The Impact of EGFR Mutation Status and Brain Metastasis for Non-Small Cell Lung Cancer Treated with Ramucirumab plus Docetaxel.

OBJECTIVES: Currently, combination therapy of ramucirumab (RAM) + docetaxel (DOC) must play a more important role as a second-line treatment. Epithelial growth factor receptor (EGFR) mutation accounts for around 50% of oncogenic driver mutations in patients with advanced non-small cell lung cancer (NSCLC) in Asian subsets. The number of brain metastases (BM) is relatively higher in EGFR mutation-positive patients compared to EGFR wild-type patients. The objective of this study is to evaluate the efficacy of RAM + DOC focusing on EGFR mutation and BM. METHODS: We retrospectively reviewed consecutive advanced NSCLC patients who received combination therapy of RAM + DOC at three institutions. A total of 112 patients with NSCLC were enrolled for efficacy analyses. We evaluated the efficacy of RAM + DOC for EGFR-mutated NSCLC with endpoints including progression-free survival (PFS), time to treatment failure (TTF) and overall survival. RESULTS: Median PFS was 5.7 months for the EGFR mutant group compared with 3.6 months for the EGFR wild-type group (HR 0.53, 95% CI 0.32-0.87; p = 0.01). Median TTF was 5.1 months for the EGFR mutant group compared with 2.8 months for the EGFR wild-type group (HR 0.53, 95% CI 0.33-0.85; p = 0.007). Median PFS and TTF of the EGFR mutant group was significantly longer than median PFS and TTF of the EGFR wild-type group. The multivariate analysis identified EGFR mutation status as an independent favorable factor of PFS. In subset analyses of BM, median PFS of the EGFR mutant group (2.8 months) was significantly shorter than that of the EGFR wild-type group (5.1 months) (HR 7.27, 95% CI 1.78-29.68; p = 0.002). CONCLUSION: This study revealed that EGFR mutation status and BM might be predictive or prognostic factors for PFS.

Effectiveness and Safety of Omalizumab in Patients with Allergic Bronchopulmonary Aspergillosis Complicated by Chronic Bacterial Infection in the Airways.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence of predisposing conditions such as asthma and cystic fibrosis. Even ABPA accompanied by asthma is often complicated by chronic Pseudomonas aeruginosa or nontuberculous mycobacterial infection of the lower respiratory tract, rendering treatment with corticosteroids difficult. There have been several reports on the effectiveness of omalizumab, an anti-IgE antibody, in patients with ABPA. We analyzed the effectiveness and adverse effects of omalizumab in ABPA patients with chronic respiratory infections. METHODS: Using our nationwide survey database and published case reports, we identified patients with severe asthma and ABPA who fulfilled the International Society for Human and Animal Mycology criteria and who had been treated with omalizumab. Exacerbation rates, control of symptoms, doses of oral corticosteroids, and pulmonary function were evaluated. RESULTS: Among 25 patients with ABPA treated with omalizumab (median age 62 years, range 33-83 years), 12 patients had a chronic bacterial infection of the lower airways attributable to P. aeruginosa (n = 6) or nontuberculous mycobacteria (n = 6) at the initiation of omaliz-umab. Treatment with omalizumab reduced the frequency of exacerbations and systemic corticosteroid doses and improved pulmonary function. There were no significant adverse events or worsening of infection during treatment with omalizumab, except for injection-site reactions. CONCLUSIONS: Treatment with omalizumab was effective and safe in patients with ABPA, regardless of comorbid chronic respiratory tract infections.

The efficacy and safety of ramucirumab plus docetaxel in older patients with advanced non-small cell lung cancer.

BACKGROUND: Ramucirumab plus docetaxel (RAM+DOC) is expected to prolong survival in patients with advanced non-small cell lung cancer (NSCLC); however, the efficacy and safety for older patients remains unknown. The objective of this study was to evaluate the efficacy and safety of RAM+DOC in patients 75 years and older. METHODS: We retrospectively reviewed consecutive patients with advanced NSCLC who had received RAM+DOC treatment at three institutions. We compared the efficacy and safety in patients 75 years and older to those under 75 years of age. RESULTS: A total of 114 patients were identified. The median progression-free survival, time to treatment failure and overall survival was 3.6 (95% CI: 0.4-6.7), 3.1 (95% CI: 2.4-3.9) and 11.2 months (95% CI: 5.6-16.8) in the older group (N = 23), and 4.2 (95% CI: 3.3-5.0), 3.4 (95% CI: 3.3-5.0) and 12.2 months (95% CI: 9.1-15.4) in the younger group (N = 91), respectively. Survival curves were similar for each group, while the objective response rate was 30.4% (95% CI: 13.2-52.9%) in older patients and 35.2% (95% CI, 25.4-45.9%) for the younger group. A total of 22 older patients (95.7%) and 73 (80.2%) younger patients received primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF). Four older patients (17.3%) and 14 younger patients (15.3%) discontinued RAM+DOC due to adverse events. CONCLUSIONS: RAM+DOC is expected to be efficacious and tolerable in older patients when supported with prophylactic PEG-G-CSF therapy. KEY POINTS: Significant findings of the study ・PFS, OS, and ORR in older patients were similar to those under 75 years of age. ・Safety of RAM+DOC was well tolerated in older patients with prophylactic PEG-G-CSF. ・Prophylactic PEG-G-CSF with RAM+DOC may contribute to better efficacy. What this study adds ・This study suggests that RAM+DOC with prophylactic PEG-G-CSF is expected to be a useful option in older patients with advanced NSCLC.

The Incidence of Hemorrhagic Complications Was Lower With the Guide Sheath Than With the Conventional Forceps Biopsy Method: Results of Bronchoscopy in the 2016 Nationwide Survey by the Japan Society for Respiratory Endoscopy.

BACKGROUND: The Japan Society for Respiratory Endoscopy performed a nationwide survey to evaluate the current status and complications of bronchoscopy. Data on deaths due to bronchoscopy, complications after bronchoscopy, and particularly, complications of forceps biopsy were surveyed. METHODS: The survey form was mailed to 532 facilities accredited by the society. The numbers of procedures, complications, and deaths were investigated. RESULTS: The response rate was 79.1% (421 facilities). Deaths attributable to diagnostic bronchoscopy occurred in 11 (0.011%) of 98,497 cases.In regards to forceps biopsy, the guide sheath method was applied in 23,916 cases and the conventional method in 31,419 cases was done with conventional method. Complications of forceps biopsy developed in 1019 cases in total, with an incidence rate of 1.84%. The most frequent complication was pneumothorax (0.70%), followed by pneumonia/pleurisy (0.46%) and hemorrhage (0.45%). The incidence of hemorrhagic complication was significantly lower in the guide sheath group than in the non-guide sheath group (0.29% vs. 0.58%; P<0.001). The overall incidence of complications (1.63% vs. 2.00%; P=0.002) and the mortality rate (0% vs. 0.02%; P=0.04) were significantly lower in the guide sheath group. CONCLUSION: The incidence of hemorrhagic complications in forceps biopsy of peripheral pulmonary lesions was lower when the guide sheath method was applied. It is necessary to increase the awareness for safety control in diagnostic bronchoscopy for new procedures.

[CHARACTERISTICS OF ADULT ASTHMATICS COMPLICATED WITH PULMONARY THROMBOEMBOLISM IN YOKOHAMA CITY SEIBU HOSPITAL].

BACKGROUND: Evidences have shown that bronchial asthma (BA) enhances the risk of pulmonary thromboembolism (PTE). We previously reported the cases of adult BA patients complicated with PTE. (Aim) To clarify the risk factors of PTE in BA patients, we investigated about the characteristics and risk of contrast medium about patients coexisting asthma and PTE. METHODS: We investigated adult asthmatics who visited our hospital and examined chest contrasted CT from January 2011 to 2018.March, retrospectively. RESULTS: Fifty seven times examinations (33 asthmatics) were detected from 304 times of enhanced chest CT. We examined twenty times enhanced CT without premedication, but no subjects had side effect such as asthma attack. And also, we diagnosed 12 asthmatics as PTE from 33 patients. The subjects with PTE were high BMI (p=0.024) heavy weight (p=0.033), compared with asthmatics without PTE. There were no significant changes about lung function test, smoking history, sex and the levels of D-dimer among two groups. CONCLUSION: Adult asthmatics with PTE were high BMI and heavy compared with those without PTE.

Complicating effects of obstructive sleep apnea syndrome on the severity of adult asthma.

Introduction: Bronchial asthma (BA) and obstructive sleep apnea syndrome (OSAS) are common causes of respiratory disturbance. Many cases of patients with both conditions have been reported, and BA and OSAS may exacerbate each other, but information remains sparse.Methods:We retrospectively evaluated 60 patients under treatment for BA in our department between April 2016 and March 2018 who also underwent portable polysomnography (PSG) for suspected OSAS to assess potential association between PSG results and asthma treatment or respiratory function. BA was diagnosed and treated according to the Asthma Prevention and Management Guideline 2015.Results: We found that BA treatment intensity step was significantly higher for patients with BA who had concurrent moderate or severe OSAS (p = 0.0016). However, neither respiratory function, fraction of exhaled nitric oxide (FeNO), nor forced oscillation technique (FOT) differed significantly between patients with and without OSAS, and apnea hypopnea index was not significantly correlated with respiratory function, FeNO or FOT parameters.Conclusion:We conclude that even though BA patients with OSAS had good respiratory function, their BA was more severe than that of patients without OSAS, suggesting that OSAS may exacerbate BA. Background factors and asthma parameters were not predictive of PSG results, and patients with suspected OSAS should be evaluated proactively by using PSG.

[A CASE OF BRONCHIAL ASTHMA ASSOCIATED WITH BRONCHIOLAR EOSINOPHILIA AND TREATED WITH MEPOLIZUMAB].

A 68 year-old woman with dyspnea and cough had been treated with inhaled corticosteroids for X-15 years, but her symptoms worsened in X year. High-resolution chest CT revealed small centrilobular nodules in the right upper lobe in March X year. The patient was diagnosed with asthma and diffuse panbronchiolitis and treated with inhaled corticosteroids, a long-acting beta agonist, and clarithromycin, but her condition did not improve and her peripheral blood eosinophil count increased. In August X year, we performed a transbronchial biopsy of the right upper lung. Histopathological examination revealed eosinophilia in the bronchial secretions and mild nonspecific inflammatory changes. The diagnosis was bronchial asthma associated with bronchiolitis. The patient was treated successfully with mepolizumab.

Current status of diagnostic and therapeutic bronchoscopy in Japan: 2016 national survey of bronchoscopy.

BACKGROUND: The safety management committee of the Japan Society for Respiratory Endoscopy (JSRE) conducted national surveys to clarify the state of diagnostic and therapeutic bronchoscopy in 2016. METHODS: Questionnaire forms were mailed to 532 JSRE-accredited facilities throughout Japan. We surveyed the actual condition of clinical practice and cases of bronchoscopy during 2016. RESULTS: Four hundred and thirty-three facilities responded giving a response rate of 81.4%; 67.6% held more than 400 beds. The average number of board accredited senior Fellows and Fellows per facility was 1.9 and 3.2, respectively. Diagnostic bronchoscopy was performed in a hospitalized setting in 74.6% of all facilities. The radial type ultrasound probe was operated in 51.7% of all facilities. The number of facilities has markedly increased compared with that reported in the 2010 survey (19.6%). The bronchoscopic navigation system had been in operation in 41.7% of all facilities. Antithrombotic drugs were adjusted before biopsy in 96.8% of all facilities. For intravenous sedation, midazolam was the first choice in 76.9% of all facilities. Endobronchial ultrasound guided transbronchial lymph node needle aspiration (EBUS-TBNA) has become popular over the decade (19.6% in 2010 to 68.1% in 2016). The mean number of the board accredited senior Fellows and board accredited Fellows increased in comparison with that in 2010. As a new technique, radial type ultrasound-guided peripheral approach has become popular. CONCLUSIONS: Through this survey, the advanced safety of bronchoscopic examination has been secured in many facilities. A continuous monitoring of bronchoscopic practices with respect to safety management is recommended.

[A CASE OF PERTUSSIS IN ADULT THAT COULD BE DIAGNOSED BY DETECTION OF BORDETELLA PERTUSSIS FROM SPUTUM].

Bordetella pertussis isolation by culture has low detection sensitivity for diagnosing pertussis; the diagnosis is confirmed by measuring serum anti-pertussis toxin (anti-PT) or anti-filamentous hemagglutinin antibody titers, and by genetic testing (polymerase chain reaction/loop-mediated isothermal amplification). Isolation of B. pertussis in adults is difficult, resulting in a delayed diagnosis, as a delayed cough may present ≥3 months after onset. Differentiation from bronchial asthma is also important. We encountered an adult patient in whom B. pertussis was isolated by culture who previously received rituximab for mucosa-associated lymphoid tissue (MALT) lymphoma and steroids for prolonged cough. No elevation of anti-PT antibody titers was observed in the patient.

Comparison of clinical and pathological features of lung lesions of systemic IgG4-related disease and idiopathic multicentric Castleman's disease.

AIMS: The lung lesion [immunoglobulin (Ig)G4-L] of IgG4-related disease (IgG4-RD) is a condition that occurs together with IgG4-RD and often mimics the lung lesion [idiopathic multicentric Castleman's disease (iMCD-L)] of idiopathic multicentric Castleman's disease (iMCD). Because no clinical and pathological studies had previously compared features of these diseases, we undertook this comparison with clinical and histological data. METHODS AND RESULTS: Nine patients had IgG4-L (high levels of serum IgG4 and of IgG4+ cells in lung specimens; typical extrapulmonary manifestations). Fifteen patients had iMCD-L (polyclonal hyperimmunoglobulinaemia, elevated serum interleukin-6 levels and polylymphadenopathy with typical lymphadenopathic lesions). Mean values for age, serum haemoglobin levels and IgG4/IgG ratios were higher in the IgG4-L group and C-reactive protein levels were higher in the iMCD-L group. All IgG4-RD lung lesions showed myxomatous granulation-like fibrosis (active fibrosis), with infiltration of lymphoplasmacytes and scattered eosinophils within the perilymphatic stromal area, such as interlobular septa and pleura with obstructive vasculitis. All 15 lung lesions of iMCD, however, had marked accumulation of polyclonal lymphoplasmacytes in lesions with lymphoid follicles and dense fibrosis, mainly in the alveolar area adjacent to interlobular septa and pleura without obstructive vasculitis. CONCLUSIONS: Although both lesions had lymphoplasmacytic infiltration, lung lesions of IgG4-RD were characterized by active fibrosis with eosinophilic infiltration within the perilymphatic stromal area with obstructive vasculitis, whereas lung lesions of iMCD had lymphoplasmacyte proliferating lesions mainly in the alveolar area adjacent to the perilymphatic stromal area. These clinicopathological features may help to differentiate the two diseases.

A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911.

BACKGROUND: Low-dose erlotinib may be as effective as gefitinib or erlotinib at full dose in non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR) gene. METHODS: Patients with chemotherapy pretreated NSCLC harbouring EGFR mutations received erlotinib at 50 mg/d until disease progression or unacceptable toxicities. The dose was escalated to 150 mg/d in patients showing no response (i.e. without major tumour shrinkage according to Response Evaluation Criteria in Solid Tumours (RECIST)) to the initial dose during the first 4 weeks. The primary end-point was the objective response rate at the dose of 50 mg/d. RESULTS: Thirty-four patients from seven institutes were enrolled. The study was closed early when no response was confirmed in 15 patients, excluding the possibility that the primary end-point would be met. The objective response and disease control rates at the dose of 50 mg/d as determined by an independent review committee were 54.5% and 84.8%, respectively. Four additional patients achieved partial response with increased 150 mg/d dose. Progression-free survival and median survival times during the entire period of the study were 9.5 and 28.5 months, respectively. Treatment-related toxicities were generally mild, the most common being skin disorders and diarrhoea. Only one case experienced grade 3 toxicity, which was transient increase of hepatic enzymes. CONCLUSION: The primary end-point was not met; low-dose erlotinib is not recommended for fit patients with NSCLC harbouring EGFR mutations. However, it may merit further evaluation for elderly or frail patients.

Organizing pneumonia in a patient with rheumatoid arthritis treated with etanercept.

Etanercept-induced organizing pneumonia (OP) has not been reported in Japan. We describe the case of a rheumatoid arthritis patient who developed OP during etanercept treatment and discuss the possible mechanisms underlying the development of etanercept-induced OP and the existence of factors that predispose Japanese patients to drug-induced OP.

Survey on the handling of chronic obstructive pulmonary disease by annual health check in Japan.

OBJECTIVE: Since mild COPD can be detected in the annual health check by lung function tests, we conducted a questionnaire survey on how such examinations are used to assess chronic obstructive pulmonary disease (COPD). METHODS: We mailed questionnaires to 633 facilities performing comprehensive medical check-up from June to July 2005 and obtained responses from 254 (40.1%). RESULTS: At participating facilities, the proportion of full or part-time physicians specializing in respiratory diseases was low [40 of 366 full timers (10.9%) and 114 of 2,044 part-timers (5.6%)], with very few physicians certified by the Japanese Respiratory Society (6.8%). Non respiratory physicians were involved in evaluating the results of thoracic diagnostic imaging at 32 facilities. Lung function tests were carried out at 98.2% of facilities though relatively few facilities evaluated test results with COPD in mind. All stages (mild, moderate, severe) of COPD were diagnosed in patients at 85 facilities (39.2%), while only severe COPD was targeted by chest imaging at 97 facilities (44.7%), disregarding mild and moderate cases. Counseling for smoking cessation was provided at 113 facilities (20.6%), while 30 facilities (14.4%) provided no form of smoking cessation. CONCLUSION: At most facilities performing a comprehensive medical check-up, there was not a sufficient number of respirologists to ensure early diagnosis of COPD and this may have compromised COPD diagnosis. The newly proposed Japan Society of Comprehensive Medical Check-up (Ningen-dock) Standards based on the Japanese Respiratory Society may be useful to reveal early stages of COPD.

Disseminated cryptococcal infection with eosinophilia in a healthy person.

A 23-year-old man with no recent medical history was hospitalized complaining of high fever and cough. In addition to very marked eosinophilia, chest X-ray revealed extensive bronchovascular bundle thickening. Transbronchial lung biopsy (TBLB) showed moderate eosinophil infiltration. Cryptococcus neoformans infection was diagnosed, based on blood culture, cerebrospinal fluid culture, urine culture, and lung biopsy specimens. The eosinophilia was successfully alleviated by treatment for cryptococcal meningitis. Furthermore, cryptococcal sepsis resolved with amphotericin B and 5-flucytosine treatment. Eosinophilia commonly occurs following chronic Aspergillus infection, but the present case suggests the involvement of Cryptococcus in another mechanism for eosinophilia.

Prognosis of small adenocarcinoma of the lung based on thin-section computed tomography and pathological preparations.

OBJECTIVE: We investigated the relationship between findings from tumor opacity in the mediastinal window image and solid lesions in pathological preparations and related the results to tumor recurrence. METHODS: The subjects were 115 patients with a lung adenocarcinoma of 20 mm or smaller who underwent surgical resection. The proportion of the reduction in the tumor opacity in the mediastinal window image maximum diameter to the maximum diameter of the tumor opacity was calculated as the reduction percentage, and the proportion of the maximum solid lesions in pathological preparation diameter to the maximum tumor diameter was calculated as the pathological ratio. RESULTS: The incidence of relapse was significantly higher in patients with a reduction percentage of less than 50% and in patients with a pathological ratio of less than 50%. CONCLUSIONS: Measurement of the reduction percentage and the pathological ratio may allow prediction of prognosis of small adenocarcinoma of the lung.

[Case of pulmonary MALT lymphoma with follow-up imaging for 10 years].

Although abnormal shadow in the left upper lung of an 84-year-old male patient was confirmed in an examination in November 1996, follow-up observation was discontinued. In July 2006, he first visited our department with a chief complaint of shortness of breath, and was hospitalized because of an abnormal shadow in the left upper lung field and left pleural effusion. Since atypical lymphocytes were found in the pleural effusion, and positive cellular surface markers CD19 and 20, and chromosomal aberration of t (11 ; 18) (q22 ; q21) were confirmed, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) was diagnosed. Transbronchial lung biopsy of the left upper lobe confirmed small lymphocyte-like cellular infiltration, as seen in the pleural effusion, and CD20 immunostaining was positive, leading to the diagnosis of MALT lymphoma. In addition, serum immunoelectrophoresis demonstrated the development of macroglobulinemia as a complication. This case is valuable as changes diagnostic image over 10 years can be compared.

[A case of sub-acute onset pulmonary sarcoidosis with pulmonary dysfunction].

A 60-year-old man was admitted to our hospital because of shortness of breath and dry cough. Slight pleural thickening was observed on the chest X-ray film and chest CT on presenting. Three months later, bilateral hilar lymphadenopathy and multiple small nodular shadows were shown in both lung fields by chest CT. Serum ACE level and lysozyme levels were higher than normal upper limit. Elevation of CRP and left shift of leukocytes were not detected. Restrictive ventilatory impairment was shown in the respiratory function test. This case was diagnosed as sarcoidosis most probably with histological evidence of epithelioid cell granulomas in the lung tissue obtained by transbronchial lung biopsy. After prednisolone medication (40 mg per day) was started, symptoms, pulmonary function and chest CT findings improved. Our case was considered to be a rare case of pulmonary sarcoidosis with subacute onset of symptoms and restrictive pulmonary function abnormality which improved smoothly as a result of steroid therapy.