Shinichiro Mikura

Inflammation provoked by Mycoplasma pneumoniae extract: implications for combination treatment with clarithromycin and dexamethasone

Recently, combination treatment with a macrolide and a steroid for Mycoplasma pneumoniae (Mp) pneumonia has been reported to be effective. Thus, the effect of this combination on a mouse model of lung inflammation associated with Mp extract (the LIMEX mouse) was studied. Interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were induced in Mp extract-treated RAW264.7 cells, and this induction was inhibited by dexamethasone, parthenolide, SB203580 or LY294002. This suggested that Mp extract activates nuclear factor κB-, p38- and PI-3K-linked pro-inflammatory signals. The LIMEX mice were then either treated with or without clarithromycin and/or dexamethasone. Clarithromycin administration enhanced the production of IL-6, TNF-α, macrophage inflammatory protein-1α, monocyte chemotactic protein-1 and RANTES, while their production was perfectly suppressed by the combination of clarithromycin and dexamethasone. IL-17, IL-23, keratinocyte-derived chemokine (KC) and interferon-γ levels were not affected by clarithromycin treatment, but they were significantly suppressed by the combination of dexamethasone and clarithromycin. Collectively, some components of Mp extract provoked an inflammatory reaction in the RAW 264.7 cell line and LIMEX mice. Whereas the lung reaction in LIMEX mice was further exacerbated by clarithromycin treatment, it was resolved by the combinational treatment with clarithromycin and dexamethasone.

Erythromycin prevents the pulmonary inflammation induced by exposure to cigarette smoke

The effect of erythromycin on the inflammation caused by exposure to cigarette smoke was investigated in this study. Mice were exposed either to cigarette smoke or to environmental air (control), and some mice exposed to cigarette smoke were treated with oral erythromycin (100 mg/kg/day for 8 days). Pulmonary inflammation was assessed by determining the cellular content of bronchoalveolar lavage (BAL) fluid. The messenger RNA (mRNA) levels of various mediators, including keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, surfactant protein (SP)-D, granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, interleukin (IL)-6 in lung tissue were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. The exposure to cigarette smoke increased significantly the numbers of neutrophils (P = 0.029), macrophages (P = 0.029), and lymphocytes (P = 0.029) recovered in BAL fluid. Moreover, mRNA levels of KC (P = 0.029), MIP-2 (P = 0.029), SP-D (P = 0.029), and GM-CSF (P = 0.057) in the lung tissue were higher in mice exposed to cigarette smoke than in mice exposed to environmental air. In the erythromycin-treated mice that were exposed also to cigarette smoke, both neutrophil and lymphocyte counts were significantly lower in the BAL fluid than those in the vehicle-treated mice (P = 0.029). Erythromycin-treated mice exposed to cigarette smoke showed a trend of lower mRNA levels of KC and TNF-α in the lung tissue than those in the vehicle-treated mice, although the statistical significance was not achieved (P = 0.057). Our data demonstrated that erythromycin prevented lung inflammation induced by cigarette smoke, in parallel to the reduced mRNA levels of KC and TNF-α.

Kinetics of c-reactive protein (CRP) and serum amyloid A protein (SAA) in patients with community-acquired pneumonia (CAP), as presented with biologic half-life times.

Context: In management of community-acquired pneumonia (CAP), excellent biomarkers for inflammation would be helpful in our practice. Objectives: Kinetics of c-reactive protein (CRP) and serum amyloid A (SAA) was characterized, using their biologic half-life times. Materials and methods: Time course of CRP and SAA levels in the successfully treated 36 CAP patients were investigated and their half-life times were determined and compared. Results & Discussions: SAA and CRP declined in an exponential mean and the biologic half-life times of SAA levels was 34.9 ± 28.7 h, significantly shorter than that of CRP, 46.4 ± 21.7 h (p = 0.0014). Conclusion: The kinetic evidence, presented as biologic half-life times of CRP and SAA, helps us make a clinical assessment of CAP patients.

Risk factors for bacteraemia attributable to Pseudomonas aeruginosa resistant to imipenem, levofloxacin, or gentamicin.

We studied the risk factors associated with resistance to imipenem, levofloxacin and gentamicin in Pseudomonas aeruginosa isolated from blood cultures of 175 patients in a hospital in Japan. Imipenem resistance was associated with transfer from another hospital, and receiving antifungal medication. Gentamicin resistance was associated with previous administration of a penicillin. No specific risk factors were associated with levofloxacin resistance.

Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1.

Background Repetitive genotyping is useful to assess the genetic evolution of non-small-cell lung cancer (NSCLC) during treatment, but the need for sampling by biopsy is a major obstacle. Digital polymerase chain reaction (PCR) is a promising procedure for the detection of mutant alleles in plasma of cancer patients. Methods This prospective study enrolled patients with NSCLC and known epidermal growth factor receptor (EGFR) mutations and who had experienced disease progression during ongoing EGFR-tyrosine kinase inhibitor (TKI) therapy. Eligible patients received daily gefitinib and either pemetrexed or S-1 every 3 weeks until disease progression or the development of unacceptable toxicity. Peripheral blood was collected before and after the combination therapy for digital PCR and hepatocyte growth factor measurement. Results From May 2012 to January 2014, nine patients with a median age of 67 (range 52–80) years were enrolled. Patterns of disease progression during adjacent EGFR-TKI therapy were acquired resistance, observed in seven patients, and primary resistance, observed in two patients. Known EGFR mutations were detected in plasma samples of six (67%) patients at study enrollment. Of these, T790M mutation was concurrently detected in three (50%) patients. Four patients underwent gefitinib plus pemetrexed therapy, and five patients underwent gefitinib and S-1 therapy. The median number of cycles delivered was five, and the median progression-free survival was 5.7 months. Efficacy outcomes did not differ between treatments. After the combination therapy, plasma T790M status changed to positive in two patients. Hepatocyte growth factor level did not significantly change through the combination therapy. Conclusion The usefulness of monitoring the genetic evolution of EGFR-driven tumors using noninvasive procedures was demonstrated. Since continuation of EGFR-TKI therapy with cytotoxic agents has an acceptable tolerability and a possibility of inducing T790M mutation, the combination therapy may be useful for EGFR-mutant NSCLC resistant to EGFR-TKI therapy without T790M mutation.

Interleukin-10 modulates pulmonary neutrophilic inflammation induced by cigarette smoke exposure.

ABSTRACT Aim of the Study: Interleukin (IL)-10 is an anti-inflammatory cytokine, but its role in cigarette smoke (CS)-induced inflammation and chronic obstructive pulmonary disease (COPD) has not been fully elucidated. The purpose of this study was to investigate the effect of IL-10 deficiency on CS-induced pulmonary inflammation in mice in vivo and in vitro. Materials and Methods: IL-10-deficient and wild-type control mice with a C57BL6/J genetic background were exposed to CS, and inflammatory cells in bronchoalveolar lavage fluid (BALF) and mRNA of cytokines in lung were evaluated with enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). Results: During 12 days of daily CS exposure to wild-type mice, neutrophil counts in BAL fluid and tumor necrosis factor (TNF)-α mRNA expression were increased, peaked at day 8, and then declined on day 12 when the level of IL-10 reached its peak. In IL-10-deficient mice, neutrophil recruitment and TNF-α mRNA levels induced by CS exposure were significantly greater than those in wild-type mice. Keratinocyte-derived chemokine (KC; murine ortholog of human CXCL8) and granulocyte macrophage colony-stimulating factor (GM-CSF) mRNA levels or matrix metalloproteinase(MMP)-9 protein levels were not correlated with neutrophil count. Conclusions: IL-10 had a modulatory effect on CS-induced pulmonary neutrophilic inflammation and TNF-α expression in mice in vivo and therefore appears to be an important endogenous suppressor of airway neutrophilic inflammation.

Sarcoidosis with Pancreatic Mass, Endobronchial Nodules, and Miliary Opacities in the Lung

Sarcoidosis affects multiple organs and rarely has unusual manifestations. A 78-year-old woman was referred to our hospital for coughing symptoms. A chest computed tomography (CT) scan revealed bilateral diffuse miliary patterns and right pleural effusion. Bronchoscopy showed multiple nodules in the carina and the bronchus intermedius. A CT scan of her abdomen revealed hypovascular lesions involving the pancreatic head and body. A transbronchial lung biopsy, bronchial mucosal biopsy, and endoscopic ultrasound-guided fine-needle aspiration of the pancreatic mass demonstrated non-caseating granulomas. We diagnosed the patient with sarcoidosis. She received no treatment for sarcoidosis and has been followed up for one year, during which no pulmonary disease progression had been observed and the pancreatic masses partially regressed.

Pneumothorax during Pemetrexed Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report and Literature Review

Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. A 70-year-old male presented with a stage IV non-small cell lung cancer. The patient was treated with pemetrexed as third-line chemotherapy. However, a pneumothorax occurred 16 days after the administration of the second cycle of pemetrexed. The pneumothorax was slight and the patient was observed without undergoing any additional treatment. Twenty-four days after its initial occurrence, the pneumothorax had improved. This is the first case of pneumothorax that has been observed during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication and should not be overlooked.

Early surgical resection for stage I high-grade neuroendocrine caricinoma of lung

RATIONALE: Since high-grade neuroendocrine tumors are rapidly progressive, most cases are inoperable when diagnosed. There are few reports about the prognosis of patients or the course of the disease after surgery. OBJECTIVES: To clarify the clinical course of the disease after surgery and factors influencing the prognosis. METHODS: We retrospectively assessed 27 patients receiving surgery for small cell carcinoma (22 cases) and large neuroendocrine carcinoma (5 cases) from January 2005 through January 2015 at our hospital. RESULTS: Patients were all male, with an average age of 70.9 years. Of the 27 patients, 22 had received postoperative adjuvant chemotherapy. Median progression-free survival (PFS) and overall survival (OS) were 1.1 and 5.5 years, respectively. Ten patients were recurrence-free. Ten patients who underwent surgery within 60 days after the diagnosis demonstrated a better prognosis regarding OS (p CONCLUSIONS: Early surgical resection for high-grade neuroendocrine carcinoma stage I may lead to a better prgonosis.

A Case of Rheumatoid Arthritis Complicated by Pulmonary Sarcoidosis during Treatment with Methotrexate

Akihiko Wada, Junko Tamakoshi, Toshio Suzuki, Maki Miyamoto, Kengo Murata, Shinichiro Mikura, Akira Hebisawa, Tetsuya Obara, Akira Fujita , Mikio Takamori 【要旨】 症例は63歳, 女性.関節リウマチの治療としてサラゾスルファピリジンを1年間投与後,メトトレキサート単剤,さら にメトトレキサートとブシラミンを併用して治療中に,咳,発熱が続くようになり,両側肺に多発結節が出現した.胸腔 鏡下肺生検で非乾酪性類上皮細胞肉芽腫が認められ,肉芽腫内部にPropionibacterium acnes抗体染色陽性部位が認められ た.他疾患の除外によりサルコイドーシスと診断した.PET-CTでは肺内,肺門縦隔リンパ節,脾以外に異常集積を認め なかった.経過観察したところ増悪が続いた.副腎皮質ステロイドホルモン薬(ステロイド)治療を開始したところ,咳, 発熱,結節影とも速やかに改善がみられた.メトトレキサートはステロイドとの併用でサルコイドーシスの治療にも用い られ,単剤でも症例によって有効な薬剤だが,本症例はメトトレキサートを投与中にサルコイドーシスを発症したと考え られるため報告する. [日サ会誌 2013; 33: 97-103] キーワード:サルコイドーシス,関節リウマチ,メトトレキサート