Treatment Recommendation for Dyspnea in Patients with Advanced Disease: Revised Clinical Guidelines from the Japanese Society for Palliative Medicine.

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

A randomized phase 2 study on demeclocycline in patients with mild-to-moderate COVID-19.

Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of demeclocycline in patients hospitalized with mild-to-moderate COVID-19 via an open-label, multicenter, parallel-group, randomized controlled phase 2 trial. Primary and secondary outcomes included changes from baseline (day 1, before the study treatment) in lymphocytes, cytokines, and SARS-CoV-2 RNA on day 8. Seven, seven, and six patients in the control, demeclocycline 150 mg daily, and demeclocycline 300 mg daily groups, respectively, were included in the modified intention-to-treat population that was followed until day 29. A significant change of 191.3/µL in the number of CD4+ T cells from day 1 to day 8 was observed in the demeclocycline 150 mg group (95% CI 5.1/µL-377.6/µL) (p = 0.023), whereas that in the control group was 47.8/µL (95% CI - 151.2/µL to 246.8/µL), which was not significant (p = 0.271). The change rates of CD4+ T cells negatively correlated with those of IL-6 in the demeclocycline-treated groups (R = - 0.807, p = 0.009). All treatment-emergent adverse events were of mild-to-moderate severity. The present results indicate that the treatment of mild-to-moderate COVID-19 patients with demeclocycline elicits immune responses conducive to recovery from COVID-19 with good tolerability.Trial registration: This study was registered with the Japan Registry of Clinical Trials (Trial registration number: jRCTs051200049; Date of the first registration: 26/08/2020).

Opioids for the management of dyspnea in cancer patients: a systematic review and meta-analysis.

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.

Efficacy of supplemental oxygen for dyspnea relief in patients with advanced progressive illness: A systematic review and meta-analysis.

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

Systematic review and meta-analysis of the efficacy of benzodiazepines for dyspnea in patients with cancer.

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.

Mesothelioma in Situ of the Spermatic Cord Arising from a Patent Processus Vaginalis: A Case Report.

Mesothelioma is an aggressive tumor originating from mesothelial cells. Mesothelioma of the spermatic cord is a very rare disease, and the most common presentation of this disease is that of aggressive mesothelioma with no description of mesothelioma in situ. We report an extremely rare case of mesothelioma in situ of the spermatic cord arising from a patent processus vaginalis. To our best knowledge, this is the first report of this finding. The identification of a patent processus vaginalis and investigation of single-layered atypical mesothelial cells led to the final diagnosis.

Treatment Recommendations for Respiratory Symptoms in Cancer Patients: Clinical Guidelines from the Japanese Society for Palliative Medicine.

BACKGROUND: Respiratory symptoms, dyspnea, cough, and death rattle, are common and distressing in advanced cancer patients. Palliation of respiratory symptoms is important to improve quality of life in cancer patients and their families/caregivers. Currently published clinical guidelines for the management of these respiratory symptoms in cancer patients did not cover the topics comprehensively or were not based on formal process for the development of clinical guidelines. METHODS: The Japanese Society for Palliative Medicine (JSPM) decided to develop comprehensive clinical guidelines for the management of respiratory symptoms in cancer patients following the formal guideline developing process. RESULTS: This article provides a summary of the recommendations with the rationales, as well as a short summary of the developing process, of the JSPM respiratory symptom management guidelines. We established 26 recommendations and all recommendations are based on the best available evidences and expert consensus. DISCUSSION: More future clinical researches and continuous guideline updates are required to improve the quality of respiratory symptom management in cancer patients.

Novel Therapeutic Strategies for Delirium in Patients With Cancer: A Preliminary Study.

To compare the efficacy of antipsychotics (APs) for delirium treatment in patients with cancer, 27 patients treated with 1 of the 4 APs, haloperidol (HPD), risperidone (RIS), olanzapine (OLZ), and quetiapine (QTP), were divided into 2 groups: long half-life (T1/2; HPD, RIS, and OLZ) versus short T1/2 (QTP) or the multiacting receptor-targeted APs (MARTAs; OLZ and QTP) versus the non-MARTA (HPD and RIS). The symptom severity was evaluated by the memorial delirium rating scale (MDAS) on days 0, 3, and 7 following intervention. Significant improvements in total MDAS scores were found in all groups on day 3. However, on day 7, only the short T1/2 group and MARTA group showed significant improvement. Consideration of an AP's pharmacological properties may be helpful for improving the outcomes of pharmacological delirium intervention in patients with cancer.

An inhibitory role for Sema4A in antigen-specific allergic asthma.

PURPOSE: The class IV semaphorin Sema4A is critical for efficient Th1 differentiation and Sema4a (-/-) mice exhibit impaired Th1 immune responses. However, the role of Sema4A in Th2 cell-mediated allergic diseases has not been fully studied. The aim of this study was to clarify the regulatory role possessed by Sema4A in mouse models of allergic diseases, particularly allergic asthma. METHODS: Sema4a (-/-) mice on a BALB/c background were examined for the development of allergic diseases. To induce experimental asthma, mice were sensitized with ovalbumin (OVA) followed by intranasal challenges with OVA. After challenge, airway hyperreactivity (AHR) and airway inflammation were evaluated. The role of Sema4A in asthma was examined using Sema4a (-/-) mice and Sema4A-Fc fusion proteins. The direct effects of Sema4A-Fc on antigen-specific effector CD4(+) T cells were also examined. RESULTS: A fraction of Sema4a (-/-) BALB/c mice spontaneously developed skin lesions that resembled atopic dermatitis (AD) in humans. Furthermore, AHR, airway inflammation, and Th2-type immune responses were enhanced in Sema4a (-/-) mice compared to wild type (WT) mice when immunized and challenged with OVA. In vivo systemic administration of Sema4A-Fc during the challenge period ameliorated AHR and lung inflammation and reduced the production of Th2-type cytokines in WT mice. The inhibitory effects of Sema4A on airway inflammation were also observed in mice deficient in Tim-2, a Sema4A receptor. Finally, we showed that Sema4A-Fc directly inhibited IL-4-producing OVA-specific CD4(+) T cells. CONCLUSION: These results demonstrate that Sema4A plays an inhibitory role in Th2-type allergic diseases, such as allergic asthma.

Deletion of tetraspanin CD9 diminishes lymphangiogenesis in vivo and in vitro.

Tetraspanins have emerged as key players in malignancy and inflammatory diseases, yet little is known about their roles in angiogenesis, and nothing is known about their involvement in lymphangiogenesis. We found here that tetraspanins are abundantly expressed in human lymphatic endothelial cells (LEC). After intrathoracic tumor implantation, metastasis to lymph nodes was diminished and accompanied by decreased angiogenesis and lymphangiogenesis in tetraspanin CD9-KO mice. Moreover, lymphangiomas induced in CD9-KO mice were less pronounced with decreased lymphangiogenesis compared with those in wild-type mice. Although mouse LEC isolated from CD9-KO mice showed normal adhesion, lymphangiogenesis was markedly impaired in several assays (migration, proliferation, and cable formation) in vitro and in the lymphatic ring assay ex vivo. Consistent with these findings in mouse LEC, knocking down CD9 in human LEC also produced decreased migration, proliferation, and cable formation. Immunoprecipitation analysis demonstrated that deletion of CD9 in LEC diminished formation of functional complexes between VEGF receptor-3 and integrins (α5 and α9). Therefore, knocking down CD9 in LEC attenuated VEGF receptor-3 signaling, as well as downstream signaling such as Erk and p38 upon VEGF-C stimulation. Finally, double deletion of CD9/CD81 in mice caused abnormal development of lymphatic vasculature in the trachea and diaphragm, suggesting that CD9 and a closely related tetraspanin CD81 coordinately play an essential role in physiological lymphangiogenesis. In conclusion, tetraspanin CD9 modulates molecular organization of integrins in LEC, thereby supporting several functions required for lymphangiogenesis.

Inhibitory roles of signal transducer and activator of transcription 3 in antitumor immunity during carcinogen-induced lung tumorigenesis.

Stat3 mediates a complex spectrum of cellular responses, including inflammation, cell proliferation, and apoptosis. Although evidence exists in support of a positive role for Stat3 in cancer, its role has remained somewhat controversial because of insufficient study of how its genetic deletion may affect carcinogenesis in various tissues. In this study, we show using epithelium-specific knockout mice (Stat3(Δ/Δ)) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3(Δ/Δ) mice did not show any lung defects in terms of proliferation, apoptosis, or angiogenesis, they exhibited reduced urethane-induced tumorigenesis and increased antitumor inflammation and natural killer (NK) cell immunity. Comparative microarray analysis revealed an increase in Stat3(Δ/Δ) tumors in proinflammatory chemokine production and a decrease in MHC class I antigen expression associated with NK cell recognition. Consistent with these findings, human non-small cell lung cancer (NSCLC) cells in which Stat3 was silenced displayed an enhancement of proinflammatory chemokine production, reduced expression of MHC class I antigen, and increased susceptibility to NK cell-mediated cytotoxicity. In addition, supernatants from Stat3-silenced NSCLC cells promoted monocyte migration. Collectively, our findings argue that Stat3 exerts an inhibitory effect on antitumor NK cell immunity in the setting of carcinogen-induced tumorigenesis.

Long-term amrubicin chemotherapy for small-cell lung cancer.

BACKGROUND: Amrubicin is an active agent for the treatment of small-cell lung cancer (SCLC). However, there have been no reports of long-term amrubicin use. PATIENTS AND METHODS: Twelve patients with SCLC who were treated with eight or more cycles of amrubicin chemotherapy were retrospectively reviewed. RESULTS: The median number of cycles of amrubicin chemotherapy received by the patients was 12 (range=8-20), and the median cumulative dose of amrubicin was 2076 mg (range=1200-2856 mg). The median survival time of the study patients was 1104 days (range=459-1997 days). The main adverse events observed during amrubicin chemotherapy were leukopenia and neutropenia. The cardiothoracic ratio (CTR), expressed as the mean (standard deviation) of the values measured at the initiation and termination of amrubicin chemotherapy was 46.2 (4.0), and 46.1 (5.1), respectively. The change in CTR did not reach statistical significance (p=0.92). CONCLUSION: Long-term amrubicin chemotherapy is a safe and effective treatment that is associated with a good survival prognosis in properly selected patients.

4-Hydroxy-2-nonenal induces chronic obstructive pulmonary disease-like histopathologic changes in mice.

The α,ß-unsaturated aldehyde 4-hydroxy-2-nonenal (4-HNE) is an endogenous product of oxidative stress that is found at increased levels in the lungs of patients with chronic obstructive pulmonary disease (COPD) and animal models of this lung disorder. In the present study, levels of 4-HNE adducts were increased in two different mouse models of COPD. Challenging lungs with 4-HNE enlarged the airspace and induced goblet cell metaplasia of the airways in mice, two characteristics of COPD. 4-HNE induced the accumulation of inflammatory cells expressing high levels of MMP-2 and MMP-9. Our results indicate that 4-HNE production during oxidative stress is a key pathway in the pathogenesis of COPD.

A retrospective study of chemotherapy with and without pemetrexed in malignant pleural mesothelioma.

BACKGROUND: The current standard first-line chemotherapy for malignant pleural mesothelioma (MPM) is pemetrexed and cisplatin. However, other regimens, with or without a platinum agent, are reported to be effective in the treatment of MPM. PATIENTS AND METHODS: Patients who were diagnosed with MPM and treated with chemotherapy between January 1999 and June 2010 at the Osaka Prefectural Medical Center for Respiratory and Allergic Diseases were studied, and the outcomes of these patients were retrospectively analyzed in relation to therapy. RESULTS: In total, 48 patients with MPM (42 men and 6 women) treated with chemotherapy were included in the current analysis. The median survival time (MST) and one-year survival rate in the pemetrexed-containing group were 541 days and 63.2%, respectively. The MST and one-year survival rate in the non-pemetrexed group were 516 days and 66.7%, respectively. Overall survival did not differ significantly with respect to the pemetrexed-containing regimen. CONCLUSION: The superiority of pemetrexed-containing regimens is equivocal. Non-pemetrexed-containing regimens may be potent alternatives.

Two cases of leptomeningeal metastases from lung adenocarcinoma which progressed during gefitinib therapy but responded to erlotinib.

We present two patients with leptomeningeal metastases (LM) from lung adenocarcinoma that progressed or newly developed, respectively, during gefitinib therapy which had exhibited substantial antitumor effects on widespread lesions. In both cases, a switch to erlotinib therapy brought about long-lasting dramatic symptomatic improvement and markedly prolonged survival. The first patient is a 46-year-old female who presented with progressive headache and vomiting. Multiple pulmonary, hepatic and bone metastases immediately shrank in response to gefitinib. However, 1 month after completion of concurrent whole brain radiation, dizziness and urinary retention newly emerged, worsening the symptoms observed at presentation. Magnetic resonance imaging (MRI) demonstrated enlargement of ventricles and new gadolinium (Gd)-enhanced disseminated nodules on the surface of the cerebral cortex, suggesting the existence of uncontrollable LM. Sequential erlotinib therapy resulted in symptomatic improvement with a finding of regression of Gd-enhancement on MRI. The beneficial effect lasted for 10 months, though a follow-up brain MRI showed further enlarged ventricles. She finally died due to LM after surviving for 11 months under erlotinib treatment. The other patient is a 55-year-old female in whom headache and vomiting occurred while gefitinib therapy had maintained shrinkage of all pre-existing tumors in the thorax and bones. Brain MRI strongly suggested occurrence of LM with a finding of Gd-enhanced sulci. A switch to erlotinib therapy relieved the symptoms with disappearance of Gd-enhancement. However, the symptoms recurred with a finding of further enlargement of ventricles on brain MRI after 11 months. Finally, she died due to LM after surviving for 12 months under erlotinib treatment.

Early [18F]fluorodeoxyglucose positron emission tomography at two days of gefitinib treatment predicts clinical outcome in patients with adenocarcinoma of the lung.

PURPOSE: Positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG) is increasingly used in early assessment of tumor response after chemotherapy. We investigated whether a change in [(18)F]FDG uptake at 2 days of gefitinib treatment predicts outcome in patients with lung adenocarcinoma. EXPERIMENTAL DESIGN: Twenty patients were enrolled. [(18)F]FDG-PET/computed tomographic (CT) scan was carried out before and 2 days after gefitinib treatment. Maximum standardized uptake values (SUV) were measured, and post-gefitinib percentage changes in SUV were calculated. Early metabolic response (SUV decline < -25%) was compared with morphologic response evaluated by CT scan and with progression-free survival (PFS). RESULTS: At 2 days of gefitinib treatment, 10 patients (50%) showed metabolic response, 8 had metabolic stable disease, and 2 had progressive metabolic disease. Percentage changes of SUV at 2 days were correlated with those of tumor size in CT at 1 month (R(2) = 0.496; P = 0.0008). EGFR gene was assessable in 15 patients, and of 12 patients with EGFR mutations, 8 showed metabolic response at 2 days and 6 showed morphologic response at 1 month. None of 3 patients with wild-type EGFR showed metabolic or morphologic response. Metabolic response at 2 days was not statistically associated with PFS (P = 0.095), but when a cutoff value of -20% in SUV decline was used, metabolic responders had longer PFS (P < 0.0001). CONCLUSION: Early assessment of [(18)F]FDG tumor uptake with PET at 2 days of gefitinib treatment could be useful to predict clinical outcome earlier than conventional CT evaluation in patients with lung adenocarcinoma.

Favorable response to crizotinib in three patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion-type oncogene-positive non-small cell lung cancer.

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a recently identified fusion-type oncoprotein that exists in approximately 5% of non-small cell lung cancer (NSCLC). It has been demonstrated that NSCLC driven by EML4-ALK is strongly addicted to this fusion-type oncokinase. A clinical trial of crizotinib (PF-02341066) sponsored by Pfizer has proven this oncogene addiction in humans by demonstrating a high response rate to inhibition of ALK kinase activity. In the present study, we report on three cases harboring EML4-ALK rearrangement who were enrolled in the trial (A8081001, NCT00585195). All three patients showed favorable responses to the ALK-specific tyrosine kinase inhibitor.