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BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangement is one of the most important drivers in non-small cell lung cancer (NSCLC). Despite the effectiveness to canonical 3'-ALK fusions, the clinical efficacy of ALK inhibitors in patients with complex ALK fusions, such as nonreciprocal/reciprocal translocation remains uncertain. Exploring the optimal therapeutic regimens for this subset of patients is of crucial clinical significance. CASE DESCRIPTION: We reported a female patient diagnosed with stage IVB lung adenocarcinoma (LUAD) harboring a novel ALK-RNF144A fusion, concurrent with a Huntingtin-interacting protein 1 (HIP1)-ALK fusion and a RB1 loss-of-function variant. The patient sequentially received multiple lines of treatment with ALK-tyrosine kinase inhibitor (TKI), chemotherapy, radiotherapy and ALK-TKI combined with anti-angiogenesis. Disease progression accompanied by a squamous cell carcinoma transformation was indicated after ALK-TKI combined with anti-angiogenesis and both ALK-RNF144A and HIP1-ALK fusions were retained in the tumor. The patient was subsequently treated with a third generation ALK-TKI, lorlatinib, in combination with albumin-bound paclitaxel and anlotinib, and then achieved stable disease. The patient remained on the treatment as of the last follow-up resulting in an overall survival (OS) of more than 18 months. CONCLUSIONS: We have reported an advanced NSCLC patient with a complex nonreciprocal/reciprocal ALK translocation containing a novel ALK-RNF144A fusion, concurrent with a RB1 loss-of-function mutation, who subsequently experienced pathological squamous cell carcinoma transformation. The combined treatment with ALK-TKI, chemotherapy, and anti-angiogenesis demonstrates clinical efficacy and may provide optional therapeutic strategies for this phenotype.

DOI： 10.21037/tlcr-23-656

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We describe the case of a 36-year-old man diagnosed with human immunodeficiency virus (HIV) following prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. The patient had a complication of pneumocystis pneumonia. Upon initiating highly active antiretroviral therapy, we monitored HIV RNA levels, CD4+ T-cell count, SARS-CoV-2 viral load, and IgG antibodies against SARS-CoV-2. At 167 days post SARS-CoV-2 diagnosis, the patient's CD4+ T-cell count increased to 180 cells/μL. IgG antibodies against SARS-CoV-2 were undetectable despite a decreased SARS-CoV-2 viral load. HIV screening is necessary in cases of prolonged SARS-CoV-2 pneumonia or persistent SARS-CoV-2 shedding. When diagnosed with HIV infection, it is advisable to consider the possibility of pneumocystis pneumonia.

DOI： 10.7759/cureus.51189

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The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were β-lactamase-producing ampicillin resistant and β-lactamase-negative ampicillin resistant, respectively. Extended-spectrum β-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-β-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

DOI： 10.1016/j.jiac.2023.04.008

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BACKGROUND: Tyrosine kinase inhibitors (TKIs) significantly improve clinical outcomes in patients with non-small cell lung cancer due to anaplastic lymphoma kinase (ALK) gene rearrangement. However, the rate of relapse with TKIs is high owing to the development of resistance mutations during treatment. Repeated biopsies during disease progression are crucial for elucidating the molecular mechanisms underlying the development of resistance to ALK inhibitors. Analysis of cell-free DNA (cfDNA) obtained from plasma is a novel approach for tumor genotyping. METHODS: In this mixed prospective and retrospective observational cohort study, we investigated the clinical feasibility of continuous quantitative monitoring of ALK-acquired mutations in plasma obtained from patients with ALK+ non-small cell lung cancer by using a highly sensitive and specific droplet digital polymerase chain reaction (ddPCR) assay. We enrolled nine patients, including three treatment-naïve patients recently diagnosed with ALK+ non-small cell lung cancer via tissue biopsy and expected to receive ALK TKIs and six patients already receiving ALK TKIs. Plasma samples were collected from these patients every 3 months. cfDNA was extracted from 66 samples during the study period, and 10 ALK mutations were simultaneously evaluated. RESULTS: The numbers of samples showing the G1202R, C1156Y, G1269A, F1174L, T1151ins, and I1171T mutations were 32, 16, 5, 4, 1, and 1, respectively. The L1196M, L1152R, V1180L, and S1206Y mutations were not detected. Correlation analyses between progression-free survival and the time from treatment initiation (or treatment modification) to the detection of resistance mutations revealed that although resistance mutations may occur before a drug change becomes necessary, there is a duration during which the disease does not progress. CONCLUSIONS: Our findings suggest that real-time quantitative monitoring of ALK resistance mutations during the response period could provide a time course of changes while acquiring resistance mutations. This information would be beneficial for designing an appropriate treatment strategy.

DOI： 10.21037/tlcr-22-671

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

J-GLOBAL

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations are commonly reported in non-small cell lung cancer (NSCLC) and are associated with a poor prognosis. There is insufficient evidence regarding the efficacy of immune checkpoint inhibitors (ICIs) in SMARCA4-deficient NSCLC patients with poor performance status (PS). We report two cases of advanced SMARCA4-deficient NSCLC treated with ICIs, in which marked regression of the tumor and improved general condition of the patients were achieved.

DOI： 10.7759/cureus.37656

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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INTRODUCTION: Sotorasib is a crucial therapeutic agent for patients with non-small cell lung cancer (NSCLC) harboring the KRAS p.G12C mutation. Despite its efficacy, the relationship between blood sotorasib concentrations and side effects remains largely unexplored. METHODS: This study enrolled five patients with KRAS p.G12C-positive NSCLC treated with sotorasib (LUMAKRAS® Tablets, Amgen, Japan) between July 2022 and February 2023 at Asahikawa Medical University Hospital. Blood sotorasib levels were monitored, and their association with adverse events was examined, with no adjustments made to drug dosages based on these levels. RESULTS: Variable blood sotorasib levels were observed among the participants. Notably, one patient developed interstitial pneumonitis, although a definitive attribution to sotorasib was uncertain due to prior pembrolizumab treatment. The study revealed no consistent association between blood sotorasib levels and adverse events or therapeutic outcomes, with some patients experiencing severe side effects at higher concentrations, while others did not. CONCLUSION: Preliminary findings suggested that monitoring blood sotorasib levels may aid in anticipating adverse events in this small cohort. However, future studies with larger sample sizes and extended follow-up periods are required to validate these initial observations. Such studies could potentially offer insights into personalized dosing strategies, thereby mitigating adverse effects and enhance patient care for individuals with KRAS p.G12C-positive NSCLC.

DOI： 10.3389/fonc.2023.1269991

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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INTRODUCTION: Cisplatin-based chemotherapy was established in the 1980s, and it has been improved by the development of a short hydration protocol in lung cancer therapy. However, cisplatin-based chemotherapy is still associated with renal toxicity. Because 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) is known to be a mitochondrial activator and a heme oxygenase-1 (HO-1) inducer, 5-ALA with SFC is speculated to mitigate cisplatin-induced renal inflammation. METHODS: We investigated the effects of oral administration of 5-ALA with SFC for preventing cisplatin-based nephrotoxicity in patients with lung cancer and evaluated its benefits for patients who received cisplatin-based chemotherapy. The primary endpoint was the significance of the difference between the serum creatinine (sCr) levels of the patients administered 5-ALA with SFC and those given placebo after course 1 of chemotherapy. The difference in the estimated glomerular filtration rate (eGFR) between the two groups was also evaluated as the secondary endpoint. RESULTS: The double-blind, randomized two-arm studies were conducted at 15 medical facilities in Japan; 54 male and 20 female patients with lung cancer who received cisplatin-based chemotherapy between the ages of 42 and 75 years were included in the study. The compliance rate was greater than 94% in the primary assessment and subsequent drug administration periods. All enrolled patients completed the four cycles of cisplatin-based chemotherapy with short hydration. The average level of sCr on day 22 of course 1 was 0.707 mg/dL in the group treated with 5-ALA and SFC and 0.735 mg/dL in the placebo group, respectively, and the sCr in the test group was significantly lower than that in the placebo group (p = 0.038). In addition, the eGFR was significantly higher in the SPP-003 group than in the placebo group up to day 1 of course 3 (84.66 and 75.68 mL/min/1.73 m2, respectively, p = 0.02) and kept better even after the last administration of the study drug (82.37 and 73.49 mL/min/1.73 m2, respectively, p = 0.013). CONCLUSIONS: The oral administration of 5-ALA with SFC is beneficial to patients undergoing cisplatin-based chemotherapy for lung cancer with short hydration.

DOI： 10.1159/000526977

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Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1-73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9-23.9) months. The median overall survival was not reached (95% confidence interval 24.6-not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

DOI： 10.1038/s41598-021-02561-z

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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BACKGROUND: Combination therapy with the B-Raf inhibitor, dabrafenib, and the MEK inhibitor, trametinib (DT) is commonly used to treat patients with B-Raf proto-oncogene, serine/threonine kinase V600E (BRAF V600E)-mutated non-small cell lung cancer (NSCLC). However, the mechanisms through which cancer develops DT resistance are unclear. Here, we investigated new mechanisms underlying acquired DT-resistant NSCLC with the BRAF V600E mutation. METHODS: We compared genomic signatures before and after DT treatment in patients with NSCLC. RESULTS: Two of four patients treated with DT developed carcinomatous pleuritis within 3 months. Target DNA sequencing and quantitative polymerase chain reaction (PCR) analyses revealed the increased expression level of cyclin-dependent kinase 4 (CDK4). We also found prominent protein expression of CDK4 after DT treatment. Induction of CDK4 expression in a cell line derived from a patient with the BRAF V600E mutation resulted in partial resistance to dabrafenib. CONCLUSIONS: Our findings suggest a possible relationship between CDK4 upregulation and acquired resistance to DT therapy.

DOI： 10.21037/tlcr-21-415

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden "stealth" antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re-expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re-expression in xenografts in BALB/c-nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T-cells with a SPESP1-derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1-specific helper T-cells were obtained; these cells produced interferon-γ against HLA-matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.

DOI： 10.1111/cas.14973

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

Triple-negative breast cancer (TNBC) has a poorer prognosis than other breast cancer subtypes; therefore, identifying markers of early recurrence is important. The present study aimed to establish a liquid biopsy protocol for droplet digital PCR-based detection of frequently mutated genes in patients with TNBC. Tumor DNA from 36 patients with TNBC who relapsed within 2 years after surgical resection was retrospectively analyzed. Somatic mutational profiles were evaluated using targeted sequencing to identify frequently mutated genes and genes associated with molecularly targeted therapies. The association between genetic alterations and associated protein phosphorylation was investigated using immunohistochemical analysis. Recurrent hot spot mutations in the plasma were monitored over time. Mutation-specific probes were used to successfully detect mutations in the blood samples of patients who were positive for PIK3CA H1047R and AKT1 E17K mutations. Somatic mutations in AKT1 (14.9%) and PIK3CA (25.5%) were frequently identified in the data. Robust phosphorylation of AKT and S6RP was more common in tumors with PIK3CA H1047R and AKT1 E17K mutational background than in tumors with wild-type PIK3CA and AKT1. In conclusion, the present study evaluated a high-sensitivity detection system for frequently mutated genes that was also applicable for cell-free DNA. The PI3K/AKT pathway was revealed to be activated in patients harboring PIK3CA H1047R and AKT1 E17K mutations; therefore, the PI3K/AKT pathway may be a promising candidate for targeted therapy in these patients.

DOI： 10.3892/ol.2021.12681

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Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.

DOI： 10.1111/cas.14879

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14879

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Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.

DOI： 10.1016/j.jtocrr.2020.100107

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本サルコイドーシス  

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DOI： 10.1016/j.ejca.2020.04.008

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INTRODUCTION/AIM: Photodynamic therapy (PDT) involves the use of a tumor-specific photosensitizer and laser irradiation, and is one of the treatment options recommended for early centrally located lung cancers, but not yet for peripheral-type lung cancers. We developed a new laser probe, the composite-type optical fiberscope (COF), which allows accurate laser irradiation of a cancer lesion with simultaneous visualization of the lesion. In this study, we attempted a new endobronchial PDT technique using the new laser probe, and evaluated the effectiveness and feasibility of this novel PDT technique for peripheral lung cancers. METHODS: This phase I study was conducted in 7 patients with peripheral lung cancers (primary tumor ≤20 mm in diameter). We performed endobronchial PDT for these patients using the new laser probe and talaporfin sodium as the photosensitizer. RESULTS: We performed PDT for 3 patients with peripheral lung cancer using a laser dose of 50 J/cm2 at 120 mW, and confirmed the feasibility of using this dose. Then, we escalated the laser dose to 100 J/cm2 in 4 additional patients. A total of 7 patients met our inclusion criteria. Evaluation at 2 weeks and 3 months after the PDT revealed no complication such as pneumonia or pneumothorax. At the evaluation conducted 6 months later, we found CR in 3 cases and SD in the remaining 4 cases. CONCLUSION: PDT was found to be a feasible and non-invasive treatment modality for early peripheral-type lung cancer. In the future, PDT could become a standard treatment option for peripheral-type lung cancer.

DOI： 10.1016/j.pdpdt.2020.101698

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Background: A recent technical advance in mRNA in situ hybridization (mRNA-ISH) assays provides simultaneous signal amplification and background suppression with a unique probe design that enables single-molecule visualization. We assessed the utility of the mRNA-ISH assay as a diagnostic tool for detecting anaplastic lymphoma receptor tyrosine kinase (ALK) mRNA in non-small-cell lung carcinoma (NSCLC). We compared the mRNA-ISH assay with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Methods: The study included 279 surgically resected lung adenocarcinomas and 44 transbronchial-biopsied (TBB) adenocarcinomas. mRNA-ISH was conducted using the RNAscope 2.0 system, which includes pre-designed probes for detecting the tyrosine kinase domain encoded in ALK mRNA. IHC was conducted on all 323 samples using ALK-specific antibodies. mRNA-ISH was performed on 279 surgical samples and 6 TBB samples. Break-apart FISH was used to examine samples that were mRNA-ISH-positive or IHC-positive. Results: ALK protein expression was detected in 11 of 279 specimens (3.9%). ALK mRNA was also detected with mRNA-ISH in ALK-positive samples, and 9 of the 11 specimens (81%) were also positive for ALK using break-apart FISH. Using the IHC results as a reference, the sensitivity and specificity of mRNA-ISH was 100%. In the TBB cohort, ALK protein expression was observed in 3 of 44 specimens (6.8%), in which ALK mRNA expression was also detected. Conclusions: The ALK mRNA-ISH data were highly correlated with the IHC data, and ALK mRNA-ISH detected ALK mRNA expression in every FISH-positive sample. We conclude that mRNA-ISH could serve as an alternative or complementary method for diagnosing ALK rearrangements in NSCLC.

DOI： 10.21037/tlcr.2020.03.04

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DOI： 10.1016/j.jtho.2019.11.015

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Acute eosinophilic pneumonia (AEP) is an eosinophilic lung disease associated with environmental substances including smoking. Although the etiology of AEP has not been fully elucidated, it has been hypothesized that IL-33 plays a central role in the pathogenesis of AEP. Turpentine oil, from resins of pine trees, is not only used in paints, but also utilized in experimental animal models of inflammation because it leads to the production of inflammatory cytokines including IL-33. Here, we report the first case of AEP following turpentine oil inhalation. A 67-year-old woman reported using urushiol with turpentine oil to repair home goods. She had fever and persistent cough after turpentine inhalation over a very short period of time. The chest X-ray image showed consolidation in the upper right lung field. Laboratory findings indicated that there was no evidence of infection, collagen vascular diseases, and other allergic diseases that cause pneumonia, but analysis of the bronchoalveolar lavage fluid revealed 29% eosinophils with a small number of lipid-laden macrophages. With these findings, the diagnostic criteria of AEP was met. We rendered a diagnosis of AEP by inhalation of turpentine because no other cause for AEP was identified even with a structured questionnaire survey. The manifestations resolved immediately after steroid therapy. This is the first report of a case of AEP caused by the inhalation of turpentine oil.

DOI： 10.1016/j.rmcr.2020.101143

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Objective: Oncogenic echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) (EML4-ALK) fusion proteins found in non-small cell lung cancers (NSCLC) are constitutively phosphorylated and activated by dimerization via the coiled-coil domain (cc) within EML4. Here, we investigated whether disruption of ALK fusion protein oligomerization via competitive cc mimetic compounds could be a therapeutic strategy for EML4-ALK NSCLC. Methods: A Ba/F3 cell model was created that expressed an ALK intracellular domain in which the dimer/monomer state is ligand-regulated. This novel cell model was used to investigate the effect of disrupting ALK fusion protein oligomerization on tumor cell growth in vitro and in vivo using nude mice. Subsequently, the antiproliferative effects of endogenous cc domain co-expression and mimetic cc peptides were assayed in EML4-ALK cancer cell lines. Results: Cells induced to express monomeric ALK in vitro did not survive. When transplanted into mice, induction of monomers abrogated tumor formation. Using a fluorescent protein system to quantify protein-protein interactions of EML4-ALK and EML4cc, we demonstrated that co-expression of EML4cc suppressed EML4-ALK assembly concomitant with decreasing the rate of tumor growth in vitro and in vivo. In EML4-ALK cancer cell lines, administration of synthetic EML4cc peptide elicited a decrease of phosphorylation of ALK leading to reduction in tumor cell growth. Conclusions: Our findings support the monomerization of ALK fusion proteins using EML4cc peptides for competitive inhibition of dimerization as a promising therapeutic strategy for EML4-ALK NSCLC. Further studies are warranted to explore the use of specific cc peptide as a therapeutic option for other lung cancers harboring driver fusion genes containing a cc or oligomerization domain within the fusion partner.

DOI： 10.3389/fonc.2020.00419

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DOI： 10.1016/j.cllc.2019.06.021

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According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

DOI： 10.1007/s10147-019-01431-z

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：SPIE  

In the area of neurosurgical tumor diagnosis, clinical research on photodynamic diagnosis using 5-aminolevulinic acid (5-ALA) has already been undertaken, and the safety of 5-ALA has also been demonstrated. 5-ALA is approved in the diagnosis of brain tumor and bladder tumor by the Ministry of Health, Labour and Welfare. 5-ALA is a natural amino acid contained in a living body and is a precursor of hemoglobin. When absorbed into the body by oral ingestion, porphyrin synthesis by heme synthesis is specifically performed in a tumor-specific manner, and accumulation of fluorescent protoporphyrin IX (pp IX) is observed. However, pp IX is metabolized and disappeared in normal tissues. When tumor tissue is irradiated with excitation light, at the site where pp IX accumulates, it exhibits red fluorescence. We applied 5-ALA for photodynamic diagnostic in thoracic malignancies.

DOI： 10.1117/12.2527526

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BACKGROUND: On-target resistance mechanisms found in one-third of patients receiving anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are secondary ALK mutations in ALK-rearranged non-small cell lung cancer (NSCLC). There are large variations in the resistant mutations, unlike the epithelial growth factor receptor (EGFR) T790 M seen with the use of EGFR-TKIs. Liquid biopsy approaches using cell-free DNA (cfDNA) are used for screening and monitoring of mutations in NSCLC. However, feasible protocol for the simultaneous detection of multiple secondary ALK mutations using droplet digital PCR (ddPCR) has not been developed. An efficient strategy using cfDNA in cancer diagnostics, the development of more accurate and cost-effective tools to identify informative multiple secondary ALK mutations is clinically required. METHODS: To establish a feasible assay to monitor ALK-TKI resistance mutations, we first evaluated the feasibility of ddPCR-based screening for cfDNA mutation detection of 10 distinct secondary ALK mutations. Positive samples were then re-analyzed using mutation-specific probes to track the growth of mutation clones with a high sensitivity. RESULTS: Blood samples from seven ALK-positive patients were analyzed using the ddPCR protocol. Secondary G1202R ALK mutations were identified in 2 of 7 patients by the screening assay. Using the mutation-specific probes, monitoring the resistant clone during the clinical course of the disease was well demonstrated in each of the patients. CONCLUSION: The protocol for ddPCR-based liquid biopsy has a feasibility for the screening of secondary ALK-TKI resistance mutations and offers a tool for a cost-effective monitoring of progression in NSCLC.

DOI： 10.1186/s12885-018-5031-0

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BACKGROUND: Immune checkpoint blockade is developed as standard treatment for non-small cell lung cancer. However immune-related adverse events (irAE) have still unknown complications. Here, we report a patient with lung squamous cell carcinoma who developed neuromyelitis optica spectrum disorder with nivolumab. CASE PRESENTATION: A 75-year-old Japanese man with lung squamous cell carcinoma was administered nivolumab as second-line treatment. Two months after treatment with nivolumab, he presented acute paralysis in the bilateral lower limbs, sensory loss. Spinal magnetic resonance imaging showed T2 hyperintense lesions between C5-6 and Th12-L1. He was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) by anti-aquaporin-4 antibody-positive in the serum and other examinations. After treatment, steroid reactivity was poor. CONCLUSION: This is the first patient who developed anti-AQP4 antibody-positive NMOSD as a nivolumab-induced irAE. Clinicians should be aware of this kind of potential neurological complication by using immune check point inhibitor and start the treatment of this irAE as soon as possible.

DOI： 10.1186/s12885-018-3997-2

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Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were ceritinib or lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK-NSCLC with acquired resistance to ALK inhibitors.

DOI： 10.3892/ijo.2017.4140

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DOI： 10.1016/j.jtho.2017.02.022

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BACKGROUND: We observed red autofluorescence emanating from bronchial cancer lesions using a sensitive color-fluorescence endoscopy system. We investigated to clarify the origin of the red autofluorescence. METHODS: The wavelengths of the red autofluorescence emanating from lesions were measured in eight patients using a spectrum analyzer and compared based on pathologic findings. Red autofluorescence at 617.3, 617.4, 619.0, and 617.1 nm was emitted by normal bronchus, inflamed tissue, tissue exhibiting mild dysplasia, and malignant lesions, respectively. Protoporphyrin, uroporphyrin, and coproporphyrin, the major porphyrin derivatives in human blood, were purchased to determine which porphyrin derivative is the source of red fluorescence when acquired de novo. We synthesized photoporphyrin, Zn-protoporphyrin and Zn-photoprotoporphyrin from protoporphyrin. RESULTS: Coproporphyrin and uroporphyrin emitted only weak fluorescence. Fluorescence was emitted by our synthesized Zn-photoprotoporphyrin at 625.5 nm and by photoprotoporphyrin at 664.0 nm. CONCLUSIONS: From these results, we conclude that Zn-photoprotoporphyrin was the source of the red autofluorescence observed in bronchial lesions. Zn-protoporphyrin is converted to Zn-photoprotoporphyrin by radiation with excitation light. Our results suggest that red autofluorescence emanating from Zn-photoprotoporphyrin in human tissues could interfere with photodynamic diagnosis using porphyrin derivatives such as Photofrin® and Lazerphyrin® with a sensitive endoscopy system, because color cameras cannot differentiate Zn-photoprotoporphyrin red fluorescence from that of other porphyrin derivatives.

DOI： 10.1186/s12885-017-3277-6

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The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)-that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0-24 h) and delayed (>24-120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC. Clinical Trial Registry Information: This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry, identification numbers UMIN 000014239 and UMIN 000014240.

DOI： 10.3389/fphar.2017.00972

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The purpose of this study was to evaluate the clinical utility of a quantitative Aspergillus IgG assay for diagnosing chronic pulmonary aspergillosis. We examined Aspergillus-specific IgG levels in patients who met the following criteria: (i) chronic (duration of >3 months) pulmonary or systemic symptoms, (ii) radiological evidence of a progressive (over months or years) pulmonary lesion with surrounding inflammation, and (iii) no major discernible immunocompromising factors. Anti-Aspergillus IgG serum levels were retrospectively analyzed according to defined classifications. Mean Aspergillus IgG levels were significantly higher in the proven group than those in the possible and control groups (P < 0.01). Receiver operating characteristic curve analysis revealed that the Aspergillus IgG cutoff value for diagnosing proven cases was 50 mg of antigen-specific antibodies/liter (area under the curve, 0.94; sensitivity, 0.98; specificity, 0.84). The sensitivity and specificity for diagnosing proven cases using this cutoff were 0.77 and 0.78, respectively. The positive rates of Aspergillus IgG in the proven and possible groups were 97.9% and 39.2%, respectively, whereas that of the control group was 6.6%. The quantitative Aspergillus IgG assay offers reliable sensitivity and specificity for diagnosing chronic pulmonary aspergillosis and may be an alternative to the conventional precipitin test.

DOI： 10.1128/JCM.01475-15

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A 70-year-old woman with lung adenocarcinoma, harbouring anaplastic lymphoma kinase gene rearrangement, was treated with crizotinib as third-line chemotherapy. After 2 months, crizotinib was discontinued because of the development of crizotinib-induced interstitial lung disease (ILD). Steroid treatment was then introduced and tapered off. Following complete resolution of the interstitial shadow, cytotoxic chemotherapy was initiated, and continued for over 2 years, until new intrapulmonary lesions developed. Although there was a risk of drug-induced interstitial pneumonia, alectinib was initiated as the fifth-line therapy, without steroid supplementation, as there was no alternative treatment. No recurrence of ILD was noted at 10 months. To our knowledge, this is the first report of successful alectinib treatment after the development of crizotinib-induced ILD without the use of prednisolone.

DOI： 10.1002/rcr2.156

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.ijantimicag.2015.10.001

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Histamine H1 antagonists rarely cause drug-induced lung injury (DLI). A woman in her 60s, who had been taking antihistaminic levocetirizine for 2 months, presented with progressive cough and shortness of breath. A chest radiograph showed patchy infiltrations on both lower lung fields. Chest computed tomography findings were consistent with non-specific interstitial pneumonia. Serum markers associated with interstitial pneumonias were elevated. Room air arterial blood gas analysis revealed hypoxemia. Restrictive ventilatory impairment was noted with reduced diffusing capacity. Transbronchial lung biopsy specimens demonstrated unclassifiable alveolitis. Steroid pulse therapy was introduced for respiratory distress, but the initial response to treatment was poor. A drug lymphocyte stimulation test was positive for levocetirizine. The interstitial pneumonia improved following withdrawal of levocetirizine. Her illness has not recurred under steroid therapy and the discontinuation of levocetirizine. Antihistaminics may have a potential risk of DLI.

DOI： 10.1002/rcr2.101

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Prostaglandin I2 (PGI2) agonist has been reported to reduce tumor metastasis by modifying tumor angiogenesis; however, the mechanisms of how PGI2 affects the endothelial cells or pericytes in tumor vessel maturation are still unclear. The purpose of this study was to clarify the effects of PGI2 on tumor metastasis in a mouse lung metastasis model using Lewis lung carcinoma (LLC) cells. The mice were treated continuously with beraprost sodium (BPS), a PGI2 analog, for 3 weeks and then examined for lung metastases. The number and size of lung metastases were decreased significantly by BPS treatment. In addition, scanning electron microscopy and immunohistochemistry revealed that BPS increased the number of tumor‑associated pericytes and improved intratumor hypoxia. Collectively, this study suggests that BPS attenuated vascular functional maturation in metastatic tumors.

DOI： 10.3892/ijo.2014.2783

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Vaccinations against the human papillomavirus (HPV) have been recommended for the prevention of cervical cancer. HPV-16/18 AS04-adjuvanted vaccines (Cervarix) are said to have favourable safety profiles. Interstitial lung diseases (ILDs) can occur following exposure to a drug or a biological agent. We report a case of ILD associated with a Cervarix vaccination. A woman in her 40's, with a history of conisation, received three inoculations of Cervarix. Three months later, she presented with a cough and shortness of breath. Findings from a computed tomography of the chest and a transbronchial lung biopsy were consistent with non-specific interstitial pneumonia. Workup eliminated all other causes of the ILD, except for the vaccination. Over the 11 months of the follow-up period, her symptoms resolved without steroid therapy. The onset and spontaneous resolution of the ILD showed a chronological association with the HPV vaccination. The semi-quantitative algorithm revealed that the likelihood of an adverse drug reaction to Cervarix was "Probable". The outcome was relatively good, but more attention should be paid to a potential risk for HPV vaccinations to cause ILDs. Wherever possible, chest radiographic examinations should be performed in order not to overlook any ILDs.

DOI： 10.1016/j.rmcr.2015.06.003

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The efficacy of adjuvant chemotherapy with S-1 in patients with completely resected non-small cell lung cancer (NSCLC) has yet to be clarified, and the appropriate schedule for the adjuvant chemotherapy with S-1 remains unknown. A phase II study was conducted to evaluate the feasibility and efficacy of adjuvant chemotherapy with S-1. Patients enrolled in this study were 20-75 years old, had pathological stage IB-IIIA NSCLC, and had received complete resection of NSCLC. S-1 (80 mg/m2) was administered orally to the patients for four weeks followed by a two-week rest period (conventional schedule), for a maximum of eight cycles. The primary endpoint was relative dose intensity (RDI), while the secondary endpoints were safety and 1 year of disease-free survival (1y-DFS). Between May 2007 and October 2009, 28 patients were enrolled. The RDI was 63.1% (95% CI, 48.6-77.7). No grade 3 or worse hematological toxicity was observed. Grade 3 non-hematological toxicities were observed in four patients. No grade 4 or worse hematological toxicity was detected. The probability of 1y-DFS was 85.7% (95% CI, 72.8-98.6). In the subgroup analysis, the median RDI of patients over 65 years old was lower compared to the other patients (44.8 vs. 100%; P=0.013; Mann-Whitney U test). Creatinine clearance (CCr) was lower in the older group, with more grade 2 or 3 non-hematological toxicities in the elderly patients. These results suggest that the conventional schedule of adjuvant chemotherapy with S-1 is not likely to be feasible in older patients with completely resected NSCLC.

DOI： 10.3892/mco.2012.6

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BACKGROUND: Non-small cell lung cancer (NSCLC) often has an epidermal growth factor receptor (EGFR) gene mutation. Growth of EGFR-gene-mutated NSCLC depends predominantly on EGFR signaling and requires a large amount of intracellular ATP to activate EGFR signal transduction. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis, and it regulates intracellular ATP levels in mammalian cells. The effect of NAMPT inhibition on NSCLC has not been completely understood. METHODS: We aimed to clarify the hypothesis that NAMPT inhibition suppresses growth of EGFR-gene-mutated NSCLC through reduction of intracellular ATP levels, using NAMPT-siRNA transfection and NAMPT inhibitor FK866. We used four lung adenocarcinoma cell lines, including H358 (Wild type EGFR), LC2 (EGFR), PC9 (EGFR), and H1975 (EGFR), and evaluated the effect of FK866 on these cells and its mechanisms, using cell proliferation, Western blot, ATP, and apoptosis assay. RESULTS: We found that (1) H358, LC2, and H1975 cell lines highly expressed NAMPT-mRNA; (2) NAMPT-specific siRNA and FK866 suppressed proliferation of these NSCLCs; (3) FK866 reduced intracellular ATP levels in H1975 cells; (4) FK866 dephosphorylated EGFR signal proteins, including EGFR, Akt, Map kinase kinase 1/2, and extracellular signal-regulated kinase 1/2 (ERK 1/2); (5) FK866 induced apoptosis of H1975 cells; and (6) FK866 suppressed growth of H1975 xenograft tumors and attenuated expression of phospho-ERK 1/2 in the tumors in a tumor-bearing mouse model. CONCLUSION: These findings indicate that NAMPT is a potent therapeutic target in the treatment of EGFR-gene-mutated NSCLC.

DOI： 10.1097/JTO.0b013e318233d686

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Here we describe the synthesis and characterization of a number of 3-amino-1H-indazol-6-yl-benzamides that were designed to target the 'DFG-out' conformation of the kinase activation loop. Several compounds such as 4 and 11 exhibit single-digit nanomolar EC(50)s against FLT3, c-Kit and the gatekeeper T674M mutant of PDGFRα.

DOI： 10.1016/j.bmcl.2012.05.107

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research ({AACR})  

The identification of oncogenic alterations in subsets of patients with non-small cell lung cancer (NSCLC) is transforming clinical care. Genomic rearrangements in anaplastic lymphoma kinase (ALK) are detected in 3% to 7% of patients with NSCLC. The ALK tyrosine kinase inhibitor crizotinib has demonstrated clinical efficacy in ALK-rearranged NSCLC patients and was recently approved by the U.S. Food and Drug Administration. Crizotinib is currently under additional phase III clinical development as both initial and second-line therapy for advanced ALK-rearranged NSCLC. However, new challenges in the diagnosis and treatment of this subset of NSCLC have emerged, including the need to determine the most effective means of diagnosing ALK-rearranged NSCLC and the emergence of acquired drug resistance to crizotinib. In this review, we discuss current strategies for treatment and diagnosis, as well as the current knowledge about mechanisms of acquired resistance to crizotinib. Finally, we discuss the strategies that are underway to clinically overcome acquired drug resistance.

DOI： 10.1158/1078-0432.CCR-11-1404

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A high-dose administration of inhaled corticosteroid is effective in the majority of patients with bronchial asthma, but is often difficult to attain sufficient control in certain subsets of patients. Omalizumab has recently emerged as a promising drug for bronchial asthma. To assess its add-on effect we administered omalizumab to patients with uncontrolled atopic asthma for more than 16 weeks and gave them questionnaires. The study population comprised 9 patients with frequent asthmatic symptoms despite the administration of high-dose inhaled corticosteroid and other disease controllers. We scored disease control using the Asthma Health Questionnaire-33-Japan and the Asthma Control Test, and evaluated the frequencies of short-acting beta2-agonist use for rescue and drip infusion of theophyllines and/or systemic steroids in a retrospective fashion. Asthmatic scores were significantly improved after 16 weeks of omalizumab therapy. The frequencies of reliever use and drip infusion were also decreased. These trends were present even in patients in whom no aeroallergen-specific IgE antibodies were detected. No statistically significant side effects were observed. Our study confirmed the add-on effect of omalizumab based on evaluation by simple questionnaires. Further studies are needed to clarify whether omalizumab therapy is suitable for patients without specific IgE antibodies.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.

DOI： 10.1158/0008-5472.CAN-11-1340

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A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC50 values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, 15a and 23a potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy.

DOI： 10.1021/ml200002a

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The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers.

DOI： 10.1158/0008-5472.CAN-10-2956

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Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRASor EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement.

DOI： 10.1158/0008-5472.CAN-10-1671

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p130Cas, Crk-associated substrate (Cas), is an adaptor/scaffold protein that plays a central role in actin cytoskeletal reorganization. We previously showed that mice in which Cos was deleted (Cas(-/-)) died in utero because of early cardiovascular maldevelopment. To further investigate the in vivo roles of Gas, we generated mice with a hypomorphic Gas allele lacking the exon 2-derived region (Cas(Delta ex2/Delta ex2).) which encodes Src homology domain 3 (SH3) of Cas.Cas(Delta ex2/Delta ex2) mice again died as embryos, but they particularly showed progressive liver degeneration with hepatocyte apoptosis. Because Cas expression in the liver is preferentially detected in sinusoidal endothelial cells (SECs), the observed hepatocyte apoptosis was most likely ascribable to impaired function of SECs. To address this possibility, we stably introduced a Gas mutant lacking the SH3 domain (Gas ASH3) into an SEC line (NP31). Intriguingly, the introduction of Gas ASH3 induced a loss of fenestrae, the characteristic cell-penetrating pores in SECs that serve as a critical route for supplying oxygen and nutrients to hepatocytes. The disappearance of fenestrae in Gas ASH3-expressing cells was associated with an attenuation of actin stress fiber formation, a marked reduction in tyrosine phosphorylation of Gas, and defective binding of Gas to CrkII. Conclusion: Gas plays pivotal roles in liver development through the reorganization of the actin cytoskeleton and formation of fenestrae in SECs. (HEPATOLOGY 2010;52:1089-1099)

DOI： 10.1002/hep.23767

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The fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) has recently been identified in a subset of non-small cell lung cancers (NSCLCs). EML4-ALK is most often detected in never smokers with lung cancer and has unique pathologic features. EML4-ALK is oncogenic both in vitro and in vivo and ALK kinase inhibitors are quite effective in pre-clinical model systems. More recently ALK inhibitors have entered clinical development and remarkably clinical efficacy has been observed in NSCLC patients harbouring EML4-ALK translocations. This review will focus on the biology, clinical characteristics, diagnosis and treatment of EML4-ALK NSCLC.

DOI： 10.1016/j.ejca.2010.04.002

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OBJECTIVE: Endothelial progenitor cells (EPCs) play an important role in the self-healing of a vascular injury by participating in the reendothelialization that limits vascular remodeling. We evaluated whether prostaglandin I(2) plays a role in the regulation of the function of EPCs to limit vascular remodeling. METHODS AND RESULTS: EPCs (Lin(-)cKit(+)Flk-1(+) cells) were isolated from the bone marrow (BM) of wild-type (WT) mice or mice lacking the prostaglandin I(2) receptor IP (IP(-/-) mice). Reverse transcription-polymerase chain reaction analysis showed that EPCs among BM cells specifically express IP. The cellular properties of EPCs, adhesion, migration, and proliferation on fibronectin were significantly attenuated in IP-deficient EPCs compared with WT EPCs. In contrast, IP agonists facilitated these functions in WT EPCs, but not in IP-deficient EPCs. The specific deletion of IP in BM cells, which was performed by transplanting BM cells of IP(-/-) mice to WT mice, accelerated wire injury-mediated neointimal hyperplasia in the femoral artery. Notably, transfused WT EPCs, but not IP-deficient EPCs, were recruited to the injured vessels, participated in reendothelialization, and efficiently rescued the accelerated vascular remodeling. CONCLUSIONS: These findings clearly indicate that the prostaglandin I(2)-IP system is essential for EPCs to accomplish their function and plays a critical role in the regulation of vascular remodeling.

DOI： 10.1161/ATVBAHA.109.193730

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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侵襲性肺炎球菌感染症は肺炎球菌が髄液または血液から検出された感染症である.当院で新型コロナウイルス感染症(coronavirus disease 2019:COVID-19)の症例にて,肺炎球菌が血液培養で検出された侵襲性肺炎球菌感染症を2例経験した.COVID-19はインフルエンザウイルス感染症と同様に肺炎球菌感染を合併することに留意する必要がある.COVID-19において血清プロカルシトニンが陽性または比較的高値の場合には菌血症の合併を疑い,血液培養や抗菌薬投与を検討する必要がある.(著者抄録)

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

はじめに.光感受性物質である5ALA(アミノレブリン酸)と自家蛍光を併用した胸膜悪性病変に対する診断法の開発を行った。体外より摂取した5ALAは、ヘムの前駆体であるprotoporphyrin IXに代謝され悪性細胞内に留まり、630nm程度の赤色蛍光を呈する。5ALAの経口投与後(手術4時間前、20mg/kg)、胸膜悪性病変の観察を行った。対象と方法.2017年1月より2019年4月まで胸膜浸潤が疑われた肺癌82例、転移性肺腫瘍32例、悪性胸膜中皮腫7例、胸腔内良性疾患9例の合計130例に対し本手技を施行した。本研究は前方視的研究として施行した。結果.1)悪性病変では赤色蛍光が認識され、蛍光発色観察可能例は、転移性肺腫瘍で90.6%、悪性胸膜中皮腫で85.7%であった。2)肺癌胸膜浸潤診断は、pl0かpl1以上に対する感度は、肺腺癌に限ると感度93.9%、特異度74.3%、陽性的中率60.8%、陰性的中率96.2%であった。蛍光観察可能なpl0の88.9%が術前PL1と診断した症例であった。3)胸膜播種性病変6例のうち、2例は視認困難な症例であった。結論.胸膜近傍で胸膜浸潤を疑う腫瘍性病変であれば、病変の局在診断が可能である。肺癌では胸膜浸潤陽性例の手術方針を検討すべき診断となる。また、視認困難な胸膜播種診断にも寄与する可能性がある。(著者抄録)

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J-GLOBAL

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Language：Japanese   Publisher：北海道外科学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：北海道外科学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本サルコイドーシス  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

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Language：Japanese   Publisher：(株)医薬ジャーナル社  

＜文献概要＞気管支喘息の治療は,長期管理用の吸入ステロイド薬が導入された後に大幅に状況が改善され,これが喘息死患者の減少と密接な関係があるとされている。しかし,既存の吸入薬でも症状がコントロールできない重症喘息患者が存在し,その数は少数ではあるものの喘息総医療費の半分以上を占めるとされ,医療経済的にもその対応は重要である。近年は喘息発症の病態に基づいた抗体製剤の開発が盛んであり,臨床での使用頻度が高まってきた。慢性閉塞性肺疾患(chronic obstructive pulmonary disease:COPD)領域の治療薬では,新たな吸入薬が市販される予定である。

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本サルコイドーシス  

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Language：English   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本サルコイドーシス  

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Language：Japanese   Publisher：(NPO)日本緩和医療学会  

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Language：Japanese   Publisher：(NPO)日本緩和医療学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本臨床薬理学会  

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Language：Japanese   Publisher：(一社)日本臨床薬理学会  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：(NPO)日本緩和医療学会  

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Language：Japanese   Publisher：(NPO)日本緩和医療学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：日本サルコイドーシス  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2016-2121

Web of Science

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

DOI： 10.2482/haigan.55.1108

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Language：Japanese  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

Web of Science

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2015-1770

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2015-3501

Web of Science

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

背景. 出血・気道狭窄を伴う中枢気道の腫瘍に対する治療戦略として、緊急の止血・呼吸管理に加えて、局所的な腫瘍制御が重要である。症例. 59歳女性。右肺扁平上皮癌にて右中下葉切除術後、大量喀血を伴う呼吸不全のため気管挿管、人工呼吸管理となった。気管支内視鏡で、右主気管支を占拠する腫瘍塊と、その末梢からの出血を確認した。12時間後に気管支動脈塞栓術を施行したが、止血後も高濃度酸素下の呼吸管理を要した。高出力レーザー治療は危険性が高いと判断し、7日後に気道狭窄の軽減を目的として光線力学的治療(Photodynamic Therapy;PDT)を施行した。腫瘍は縮小し、人工呼吸器を離脱した。縦隔外部照射を追加し、局所再発病変は制御された。結論. 人工呼吸管理下においても、PDTは安全に施行可能である。中枢気道腫瘍に対して、PDTは緊急止血処置に続く待機的治療として有用である。(著者抄録)

DOI： 10.18907/jjsre.37.4_429

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

背景. 出血・気道狭窄を伴う中枢気道の腫瘍に対する治療戦略として、緊急の止血・呼吸管理に加えて、局所的な腫瘍制御が重要である。症例. 59歳女性。右肺扁平上皮癌にて右中下葉切除術後、大量喀血を伴う呼吸不全のため気管挿管、人工呼吸管理となった。気管支内視鏡で、右主気管支を占拠する腫瘍塊と、その末梢からの出血を確認した。12時間後に気管支動脈塞栓術を施行したが、止血後も高濃度酸素下の呼吸管理を要した。高出力レーザー治療は危険性が高いと判断し、7日後に気道狭窄の軽減を目的として光線力学的治療(Photodynamic Therapy;PDT)を施行した。腫瘍は縮小し、人工呼吸器を離脱した。縦隔外部照射を追加し、局所再発病変は制御された。結論. 人工呼吸管理下においても、PDTは安全に施行可能である。中枢気道腫瘍に対して、PDTは緊急止血処置に続く待機的治療として有用である。(著者抄録)

DOI： 10.18907/jjsre.37.4_429

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Language：Japanese   Publisher：(株)東京医学社  

呼吸器系はさまざまな臓器が必要とする酸素を肺から取り入れて、ヘモグロビンに渡す重要な働きを持つ。呼吸器系の機能が大きく損なわれると、主要な臓器の低酸素症を引き起こして生命の維持に障害をきたす。このような重要な生理機能を持った呼吸器系のエマージェンシーの診療では、初期判断を誤れば生命に危険が及ぶ場合がある。そのため、外来患者が呼吸器系の強い症状を訴えて受診した時の診療は、呼吸器専門医でも極度の緊張が強いられることがある。呼吸器系の症状を訴えて来院する患者は多いが、実際は、致死的な呼吸器系のエマージェンシーの頻度は決して高くない。このことを心において、冷静な診療を行うように心掛けることが肝要である。呼吸器疾患のエマージェンシーには上気道の狭窄、喀血による窒息、肺血栓塞栓症、慢性疾患の急性増悪など、命に直結する重要な疾患が含まれる。(著者抄録)

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.Special_S209_2

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.Special_S172_3

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.Special_S279_1

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.6_681_3

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.6_682_1

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.6_682_1

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.6_681_3

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：American Association for Cancer Research ({AACR})  

DOI： 10.1158/1538-7445.am2014-3720

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Language：English   Publisher：American Association for Cancer Research ({AACR})  

DOI： 10.1158/1538-7445.am2014-4656

Web of Science

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Language：English   Publisher：American Association for Cancer Research ({AACR})  

DOI： 10.1158/1538-7445.am2014-3716

Web of Science

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：Japanese   Publisher：Japan Lung Cancer Society  

背景. 2012年3月の承認以後、クリゾチニブがALK陽性肺癌に対し使用可能となったが、稀な副作用については不明な点も多い。症例. 43歳女性。EML4/ALK融合遺伝子陽性肺腺癌(cT4N3M1b:Stage IV)で二次治療としてクリゾチニブ250mgを1日2回(昼食後・就寝前)で開始した。初回投与後数時間で悪心・嘔吐が出現し、投与2日目よりGrade 3の食道痛が出現、経口摂取が著しく低下した。投与4日目で内服不能となり休薬したところ、速やかに症状は消失した。200mgを1日2回(昼食後・就寝前)で減量して再開したところ、再度嚥下痛を認め内服不能となり投与7日目より休薬した。休薬中施行したFDG-PETで中下部食道に全周性のFDG集積を認め、上部消化管内視鏡検査にて炎症性変化を確認した。クリゾチニブの休薬・再投与に伴う症状変化に再現性を認め、薬剤性食道炎と診断した。症状消失後から200mgを1日1回(朝食後)で再開した。忍容性を確認しながら現在7ヵ月間継続中であり、病変はSDを維持している。結論. クリゾチニブによる副作用としての食道炎の報告は稀であるが、本例では両者に強い因果関係が示唆された。(著者抄録)

DOI： 10.2482/haigan.54.68

Scopus

J-GLOBAL

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.Special_S252_1

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.Special_S175_3

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.Special_S247_3

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.Special_S252_1

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.Special_S247_3

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.Special_S175_3

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.6_682_4

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.6_683_1

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.6_682_4

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.6_682_1

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.6_683_1

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：北海道医師会  

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.Special_S225_1

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Language：Japanese   Publisher：医歯薬出版(株)  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本結核病学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：旭川医科大学  

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.6_642_1

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Language：Japanese   Publisher：(株)東京医学社  

・ヒトの呼吸器系は大量の空気が出入りするために幾重もの感染防御機構によって病原体の侵入から守られている。・病原体の感染性、病原性と宿主の自然免疫、獲得免疫の兼ね合いによって感染症が発症する。・病原体の毒性(ビルレンス)と病原体自体や組織破壊に対する生体の反応によって肺炎の臨床所見や胸部画像上の異常が現れる。・自然免疫、獲得免疫の障害によってコンプロマイズド・ホストになる。・造血器疾患患者、HIV感染者、臓器移植患者、糖尿病患者、透析患者、COPD患者などでの易感染性が知られている。・コンプロマイズド・ホストは感染性や病原性の低い病原体による感染症を発症することがあり、獲得免疫の障害によって非典型的な症状や臨床所見を示すことがある。・日和見感染症としての肺炎では菌交代現象に留意する。診断のためには、血液培養、血清検査、病巣検体の検査などを考慮する。(著者抄録)

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.6_642_1

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Language：Japanese   Publisher：東京医学社  

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Language：Japanese   Publisher：ライフサイエンス出版(株)  

40歳女。10歳時と12歳時に吐血し、特発性門脈閉塞症による門脈圧亢進症と診断された。27歳時に労作時の息切れ、下腿の浮腫を認め、右心カテーテル検査で門脈肺高血圧症と診断した。利尿薬と在宅酸素療法で外来通院した。30歳時、右心不全の悪化と肝性脳症で再入院し、高アンモニア血症と高度の肺高血圧を認めた。肝不全の治療とともにエポプロステノール(PGI2)持続静注療法を開始した。自覚症状・心エコー所見の改善を認め退院した。自宅療養していたが、徐々に動悸感、全身倦怠を自覚し、血中BNPが高値で、心エコー上推定三尖弁収縮期圧格差が再上昇した。原発性甲状腺機能亢進症の診断で内服治療を併用した。40歳時に労作時の息切れや三尖弁収縮期圧格差の増大を認め入院した。シルディナフィルを追加したところ副作用の出現はなく、自覚症状の改善と三尖弁収縮期圧格差の低下を認め、在宅酸素療法を再開し退院となった。

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.Special_S188_2

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Language：Japanese   Publisher：日本工業出版  

CiNii Books

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.Special_S188_2

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-4379

Web of Science

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Language：Japanese   Publisher：(株)へるす出版  

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Language：Japanese   Publisher：(株)先端医学社  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.1_86_3

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.1_86_3

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

ヒト化抗ヒトIgEモノクローナル抗体製剤(オマリズマブ)を難治性アトピー型喘息9例(男性3例、女性6例、平均総IgE値126IU/ml)に投与し、喘息コントロール状態を開始前と開始16週後で比較検討した。コントロール状態は質問紙(Asthma Health Questionnaire-33-Japanおよび喘息コントロールテスト)を用いて定量化した。副次項目として、短時間作用性吸入β2刺激薬の使用頻度、アミノフィリンまたはステロイド剤の点滴回数を遡及的に調査した。オマリズマブ開始後に喘息スコアは改善し、レスキュー薬使用頻度や点滴回数も減少していた。同様の傾向は特異的IgE抗体陰性の症例においても認めた。重篤な副作用は発現しなかった。今回用いた質問紙法は、オマリズマブの有効性を評価する上で有用と考えられた。オマリズマブは難治性喘息に対する追加治療薬として有用性が高く、今後の適応拡大に向けてさらに検討が必要である。(著者抄録)

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Language：Japanese   Publisher：(株)ライフメディコム  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.33.Special_S221_3

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2011-1576

Web of Science

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Language：English   Publisher：American Association for Cancer Research ({AACR})  

DOI： 10.1158/1538-7445.am2011-1541

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2011-964

Web of Science

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRAS or EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement. Cancer Res; 70(23); 9827-36. (C)2010 AACR.

DOI： 10.1158/0008-5472.CAN-10-1671

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers. Cancer Res; 70(24); 10038-43. (C) 2010 AACR.

DOI： 10.1158/0008-5472.CAN-10-2956

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：ELSEVIER SCI LTD  

The fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK),has recently been identified in a subset of non-small cell lung cancers (NSCLCs). EML4-ALK is most often detected in never smokers with lung cancer and has unique pathologic features. EML4-ALK is oncogenic both in vitro and in vivo and ALK kinase inhibitors are quite effective in pre-clinical model systems. More recently ALK inhibitors have entered clinical development and remarkably clinical efficacy has been observed in NSCLC patients harbouring EML4-ALK translocations. This review will focus on the biology, clinical characteristics, diagnosis and treatment of EML4-ALK NSCLC. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ejca.2010.04.002

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective-Endothelial progenitor cells (EPCs) play an important role in the self-healing of a vascular injury by participating in the reendothelialization that limits vascular remodeling. We evaluated whether prostaglandin I-2 plays a role in the regulation of the function of EPCs to limit vascular remodeling.
Methods and Results-EPCs (Lin(-)cKit(+)Flk-1(+) cells) were isolated from the bone marrow (BM) of wild-type (WT) mice or mice lacking the prostaglandin I-2 receptor IP (IP-/- mice). Reverse transcription-polymerase chain reaction analysis showed that EPCs among BM cells specifically express IP. The cellular properties of EPCs, adhesion, migration, and proliferation on fibronectin were significantly attenuated in IP-deficient EPCs compared with WT EPCs. In contrast, IP agonists facilitated these functions in WT EPCs, but not in IP-deficient EPCs. The specific deletion of IP in BM cells, which was performed by transplanting BM cells of IP-/- mice to WT mice, accelerated wire injury-mediated neointimal hyperplasia in the femoral artery. Notably, transfused WT EPCs, but not IP-deficient EPCs, were recruited to the injured vessels, participated in reendothelialization, and efficiently rescued the accelerated vascular remodeling.
Conclusion-These findings clearly indicate that the prostaglandin I-2-IP system is essential for EPCs to accomplish their function and plays a critical role in the regulation of vascular remodeling. (Arterioscler Thromb Vasc Biol. 2010;30:464-470.)

DOI： 10.1161/ATVBAHA.109.193730

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：SPANDIDOS PUBL LTD  

Heavy smokers with central type squamous cell carcinoma (SCC) frequently have multiple cancerous lesions in the bronchus. Autofluorescence bronchoscopy (AFB) is useful in the detection of early bronchogenic cancer and dysplastic lesions. We investigated the loss of heterozygosity (LOH) and microsatellite instability (MSI) and expression of four proteins in 13 early stage SCC (early SCC) and 9 squamous dysplasia detected by AFB and 19 cases of surgically resected invasive SCC (invasive SCC). In early SCC and squamous dysplasia, LOH/MSI of chromosome 1p36 was found in 62 and 33%, respectively, and of 9p21 in 54 and 63%, respectively. TAp73 expression of early SCC and squamous dysplasia was lower than that of normal bronchial epithelium, and p16 expression was not detectable in these lesions. These results suggested that the genetic abnormalities had already developed in the early stage of carcinogenesis of SCC, including squamous dysplasia. The AFB system was able to reveal abnormal autofluorescence in these precancerous lesions, including squamous dysplasia.

DOI： 10.3892/or_00000409

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Language：Japanese   Publisher：日本肺癌学会  

Objective. Single-agent chemotherapy with a third-generation drug is recommended as standard treatment for elderly patients with advanced non-small cell lung cancer (NSCLC). However, the efficacy and safety of platinum-based combination chemotherapy for elderly patients aged 75 years and over with adequate organ function, is still controversial. We conducted the present phase I trial to determine the dose-limited toxicity (DLT), and recommended dose (RD), as well as the safety and efficacy of paclitaxel and carboplatin combination chemotherapy in elderly patients (≥75 years old) with advanc...

DOI： 10.2482/haigan.49.146

J-GLOBAL

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J01244&link_issn=&doc_id=20090528340002&doc_link_id=%2Fec7jaluc%2F2009%2F004902%2F002%2F0146-0150%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2009%2F004902%2F002%2F0146-0150%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.31.1_42_1

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J00298&link_issn=&doc_id=20090219330016&doc_link_id=%2Fcf0brond%2F2009%2F003101%2F019%2F0042-0042%26dl%3D2&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2009%2F003101%2F019%2F0042-0042%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

Language：Japanese   Publisher：日本肺癌学会  

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Language：Japanese   Publisher：日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J01244&link_issn=&doc_id=20081016270406&doc_link_id=%2Fec7jaluc%2F2008%2F004805%2F196%2F0508-0508%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2008%2F004805%2F196%2F0508-0508%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J01244&link_issn=&doc_id=20081016270387&doc_link_id=%2Fec7jaluc%2F2008%2F004805%2F183%2F0503-0503%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2008%2F004805%2F183%2F0503-0503%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publisher：PROFESSOR D A SPANDIDOS  

Angiogenesis is mediated mainly by vascular endothelial growth factor (VEGF), and VEGF causes rapid growth in cancers, including human small-cell lung cancer (SCLC). The anti-angiogenic strategy of treating cancer using VEGF receptor (VEGFR) inhibition is currently of great interest. We tested the effects of the VEGFR2 tyrosine kinase inhibitor (TKI) vandetanib on the proliferation of two kinds of SCLC cell lines: SBC-1 cells, with detectable VEGFR2 expression and MS-1-L cells, without detectable VEGFR2 expression. To evaluate the anti-tumor and anti-angiogenic effects of vandetanib in vivo, we grafted SBC-1 and MS-1-L cells into mice. After a 3-week treatment, we measured the tumor size and histologically evaluated necrosis and apoptosis using H&E and TUNEL staining, respectively. The microvessels in the xenografts were also quantified by immunostaining of CD31. Vandetanib did not affect the proliferation of SBC-1 cells, but stimulated the growth of MS-1-L cells. In the SCLC xenograft model, vandetanib inhibited growth and tumor angiogenesis in a dose-dependent manner in SBC-1 xenografts. Vandetanib inhibited the growth of MS-1-L xenografts at a low dose (<12.5 mg/kg/day), but it did not affect tumor size or change microvessel counts at a higher dose. Interestingly, secretion of VEGF increased significantly in the MS-1-L cell line in the presence of a high dose of vandetanib in vitro. The effects of vandetanib on tumor angiogenesis were different in SBC-1 and MS-1-L cell lines. Production of angiogenic factors such as VEGF by the tumor potentially stimulates tumor angiogenesis and results in the acquisition of resistance to VEGFR TKI.

DOI： 10.3892/ijo_00000036

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.30.Special_S138_1

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J00298&link_issn=&doc_id=20080521390122&doc_link_id=10.18907%2Fjjsre.30.Special_S138_1&url=https%3A%2F%2Fdoi.org%2F10.18907%2Fjjsre.30.Special_S138_1&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.30.1_46_1

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.30.1_46_1

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J00298&link_issn=&doc_id=20080229340008&doc_link_id=%2Fcf0brond%2F2008%2F003001%2F011%2F0046-0046%26dl%3D2&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2008%2F003001%2F011%2F0046-0046%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

Language：Japanese   Publisher：日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J01244&link_issn=&doc_id=20071019290108&doc_link_id=%2Fec7jaluc%2F2007%2F004705%2F108%2F0464-0464%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2007%2F004705%2F108%2F0464-0464%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：English   Publisher：BLACKWELL PUBLISHING  

Alveolar hydatid disease is a highly malignant form of echinococcosis caused by the larvae of the cestode Echinococcus multilocularis. Alveolar hydatid disease always affects the liver and can metastasise to the lungs and brain. The case reports describe the radiological features of alveolar hydatid disease of the lung caused by E. multilocularis. Multiple nodules which varied in size and shape were seen on CXR, CT showed most nodules to be lobulated, well circumscribed and of varying shape. Multiple lobulated lesions located between two segments of the lung and of varying shape appear to be characteristic of pulmonary alveolar hydatid disease caused by E. multilocularis.

DOI： 10.1111/j.1400-1843.2007.01055.x

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.29.1_59_1

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.29.1_59_4

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.29.1_59_1

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J00298&link_issn=&doc_id=20070425310016&doc_link_id=%2Fcf0brond%2F2007%2F002901%2F019%2F0059-0059%26dl%3D2&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2007%2F002901%2F019%2F0059-0059%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

Language：Japanese   Publisher：(株)メディカルレビュー社  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J02789&link_issn=&doc_id=20070124400002&doc_link_id=%2Fai1lupvd%2F2007%2F001501%2F002%2F0002-0008%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai1lupvd%2F2007%2F001501%2F002%2F0002-0008%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会