A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study).

Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44-3.12) years. The ORR was 50.9% (95% CI 41.2-60.6) and the DCR was 84.5% (95% CI 76.4-90.7). Median PFS was 7.4 (95% CI 6.0-9.3) months; median OS was 1.63 (95% CI 1.35-2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.

Clinical and chest radiographic features of missed lung cancer and their association with patient outcomes.

PURPOSE: To examine clinical and chest radiographic features of missed lung cancer (MLC) and explore their association with patient outcomes. METHODS: We retrospectively reviewed chest radiographs obtained at least six months before lung cancer (LC) diagnosis in 95 patients to identify the first positive chest radiograph showing MLC. We assessed chest radiographic features of MLC and their association with patient outcomes. RESULTS: Seventy-five (78.9%) patients (39 men, 36 women; mean age, 64.5 ± 10.5 years) had MLC. The median diagnostic delay was 31.3 months (6.6-128.0 months). The median MLC size was 16 mm (5-57 mm), and 54.7%, 68.0%, and 74.7% of MLC were in the left lung, the middle/lower zones, and the outer two-thirds of the lung, respectively. MLC exhibited a round/oval shape, partly/poorly defined margin, irregular/spiculated border, a density less than the aortic knob, and anatomical superimposition in 57.3%, 77.3%, 61.3%, 85.3%, and 88.0% of cases, respectively. Thirty-five (46.7%) patients had stage III + IV LC at diagnosis. Thirty-one (41.3%) patients died. MLC in the inner one-third of the lung, exhibiting a density equal to/greater than the aortic knob, or superimposed by midline structures was significantly associated with stage III + IV LC at diagnosis. The 3-year all-cause mortality significantly increased when MLC was in the upper zone, superimposed by pulmonary vessels, superimposed by pulmonary vessels plus ribs, or superimposed by pulmonary vessels plus in the inner one-third of the lung. CONCLUSION: MLC with some radiographic features pertaining to their location, density, and superimposed structures was found to portend a worse outcome.

Gastrointestinal microbiota profile and clinical correlations in advanced EGFR-WT and EGFR-mutant non-small cell lung cancer.

INTRODUCTION: Difference in clinical responses to cancer therapy in each patient is from several factors. Gastrointestinal microbiota is one of the reasons. However, this correlation remains unknown. This study aims to explore correlation between gastrointestinal microbiota profile and clinical outcomes in Thai advanced non-small cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) status. METHODS: We enrolled 13 patients with advanced EGFR-wild-type (WT) NSCLC who received chemotherapy and 15 patients with EGFR-mutant NSCLC who received EGFR tyrosine kinase inhibitors. We collected fecal samples at baseline and first disease evaluation and performed 16S rRNA gene sequencing by NGS to assess microbiota profile. The correlations between gastrointestinal microbiota and clinical variables were studied. RESULTS: The clinical characteristics were balanced between the cohorts, excluding significantly higher albumin levels in the EGFR-mutant group. Albumin was the only significant clinical factor affecting the treatment response in multivariate analysis (ORR 15.6%, P = 0.03). Proteobacteria counts were higher in the EGFR-WT group, whereas Bacteroidetes and Firmicutes counts were higher in the EGFR-mutant group. The alpha diversity of the gastrointestinal microbiome was significantly higher in the EGFR-mutant group (Shannon index: 3.82 vs. 3.25, P = 0.022). Following treatment, Proteobacteria counts were lower and Bacteroidetes and Firmicutes counts were higher in both cohorts; the changes were more prominent in the EGFR-WT cohort. No significant correlation between microbiota profile and treatment response were demonstrated in our study. However, beta diversity was significantly different according to severity of adverse events. Enrichment of Clostridia and Bacteroidia was associated with higher adverse event risk in the EGFR-WT cohort. CONCLUSIONS: Proteobacteria was dominant in Thai lung cancer patients both EGFR-WT and EGFR-mutant, and this phylum maybe associate with lung cancer carcinogenesis. Chemotherapy altered the gastrointestinal microbiota, whereas EGFR-TKIs had less effects. Our findings highlight the potential predictive utility of the gastrointestinal microbiota for lung cancer carcinogenesis. Studies with larger cohorts and comparison with the healthy Thai population are ongoing to validate this pilot study.

Combined Pulmonary Tuberculosis with Pulmonary and Pleural Cryptococcosis in a Patient Receiving Ruxolitinib Therapy.

With an advance in therapy, there are increasing emerging and re-emerging opportunistic infections among patients with hematologic conditions and malignancy. Herein, we present a 56-year-old woman with primary myelofibrosis who developed combined tuberculosis (TB) and cryptococcosis with extensive pulmonary, pleural, and nodal involvement during ruxolitinib therapy. Marked clinical and radiologic improvements were undoubtedly evident after receiving anti-TB and antifungal therapies and pleural drainage. Hence, the presence of atypical clinical and radiologic manifestations and incomplete responses, despite receiving adequate antimicrobial treatment, should raise concerns regarding the combined emerging and re-emerging opportunistic infections and the possibility of unusual radiologic manifestations of cryptococcosis in a ruxolitinib-treated patient.

Non-Small Cell Lung Carcinoma with Concomitant Localized Pulmonary Melioidosis: A Rare Co-Existing Disease.

Melioidosis is caused by Burkholderia pseudomallei, water-and-soil gram-negative bacteria predominantly found in Southeast Asia and Australia. Herein, we reported a 63-year-old Thai man presenting with prolonged fever, non-productive cough, and weight loss for 3 months. He underwent deceased donor kidney transplantation 4 years ago and was on many immunosuppressive agents after transplantation. At presentation, his chest radiograph showed a mass-like lesion in the left upper lobe. Histopathological examination of a transthoracic needle lung biopsy yielded adenocarcinoma, while tissue culture grew for B. pseudomallei. He was diagnosed with stage IIIA non-small cell lung cancer (T4N0M0) co-existing with localized pulmonary melioidosis. After intensive and eradication therapy for melioidosis, his well-being improved with the resolution of fever. He sequentially underwent left upper lobectomy, but the procedure was not accomplished due to severe adhesions surrounding the left lung and great vessels. After surgery, he received concurrent chemoradiation therapy for his lung cancer. Nevertheless, the disease progressed, and he finally passed away. Since fever is not a common manifestation of lung cancer, co-existing infection, such as tuberculosis, fungal infection, and melioidosis, should always be excluded in patients suspected of having lung cancer presenting with unexplained fever.

Initial diagnosis and successful treatment of pulmonary tumor embolism manifesting as the first clinical sign of prostatic adenocarcinoma.

Although pulmonary tumor embolism (PTE) is a well-recognized end-stage form of pulmonary metastases at postmortem examination, the entity is rarely the first clinical sign of prostate cancer. Diagnosis of this condition in patients who have no previous history of malignancy is a challenge. Herein, we reported a 79-year-old man presented with progressive, unexplained dyspnea on exertion. Microscopic PTE coinciding with pulmonary lymphangitic carcinomatosis were readily recognized based on the presence of multifocal dilatation and beading of the peripheral pulmonary arteries with thickening of the bronchial walls and interlobular septa on the initial thin-section chest CT images. Pathologic examination of the transbronchial lung biopsy specimen revealed tumor emboli occluding both the small muscular pulmonary arteries and lymphatic vessels. These tumor cells were positive for prostatic specific antigen on immunohistochemical staining. The final diagnosis of prostatic adenocarcinoma was confirmed. Remarkable clinical and radiographic improvement was achieved following bilateral orchiectomies and anti-androgen treatment.

Relationship between the presence of bronchiectasis and acute exacerbation in Thai COPD patients.

Background: The prevalence rate of bronchiectasis in COPD is variable. Coexisting bronchiectasis and COPD may influence COPD severity and exacerbation. Objective: We investigated whether bronchiectasis is associated with frequent or severe COPD exacerbation. Lower airway bacterial and mycobacterial infections are a possible mechanism for bronchiectasis. Materials and methods: A cross-sectional study was conducted in 2013-2014. COPD exacerbations and hospitalizations were reviewed. Spirometry and CT were performed. COPD symptoms were assessed by using the COPD assessment test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. Sputum inductions were performed and specimens were sent for microbiology. Results: We recruited 72 patients. Global Initiative for Chronic Obstructive Lung Disease (GOLD) A, B, C, and D, were noted in 20%, 27.1%, 14.3%, and 38.6% of the patients, respectively. Frequent exacerbations (≥2) and/or ≥1 hospitalization in the previous year were observed in 40.3% of patients. Median mMRC of COPD with frequent and non-frequent exacerbations was 1.0 (range 1-2) and 2.0 (range 1-3), (p=0.002), respectively. Median CAT of COPD with frequent and non-frequent exacerbations was 20.5 (3-37) and 11.0 (2-32), (p=0.004), respectively. CT-detected bronchiectasis was observed in 47.2% of patients. Median mMRC of COPD with and without bronchiectasis was 1.0 (0-4) and 1.0 (0-4) (p=0.22), respectively. Median CAT of COPD with and without bronchiectasis was 16.2 (95% CI: 12.9-19.6) and 13.0 (3-37), (p=0.49), respectively. The lower post-bronchodilator forced expiratory volume in 1 second (FEV1) of COPD with frequent exacerbations than those without was noted (p=0.007). The post-bronchodilator forced expiratory volume at 1 second percent in patients with and without bronchiectasis was not different (p=0.91). After adjusting for gender, severity of airflow obstruction, severity of COPD symptoms, the odds ratio for bronchiectasis with frequent and/or severe exacerbation was 4.99 (95% CI: 1.31-18.94), (p=0.018). Neither bacterial nor mycobacterial airway infection was associated with bronchiectasis or frequent exacerbation. Conclusions: Bronchiectasis is common in Thai COPD. It was associated with frequent exacerbation or hospitalization. Mycobacterial tuberculosis in COPD patients with bronchiectasis was uncommon.

Thin-section CT findings of thoracolithiasis.

PURPOSE: To review thin-section CT findings of thoracolithiasis. MATERIALS AND METHODS: Thirty-three thin-section CT scans of 9 patients with thoracolithiasis diagnosed between 2008 and 2016 were reviewed for the location, shape, longest diameter, and calcification of each freely mobile nodule (thoracolith) and for the presence of coexisting abnormalities. RESULTS: The mean age of 9 patients (5 women) was 65.8 years (SD 14.9; range 37-83 years). Eight were > 50 years of age. Three patients had two thoracoliths, and the remaining 6 patients had one. Thoracoliths were in the left (n = 9) or right (n = 3) pleural cavity, with most in the lower pleural cavity. Nine thoracoliths were found to be larger at follow-up. The median diameters of the 12 thoracoliths were 4.9 mm (range 2.1-10.6 mm) and 6.2 mm (range 3.6-11.0 mm) on the initial and latest follow-up CT scans, respectively. Concomitant old granulomatous disease (n = 6) and diffuse systemic sclerosis-related interstitial lung disease (n = 2) were noted. CONCLUSION: Thoracolithiasis can manifest as one or two small calcified nodules. It tends to occur in the left lower pleural cavity, occur in a patient aged > 50 years, be larger on follow-up, and coincide with other diseases.

Chronic Klebsiella pneumonia: a rare manifestation of Klebsiella pneumonia.

K. pneumoniae can present as two forms of community-acquired pneumonia, acute and chronic. Although acute pneumonia may turn into necrotizing pneumonia, which results in a prolonged clinical course, it often has a rapidly progressive clinical course. In contrast, chronic Klebsiella pneumonia runs a protracted indolent course that mimics other chronic pulmonary infections and malignancies. Herein, we present two cases of chronic Klebsiella pneumonia. The diagnosis was made by microorganism identification, as well as absence of other potential causes. Clinical and radiographic findings improved after a prolonged course of antibiotic therapy.

Thoracic endometriosis with catamenial haemoptysis and pneumothorax: computed tomography findings and long-term follow-up after danazol treatment.

Thoracic endometriosis (TE) is an uncommon disorder affecting women of childbearing age. We herein report clinical and thin-section computed tomography (CT) findings of two cases, in which one woman presented with catamenial haemoptysis (CH) alone and another woman presented with bilateral catamenial pneumothoraces (CP) coinciding with CH, a rare manifestation of TE. The dynamic changes demonstrated on thin-section chest CT performed during and after menses led to accurate localisation and presumptive diagnosis of TE in both patients. Following danazol treatment, the patient with CH alone had a complete cure, while the patient with CP and CH had an incomplete cure and required long-term danazol treatment. We discuss the role of imaging studies in TE, with an emphasis on the appropriate timing and scanning technique of chest CT in women presenting with CH, potential mechanisms, treatment and patient outcomes.

Clinical and radiologic manifestations of pulmonary cryptococcosis in immunocompetent patients and their outcomes after treatment.

PURPOSE: We aimed to investigate clinical and radiologic manifestations of pulmonary cryptococcosis in immunocompetent patients and their outcomes after treatment. MATERIALS AND METHODS: We retrospectively reviewed the medical records, initial and follow-up chest computed tomography scans and/or radiographs for initial clinical and radiologic manifestations and outcomes following antifungal treatment of 12 immunocompetent patients diagnosed with pulmonary cryptococcosis between 1990 and 2012. RESULTS: Twelve patients (age range, 21-62 years; males, eight patients [66.7%]) were included. Nine (75%) patients were symptomatic, eight of whom had disseminated infection with central nervous system involvement. Initial pulmonary abnormalities consisted of single nodules/masses (n=5), single segmental or lobar mass-like consolidation (n=3), multiple cavitary and noncavitary nodules (n=1), and multifocal consolidation plus nodules (n=3). These lesions ranged from less than 1 cm to 15 cm in greatest diameter. Distinct subpleural and lower lung predominance was observed. Seven patients (58.3%) had one or more atypical/aggressive findings, namely endobronchial obstruction (n=4), calcified (n=1) or enlarged (n=4) mediastinal/hilar lymph nodes, vascular compression (n=1), pericardial involvement (n=1), and pleural involvement (n=2). Following antifungal therapy, radiologic resolution was variable within the first six months of eight nonsurgical cases. Substantial (>75%) improvement with some residual abnormalities, bronchiectasis, cavitation, and/or fibrotic changes were frequently observed after 12-24 months of treatment (n=6). CONCLUSION: Pulmonary cryptococcosis in immunocompetent patients frequently causes disseminated infection with atypical/aggressive radiologic findings that are gradually and/or incompletely resolved after treatment. The presence of nonenhanced low-attenuation areas within subpleural consolidation or mass and the absence of tree-in-bud appearance should raise concern for pulmonary cryptococcosis, particularly in patients presenting with meningitis.

Tracheobronchial involvement in relapsing polychondritis diagnosed on endobronchial ultrasound.

Respiratory tract chondritis is not uncommon in patients with relapsing polychondritis (RP); however, diagnosing this condition remains problematic, especially in patients whose extrapulmonary manifestations do not predominate, as there are broad differential diagnoses of airway obstruction. We herein report the case of a 56-year-old man who presented with cough and dyspnea. Computed tomography of the chest demonstrated diffuse smooth thickening of the visualized tracheobronchial wall with a moderately narrowed lumen. Airway chondritis was diagnosed on endobronchial ultrasound following demonstration of thickening of the submucosal and cartilaginous layers in the anterior and lateral aspects of the bronchial wall, while the posterior region expressed less involvement. In conjunction with nasal and auricular chondritis, which were previously overlooked, RP was finally diagnosed.

Bronchial anthracostenosis with mediastinal fibrosis associated with long-term wood-smoke exposure.

Bronchial anthracostenosis describes a disease entity consisting of bronchial destruction, deformity and stenosis related to dark pigmentation on bronchoscopy in patients with a history of coal workers' pneumoconiosis or chronic exposure to biomass smoke. The combined occurrence of bronchial anthracostenosis and mediastinal fibrosis in association with wood-smoke exposure has not been previously reported. This case report describes a non-cigarette smoking elderly woman who developed bronchial anthracostenosis and mediastinal fibrosis after long-term exposure to wood smoke. Clinical and radiological improvements were achieved after treatment with corticosteroid and tamoxifen. Awareness of this unusual entity will help to avoid misdiagnosis of malignancy or unnecessary thoracotomy.

Primary polymorphous low-grade adenocarcinoma of the bronchus: complete tumor removal with bronchoscopic resection.

Primary polymorphous low-grade adenocarcinoma (PLGA) is an uncommon malignant tumor arising from the minor salivary glands, but its occurrence as a primary tumor of the tracheobronchial tree is very rare. Herein, we have reported a rare case of endobronchial PLGA in a 56-year-old woman presenting with chronic cough and progressive exertional dyspnea. Chest CT clearly demonstrated an endobronchial tumor obstructing the distal part and bifurcation of the left main bronchus and causing distal atelectasis. She underwent rigid bronchoscope with electrocautery and bronchoscopic resection of the tumor. PLGA was diagnosed histologically. Subsequent left pneumonectomy was performed and showed no evidence of residual tumor.

Massive hemothorax in a beta-thalassemic patient due to spontaneous rupture of extramedullary hematopoietic masses: diagnosis and successful treatment.

Intrathoracic extramedullary hematopoiesis is an unusual but well-described entity. The condition is typically found in patients who have chronic hemolytic anemias, especially thalassemia. We report a case of a 38-year-old man with underlying beta thalassemia/hemoglobin E who developed intrathoracic extramedullary hematopoiesis. The hematopoietic masses spontaneously ruptured, resulting in massive hemothorax. The condition was confirmed by video-assisted thoracoscopy and successfully treated with surgery, hydroxyurea, and radiation.