Optical Biopsies Using Probe-Based Confocal Laser Endomicroscopy for Autoimmune Pulmonary Alveolar Proteinosis.

INTRODUCTION: Increasing numbers of cases of mild asymptomatic pulmonary alveolar proteinosis (PAP) are being reported with the recent increase in chest computed tomography (CT). Bronchoscopic diagnosis of mild PAP is challenging because of the patchy distribution of lesions, which makes it difficult to obtain sufficient biopsy samples. Additionally, the pathological findings of mild PAP, particularly those that differ from severe PAP, have not been fully elucidated. This study aimed to clarify the pathological findings of mild PAP and the usefulness of optical biopsy using probe-based confocal laser endomicroscopy (pCLE). METHODS: We performed bronchoscopic optical biopsy using pCLE and tissue biopsy in 5 consecutive patients with PAP (three with mild PAP and two with severe PAP). We compared the pCLE images of mild PAP with those of severe PAP by integrating clinical findings, tissue pathology, and chest CT images. RESULTS: pCLE images of PAP showed giant cells with strong fluorescence, amorphous substances, and thin alveolar walls. Images of affected lesions in mild PAP were equivalent to those obtained in arbitrary lung lesions in severe cases. All 3 patients with mild PAP spontaneously improved or remained stable after ≥3 years of follow-up. Serum autoantibodies to granulocyte-macrophage colony-stimulating factor were detected in all 5 cases. CONCLUSION: Optical biopsy using pCLE can yield specific diagnostic findings, even in patients with mild PAP. pCLE images of affected areas in mild and severe PAP showed similar findings, indicating that the dysfunction level of pathogenic alveolar macrophages in affected areas is similar between both disease intensities.

Clinical utility of liquid biopsy for EGFR driver, T790M mutation and EGFR amplification in plasma in patients with acquired resistance to afatinib.

BACKGROUND: Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib. METHODS: We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E. RESULTS: The detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161). CONCLUSION: The detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.

Propensity score analysis of overall survival between first- and second-generation EGFR-TKIs using real-world data.

We constructed a data set of EGFR-mutant non-small-cell lung carcinoma (NSCLC) patients, and compared the overall survival of first-generation (1G), and second-generation (2G) EGFR-tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR-mutated NSCLC patients who received EGFR-TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR-TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR-TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5-33.5] in the 1G group (gefitinib, 32.0 [28.1-35.8]; erlotinib, 27.5 [23.9-31.7]), and 38.6 [32.2-NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR-TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P < .0001; adjusted by matching, HR 0.725, P = .0418). Exploratory analysis showed that OS using the 2G EGFR-TKI was superior to that of the 1G EGFR-TKIs, suggesting the potential of sequential therapy of 2G EGFR-TKI followed by osimertinib. (HR 0.419, P = .0519) Real-world data analysis using 1354 data records, using propensity scoring, indicated that 2G EGFR-TKI had a trend of longer OS compared with 1G EGFR-TKIs.

Risk Factors of Infectious Complications After Endobronchial Ultrasound-Guided Transbronchial Biopsy.

BACKGROUND: Infectious complications after endobronchial ultrasound-guided transbronchial biopsy with a guide sheath (EBUS-GS-TBB) are serious in that they may delay or change scheduled subsequent therapy. The aim of this study was to identify risk factors for infection after EBUS-GS-TBB. RESEARCH QUESTION: What are the risk factors for infection after EBUS-GS-TBB? STUDY DESIGN AND METHODS: We retrospectively reviewed the medical records of 1,045 consecutive patients who had undergone EBUS-GS-TBB for peripheral lung lesions between January 2013 and December 2017 at Fujita Health University Hospital. We evaluated the following risk factors for infectious complications after EBUS-GS-TBB: relevant patient characteristics (age and comorbidities), lesion size, CT scan features of target lesion (intratumoral low-density areas [LDAs] and cavitation), stenosis of responsible bronchus observed by bronchoscopy, and laboratory data before EBUS-GS-TBB (WBC count and C-reactive protein concentration). RESULTS: Forty-seven of the study patients developed infectious complications (24 with pneumonia, 14 with intratumoral infection, three with lung abscess, three with pleuritis, and three with empyema), among whom the complication caused a delay in cancer treatment in 13 patients, cancellation of cancer treatment in seven patients, and death in three patients. Multivariate analysis showed that cavitation (P = .007), intratumoral LDAs (P < .001), and stenosis of responsible bronchus observed by bronchoscopy (P < .001) were significantly associated with infectious complications after EBUS-GS-TBB. Prophylactic antibiotics had been administered to 13 patients in the infection group. Propensity matched analysis could not show significant benefit of prophylactic antibiotics in preventing post-EBUS-GS-TBB infections. INTERPRETATION: Cavitation, LDAs for CT scan features of target lesions, and stenosis of responsible bronchus observed by bronchoscopy are risk factors of post-EBUS-GS-TBB infection. In the cohort, prophylactic antibiotics failed to prevent infectious complications.

Bronchus sign on thin-section computed tomography is a powerful predictive factor for successful transbronchial biopsy using endobronchial ultrasound with a guide sheath for small peripheral lung lesions: a retrospective observational study.

BACKGROUND: Recent advances in bronchoscopy, such as transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS), have improved the diagnostic yield of small-sized peripheral lung lesions. In some cases, however, it is difficult to obtain adequate biopsy samples for pathological diagnosis. Adequate prediction of the diagnostic accuracy of TBB with EBUS-GS is important before deciding whether bronchoscopy should be performed. METHODS: We retrospectively reviewed 149 consecutive patients who underwent TBB with EBUS-GS for small-sized peripheral lung lesions (≤30 mm in diameter) from April 2012 to March 2013. We conducted an exploratory analysis to identify clinical factors that can predict an accurate diagnosis by TBB with EBUS-GS. All patients underwent thin-section chest computed tomography (CT) scans (0.5-mm slices), and the CT bronchus sign was evaluated before bronchoscopy in a group discussion. The final diagnoses were pathologically or clinically confirmed in all studied patients (malignant lesions, 110 patients; benign lesions, 39 patients). RESULTS: The total diagnostic yield in this study was 72.5% (95% confidence interval: 64.8-79.0%). Lesion size, lesion visibility on chest X-ray, and classification of the CT bronchus sign were factors significantly associated with the definitive biopsy result in the univariate analysis. In the multivariate analysis, only the CT bronchus sign remained as a significant predictive factor for successful bronchoscopic diagnosis. The CT bronchus sign was also significantly associated with the EBUS findings of the lesions. CONCLUSION: Our results suggest that the CT bronchus sign is a powerful predictive factor for successful TBB with EBUS-GS.

[Efficacy and safety of cisplatin plus pemetrexed as a first-line treatment for Japanese patients with advanced non-squamous non-small-cell lung cancer -- a retrospective analysis].

BACKGROUND: Cisplatin plus pemetrexed is considered the standard of care for the first-line treatment of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). However, little is known about the efficacy and safety of this regimen in Japanese patients in a daily clinical setting. METHODS: We retrospectively analyzed 40 patients who received cisplatin (75 mg/m/(2)) and pemetrexed (500 mg/m(2)) as a first-line treatment for advanced non-squamous NSCLC. RESULTS: Recorded Grade 3 or 4 hematological toxicities included neutropenia in 7 cases (17.5%), leukopenia in 5 cases (12.5%), anemia in 1 case (2.5%), thrombocytopenia in 1 case (2.5%), and febrile neutropenia in 1 case (2.5%). Grade 3 or 4 nonhematological toxicities included anorexia in 3 cases (7.5%), infection in 1 case (2.5%), rash in 1 case (2.5%), and increased transaminase expression in 1 case (2.5%). Therefore, the adverse events were mostly mild. There were no treatment related deaths. The overall response rate was 37.5%, median progression free survival was 5.6 months, and median overall survival (OS) was 18.8 months. In an epidermal growth factor receptor (EGFR) mutation status subgroup analysis, the median OS of patients with wild-type EGFR or unknown status (n=28)was 16.8 months. CONCLUSION: Cisplatin plus pemetrexed was well tolerated as a first-line treatment and effective in Japanese patients with advanced non-squamous NSCLC.