The Whole Picture of First-Line Osimertinib for EGFR Mutation-Positive Advanced NSCLC: Real-World Efficacy, Safety, Progression Pattern, and Posttreatment Therapy (Reiwa Study).

Introduction: Osimertinib is used as the first-line treatment for EGFR mutation-positive NSCLC. Nevertheless, its efficacy and safety in clinical practice remain to be fully elucidated and the pattern of progression and the optimal subsequent treatment after osimertinib remains unclear. Methods: This was a multicenter prospective observational study. EGFR mutation-positive patients with NSCLC who started first-line osimertinib from September 2018 to August 2020 were enrolled and followed up until August 2022. Results: A total of 583 patients received osimertinib. The median progression-free and overall survival were 20.0 (95% confidence interval [CI]: 17.6-21.7) months and 41.0 (95% CI: 37.1-44.1) months, respectively. Grade 3 or worse adverse events were observed in 136 patients (23.3%). Progression patterns were categorized as central nervous system only, oligo-progression, and multiple organs on the basis of the Response Evaluation Criteria in Solid Tumors-progressive disease and occurred in 37 (10.8%), 156 (45.4%), and 151 patients (43.9%). The patient's condition on progression was asymptomatic in 195 patients (56.7%). Osimertinib was continued in 163 patients (47.4%) after confirming progression. In clinically stable population with progressive disease (n = 247), survival after progression was 13.3 (95% CI: 10.9-16.4) months for those who continued osimertinib beyond progressive disease (n = 124), and 24.1 (95% CI: 17.7-34.0) months for those who discontinued osimertinib (n = 123) (hazard ratio = 2.01, 95% CI: 1.38-2.91, p = 0.0002). Platinum plus pemetrexed had the best overall survival benefits after osimertinib. Conclusions: First-line osimertinib was found to have good effectiveness comparable to that reported in pivotal studies. Nevertheless, osimertinib should be discontinued among those who develop progression. Trial registration number: UMIN000038683.

Bayesian parametric estimation based on left-truncated competing risks data under bivariate Clayton copula models.

In observational/field studies, competing risks and left-truncation may co-exist, yielding 'left-truncated competing risks' settings. Under the assumption of independent competing risks, parametric estimation methods were developed for left-truncated competing risks data. However, competing risks may be dependent in real applications. In this paper, we propose a Bayesian estimator for both independent competing risks and copula-based dependent competing risks models under left-truncation. The simulations show that the Bayesian estimator for the copula-based dependent risks model yields the desired performance when competing risks are dependent. We also comprehensively explore the choice of the prior distributions (Gamma, Inverse-Gamma, Uniform, half Normal and half Cauchy) and hyperparameters via simulations. Finally, two real datasets are analyzed to demonstrate the proposed estimators.

Effectiveness of Amikacin liposome inhalation suspension for refractory Mycobacterium avium complex pulmonary disease at 6 months post initiation.

BACKGROUND: Amikacin  liposome inhalation suspension (ALIS) improved sputum culture conversion rate at 6 months for patients with refractory Mycobacterium avium complex pulmonary disease (MAC-PD) in an international phase 3 trial. Patient characteristics and chest high-resolution CT (HRCT) findings associated with ALIS effectiveness are poorly documented. OBJECTIVE: We aimed to clarify ALIS effectiveness for refractory MAC-PD at 6 months, elucidating associated patient characteristics and chest CT findings. METHODS: We reviewed medical records of 12 patients with refractory MAC-PD for whom ALIS treatment was initiated at Toho University Omori Medical Center from November 2021 through September 2022. All patients demonstrated treatment persistence for at least 3 months. They were divided into culture conversion and non-conversion groups using sputum culture conversion status after 6-month ALIS treatment initiation. Clinical and radiological characteristics were compared. RESULTS: Seven of the 12 patients (58.3%) achieved sputum culture conversion within 6 months. The culture conversion group had shorter pre-ALIS initiation treatment duration [21 months (16-25) vs. 62 months (32-69); p = 0.045]; lower cavitary lesion incidence on HRCT (28.6% vs. 100%; p = 0.028); and fewer clarithromycin (CLA)-resistant strains [0/7 (0%) vs. 3/5 (60%); p = 0.045]. Chest HRCT findings improved in 4 of 7 (57.1%) and 1 of 5 (20%) patients in the culture conversion and non-conversion groups, respectively. CONCLUSION: ALIS facilitated sputum culture conversion within 6 months in 58.3% of patients with refractory MAC-PD. Sputum culture conversion was significantly more frequent for CLA-susceptible strains and patients with fewer cavitary lesions. Improved CT findings after ALIS did not always correspond to sputum culture conversion.

Preoperative risk factors for skeletal muscle mass loss in patients with biliary tract cancer.

BACKGROUND: Endoscopic retrograde cholangiography (ERC)-related procedures, usually performed before biliary tract cancer (BTC) surgery, are associated with increased risk for various complications, which can cause sarcopenia. No study has previously elucidated the relationship between preoperative ERC-related procedures and sarcopenia/skeletal muscle mass loss. METHODS: Patients with BTC who underwent radical surgical resection following ERC-related procedures were included. Skeletal muscle mass was evaluated using the psoas muscle mass index (PMI), which was determined using computed tomography images, and the change in PMI before the initial pre-ERC and surgery (ΔPMI) was calculated. Risk factors for advanced skeletal muscle mass loss, defined as a large ΔPMI, were evaluated. RESULTS: The study cohort included 90 patients with a median age of 72 (interquartile range, 65-75) years. The median PMI pre-ERC and surgery was 4.40 and 4.15 cm2/m2, respectively (p < .01). The median ΔPMI was -6.2% (interquartile range, -10.9% to 0.5%). By multivariate analysis, post-ERC pancreatitis and cholangitis before surgery were independent predictive factors for large PMI loss (odds ratio, 4.57 and 3.18, respectively; p = .03 and p = .02, respectively). CONCLUSIONS: Skeletal muscle mass decreases preoperatively in most patients with BTC undergoing ERC. Post-ERC pancreatitis and cholangitis before surgery were independent risk factors for large skeletal muscle mass loss.

Impact of Controlling Nutritional Status Score on Mortality in Elderly Patients with Idiopathic Pulmonary Fibrosis.

Background: There are only a few reports on the nutritional status and mortality of patients with idiopathic pulmonary fibrosis (IPF). As such, this study aims to investigate the relationship between controlling nutritional status (CONUT) and the mortality of elderly patients with IPF. Methods: A total of 170 IPF patients aged ≥65 years old who visited the rehabilitation department of our hospital between July 2014 and July 2021 (mean age: 75.7 ± 6.3 years, sex (male/female): 138/32, %FVC: 78.3 ± 18.3%) were retrospectively analyzed. The Kaplan-Meier method and log-rank test were applied. Furthermore, using a Cox proportional hazards model with multivariate analysis, we analyzed the relationship between all-cause mortality and baseline characteristics including CONUT. Results: Based on the CONUT score, the normal group included 101 cases, the mild group included 58 cases, the moderate group included 11 cases, and the severe group had 0 cases. There were 49 cases of all-cause mortality events, suggesting that the mortality of the moderate group was significantly poorer than that of the normal and mild groups (p < 0.05). Furthermore, multivariate analysis identified GAP stage (HR: 5.972, 95%CI: 2.901~12.291, p < 0.0001), mMRC scale (HR: 0.615, 95%CI: 0.389~0.971, p = 0.009), and CONUT (HR: 2.012, 95%CI: 1.192~3.395, p = 0.037) as factors significantly influencing mortality. Conclusions: Severe malnutrition was not observed in elderly patients with IPF. Moderate malnutrition was associated with a significantly higher risk of all-cause mortality, suggesting that CONUT is an important indicator for predicting mortality.

Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy.

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy's effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25-8.8). Median survival time was 9.9 months (95% CI 9.2-10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889-9.328; 60 days, HR: 2.351, 95% CI 1.104-5.009; 90 days, HR: 2.416, 95% CI 1.232-4.739; and 120 days, HR: 2.521, 95% CI 1.357-4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

Endobronchial cryptococcosis without pulmonary parenchymal involvement caused by Cryptococcus neoformans in an immunocompetent host.

Cryptococcus is a yeast-like fungus. Pulmonary lesions caused by Cryptococcus neoformans typically present as single or multiple nodules or infiltrative lesions in the lungs; however, endobronchial lesions are rare. A 40-year-old previously healthy Japanese man was referred to our hospital due to an abnormality detected on chest computed tomography. The analysis revealed focal bronchiectasis and bronchial wall thickening in the right upper lobe, which persisted for 6 months. Bronchoscopy showed reddish and edematous mucosa, stenosed bronchi (right B1 and B3), and white moss at the bifurcation of the right upper bronchus. Transbronchial biopsy revealed numerous yeast-like fungi and an encapsulated body. Bronchial washing for fungus culture identified Cryptococcus neoformans. Although analysis for serum cryptococcal antigen was negative, bronchoscopy led to a definitive diagnosis. Antifungal treatment improved the bronchial wall thickening. This is a rare case of endobronchial cryptococcosis caused by Cryptococcus neoformans without pulmonary parenchymal involvement in an immunocompetent host.

BRCA2-positive lung adenocarcinoma treated with olaparib: A case report.

A 66-year-old woman was found to have abnormal shadows on a chest radiograph at a previous hospital 4 years ago, which led to a diagnosis of lung adenocarcinoma, cT2aN1M1b stage IVA. First-line treatment included carboplatin and paclitaxel plus thoracic radiotherapy and stereotactic radiation therapy for brain metastases. The patient later underwent second-line pemetrexed treatment, followed by third-line nivolumab, fourth-line docetaxel and bevacizumab, fifth-line tegafur-gimeracil-oteracil, and sixth-line gemcitabine. Two years ago, after observing an increase in the primary lesion and carcinoembryonic antigen levels (104.0 ng/mL), a computed tomography-guided biopsy was performed from the primary site of lung cancer. A cancer genomic profiling test (FoundationOne® CDx cancer genome profile) revealed a breast cancer susceptibility (BRCA) 2 gene mutation. Therefore, she started taking olaparib. The treatment led to stable disease for approximately 2 years.

Japanese guidelines for the treatment of idiopathic pulmonary fibrosis 2023:Revised edition.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an unknown cause that generally progresses to pulmonary fibrosis and leads to irreversible tissue alteration. The "Guidelines for the treatment of idiopathic pulmonary fibrosis 2017," specializing in the treatment of IPF for the first time in Japan and presenting evidence-based standard treatment methods suited to the state of affairs in Japan, was published in 2017, in line with the 2014 version of "Formulation procedure for Minds Clinical Practice Guidelines." Because new evidence had accumulated, we formulated the "Guidelines for the treatment of Idiopathic Pulmonary Fibrosis 2023 (revised 2nd edition)." While keeping the revision consistent with the ATS/ERS/JRS/ALAT IPF treatment guidelines, new clinical questions (CQs) on pulmonary hypertension were added to the chronic stage, in addition to acute exacerbation and comorbid lung cancer, which greatly affect the prognosis but are not described in the ATS/ERS/JRS/ALAT IPF guidelines. Regarding the advanced stages, we additionally created expert consensus-based advice for palliative care and lung transplantation. The number of CQs increased from 17 in the first edition to 24. It is important that these guidelines be used not only by respiratory specialists but also by general practitioners, patients, and their families; therefore, we plan to revise them appropriately in line with ever-advancing medical progress.

Immune checkpoint inhibitors in patients with lung cancer having chronic interstitial pneumonia.

Background: In interstitial pneumonia (IP)-associated lung cancer, immune checkpoint inhibitor pneumonitis (ICIP) is common with immune checkpoint inhibitor (ICI) treatment. The purpose of the present study was to clarify the safety and efficacy of ICI treatment for patients with lung cancer with IP. Methods: This multicentre retrospective observational study was conducted from June 2016 to December 2020 in patients with primary lung cancer with IP who received ICI treatment. Results: A total of 200 patients (median age 70 years; male/female, 176/24) were enrolled from 27 institutions. ICIP occurred in 61 patients (30.5%), pneumonitis grades 3-5 in 32 patients (15.5%) and death in nine patients (4.5%). The common computed tomography pattern of ICIP was organising pneumonia in 29 patients (47.5%). Subsequently, diffuse alveolar damage (DAD) pattern was observed in 19 patients (31.1%) who had a significantly worse prognosis than those with a non-DAD pattern (median progression-free survival (PFS) 115 days versus 226 days, p=0.042; median overall survival (OS) 334 days versus 1316 days, p<0.001). Immune-related adverse events (irAEs) occurred in approximately 50% of patients. Patients with irAEs (n=100) had a better prognosis than those without irAEs (n=100) (median PFS 200 days versus 77 days, p<0.001; median OS 597 days versus 390 days p=0.0074). The objective response rate and disease control rate were 41.3% and 68.5%, respectively. Conclusions: Although ICI treatment was effective for patients with lung cancer with IP, ICIP developed in approximately 30% of patients. Patients with irAEs had a significantly better PFS and OS than those without irAEs.

The First Case of Mycobacterium interjectum Pulmonary Disease in Japan.

We herein report a case of Mycobacterium interjectum pulmonary disease (M. interjectum-PD) that improved considerably after azithromycin (AZM), rifampicin (RFP), and ethambutol (EB) therapy. A 69-year-old woman, managed locally for suspected NTM-PD based on chest computed tomography (CT) findings was referred to our hospital for worsening productive cough six years after the initial diagnosis. High-resolution chest CT showed right middle and left lower lobe bronchiectasis with middle and centrilobular nodules. Bronchial washing and sputum culture yielded M. interjectum. Treatment with AZM, RFP, and EB resulted in sputum culture conversion, and the chest CT findings subsequently improved. This is the first reported case of M. interjectum-PD in Japan.

Intrinsic clarithromycin heteroresistance in Mycobacterium avium.

BACKGROUND: Mycobacterium avium is associated with pulmonary disease in otherwise healthy adults. Several clarithromycin-refractory cases have been reported, including some cases caused by clarithromycin-susceptible strains. OBJECTIVES: To characterize the reason for the discrepancy between clinical response and antibiotic susceptibility results. METHODS: We conducted population analysis of clarithromycin-tolerant and heteroresistant subpopulations of M. avium cultured in vitro and in homogenates of infected lungs of mice. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for 28 M. avium and two M. kansasii strains. Mice were intranasally infected with M. avium and treated with or without clarithromycin (100 mg/kg) thrice weekly. They were sacrificed on day 35 and the bacteria in lung homogenates were tested for clarithromycin resistance. Population analysis assays were performed based on colony growth on plates containing two-fold dilutions of clarithromycin. RESULTS: The MBC/MIC ratios were ≥8 in all 28 strains of M. avium tested. In the population analysis assay, several colonies were observed on the plates containing clarithromycin concentrations above the MIC (2-64 mg/L). No growth of M. kansasii colonies was observed on the plates containing clarithromycin concentrations ≥2 mg/L. M. avium in the homogenates of infected lungs showed clearer clarithromycin-resistant subpopulations than in vitro, regardless of clarithromycin exposure. CONCLUSION: M. avium shows intrinsic heterogeneous resistance (heteroresistance) to clarithromycin. This may explain the observed discrepancies between clarithromycin susceptibility testing results and clinical response to clarithromycin treatment. Further studies are needed to confirm a link between heteroresistance and clinical outcomes.

First-line nivolumab plus ipilimumab with or without chemotherapy for Japanese patients with non-small cell lung cancer: LIGHT-NING study.

OBJECTIVE: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. METHODS: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. RESULTS: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. CONCLUSIONS: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.

Outcomes and prognosis of progressive pulmonary fibrosis in patients with antineutrophil cytoplasmic antibody-positive interstitial lung disease.

Approximately one-third of fibrosing interstitial lung diseases exhibit progressive pulmonary fibrosis (PPF), a clinicopathological condition distinct yet resembling idiopathic pulmonary fibrosis (IPF). PPF in ANCA-positive ILD (ANCA-ILD) is poorly documented. To clarify incidence, predictors of PPF in ANCA-ILD, and their prognostic impact, 56 patients with ANCA-ILD were followed for ≥ 1 year (April 2004 to April 2021). PPF was defined per ATS/ERS/JRS/ALAT PPF 2022 guideline. We compared PPF and non-PPF in 38 patients with pulmonary function tests and ≥ 1 year follow up. ANCA-ILD (19 male, 19 female; mean age 72 years) comprised 21 patients with microscopic polyangiitis ILD (MPA-ILD) and 17 with ANCA-positive IP without systemic vasculitis (ANCA-IP). PPF occurred in 15/38 (39.5%) overall, and 27% of patients with MPA-ILD and 53% with ANCA-IP. Patient characteristics did not differ between PPF and non-PPF, however, the survival was significantly worse in patients with PPF than those with non-PPF. On multivariate regression analysis, higher age, higher serum SP-D level, and lower baseline %FVC were associated with PPF. In ANCA-ILD, 39.5% of patients demonstrated PPF, which is associated with increased mortality. Predictors of PPF were older age, higher SP-D, and lower baseline %FVC.

Successful treatment with inhaled corticosteroid/long-acting ß2-agonist in a case of allergic bronchopulmonary mycosis caused by Schizophyllumcommune.

Allergic bronchopulmonary mycosis (ABPM) is a chronic immune-mediated pulmonary disease, which is caused by fungal infection of the airways. Aspergillus species are the main causative fungi and standard treatment typically comprises systemic corticosteroid therapy with or without adjunct antifungal agents. We describe our experience with a case of ABPM caused by Schizophyllum commune (S. commune), with satisfactory response to treatment with a combination of an inhaled corticosteroid and a long-acting ß 2-agonist. The patient was a 61-year-old man who was referred to our hospital with dry cough and abnormal findings on chest radiography. He had peripheral blood eosinophilia and elevated levels of total serum IgE. High-resolution CT showed multiple areas of patchy consolidation with high-attenuation mucus plugs in the right upper lobe. Bronchoscopy revealed mucus plug impaction in the bronchial lumen, and Grocott's staining of the mucus detected fungal hyphae. Bronchioalveolar lavage fluid culture yielded white woolly colonies, which was subsequently identified as S. commune by MALDI-TOF MS and gene sequencing. Serology was positive for S. commune-specific IgE and IgG. We made a definitive diagnosis of ABPM caused by S. commune. Symptoms and chest CT findings improved considerably with inhaled combined fluticasone furoate/vilanterol trifenatate therapy, without the use of systemic corticosteroids or antifungal agents.

Metabolomics of Duodenal Juice for Biliary Tract Cancer Diagnosis.

The poor prognosis of malignant biliary diseases is partially caused by their difficult early diagnosis. Therefore, many patients are only diagnosed at advanced stages. This study aimed to improve diagnosis by clarifying the differences in the duodenal juice metabolomes of benign and malignant biliary diseases. From October 2021 to January 2023, duodenal juice was obtained from 67 patients with suspected biliary diseases who required endoscopic ultrasonography and endoscopic retrograde cholangiography for diagnosis/treatment. The samples metabolomes were analyzed via nuclear magnet resonance spectroscopy using an 800-MHz spectrometer. Metabolomes of malignant and benign diseases were then compared, and multivariate analysis was performed to determine the relevant factors for malignancy/benignancy. For benignancy, no significant predictors were observed. For malignancy, acetone was a significant predictor, with higher concentrations in the malignant group than in the benign group. Regarding the receiver operating characteristic curve analysis for biliary tract carcinoma diagnosis, the predictive value of acetone in duodenal juice was comparable with serum CA19-9 levels (area under the curve: 0.7330 vs. 0.691, p = 0.697). In conclusion, duodenal juice metabolomics is a feasible method that is available for differential diagnosis in the biliary disease field.

Entrectinib-induced syndrome of inappropriate antidiuretic hormone secretion in a patient with ROS1-rearranged non-small cell lung cancer.

A 75-year-old woman was referred to our hospital because of a productive cough and an abnormal shadow on chest radiography. She was diagnosed as having metastatic lung adenocarcinoma harbouring ROS proto-oncogene 1 (ROS1). First-line therapy was instituted with entrectinib 600 mg daily, and a gradual decrease in serum sodium level was noticed on day 6, which deteriorated to Grade 3 hyponatremia on day 12. Despite a partial therapeutic response to entrectinib, she developed fatigue and dizziness, so the drug was withdrawn. The clinical findings and laboratory workup were compatible with a diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to entrectinib. The hyponatremia subsequently improved and entrectinib was resumed at a reduced dose of 400 mg daily, which has been continued to date, with no recurrence of SIADH.

ATS/JRS/ALAT Hypersensitivity Pneumonitis Guidelines for Diagnosis of humidifier lung and summer-type hypersensitivity pneumonitis.

BACKGROUND: The ATS/JRS/ALAT Guidelines for the Diagnosis of Hypersensitivity Pneumonitis (GL for HP) were published in 2020. Humidifier lung and summer-type HP are forms of HP, but it is unclear whether they can be diagnosed using GL for HP. This study examined the level of confidence where humidifier lung and summer-type HP can be diagnosed with GL for HP. METHODS: Data from 23 patients with humidifier lung and 20 patients with summer-type HP (mean age, 67.3 and 57.4 years, respectively) diagnosed between October 2012 and January 2022 were retrospectively reviewed. We evaluated high resolution computed tomography (HRCT) patterns, bronchoalveolar lavage fluid (BALF) findings, exposures, and histopathological findings to determine the level of confidence where a diagnosis of HP could be made using the GL for HP. RESULTS: HRCT pattern was classified as typical HP in 5 (22%) and compatible with HP in 18 (78%) patients with humidifier lung and considered as typical HP in 17 (85%) and compatible with HP in 3 (15%) patients with summer-type. The confidence level for diagnosis of HP was definite in 2 (8.7%), moderate in 14 (60.9%), and low in 7 (30.4%) patients with humidifier lung. It was definite in 12 (60%), high in 3 (15%), and moderate in 5 (25%) patients with summer-type HP. CONCLUSIONS: GL for HP showed utility in diagnosing humidifier lung in many patients with a moderate to low confidence. However, there was a definite to high confidence for patients with summer-type HP.

Upregulation of long non­coding RNA LINC00460 in EGFR­mutant lung cancer indicates a poor prognosis in patients treated with osimertinib.

The long non-coding RNA (lncRNA) LINC00460 is involved in tumor growth, metastasis and drug resistance. The present study investigated the clinical significance of LINC00460 expression in patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer treated with osimertinib. Osimertinib-resistant cells we derived from EGFR-mutant non-small-cell lung cancer (NSCLC) cell lines, after which, small interfering RNA (siRNA)-mediated silencing and in vitro-transcribed (IVT), synthetic LINC00460 RNA transfection were used to investigate the effects of LINC00460 expression on acquired resistance to osimertinib. Reverse transcription-quantitative polymerase chain reaction was performed to evaluate LINC00460 expression in 54 samples (RNA extracted from the tumor tissues of 30 cases and cell-free RNA from 24 cases) obtained from patients with EGFR mutation-positive lung cancer who had received osimertinib as the initial treatment. The acquisition of osimertinib resistance increased the expression of LINC00460 in the EGFR-mutant NSCLC cell lines. By contrast, knockdown of LINC00460 in osimertinib-resistant cell lines increased their sensitivity to osimertinib, whereas treatment of NSCLC cells with IVT LINC00460 RNA decreased their sensitivity to osimertinib. The present study examined LINC00460 expression at the primary tumor site and demonstrated that compared with in the low-expression group (n=24), the high-expression group (n=6) had a significantly lower best overall response rate to osimertinib (16.6% vs. 60.0%; P=0.044), significantly shorter median progression-free survival (PFS; 224 days vs. 669 days; P=0.001) and significantly shorter median overall survival (724 days vs. not reached; P=0.011). Moreover, following osimertinib therapy, PFS was significantly shorter for patients with high LINC00460 expression in plasma cell-free RNA (n=12) than for those with low LINC00460 expression (n=12) (median PFS: 655 days vs. 210 days; P=0.020). In conclusion, the upregulation of LINC00460, the expression of which is implicated in osimertinib resistance, in the primary site and plasma of patients with EGFR mutation-positive lung cancer may be associated with a poor prognosis in those treated with osimertinib.

Carboplatin and weekly paclitaxel in combination with bevacizumab for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias: A feasibility study.

BACKGROUND: Idiopathic interstitial pneumonias are an independent risk factor of lung cancer, and a chemotherapy-induced acute exacerbation is the most common lethal complication in Japanese patients. The safety and efficacy of carboplatin and weekly paclitaxel for the treatment of non-small cell lung cancer with idiopathic interstitial pneumonias has been previously reported in prospective studies. However, carboplatin + paclitaxel with bevacizumab is currently the standard therapy. We conducted a multicenter, phase II study to confirm the safety and efficacy of carboplatin + weekly paclitaxel + bevacizumab for the treatment of patients with lung cancer complicated by idiopathic interstitial pneumonias. METHODS: Chemotherapy-naïve patients with advanced-stage or patients with post-operative recurrent non-squamous non-small cell lung cancer complicated by idiopathic interstitial pneumonias were enrolled. Patients received carboplatin (area under the curve: 5.0) and bevacizumab (15 mg/kg) on day 1 and paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 4-week cycle. RESULTS: Seventeen patients less than the predetermined number were enrolled and received a median of four treatment cycles (range: 1-6). One patient (5.9%; 95% confidence interval: 0.1-28.7%) had acute exacerbation of interstitial pneumonia related to the study treatment which improved after corticosteroid treatment. The overall response rate was 52.9%. The median progression-free survival, median survival time, and 1-year survival were 5.7 months, 12.9 months, and 52.9%, respectively. CONCLUSION: The addition of bevacizumab to carboplatin and weekly paclitaxel might be safe and effective for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008189.