Effect of Systemic Corticosteroid Therapy on the Efficacy and Safety of Nivolumab in the Treatment of Non-Small-Cell Lung Cancer.

INTRODUCTION: Corticosteroids are used to treat immune-related adverse events (irAEs) associated with nivolumab. However, patients with non-small-cell lung cancer who are administered corticosteroids before the initiation of nivolumab treatment are commonly excluded from clinical trials. The appropriate timing for corticosteroid administration in relation to nivolumab treatment, effects of corticosteroids on the efficacy of nivolumab, and resulting adverse events are not clearly understood. In this study, the effects of differences in the timing of corticosteroid administration on nivolumab efficacy and the resulting adverse events were examined. METHODS: A retrospective study was conducted with 109 patients who were treated with nivolumab at Sapporo Minami-Sanjo Hospital between December 2015 and March 2018. RESULTS: Of the 109 patients treated with nivolumab, 12 patients were administered corticosteroids before the first cycle of nivolumab (pre-CS), and 33 patients were administered corticosteroids after the first cycle of nivolumab (post-CS). These 2 groups were compared with the control group comprising 64 patients who were not administered corticosteroids (non-CS). The objective response rate in the post-CS group was significantly higher than that in the non-CS group, and the disease control rate in the pre-CS group was significantly lower than that in the non-CS group. The overall survival time and progression-free survival time in the pre-CS group were significantly shorter than those observed in the non-CS group; however, these did not differ from those in the post-CS group. CONCLUSIONS: These results suggest that corticosteroids administered to patients with non-small-cell lung cancer after initiation of nivolumab treatment did not affect the disease prognosis. Thus, corticosteroids can be administered immediately for rapid treatment of irAEs.

Anti-CTLA-4 Antibody Might Be Effective Against Non-small Cell Lung Cancer With Large Size Tumor.

BACKGROUND/AIM: Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Although several ICI options are available, the treatment regimen for NSCLC with large size tumors (large NSCLC) is controversial and the efficacy of anti-CTLA-4 antibody is unclear. This study thus investigated potential biomarkers for CTLA-4 blockade. PATIENTS AND METHODS: The correlation between tumor diameter and treatment duration was examined in patients with advanced NSCLC treated with anti-PD-1 antibody monotherapy in our institution. In addition, the ratio of tumor-infiltrating CD8+ T cells and regulatory T (Treg) cells in small and large size NSCLC was also evaluated using immunohistochemical staining. Finally, the efficacy of treatment with anti-CTLA-4 antibody against large NSCLC was investigated. RESULTS: A negative correlation was found between tumor diameter and treatment duration in patients treated with anti-PD-1 antibody monotherapy. Immuno-histochemical staining revealed that Treg cell infiltration was significantly higher in large NSCLC tumors than in small tumors. Among the patients with large NSCLC, the ICI regimen including anti-CTLA-4 antibody showed significant efficacies. CONCLUSION: Anti-PD-1 antibody monotherapy might be less effective against large NSCLC due to the infiltration of Treg cells. Therefore, it might be appropriate for large NSCLC to select a treatment including an anti-CTLA-4 antibody, which can target Treg cells.

[A case of hypersensitity pneumonitis due to the contamination of a dehumidifier by Thermoactinomyces vulgaris].

A 22-year-old man was admitted to our hospital because of high fever and shortness of breath. A chest CT showed centrilobular nodules and ground-glass attenuation in both lungs. Transbronchial lung biopsy specimens showed alveolitis including the infiltration of mononuclear cells and granulomas. He responded to treatment, but upon returning home the radiological findings and clinical symptoms reappeared. We focused on a dehumidifier because it had been used continuously in his room. Thermoactinomyces vulgaris presented in the air filter of the dehumidifier. The test of precipitation in response to Thermoactinomyces vulgaris was positive. The condition inside the dehumidifier of a high temperature and high humidity were suitable for the proliferation of Thermoactinomyces vulgaris. We diagnosed hypersensitity pneumonitis due to a dehumidifier contaminated by Thermoactinomyces vulgaris.

Large Cell Neuroendocrine Carcinoma Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement with Response to Alectinib.

Anaplastic lymphoma kinase (ALK) rearrangement is most commonly observed in lung adenocarcinoma in a subset of lung cancer. Large cell neuroendocrine carcinoma (LCNEC) harboring an ALK rearrangement is very rare. Based on the findings from a transbronchial lung biopsy, a 75-year-old non-smoking woman was diagnosed with LCNEC with multiple liver and bone metastases. After seven cycles of cytotoxic chemotherapy, her genotype testing demonstrated ALK rearrangement. Subsequently, she was administered alectinib and exhibited a partial response.

Role of interleukin-18 and T-helper type 1 cytokines in the development of Mycoplasma pneumoniae pneumonia in adults.

STUDY OBJECTIVE: Interleukin (IL)-18 is a proinflammatory cytokine, originally termed interferon (IFN)-gamma-inducing factor, which promotes T-helper type 1 (Th1) cytokine responses. We recently reported that serum IL-18 levels were elevated in children with Mycoplasma pneumoniae pneumonia (MP). In this study, we investigated the contribution of IL-18 to the infection and assessed the Th1 cytokine response to pulmonary involvement in adults. METHODS: We investigated the clinical course, pulmonary involvement, and serum levels of IL-18, IFN-gamma, IL-12p40, and soluble IL-2 receptor (sIL-2R) in 21 patients with acute-stage MP and in 21 age- and sex-matched control subjects. RESULTS: Significantly (p < 0.001) increased serum IL-18 (median, 248 pg/mL [range, 89 to 441 pg/mL] vs. median, 126 pg/mL [range, 47 to 217 pg/mL]) and sIL-2R (median, 617 U/mL [range, 410 to 1,032 U/mL] vs. median, 425 U/mL [range, 268 to 601 U/mL]) were found in patients with MP as compared with healthy control subjects, and there was a tendency toward increased serum IFN-gamma and IL-12p40. Circulating IL-18 values had a positive correlation with serum sIL-2R levels (r = 0.62, p = 0.028) and the number of affected pulmonary lobes (sigma = 0.61, p = 0.024), but not with the serum levels of antibodies to M pneumoniae, IFN-gamma, or IL-12p40. Serum IL-18 and sIL-2R values in severe cases were significantly higher (p < 0.03) than those in mild cases. IFN-gamma and sIL-2R levels in four patients with pleural effusion were significantly (p < 0.05) higher than those in the other 17 subjects. CONCLUSIONS: Serum levels of IL-18 were raised during the acute phase of MP. We suggest IL-18 and Th1 cytokines may play a significant role in the immunopathologic responses in MP.

Workplace-related chronic cough on a mushroom farm.

BACKGROUND: Mushroom spores have frequently been associated with respiratory allergy. The aims of this study were to elucidate the incidence and causes of chronic cough in a mushroom farm. METHODS: Participants were 69 mushroom workers who produce Hypsizigus marmoreus (Bunashimeji) and 35 control subjects. We excluded six workers because they had had asthma or allergic rhinitis before working. Participants completed a cross-sectional health survey 2 years after starting work at the mushroom farm. RESULTS: The mean airborne endotoxin levels in the harvesting and packing rooms were approximately 60-fold higher than those in the offices. Of 63 workers, 42 workers (67%) reported chronic cough after working on this farm, 19 workers had no cough, while 2 workers had hypersensitivity pneumonitis develop to the spore, which has been previously reported by us. Of the 42 workers with cough, 6 workers had organic dust toxic syndrome (ODTS), 18 workers had postnasal drip syndrome, 15 workers had cough variant asthma, and 3 workers had eosinophilic bronchitis. Seventy-one percent of the workers noticed the cough in the first 3 months, and the mean latent period in ODTS workers was the shortest. The cough had a trend to improve or disappear after weekend holidays. Bronchial hyperresponsiveness but not FEV(1)/FVC% in the 42 workers with cough was significantly (p < 0.001) increased as compared with the control subjects. CONCLUSIONS: Working on a mushroom farm carries a significant risk for chronic cough from inhalation of mushroom spores, and we suggest that elevated airborne endotoxin on this farm is the cause.

Successful treatment of hypersensitivity pneumonitis caused by Grifola frondosa (Maitake) mushroom using a HFA-BDP extra-fine aerosol.

We successfully treated a patient with occupational hypersensitivity pneumonitis (HP) caused by Grifola frondosa (Maitake) mushroom spore with an extra-fine aerosol corticosteroid; beclomethasone dipropionate (BDP) dissolved in hydrofluoroalkane-134a (HFA). A 49-year-old woman developed respiratory symptoms 3 months after beginning work on a mushroom farm. She was diagnosed as HP based on radiological and serological findings. Oral prednisolone therapy improved her HP and she returned to the same farm. Her HP relapsed after 5 months, and daily 400 microg of HFA-BDP was administered with gradual improvement. An extra-fine particle inhaled corticosteroid might reach appropriate alveoli to be effective therapy for mild HP.

Hypersensitivity pneumonitis induced by the spore of Pleurotus Eryngii (Eringi).

We reported the first case of hypersensitivity pneumonitis (HP) by an edible mushroom, Pleurotus Eryngii (Eringi). A 54-year-old woman had worked in a Bunashimeji mushroom factory for 42 months, and she moved to a new factory producing Eringi. Two months after, she was found to have HP by the spore of Eringi. Although no radiological finding was detected 6 months before the onset of HP, serum surfactant protein D (SP-D) had been elevated. We speculated that type II pneumocyte activation might prepare the ground for HP during the former exposure to Bunashimeji, and serum SP-D levels might reflect their conditions.

Peripheral primitive neuroectodermal tumor of the chest wall of a 69-year-old man.

We report a case of peripheral primitive neuroectodermal tumor (pPNET), which belongs to the pPNET/Ewing's sarcoma family, arising in the chest wall of a 69-year-old man. He had high levels of serum neuron-specific enolase and pro-gastrin-releasing peptide, which are believed to be useful diagnostic blood markers for small cell lung carcinoma (SCLC). Microscopically, the tumor was composed of solid nests and sheets of monotous, primitive, small round cells with a few rosettes, making it difficult to distinguish from SCLC. Immunohistochemically, the tumor cells showed intense cell membranous immunoreactivity for MIC2 protein (CD99). EWS/FLI-1 chimeric mRNA that originated from the characteristic t(11;22)(q24;q12) chromosomal translocation was detected by RT-PCR and nucleotide sequence analysis. These results confirmed the diagnostic validity of the present tumor being a pPNET, thus raising the possibility that in the past, pPNETs which have arisen in the chest have been mistakenly diagnosed as SCLC.

Endobronchial closure of a bronchopleural fistula using a fibrin glue-coated collagen patch and fibrin glue.

Bronchopleural fistulas associated with empyema can occur as life-threatening sequelae after pulmonary resection, occurring most frequently after pneumonectomy. Three bronchopleural fistulas, 5-6 mm in diameter, were successfully treated using a fibrin glue-coated collagen patch (FGCCP) and fibrin glue (FG) at the site of a bronchopleural fistula. Through the clinical experiences, we introduce the methodology to perform the endobronchial closure of bronchopleural fistulas.Data were collected by reviewing the clinical charts of patients diagnosed with post-lobectomy bronchopleural fistula at Sapporo Minami-Sanjo Hospital from June 2004 to December 2010. Bronchopleural fistula was diagnosed by means of endoscopic visualization. Three cases of post-lobectomy and one case of post-pneumonectomy bronchopleural fistula were collected.A FGCCP fragment was packed within the fistula, and the fragment grasped with the forceps was kept in this position for approximately a minute, a time during which a FGCCP becomes adhesive, and the patch fragment was released. After releasing the patch fragment, the FG was applied directly on the FGCCP using a two-channel catheter.There have been few reports of the bronchoscopic closure of bronchopleural fistulas using a FGCCP and FG. Closure of small bronchopleural fistulas with the application of a FGCCP and FG may offer a valuable therapeutic alternative.

Reduction of eosinophils in small airways by inhaled steroids is insufficient in patients with adult asthma.

BACKGROUND: Recent reports suggest that small airway as well as large airway involvement in asthma is important. We investigate the therapeutic effects of a meter-dose inhaler of chrolofluorocarbon-beclomethasone dipropionate (CFC-BDP) and dry-powder fluticasone (DP-FP). METHODS: Lung specimens obtained at operation due for small size lung cancer in 16 asthmatic patients and 16 controls were evaluated immunohistochemically using antibodies of EG2 (eosinophil), AA1 (mast cell), CD68 (macrophage), and CD34 (pluripotent hematopoietic stem cell). We calculated the number of each cell type in 5 fields in the inner and outer areas of large airways (luminal diameter; > or =2 mm) and small airways (<2 mm) using computer software. RESULTS: In asthmatic patients eosinophils were significantly increased in both inner and outer areas of small airways and the number of CD34+ cells was significantly elevated in inner areas as compared with controls. Although the density of eosinophils in the inner area of large airways was significantly suppressed (p < 0.02), there was no such suppression in the inner areas of small airways in asthmatic patients treated with CFC-BDP or DP-FP. CONCLUSIONS: It was speculated that inhaled CFC-BDP and DP-FP might deposit mainly in large airways and fail to fully reach small airways, consequently allowing eosinophilic inflammation to continue in small airways.

Gefitinib-induced interstitial lung disease showing improvement after cessation: disassociation of serum markers.

Gefitinib (ZD1839), a small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, is an anticancer agent for patients with non-small cell lung carcinoma. Recently, however, as a result of accumulating evidence, it has been recognized that gefitinib can give rise to lethal lung toxicity. The authors report a case of interstitial lung disease (ILD) induced by gefitinib, which improved promptly following cessation of the administration of the agent. Clinical signs suggesting a good prognosis were noted, namely, findings similar to acute eosinophilic pneumonia on CT and a disassociation in the elevation of specific serum markers of ILD. At the time of onset of ILD, serum concentrations of surfactant protein (SP)-A and SP-D were significantly increased, whereas that of KL-6 was not increased. A previous study of three cases of lethal lung toxicity resulting from gefitinib administration revealed a significant and almost equal increase in KL-6, SP-A and SP-D. These results suggest that SP-A and SP-D may be indicators of gefitinib-induced ILD and that KL-6 is a predictor of outcome. Using a combination of these markers may help to establish a differential prognosis in patients with gefitinib-induced ILD.

Increased airway vascularity in newly diagnosed asthma using a high-magnification bronchovideoscope.

Hypervascularity in the bronchial wall is part of airway remodeling, but has remained an ill-defined process in asthma pathogenesis. Previous morphologic assessment has been limited to biopsy specimens, and therefore a high-magnification bronchovideoscope (side-viewing type) was developed for less invasive examination of subepithelial vessels. We evaluated vascularity in the lower trachea, using this novel scope in 12 normal control subjects, 13 patients with chronic obstructive pulmonary disease, and 24 subjects with stable asthma; 8 were steroid naive with newly diagnosed asthma (Group A) and 16 had been treated with inhaled corticosteroids for more than 5 years (Group B). The redness of bronchial mucosa in patients with asthma observed by conventional fiberoptic bronchoscopy proved to be due to a fine vascular network. Morphometric measurements of subepithelial vessels showed that both vessel area density and vessel length density were significantly (p<0.0001) increased in subjects with asthma as compared with control subjects and patients with chronic obstructive pulmonary disease. The degree of increase in vessels did not differ between Group A and Group B. The increase in subepithelial vessels of the airway is present even in newly diagnosed asthma. This novel bronchovideoscope is useful for assessment of vessel network in the surface of the airway lumen in vivo.