-naïve: 5.2%, low-to-moderate: 11.5%, high: 26.0%). The proportion of participants reporting that they frequently or very frequently 'administer or titrate an opioid' decreased with baseline opioid dose (opioid-naïve: 83.3%, low-to-moderate: 73.4%, high: 41.1%). The pattern was similar for patients with anxiety, although more respondents said they prescribe benzodiazepine for these patients (naïve: 22.4%, low-to-moderate: 34.4%, high: 45.8%) and fewer prescribed an opioid. Alprazolam and lorazepam are frequently used., Conclusion: Patients with anxiety or receiving a high baseline opioid dose could be potential candidates for future studies investigating the effectiveness of benzodiazepines against cancer dyspnoea., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Proteasomes are essential protease complexes that maintain cellular homeostasis, and aberrant proteasomal activity supports cancer development. The regulatory mechanisms and biological function of the ubiquitin-26S proteasome have been studied extensively, while those of the ubiquitin-independent 20S proteasome system remain obscure. Here, we show that the cap 'n' collar (CNC) family transcription factor NRF3 specifically enhances 20S proteasome assembly in cancer cells and that 20S proteasomes contribute to colorectal cancer development through ubiquitin-independent proteolysis of the tumor suppressor p53 and retinoblastoma (Rb) proteins. The NRF3 gene is highly expressed in many cancer tissues and cell lines and is important for cancer cell growth. In cancer cells, NRF3 upregulates the assembly of the 20S proteasome by directly inducing the gene expression of the 20S proteasome maturation protein POMP. Interestingly, NRF3 knockdown not only increases p53 and Rb protein levels but also increases p53 activities for tumor suppression, including cell cycle arrest and induction of apoptosis. Furthermore, protein stability and cell viability assays using two distinct proteasome inhibitor anticancer drugs, the 20S proteasome inhibitor bortezomib and the ubiquitin-activating enzyme E1 inhibitor TAK-243, show that the upregulation of the NRF3-POMP axis leads to ubiquitin-independent proteolysis of p53 and Rb and to impaired sensitivity to bortezomib but not TAK-243. More importantly, the NRF3-POMP axis supports tumorigenesis and metastasis, with higher NRF3/POMP expression levels correlating with poor prognoses in patients with colorectal or rectal adenocarcinoma. These results suggest that the NRF3-POMP-20S proteasome assembly axis is significant for cancer development via ubiquitin-independent proteolysis of tumor suppressor proteins., (Copyright © 2020 Waku et al.)

Background: The objective of this study was to explore the underlying etiologies associated with the resolution and improvement of delirium in ill-hospitalized cancer patients., Methods: We conducted a secondary analysis of a multicenter, prospective, observational study to estimate the effectiveness of pharmacotherapy for delirium. Participants were cancer patients with delirium. We assessed the Delirium Rating Scale, Revised-98 (DRS-R98) severity scale score at baseline and three days after pharmacotherapy initiation. Delirium resolution was defined as a DRS-R98 severity scale score ≤9, and improvement was defined as ≥50% reduction at Day 3., Results: We enrolled 566 patients (491 patients had performance status of 3 or 4). The resolution and improvement rates in all patients were 22.6% and 19.3%, respectively. Univariate analysis determined that nonrespiratory infection (OR 2.18, 95% CI 1.38-3.45) was significantly associated with greater resolution, while dehydration (0.40, 0.19-0.87), organic damage to the central nervous system (CNS) (0.32, 0.43-0.72), hypoxia (0.25, 0.12-0.52), and hyponatremia (0.34, 0.12-0.97) were significantly associated with no resolution. Potential causes associated with delirium improvement were nonrespiratory infection (1.93, 1.19-3.13), organic damage to the CNS (0.40, 0.18-1.90), and hypoxia (0.32, 0.16-0.65). After multivariate analysis, dehydration (0.34, 0.15-0.76), organic damage to the CNS (0.25, 0.10-0.60), and hypoxia (0.29, 0.14-0.61) were significantly associated with no resolution., Conclusions: Delirium caused by nonrespiratory infection may be reversible, while delirium associated with dehydration, organic damage to the CNS, hypoxia, or hyponatremia seems to be irreversible in ill-hospitalized cancer patients., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Breathlessness is among the most common and deteriorating symptoms in patients with advanced cancer, which may worsen towards the end of life. Breathlessness in patients with estimated life expectancy of weeks to days has unique clinical features: it tends to worsen rapidly over days to hours as death approaches often despite current symptom control measures. Breathlessness in patients during the last weeks to days of life can be called 'terminal breathlessness'. While evidence has accumulated for the management of breathlessness in patients with cancer who are not dying, such evidence may not be fully applied to terminal breathlessness. Only a few studies have investigated the best practice of terminal breathlessness in patients with cancer. In this paper, we summarise the current evidence for the management of terminal breathlessness, and propose future directions of clinical research., (© 2020 THE AUTHORS. Published by Elsevier Limited on behalf of European Society for Medical Oncology.)

Surgery remains one of the main treatments of cancer and both precise pre- and intraoperative diagnoses are crucial in order to guide the operation. We consider that using an identical probe for both pre- and intra-operative diagnoses would bridge the gap between surgical planning and image-guided resection. Therefore, in this study, we developed gold nanorods (AuNRs) conjugated with radiolabeled anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and investigated their feasibility as novel HER2-targeted dual-imaging probes for both single photon emission computed tomography (SPECT) (preoperative diagnosis) and photoacoustic (PA) imaging (intraoperative diagnosis). To achieve the purpose, AuNRs conjugated with different amount of trastuzumab (Tra) were prepared, and Tra-AuNRs were labeled with indium-111. After the evaluation of binding affinity to HER2, cell binding assay and biodistribution studies were carried out for optimization. AuNRs with moderate trastuzumab conjugation (Tra2-AuNRs) were proposed as the novel probe and demonstrated significantly higher accumulation in NCI-N87 (HER2 high-expression) tumors than in SUIT2 (low-expression) tumors 96 h post-injection along with good affinity towards HER2. Thereafter, in vitro PA imaging and in vivo SPECT imaging studies were performed. In in vitro PA imaging, Tra2-AuNRs-treated N87 cells exhibited significant PA signal increase than SUIT2 cells. In in vivo SPECT, signal increase in N87 tumors was more notable than that in SUIT2 tumors. Herein, we report that the Tra2-AuNRs enabled HER2-specific imaging, suggesting the potential as a robust HER2-targeted SPECT and PA dual-imaging probe.

Background : Tumor fever and infection are common febrile etiologies among advanced cancer patients. To date, only few studies have been conducted to differentiate between tumor fever and infections. Objective: This study aimed to identify discriminating factors that provide rapid results and are feasible and minimally invasive for discriminating between tumor fever and infection in advanced cancer patients. Methods : This is a retrospective cohort study. Advanced cancer patients with clinically diagnosed tumor fever or infection, who received medical treatment from palliative care specialists in 10 nationwide Japanese hospitals, were consecutively identified during August 2012 and November 2014. The symptoms, physical findings, blood test results at baseline and during fever, imaging findings, and sociodemographic factors of these patients were retrospectively extracted. Results : Thirty-three patients with tumor fever and 72 patients with infection were identified. Their mean age was 68.8 years, 68 (64.8%) were men, and the median palliative performance status (PPS) was 50. Statistically significant factors predicting tumor fever by logistic regression analysis were as follows: deterioration of PPS (odds ratio, 0.078), shaking chills during fever (0.067), and change from baseline data of neutrophil/lymphocyte ratio of ≥5 (0.14). Conclusions : Shaking chills during fever, and changes from baseline of performance status and white blood cell differentiation can be useful to differentiate between tumor fever and infection among advanced cancer patients. Further confirmatory studies are needed.

Context: Morphine is recommended as the first-line pharmacological therapy for cancer dyspnea. However, the detailed practice of morphine has not been evaluated and consensus about other opioids for cancer dyspnea has not been established., Objectives: To explore the physician-reported practice of opioid for cancer dyspnea., Methods: A nationwide mail-questionnaire survey was conducted among 536 Japanese certified palliative care physicians. We randomly selected 268 and asked the following: 1) how the physicians themselves initiate and use morphine for cancer dyspnea, 2) opioid choice for dyspnea in patients who have already used opioid other than morphine regularly, and 3) opioid choice for dyspnea in patients with various degrees of renal impairment in their daily practice., Results: Overall, 192 physicians responded (response rate, 71.6%). The major (58.3%) practice of initiating morphine was "immediate-release morphine as needed" in opioid-naïve patients, and the mean % increase when they titrate morphine for cancer dyspnea was 29.4 ± 11.3% of the baseline dose. Although "titrate baseline oxycodone" was the most frequent (42.3%) for low-to-moderate-dose regular oxycodone cases, "stepwise switch to morphine" (30.0%) and "add morphine on baseline oxycodone" (27.1%) were the more frequent practices for high-dose regular oxycodone. Regardless of the baseline dose, "add morphine on baseline fentanyl" was the most frequent practice for regular transdermal fentanyl cases. Oxycodone was the most frequent choice in renal insufficiency cases, regardless of its degree., Conclusions: Among Japanese palliative care physicians, using oxycodone for cancer dyspnea was relatively popular practice, whereas fentanyl was not. Oxycodone was the most preferred opioid for cancer dyspnea in the setting of renal insufficiency among Japanese palliative care physicians. We should conduct studies to confirm the safety and effectiveness of these opioid practices for cancer dyspnea., (Copyright © 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Patients receiving cancer chemotherapy may experience a number of potentially severe adverse drug reactions. It is crucial for all members of the health care team to monitor the effect of medicines on the patient to ensure the safety and efficacy of the chemotherapy. The present study prepared medication instruction sheets (MISs) on hematological malignancy and conducted a questionnaire survey to verify their usefulness among physicians, dentists, and nurses. MISs were prepared for 103 chemotherapy and 44 pretreatment regimens for hematopoietic stem cell transplantation in the Department of Hematology at Kyushu University Hospital. Eight questions were prepared to investigate whether MISs could help physicians, dentists, and nurses manage cancer chemotherapy more safely, effectively, and efficiently, as well as in the sharing of information. A total of 35 medical staff working in inpatient wards, including 8 physicians, 3 dentists, and 24 nurses, participated in the questionnaire survey. All of the staff responded to the questionnaire survey, which showed that the MISs were favorably accepted by the participants. There was no negative opinion on the management of chemotherapy using the MISs. The MIS was a useful tool for sharing information on cancer chemotherapy between patients and medical staff and for enabling efficient management, thereby improving the safety and efficacy of treatment.

Cancer chemotherapy has progressed remarkably with conventional and molecular-targeted anticancer drugs as well as immune checkpoint inhibitors. However, adverse drug reaction (ADR) management remains a challenge in cancer chemotherapy. Therefore, improving the quality of medical care through clinical pharmacology research is warranted. Intravenous injection of bendamustine in patients with follicular or mantle cell lymphoma frequently causes venous irritation. Because the underlying mechanisms are not clear, we investigated the factors responsible for bendamustine-induced venous irritation. Based on the results of our analysis, we altered the administration regimen and observed that the incidence of venous irritation, which manifested in a concentration-dependent manner following conventional approaches, significantly decreased when following the modified regimen. Guidelines on the management of chemotherapy-induced nausea and vomiting recommend aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist, 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonists, and dexamethasone as prophylactic antiemetics. Pretreatment with high-dose chemotherapy before hematopoietic stem cell transplantation has extremely high emetogenic potential. This can be countered by using aprepitant in combination with conventional antiemetics. However, the safety and efficacy of such combinations are unexplored. Upon evaluation, we observed improved antiemetic effects without an increase in ADRs. At this symposium, I highlight the significance of clinical pharmacology research for promoting individualized cancer chemotherapy.

Introduction: There have been no reports about predicting survival of patients with advanced cancer constructed entirely with objective variables. We aimed to develop a prognostic model based on laboratory findings and vital signs using a fractional polynomial (FP) model., Methods: A multicentre prospective cohort study was conducted at 58 specialist palliative care services in Japan from September 2012 to April 2014. Eligible patients were older than 20 years and had advanced cancer. We developed models for predicting 7-day, 14-day, 30-day, 56-day and 90-day survival by using the FP modelling method., Results: Data from 1039 patients were analysed to develop each prognostic model (Objective Prognostic Index for advanced cancer [OPI-AC]). All models included the heart rate, urea and albumin, while some models included the respiratory rate, creatinine, C-reactive protein, lymphocyte count, neutrophil count, total bilirubin, lactate dehydrogenase and platelet/lymphocyte ratio. The area under the curve was 0.77, 0.81, 0.90, 0.90 and 0.92 for the 7-day, 14-day, 30-day, 56-day and 90-day model, respectively. The accuracy of the OPI-AC predicting 30-day, 56-day and 90-day survival was significantly higher than that of the Palliative Prognostic Score or the Prognosis in Palliative Care Study model, which are based on a combination of symptoms and physician estimation., Conclusion: We developed highly accurate prognostic indexes for predicting the survival of patients with advanced cancer from objective variables alone, which may be useful for end-of-life management. The FP modelling method could be promising for developing other prognostic models in future research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Guidelines recommend morphine as the first-line pharmacological treatment for cancer dyspnoea. However, trials with other opioids have not been performed. Our aim was to demonstrate the non-inferiority of oxycodone to morphine for relieving dyspnoea in cancer patients., Methods: We conducted a multicentre, open-label, parallel-group, randomized control trial. We randomly and equally assigned cancer patients on regular oxycodone who developed dyspnoea to get a single dose of oral immediate-release oxycodone or morphine. We evaluated the change in dyspnoea intensity (numeric rating scale: 0-10) and adverse events after the medication administration., Results: This study was preconfidence interval -maturely terminated. All 17 enroled patients (8 using oxycodone, 9 using morphine) completed evaluations. In the oxycodone group, dyspnoea intensity decreased 1.75 points [95% confidence interval, 0.72-2.78] at 60 min and 1.50 points (95% confidence interval, -0.11 to 3.11) at 120 min. In the morphine group, dyspnoea decreased 1.33 points (95% confidence interval, 0.41-2.25) at 60 min and 1.00 point (95% confidence interval, -0.08 to 2.08) at 120 min. The differences did not fulfil the non-inferiority requirement. Although two and four patients in morphine group developed drowsiness at 60 and 120 min, no patient in oxycodone group developed significant adverse events., Conclusions: Although we did not show the non-inferiority of oxycodone, oxycodone may have some effectiveness for cancer dyspnoea without significant safety concern., Clinical Trial Registration: UMIN-CTR: UMIN 000005760.

Aim: Dyspnea is among symptoms that decrease quality of life for terminal cancer patients. There are few reports of the positive effects of oxycodone for the treatment of dyspnea, and no studies have focused on opioid-naïve patients. This study aimed to determine the efficacy and safety of continuous intravenous oxycodone infusion for opioid-naïve cancer patients with dyspnea., Methods: Eligible patients were opioid-naïve cancer inpatients who received continuous oxycodone infusion as a treatment for dyspnea under the care of the palliative care team at Komaki City Hospital between November 2013 and December 2016. We retrospectively investigated the improvement of dyspnea following continuous oxycodone infusion from the medical records., Results: This study included 19 patients, and the response rate to oxycodone infusion for dyspnea was 68.4%. Most participants were terminal cancer patients with performance status 3 or 4. Median survival of participants following continuous oxycodone infusion was 6 (range 1-377) days. No serious adverse events such as respiratory depression or somnolence were noted., Conclusion: Continuous oxycodone infusion could be a reasonable treatment option in the management of dyspnea in opioid-naïve cancer patients.