Lysophosphatidic Acid Induces Allergic Inflammation

Background: Lysophosphatidic acid (LPA), a prototypic member of a large family of lysophospholipids, has been recently shown to play a role in immune responses to respiratory diseases. The involvement of LPA in allergic airway inflammation has been reported, but the mechanism remains unclear. Object: We analyzed the biological activity of LPA in vitro and in vivo and investigated its role in allergic inflammation in mice using an LPA receptor 2 (LPA2) antagonist. Methods: We used a murine model with acute allergic inflammation, in which mice are sensitized and challenged with house dust mite, and analyzed airway hyperresponsiveness (AHR), pathological findings, Th2 cytokines, and IL-33 in bronchoalveolar lavage fluid (BALF) and lung homogenates. The effect of LPA on Th2 differentiation and cytokine production was examined in vitro using naive CD4+ T cells isolated from splenocytes. We also investigated in vivo the effects of LPA on intranasal administration in mice. Results: The LPA2 antagonist suppressed the increase of AHR, the number of total cells, and eosinophils in BALF and lung tissue. It also decreased the production of IL-13 in BALF and IL-33 and CCL2 in the lung. LPA promoted Th2 cell differentiation and IL-13 production by Th2 cells in vitro. Nasal administration of LPA significantly increased the number of total cells and IL-13 in BALF via regulating the production of IL-33 and CCL-2-derived infiltrating macrophages. Conclusion: These findings suggest that LPA plays an important role in allergic airway inflammation and that the blockade of LPA2 might have therapeutic potential for bronchial asthma

Reactions of excited-state benzophenone ketyl radical in a room-temperature ionic liquid

金沢大学理工研究域自然システム学系The photochemistry of the benzophenone ketyl radical in D1 excited state, BPH(D1), was studied by means of two-color dual-pulse laser flash photolysis (355 and 532 nm) in a room-temperature ionic liquid, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (Bmim-TFSA), and in methanol. Upon excitation with the 532 nm pulse, BPH(D1) emitted strong fluorescence. The transient absorption and fluorescence spectra of BPH(D1) were measured with nanosecond and sub-nanosecond time resolution, respectively. The observed Stokes shift was 1700 cm-1 in Bmim-TFSA, and this shift was close to that in acetonitrile. The fluorescence lifetime of BPH(D1) was determined to be 5 ns in Bmim-TFSA, and again the value was close to that in acetonitrile. The rate constant of the reaction of BPH(D1) with CCl4 in Bmim-TFSA was determined to be (2.1 ± 0.4) × 109 M-1 s-1, which was 10 times the rate constant calculated on the basis of the bulk viscosity of Bmim-TFSA. The results are discussed in terms of the effective microscopic viscosity of the ionic liquid that was recently reported for the cage effect. © 2010 the Owner Societies

EGFR遺伝子陽性NSCLCにニボルマブが有効であった１例

Nivolumab is approved for the treatment of patients with advanced non-small cell lung cancer （NSCLC）who experience progression of disease on or after standard platinum-based chemotherapy. But there are still a few reports of nivolumab treatment in after EGFR-TKI treatment since NSCLC patients with EGFR mutations has been said to have poor effect on anti-PD-1/PD-L1 agents. Also, there are several reports of severe interstitial pneumonitis when Nivolumab is used after EGFR-TKI treatment. A88‐year‐old woman was diagnosed with lung adenocarcinoma with an EGFR exon21 L861Q mutation（clinical stage ⅢA ; cT4N0M0）. She had received Gefitinib for 18 months, until she had disease progression（PD）. Re-biopsy showed T790M-negative, ALK-negative and PD-L1 0%. Several other drugs were attempted after Gefitinib, but none of them showed any effect. Nivolumab treatment was initiated as her sixth chemotherapy, four and a half years after being diagnosed. Her tumor responded well to Nivolumab treatment and still remains effective without any severe side effects such as interstitial pneumonitis. Our case suggests that Nivolumab treatment is a treatment option for NSCLC patients with EGFR uncommon mutations who are refractory to EGFR-TKI treatment

クリゾチニブ ガ ソウコウ シタ Performance Status フリョウ anaplastic lymphoma kinase イデンシ テンザ ヨウセイ ハイセンガン ノ 1レイ

A ２７-year-old female was referred to our hospital for further examination of hoarseness, cough, and hemoptysis. Positron emission tomography-computed tomography revealed FDG accumulation in a huge mass in the left lower lobe, lymph nodes in the hilum, mediastinum and right cervical lesion left scapula and vertebral body. Further examination yielded the diagnosis of primary lung adenocarcinoma （cT２aN３M１b : Stage IV） harboring the anaplastic lymphoma kinase （ALK） fusion oncogene. Although her general condition was getting worse due to rapid increase of the pleural effusion, crizotinib promptly diminish the pleural effusion and ameliorated the patient’s condition. The adverse events of crizotinib, such as nausea, vomiting and visual disturbance, were generally mild and well tolerable during treatment. These findings suggest that crizotinib is a promising candidate for ALK-positive non-small cell lung cancer patients even with poor performances

気管・気管支内腔に多発ポリープ様病変を呈した小細胞癌の１例

It is rare that small cell carcinoma has multiple polypoid lesions. There is few report of small cell carcinoma in trachea and bronchus. We experienced a case of multiple polypoid lesions of small cell carcinoma. In January ２０１X, Woman in ６０s had operation for esophageal squamous cell carcinoma. In July ２０１X, thoracic and abdominal CT for postoperative follow-up revealed many nodules in the trachea, the bronchus, the lungs, and the liver, and mediastinum lymphadenopathy. We examined bronchoscopy and there were multiple polypoid lesions in the trachea and bronchus. Left main bronchus were almost occluded by maximum lesion, and we performed biopsy. We suspected recurrence of esophageal squamous cell carcinoma, therefore quickly started chemotherapy（CDDP＋５‐FU）and radiation for the left main bronchus. However, the pathological diagnosis was small cell carcinoma, we stopped the chemotherapy for esophageal squamous cell carcinoma. This case suggests we should examine to differentiate primary tumor or metastasis when we find a new lesion

Clinical features and outcome of acute exacerbation of interstitial pneumonia associated with connective tissue disease.

Acute exacerbation (AE) of interstitial lung disease is reported to be developed in not only idiopathic pulmonary fibrosis but also connective tissue disease-associated interstitial pneumonia (CTD-IP). As the significance of AE of CTD-IP has not been so widely recognized, its clinical feature is not fully elucidated. In the present study, we investigated the incidence, clinical features and outcome of AE of CTD-IP. We retrospectively reviewed admitted cases in our department with medical record from 2011 to 2015. Among 155 patients with CTD-IP, 10 (6.5%) cases developed AE (6 rheumatoid arthritis, 2 polymyositis/dermatomyositis, 1 systemic lupus erythematosus, 1 Sjögren syndrome), and one died of AE within 30 days. Median survival time after the onset of AE was 169 days in all 10 patients. The treatment with immunosuppressant just before AE onset might improve the prognosis of AE. The median survival time after the onset of AE was significantly longer in patients showing good response to corticosteroid compared with those with poor response to corticosteroid (805 days and 45 days, respectively) (p<0.05), suggesting that there are some cases in CTD-IP, showing the good response to corticosteroid even when AE was complicated

Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats

Background : Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been reported to be associated with interstitial lung disorders, and their high incidence and mortality have become a matter of great concern, especially in Japan. In this study, we investigated the effect of gefitinib on different phases of radiationinduced lung disorders in an experimental model. Methods : The thoraxes of Wistar rats were irradiated on day 1 with a single X-ray dose of 20 Gy, and gefitinib (50 mg/kg/day) was orally administered from day 1 to 14. The rat lungs were harvested on days 15 and 57 and the bronchoalveolar lavage (BAL) was performed. Results : Gefitinib treatment increased the infiltration of inflammatory cells, which produced more pro-inflammatory cytokines (IL-6, IL-1β), in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57. Conclusions : In irradiated rats, gefitinib treatment augmented lung inflammation, including inflammatory cell infiltration and pro-inflammatory cytokine expression, while gefitinib treatment attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation

Analysis of the Prognostic Factors of Extensive Disease Small-Cell Lung Cancer Patients in Tokushima University Hospital

Background : Small-cell lung cancer (SCLC) presents aggressive clinical behavior, and its prognosis is still poor. Previously, performance status (PS), or the existence of brain, bone, or liver metastasis were reported to be unfavorable prognostic factors. Given the recent progress of treatment modalities such as radiotherapy techniques and bone modifying agents, the prognostic factors might be different from previous findings. Therefore, we analyzed the prognostic factors of extensive disease SCLC (ED-SCLC) in recent years. Methods : ED-SCLC patients treated in Tokushima University Hospital between 2010 and 2016 were analyzed. Log-rank test and the Cox proportional hazards regression model was used in univariate and multivariate analysis, respectively. Results : Totally, 79 patients were analyzed. In the univariate analysis, age, PS, interstitial pneumonia (IP), liver metastasis, pleural dissemination, neutrophil counts, hypoalbuminemia, hypercalcemia and several liver and biliary enzymes were identified as poor prognostic factors. In the multivariate analysis, age, PS, IP, and liver and biliary enzymes were identified. Moreover, the PS in patients with liver metastasis was significantly worsened. Conclusions : In this study, we newly demonstrated that IP was a significant poor prognostic factor of ED-SCLC. Although liver metastasis was not extracted in multivariate analysis, it may have an impact on the prognosis of ED-SCLC

Investigation of the outpatient chemotherapy for lung cancer patients in Tokushima University Hospital

Platinum-doublet regimens and docetaxel as first- and second-line chemotherapy, respectively, are shown to prolong the survival of lung cancer patients in various randomized phase III studies. However, the evidence for the efficacy of chemotherapy for lung cancer in the clinical practice is still insufficient. In the present study, we investigated the effectiveness and safety of outpatient chemotherapy for lung cancer in the clinical practice. Ninety-four lung cancer cases were retrospectively analyzed. Among these cases, 67 (71.3%) were non-small cell lung cancer (NSCLC) and 27 (28.7%) were small cell lung cancer (SCLC). The response rates in SCLC and NSCLC patients were 55.6% (15/27) and 16.9% (11/65), respectively. Objective tumor response rates for the patients were found to decrease substantially with each line of treatment as described previously. All adverse events were well tolerated and no treatment-related death was observed. Median time to treatment failures (TTFs) of first-line treatment were 10.1 months and 4.8 months in SCLC and NSCLC, respectively. These findings indicate that even in the setting of clinical practice, the efficacy and safety of chemotherapy is strictly insured by the appropriate therapeutic management