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.

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.

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.

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.

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.

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.

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).

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.

Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity.

T cell Ig-like mucin-like-1 (TIM-1) is an important asthma susceptibility gene, but the immunological mechanisms by which TIM-1 functions remain uncertain. TIM-1 is also a receptor for phosphatidylserine (PtdSer), an important marker of cells undergoing programmed cell death, or apoptosis. We now demonstrate that NKT cells constitutively express TIM-1 and become activated by apoptotic cells expressing PtdSer. TIM-1 recognition of PtdSer induced NKT cell activation, proliferation, and cytokine production. Moreover, the induction of apoptosis in airway epithelial cells activated pulmonary NKT cells and unexpectedly resulted in airway hyperreactivity, a cardinal feature of asthma, in an NKT cell-dependent and TIM-1-dependent fashion. These results suggest that TIM-1 serves as a pattern recognition receptor on NKT cells that senses PtdSer on apoptotic cells as a damage-associated molecular pattern. Furthermore, these results provide evidence for a novel innate pathway that results in airway hyperreactivity and may help to explain how TIM-1 and NKT cells regulate asthma.

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.

Involvement of endothelial apoptosis underlying chronic obstructive pulmonary disease-like phenotype in adiponectin-null mice: implications for therapy.

RATIONALE: Chronic obstructive pulmonary disease is frequently complicated with comorbidities, such as cardiovascular disease, osteoporosis, and body weight loss, but the causal link remains unclear. OBJECTIVES: To investigate the role of adiponectin in the pathogenesis of chronic obstructive pulmonary disease and its potential use in therapy. METHODS: Adiponectin localization and dynamics in the lung were analyzed in an elastase-induced emphysema model. Next, the lung of adiponectin-knockout mice, extrapulmonary effects, and the underlying mechanism were investigated. Finally, we tested whether exogenous adiponectin could ameliorate the emphysematous change in adiponectin-knockout mice. MEASUREMENTS AND MAIN RESULTS: Adiponectin expression in lung vasculature and plasma concentration of adiponectin were reduced after elastase-instillation. Notably, adiponectin-knockout mice showed progressive alveolar enlargement and increased lung compliance. They further exhibited not only systemic inflammation, but also extrapulmonary phenotype, such as body weight loss, fat atrophy, and osteoporosis. Moreover, endothelial apoptosis was enhanced in the lungs of adiponectin-knockout mice, as evidenced by caspase-3 activity. Consistent with this, expressions of vascular endothelial growth factor receptor-2 and platelet endothelial cell adhesion molecule-1 on endothelial cells were decreased in the adiponectin-knockout mice. Finally, adenovirus-mediated adiponectin supplementation ameliorated the emphysematous phenotype. CONCLUSIONS: Adiponectin-knockout mice develop progressive chronic obstructive pulmonary disease-like phenotype with systemic inflammation and extrapulmonary phenotypes. Hypoadiponectinemia could thus play a critical role in the progression of chronic obstructive pulmonary disease and concomitant comorbidities through endothelial dysfunction. Together, adiponectin could be a novel target for chronic obstructive pulmonary disease therapy.

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.

Tetraspanin CD9 negatively regulates lipopolysaccharide-induced macrophage activation and lung inflammation.

Tetraspanins facilitate the formation of multiple molecular complexes at specialized membrane microdomains and regulate cell activation and motility. In the present study, the role of tetraspanin CD9 in LPS-induced macrophage activation and lung inflammation was investigated in vitro and in vivo. When CD9 function was ablated with mAb treatment, small interfering RNA transfection, or gene knockout in RAW264.7 cells or bone marrow-derived macrophages, these macrophages produced larger amounts of TNF-alpha, matrix metalloproteinase-2, and -9 upon stimulation with LPS in vitro, when compared with control cells. Sucrose gradient analysis revealed that CD9 partly colocalized with the LPS-induced signaling mediator, CD14, at low-density light membrane fractions. In CD9 knockout macrophages, CD14 expression, CD14 and TLR4 localization into the lipid raft, and their complex formation were increased whereas IkappaBalpha expression was decreased when compared with wild-type cells, suggesting that CD9 prevents the formation of LPS receptor complex. Finally, deletion of CD9 in mice enhanced macrophage infiltration and TNF-alpha production in the lung after intranasal administration of LPS in vivo, when compared with wild-type mice. These results suggest that macrophage CD9 negatively regulates LPS response at lipid-enriched membrane microdomains.

Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma.

BACKGROUND: Cyclic AMP (cAMP) signaling modulates functions of inflammatory cells involved in the pathogenesis of asthma, and type 4 cAMP-specific phosphodiesterases (PDE4s) are essential components of this pathway. Induction of the PDE4 isoform PDE4B is necessary for Toll-like receptor signaling in monocytes and macrophages and is associated with T cell receptor/CD3 in T cells; however, its exact physiological function in the development of allergic asthma remains undefined. OBJECTIVES: We investigated the role of PDE4B in the development of allergen-induced airway hyperresponsiveness (AHR) and T(H)2-driven inflammatory responses. METHODS: Wild-type and PDE4B(-/-) mice were sensitized and challenged with ovalbumin and AHR measured in response to inhaled methacholine. Airway inflammation was characterized by analyzing leukocyte infiltration and cytokine accumulation in the airways. Ovalbumin-stimulated cell proliferation and T(H)2 cytokine production were determined in cultured bronchial lymph node cells. RESULTS: Mice deficient in PDE4B do not develop AHR. This protective effect was associated with a significant decrease in eosinophils recruitment to the lungs and decreased T(H)2 cytokine levels in the bronchoalveolar lavage fluid. Defects in T-cell replication, T(H)2 cytokine production, and dendritic cell migration were evident in cells from the airway-draining lymph nodes. Conversely, accumulation of the T(H)1 cytokine IFN-γ was not affected in PDE4B(-/-) mice. Ablation of the orthologous PDE4 gene PDE4A has no impact on airway inflammation. CONCLUSION: By relieving a cAMP-negative constraint, PDE4B plays an essential role in T(H)2-cell activation and dendritic cell recruitment during airway inflammation. These findings provide proof of concept that PDE4 inhibitors with PDE4B selectivity may have efficacy in asthma treatment.

Recurrent allergic bronchopulmonary aspergillosis in a patient with rheumatoid arthritis treated with etanercept and tocilizumab.

We report the case of a 68-year-old woman with Stage III and Class II rheumatoid arthritis (RA) that was resistant to prednisolone, methotrexate, and infliximab. After treatment with etanercept or tocilizumab, suspicious allergic bronchopulmonary aspergillosis (ABPA) repeatedly occurred and then rapidly improved after the withdrawal of each drug. We suspect that administration of etanercept and tocilizumab caused suspicious ABPA in this patient. The relevance to the pathogenesis of ABPA under these biological drugs is also discussed.

Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13.

BACKGROUND: Atopic dermatitis (AD) is characterized by local and systemic T(H)2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of T(H)2 cytokines has been suggested as therapy for AD. OBJECTIVES: We sought to examine the effect of the absence of IL-4 and IL-13 on the T(H)17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD. METHODS: Wild-type, IL4 knockout (KO), IL13 KO and IL4/13 double KO (DKO) mice were subjected to epicutaneous sensitization with ovalbumin (OVA) or saline and airway challenged with OVA. Systemic immune responses to OVA, skin and airway inflammation, and airway hyperresponsiveness were examined. RESULTS: OVA-sensitized DKO mice exhibited impaired T(H)2-driven responses with undetectable OVA-specific IgE levels and severely diminished eosinophil infiltration at sensitized skin sites but intact dermal infiltration with CD4(+) cells. DKO mice mounted exaggerated IL-17A but normal IFN-gamma and IL-5 systemic responses. Airway challenge of these mice with OVA caused marked upregulation of IL-17 mRNA expression in the lungs, increased neutrophilia in bronchoalveolar lavage fluid, airway inflammation characterized by mononuclear cell infiltration with no detectable eosinophils, and bronchial hyperresponsiveness to methacholine that were reversed by IL-17 blockade. IL-4, but not IL-13, was identified as the major T(H)2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice. CONCLUSION: Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated T(H)17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness.

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.

Gefitinib-sensitive EGFR lacking residues 746-750 exhibits hypophosphorylation at tyrosine residue 1045, hypoubiquitination, and impaired endocytosis.

Gefitinib-sensitive nonsmall cell lung cancers (NSCLC) are characterized by somatic mutations in the kinase domain of epidermal growth factor receptor (EGFR). The mutant EGFR forms are reported to mediate characteristic signal transduction pathways that are different from those mediated by the wild-type EGFR and are involved in transformation in vivo. We have examined signal transduction pathways initiated from a frequently identified gefitinib-sensitizing mutant EGFR lacking residues 746-750 by employing a mouse fibroblast cell line that is free of endogenous EGFR and transiently transfected COS-7 cells. Upon EGF stimulation, the deletion-mutant EGFR mediated prolonged downstream signals. The analysis of the phosphotyrosine patterns of the receptor revealed that the deletion-mutant EGFR lacked phosphorylation at tyrosine residue 1045, which is the major binding site of Cbl. The EGF-induced endocytosis of the deletion-mutant EGFR was impaired. The ubiquitination and downregulation of the deletion-mutant EGFR were also reduced. On the other hand, another mutant, EGFR, possessing a L858R substitution, exhibited phosphorylation at 1045 and its downstream signalings were not prolonged. These data suggest that the signal transduction pathways initiated from these mutant forms are different, and that impaired endocytosis might be responsible for the prolonged signals mediated by the deletion-mutant EGFR.

Short-term gefitinib treatment brought about a long-term regression of bronchioloalveolar carcinoma without EGFR gene alterations: a case report.

The tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) gefitinib has beneficial effect in some patients with refractory advanced non-small cell lung cancer (NSCLC). However, the majority of responders eventually develop acquired resistance during the course of prolonged continuous treatment. Here we present a case of 76-year-old Japanese female, who had never smoked, with poor performance status from bronchioloalveolar carcinoma (BAC), in whom a brief initial 5-week administration of gefitinib resulted in dramatic antitumor effects that lasted approximately 8.5 months after cessation of the treatment. Furthermore, the relapsed tumor later regressed again by re-treatment with the TKI. She survived 26 months since she first took gefitinib. Unexpectedly, neither sensitizing mutations for EGFR-TKIs nor increased copy numbers were detected in EGFR gene of her BAC cells. This case suggests that, in some patients with NSCLC, even short-term administration of gefitinib may bring about clinical benefits and disease response comparable to the standard long-term daily dosing schedule. Short-term use of gefitinib will also be able to minimize the expensive medical cost of the TKI. The potential role of short-term or pulse-dose therapy with EGFR-TKIs should be clarified in further prospective studies. Moreover, it is urgent to develop better strategies by which we could distinguish responders to the TKIs from nonresponders among patients who do not have any EGFR gene alterations.

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.