METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival.
RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).
CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).
MATERIALS AND METHODS: Patients diagnosed with adenocarcinoma of the lung between 2010 and 2014 were tested for EGFR mutations. Of these, 92 cases were identified as EGFR wild type and suitable candidates for ALK testing utilising immunohistochemistry and the rabbit monoclonal antibody D5F3. The reliability of the IHC was confirmed by validating the results against those achieved by fluorescence in situ hybridisation (FISH) to detect ALK gene rearrangements.
RESULTS: Twelve (13%) cases were positive for ALK expression using immunohistochemistry. Of the 18 evaluable cases tested by FISH, there was 100% agreement with respect to ALK rearrangement/ALK expression between the assays, with 11 cases ALK negative and 7 cases ALK positive by both assays. ALK tumour expression was significantly more common in female compared to male patients (29.6% vs. 6.2%, P
METHODS: Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF25-75) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV1/FVC ≥ LLN).
RESULTS: Almost a fifth of the participants had spirometric SAO (19% for FEF25-75; 17% for FEV3/FVC). Using FEF25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77-2.70), chronic cough (OR = 2.56, 95% CI 2.08-3.15), chronic phlegm (OR = 2.29, 95% CI 1.77-4.05), wheeze (OR = 2.87, 95% CI 2.50-3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11-1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV3/FVC. Isolated spirometric SAO (10% for FEF25-75; 6% for FEV3/FVC), was also associated with respiratory symptoms and cardiovascular disease.
CONCLUSION: Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF25-75 and FEV3/FVC, in addition to traditional spirometry parameters.
MATERIALS AND METHODS: This cross-sectional study with retrospective record review was conducted in Hospital Tengku Ampuan Rahimah, Selangor, Malaysia. We included all hospitalised patients with confirmed COVID-19 infection who had undergone CT pulmonary angiogram (CTPA) examinations for suspected PTE disease between April 2021 and May 2021. Clinical data and laboratory data were extracted by trained data collectors, whilst CT images retrieved were analysed by a senior radiologist. Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 20.
RESULTS: We studied 184 COVID-19 patients who were suspected to have PTE disease. CTPA examinations revealed a total of 150 patients (81.5%) suffered from concomitant PTE disease. Among the PTE cohort, the commonest comorbidities were diabetes mellitus (n=78, 52.0%), hypertension (n=66, 44.0%) and dyslipidaemia (n=25, 16.7%). They were generally more ill than the non-PTE cohort as they reported a significantly higher COVID-19 disease category during CTPA examination with p=0.042. Expectedly, their length of both intensive care unit stays (median number of days 8 vs. 3; p=0.021) and hospital stays (median number of days 14.5 vs. 12; p=0.006) were significantly longer. Intriguingly, almost all the subjects had received either therapeutic anticoagulation or thromboprophylactic therapy prior to CTPA examination (n=173, 94.0%). Besides, laboratory data analysis identified a significantly higher peak C-reactive protein (median 124.1 vs. 82.1; p=0.027) and ferritin levels (median 1469 vs. 1229; p=0.024) among them. Evaluation of CT features showed that COVID-19 pneumonia pattern (p<0.001) and pulmonary angiopathy (p<0.001) were significantly more profound among the PTE cohort. To note, the most proximal pulmonary thrombosis was located in the segmental (n=3, 2.0%) and subsegmental pulmonary arteries (n=147, 98.0%). Also, the thrombosis predominantly occurred in bilateral lungs with multilobar involvement (n=95, 63.3%).
CONCLUSION: Overall, PTE disease remains prevalent among COVID-19 patients despite timely administration of thromboprophylactic therapy. The presence of hyperinflammatory activities, unique thrombotic locations as well as concurrent pulmonary parenchyma and vasculature aberrations in our PTE cohort implicate immunothrombosis as the principal mechanism of this novel phenomenon. We strongly recommend future researchers to elucidate this important clinical disease among our post- COVID vaccination populations.