Identification of exhaled volatile organic compounds that characterize asthma phenotypes: A J-VOCSA study.

BACKGROUND: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma. METHODS: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS). RESULTS: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1-5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p < 0.05 adjusted by false discovery rate (FDR). Comparison of these phenotypes yielded several VOCs showing different trends (p < 0.05); however, no VOCs showed p < 0.05 adjusted by FDR. CONCLUSIONS: Exhaled VOC profiles may be useful for distinguishing asthma and asthma phenotypes; however, these findings need to be validated, and their pathological roles should be clarified.

Classifications of moderate to severe asthma phenotypes in Japan and analysis of serum biomarkers: A Nationwide Cohort Study in Japan (NHOM Asthma Study).

BACKGROUND: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes. METHODS: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences. RESULTS: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes. CONCLUSIONS: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.).

A phase II study of Osimertinib for patients with radiotherapy-naïve CNS metastasis of non-small cell lung cancer: treatment rationale and protocol design of the OCEAN study (LOGIK 1603/WJOG 9116L).

BACKGROUND: Patients with activating epidermal growth factor receptor (EGFR) mutations are highly responsive to EGFR-tyrosine kinase inhibitors (TKIs). However, it has been reported that approximately 15-30% of patients treated with EGFR-TKIs experience central nervous system (CNS) progression, and patients with EGFR mutations exhibit a higher incidence of brain metastasis than those without such mutations. The efficacy of osimertinib for treating CNS metastasis has been reported, but its efficacy for CNS metastasis in radiotherapy-naïve patients is unclear. METHODS: In the present prospective two-cohort phase II trial, 65 patients (T790M cohort, 40 patients; first-line cohort, 25 patients) with radiotherapy-naïve CNS metastasis of EGFR mutation-positive non-small cell lung cancer (NSCLC) will be included. Patients will be treated once-daily with osimertinib 80 mg. The primary endpoint is the response rate of brain metastasis as assessed using the PAREXEL criteria. Key secondary endpoints are progression-free survival and the response rate of brain metastasis as assessed using the RECIST criteria. We will exploratorily analyze the relationships of the blood concentration of osimertinib with its efficacy against brain metastasis of NSCLC and the accumulation of osimertinib in cerebrospinal fluid and evaluate tumor-derived DNA from plasma specimens for mutations in EGFR and other genes. Recruitment, which in October 2016, is ongoing. DISCUSSION: Although previous reports revealed the efficacy of osimertinib for CNS metastasis, these reports only involved subgroup analysis, and the efficacy of osimertinib for patients with previously untreated CNS metastasis remains unclear. The OCEAN study is the only trial of osimertinib for patients with untreated brain metastasis of NSCLC. This study should provide novel data about osimertinib. If the results of the OCEAN study are positive, then avoidance of radiotherapy will be recommended to patients harboring EGFR mutations and brain metastasis. TRIAL REGISTRATION: UMIN identifier: UMIN000024218 (date of initial registration: 29 September 2016). jRCT identifier: jRCTs071180017 (date of initial registration: 13 February 2019).

Prospective observational study to explore genes and proteins predicting efficacy and safety of brigatinib for ALK-gene rearranged non-small-cell lung cancer: study protocol for ABRAID study (WJOG11919L).

Background: ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. Objectives: This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. Design: Prospective observational study. Ethics: This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. Methods and analysis: This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. Discussion: This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. Trial registration: UMIN000042439.

Prophylactic treatment of dacomitinib-induced skin toxicities in epidermal growth factor receptor-mutated non-small-cell lung cancer: A multicenter, Phase II trial.

BACKGROUND: Dacomitinib significantly improves progression-free survival and overall survival (OS) compared with gefitinib in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. However, dacomitinib often causes skin toxicities, resulting in treatment discontinuation. We aimed to evaluate a prophylactic strategy for skin toxicity induced by dacomitinib. METHODS: We performed a single-arm, prospective, open-label, multi-institutional phase II trial for comprehensive skin toxicity prophylaxis. Patients with NSCLC harboring EGFR-activating mutations were enrolled and received dacomitinib with comprehensive prophylaxis. The primary endpoint was the incidence of skin toxicity (Grade ≥2) in the initial 8 weeks. RESULTS: In total, 41 Japanese patients participated between May 2019 and April 2021 from 14 institutions (median age 70 years; range: 32-83 years), 20 were male, and 36 had a performance status of 0-1. Nineteen patients had exon 19 deletions and L858R mutation. More than 90% of patients were perfectly compliant with prophylactic minocycline administration. Skin toxicities (Grade ≥2) occurred in 43.9% of patients (90% confidence interval [CI], 31.2%-56.7%). The most frequent skin toxicity was acneiform rash in 11 patients (26.8%), followed by paronychia in five patients (12.2%). Due to skin toxicities, eight patients (19.5%) received reduced doses of dacomitinib. The median progression-free survival was 6.8 months (95% CI, 4.0-8.6 months) and median OS was 21.6 months (95% CI, 17.0 months-not reached). CONCLUSION: Although the prophylactic strategy was ineffective, the adherence to prophylactic medication was quite good. Patient education regarding prophylaxis is important and can lead to improved treatment continuity.

Clinical impact of amrubicin monotherapy in patients with relapsed small cell lung cancer: a multicenter retrospective study.

Background: Topoisomerase is an essential enzyme for deoxyribonucleic acid replication, and its inhibitors suppress tumor progression. Amrubicin, a topoisomerase II inhibitor, is mainly used in the second-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). However, the impact of different types of topoisomerase inhibitors for first-line chemotherapy on the efficacy of amrubicin remains unclear. In the present study, we aimed to evaluate the efficacy of second-line amrubicin in patients with relapsed SCLC who were previously treated with platinum-based chemotherapy, including topoisomerase I and II inhibitors. Methods: This study retrospectively analyzed patients with ES-SCLC who experienced recurrence and were treated with amrubicin at 22 institutions in Japan between April 2015 and November 2020. The progression-free survival of amrubicin monotherapy was investigated using the Kaplan-Meier method. Results: A total of 320 patients were enrolled in this study, with 59 (18%) receiving platinum plus topoisomerase I inhibitor irinotecan and 261 (82%) receiving platinum plus topoisomerase II inhibitor etoposide as first-line treatment. The progression-free survival of amrubicin was significantly longer in the irinotecan group than in the etoposide group (3.2 vs. 2.5 months; P=0.034). Conclusions: These results showed that different types of topoisomerase inhibitors could affect the efficacy of amrubicin monotherapy in the second-line treatment of patients with relapsed ES-SCLC.

A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L).

OBJECTIVES: Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. METHODS: The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA. RESULTS: The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively. CONCLUSIONS: This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.

Diagnostic performance of serum interferon gamma, matrix metalloproteinases, and periostin measurements for pulmonary tuberculosis in Japanese patients with pneumonia.

Serum markers that differentiate between tuberculous and non-tuberculous pneumonia would be clinically useful. However, few serum markers have been investigated for their association with either disease. In this study, serum levels of interferon gamma (IFN-γ), matrix metalloproteinases 1 and 9 (MMP-1 and MMP-9, respectively), and periostin were compared between 40 pulmonary tuberculosis (PTB) and 28 non-tuberculous pneumonia (non-PTB) patients. Diagnostic performance was assessed by analysis of receiver-operating characteristic (ROC) curves and classification trees. Serum IFN-γ and MMP-1 levels were significantly higher and serum MMP-9 levels significantly lower in PTB than in non-PTB patients (p < 0.001, p = 0.002, p < 0.001, respectively). No significant difference was observed in serum periostin levels between groups. ROC curve analysis could not determine the appropriate cut-off value with high sensitivity and specificity; therefore, a classification tree method was applied. This method identified patients with limited infiltration into three groups with statistical significance (p = 0.01), and those with MMP-1 levels < 0.01 ng/mL and periostin levels ≥ 118.8 ng/mL included only non-PTB patients (95% confidence interval 0.0-41.0). Patients with extensive infiltration were also divided into three groups with statistical significance (p < 0.001), and those with MMP-9 levels < 3.009 ng/mL included only PTB patients (95% confidence interval 76.8-100.0). In conclusion, the novel classification tree developed using MMP-1, MMP-9, and periostin data distinguished PTB from non-PTB patients. Further studies are needed to validate our cut-off values and the overall clinical usefulness of these markers.

[A case of bronchogenic cyst coexisted with intrapulmonary and pleural cysts].

A 39-year old woman presented with cough. Computed tomography showed a mass in the lower lobe of the right lung. Although bronchofiberscope was performed, accurate diagnosis of the tumor was not obtained. Based on the characteristics of the tumor from the results of chest MRI and PET-CT, a diagnosis of bronchogenic cyst with infection was suspected. Therefore, surgical resection was performed, revealing an intrapulmonary bronchogenic cyst and another tumor of the pleura on the vertebral body. Pathological findings demonstrated that the wall of the intrapulmonary tumor was covered with many ciliated epithelia and bronchial cartilages, suggesting a diagnosis of bronchogenic cyst. The tumor on the pleura was also diagnosed to be bronchogenic cyst based on pathological findings. Therefore, we diagnosed both intrapulmonary and pleural cysts.

The Presence of Coexisting Lung Cancer and Non-Tuberculous Mycobacterium in a Solitary Mass.

BACKGROUND Whereas non-tuberculous mycobacterium (NTM) pulmonary disease can mimic lung cancer as a solitary pulmonary nodule or mass, the coexistence of lung cancer and NTM pulmonary disease in a single nodule or mass is rare. We report such a rare case, highlighting that during a bronchoscopes examination which comprises taking a transbronchial lung biopsy (TBLB), bronchial brushing, and bronchial lavage, a positive mycobacterium culture result for sputum or bronchial lavage fluid does not exclude the possibility of a concomitant lung cancer. CASE REPORT An 87-year-old male was referred to our institution for evaluation of an abnormal shadow on a chest x-ray scan. He had been previously healthy with no symptoms and an unremarkable medical history. A contrast-enhanced CT scan showed a cavitating mass measuring 20×40 mm with a thick ring-enhancing irregular wall in the left lower lobe. Although the TBLB of the lesion showed no malignant cells, sputum acid-fast bacilli smear and culture of the bronchial lavage fluid yielded positive results. An NTM infection, instead of lung cancer was suspected to have caused the mass because a Mycobacterium tuberculosis polymerase chain reaction showed negative results. However, we performed the surgery because NTM pulmonary disease and lung cancer cannot be differentiated. The results of a pathological examination of the mass showed an adenocarcinoma, and M. avium complex was detected in the cancer tissue culture. CONCLUSIONS Physicians should suspect the co-existent lung cancer and NTM infection in patients with solitary lung masses that yield a positive mycobacterium culture result for sputum or bronchial lavage fluid.

[A case of lung cancer with idiopathic thrombocytopenic purpura effectively treated for Helicobacter pylori].

A 58-year-old man with cough and bloody sputum was admitted because of right lung tumor and thrombocytopenia. Idiopathic thrombocytopenic purpura (ITP) was diagnosed. For treatment of ITP, he was treated with platelet transfusions, intravenous gamma-globulin and oral prednisolone. However, the platelet count did not completely improved. Since a relationship between ITP and Helicobacter pylori (HP) infection has been reported, and result of urease test was positive, the patient was treated by HP eradication therapy. After the eradication therapy, the platelet count improved to the normal range. The diagnosis of squamous cell carcinoma of the lung was confirmed by a cervical lymph node biopsy. As a result of improvement in platelet count, we were able to perform the chemotherapy of lung cancer.

Analysis of gastrointestinal metastasis of primary lung cancer: Clinical characteristics and prognosis.

The prevalence of gastrointestinal metastasis of lung cancer is low. The aim of the present study was to analyze the frequency and clinical characteristics of metastases to the gastrointestinal tract by retrospectively assessing the clinical records of 2,066 patients with lung cancer. A total of 7 patients (0.33%) were diagnosed with gastrointestinal metastasis, including 4 patients with adenocarcinoma, 1 patient with large cell carcinoma and 2 patients with pleomorphic carcinoma. Furthermore, 3 of the patients presented with small bowel metastases, 2 with gastric metastases, 1 with large bowel metastasis and 1 with metastasis of the appendix. The mean time between the diagnosis of the lung tumors and the identification of gastrointestinal metastasis was 13.5 months (range, 3-49 months). The mean time between the identification of the gastrointestinal metastasis and mortality was 100.6 days (range, 21-145 days). In conclusion, the prognosis of patients with recurrence in distant organs, including the gastrointestinal tract, may be worse than patients with recurrence in distant organs, excluding the gastrointestinal tract, particularly those with symptomatic gastrointestinal metastasis. Therefore, the presence of clinical gastrointestinal metastasis may be life threatening; comprehensive evaluations are required to detect and monitor gastrointestinal metastasis during follow-up.

Active tuberculosis in patients undergoing hemodialysis for end-stage renal disease: a 9-year retrospective analysis in a single center.

OBJECTIVE: Tuberculosis (TB) in patients undergoing hemodialysis (HD) for end-stage renal disease (ESRD) is commonly thought to be associated with a very poor prognosis. Moreover, it is difficult to diagnose. This report was designed to describe this condition and to determine the mortality rate and risk factors associated with mortality. In addition, the study evaluated the usefulness of QuantiFERON TB-2G((R)) (QFT-2G). METHODS: Retrospective study PATIENTS: Patients with confirmed TB admitted between January 2001 and May 2009 were retrospectively identified and enrolled. The clinical, radiological, and bacteriological data at the time of admission were recorded. A multivariate analysis was performed to identify the predictive factors for mortality. RESULTS: A total 19 TB patients (6 females; median age, 73 years) were included. TB occurred in most cases within 1.3 years from the initiation of dialysis. Most patients presented with fever (84.2%) and extrapulmonary TB (57.9%). The mortality rate within 24 weeks of the initiation of TB treatment was 36.8%. The factors associated with mortality were: a short duration of dialysis (HR 8.86, 95% CI 1.03-75.7, p=0.04), and underweight (HR 10.88, 95% CI 1.28-92.6, p=0.02). The sensitivity of QFT-2G, acid-fast smear, and polymerase chain reaction was 50, 80, and 88.2% respectively. CONCLUSION: These data indicate a high incidence of TB in the early stages of HD and a high mortality rate among these patients. The clinical utility of QFT-2G was found to be limited. Hypoalbuminemia might therefore be related to either indeterminate or negative results of QFT-2G.

Mechanism of formation of the orange-colored sputum in pneumonia caused by Legionella pneumophila.

It has been said that the color of sputum from patients with Legionella pneumophila pneumonia is orange. However, why the color is orange has not been clarified. First, orange-colored sputum obtained from a patient with L. pneumophila pneumonia is presented. Then, the formation of an orange-colored pigment in a culture medium (without charcoal) after the growth of L. pneumophila is demonstrated.