Early-Onset Pulmonary Events with Combined Brigatinib and Afatinib Treatment of L858/cisT790M/cisC797S NSCLC: A Case Report.

BACKGROUND Brigatinib is used for anaplastic lymphoma kinase (ALK)-positive lung cancer treatment, and some research showed it was useful in treating triple-mutant epidermal growth factor receptor lung cancer. Clinical trials have shown some potential pulmonary toxicities of brigatinib. The early-onset pulmonary events (EOPEs) of brigatinib are associated with high dosage and older age. The successful treatment of EOPEs with steroids was reported. We present the case of a patient with epidermal growth factor receptor L858R/cis-T790M/cis-C797S triple mutations who developed EOPEs after using brigatinib together with afatinib, and the patient was successfully treated with high-dose steroids. CASE REPORT A 54-year-old woman with underlying stage IV lung adenocarcinoma, ECOG score of 0, was treated with brigatinib and afatinib due to disease progression secondary to L858R/cis-T790M/cis-C797S triple mutations. After starting brigatinib and afatinib, she developed dyspnea and dry cough within 2 days and was intubated due to hypercapnic respiratory failure. The chest X-ray showed bilateral interstitial infiltrates while chest computed tomography (CT) showed bilateral ground-glass opacities. EOPEs were suspected and methylprednisolone was prescribed. The oxygenation of the patient improved and her chest CT showed complete resolution after 2 weeks of steroid treatment. CONCLUSIONS This is the first reported case in which brigatinib combined with afatinib induced EOPEs in a patient with triple-mutant epidermal growth factor receptors of lung cancer. Use of doubled tyrosine kinase inhibitors may result in increased risk of pulmonary toxicities that require high alertness, and the respiratory symptoms should be monitored closely after prescription. The early treatment of EOPEs with high-dose steroids resulted in remarkable improvement.

Diagnosis of mediastinal tuberculous lymphadenitis using endobronchial ultrasound-guided transbronchial needle aspiration with rinse fluid polymerase chain reaction.

BACKGROUND/PURPOSE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been gradually introduced in the diagnosis of mediastinal tuberculous (TB) lymphadenitis. The purposes of this study were to evaluate the utility of polymerase chain reaction for Mycobacterium tuberculosis (TB-PCR) using EBUS-TBNA rinse fluid and to explore the factors that influence the accuracy of EBUS-TBNA. METHODS: A retrospective study with prospective data collection was carried out with patients with unselected mediastinal lymphadenopathy who underwent EBUS-TBNA and a TB-PCR study from April 2010 to July 2017. Patients without TB were excluded. The diagnostic accuracy rate for each diagnostic modality (pathology, smear, culture, and TB-PCR) was calculated respectively. The characteristics of the lymph node (LN) and the pathologic findings were analyzed as possible impact factors. RESULTS: 240 consecutive patients who received EBUS-TBNA were enrolled, and in the end, 21 patients with a diagnosis of TB lymphadenitis were included. When combined with histologic results and traditional microbiologic studies, the diagnostic accuracy of EBUS-TBNA was 57.1%. If TB-PCR was also utilized, the diagnostic accuracy would significantly increase to 71.4% (p < 0.001). Univariate and multivariate regression analysis revealed that pathology showing necrosis had a higher positive microbiologic result when using EBUS-TBNA rinse fluid. CONCLUSION: EBUS-TBNA is a valuable tool for diagnosis of mediastinal TB lymphadenitis. Using TB-PCR assay and targeting LNs with a necrotic component would improve the diagnostic performance of EBUS-TBNA.

Non-small cell lung cancer harbouring non-resistant uncommon EGFR mutations: Mutation patterns, effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors and prognostic factors.

INTRODUCTION: Non-small cell lung cancer (NSCLC) harbouring EGFR exon 19 deletions or L858R mutation usually respond to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), whereas T790M mutation and exon 20 insertion are frequently resistant to EGFR-TKIs. EGFR mutations other than those above are seldom investigated. METHODS: In this multicentre, retrospective study, we enrolled NSCLC patients with non-resistant uncommon EGFR mutations, which were defined as mutations other than L858R, exon 19 deletions, exon 20 insertions and T790M. The mutation patterns, clinical data and treatment outcomes were analysed. Patients were classified as gefitinib/erlotinib and afatinib groups according to the EGFR-TKIs received as the first-line therapy. RESULTS: A total of 177 patients were identified (177/1983, 8.9%). Sixty-six patients had more than one EGFR mutation, including those coexisting with exon 19 deletion or L858R mutation. In treatment-naïve patients with advanced stages (n = 72), the objective response rate was 35.8% for gefitinib/erlotinib group and 60.6% for afatinib group (p = 0.036). In multivariate analysis, no significant differences were found between gefitinib/erlotinib and afatinib groups in median progression-free survival (PFS) and overall survival (OS). Brain metastasis at diagnosis was associated with a shorter PFS (hazard ratio [HR] = 2.49, 95% confidence interval [CI] = 1.29-4.83) and OS (HR = 3.22, 95% CI = 1.41-7.35). CONCLUSIONS: For patients with NSCLC harbouring non-resistant uncommon EGFR mutations, afatinib use as the first-line therapy may provide a better treatment response but no survival benefit, as compared with gefitinib or erlotinib. Brain metastasis at diagnosis is associated with a poor prognosis.

Intracranial Responses to Afatinib at Different Doses in Patients With EGFR-mutated Non-small-cell Lung Carcinoma and Brain Metastases.

BACKGROUND: As the first-line treatment, afatinib is commonly used in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, dose adjustments are frequently required. The optimal dose of afatinib for brain metastasis has seldom been investigated. PATIENTS AND METHODS: From May 2014 to March 2017, treatment-naive patients with advanced EGFR-mutated NSCLC and brain metastases at diagnosis who received afatinib therapy were retrospectively enrolled. Clinical data was reviewed and analyzed, including age, gender, performance status, smoking history, EGFR mutation status, initial doses of afatinib, average daily doses of afatinib, and best intracranial treatment responses. RESULTS: A total of 74 patients were included for analysis. The overall intracranial objective response rate (IORR) and intracranial disease control rate (IDCR) were 81.1% and 95.9%, respectively. For patients treated with afatinib alone (N = 45), no significant difference between an initial daily dose of 30 mg (N = 15) and 40 mg (N = 30) (30 mg vs. 40 mg, IORR: 86.7% vs. 80.0%; P = .581 and IDCR: 93.3% vs. 93.3%; P = 1.000, respectively). The IORRs were 75.0%, 91.7%, 80.0%, and 85.7% (P = .707), and the IDCRs were 93.8%, 100.0%, 90.0%, and 85.7% (P = .638) in patients with an average daily dose of 40 mg (N = 16), < 40 mg and > 30 mg (N = 12), 30 mg (N = 10), and < 30 mg and > 20 mg (N = 7), respectively. No significant differences in intracranial treatment responses between groups treated with afatinib alone or afatinib plus local treatments. CONCLUSION: Dose reduction may not affect intracranial treatment responses to afatinib therapy, either alone or combined with local treatments, in patients with advanced EGFR-mutated NSCLC and brain metastases.

Treatment effectiveness and tolerability of afatinib at different doses in patients with EGFR-mutated lung adenocarcinoma: How low can we go?

INTRODUCTION: Afatinib is commonly used as the first-line treatment for EGFR-mutated lung adenocarcinoma. However, dose adjustments are frequently required. This study aimed to investigate the treatment effectiveness of afatinib administered at different doses to patients with EGFR-mutated lung adenocarcinoma. METHODS: Treatment-naïve patients with advanced EGFR-mutated lung adenocarcinoma who received afatinib therapy between May 2014 and September 2016 were enrolled retrospectively. Collected clinical data included age, sex, smoking history, performance status, disease stages, EGFR mutation status, initial doses of afatinib, dose adjustments, treatment responses, progression-free survival and treatment-associated adverse events. The average daily dose was calculated by dividing the summation of all doses of prescribed tablets during the treatment period by the total days of afatinib use. The patients were classified into five treatment groups based on average daily doses: 40 mg, <40 and >30 mg, 30 mg, <30 and ≥ 20 mg and <20 mg. RESULTS: A total of 254 patients were included. No significant differences were found among these five treatment groups with respect to response rates (69.3%, 68.3%, 70.5%, 77.8% and 66.7%, respectively, p = 0.920) and disease control rates (97.4%, 95.2%, 97.7%, 100% and 100%, respectively, p = 0.749). However, the treatment group with an average daily dose of <20 mg had a significant shorter progression-free survival as compared with the other groups (16.8, 12.4, 13.9, 17.0 and 5.3 months, respectively, p = 0.049). CONCLUSIONS: Dose reduction may not affect the treatment effectiveness until the average daily dose is below 20 mg. Further prospective studies of afatinib therapy at different daily doses are warranted.

Comparable clinical outcomes in patients with HER2-mutant and EGFR-mutant lung adenocarcinomas.

HER2 is a major proliferative driver in lung cancer. HER2 gene aberrations impact the prognosis of lung adenocarcinoma (ADC). A one-step reverse transcription-polymerase chain reaction was performed using RNA samples from 888 Asian lung cancer patients to detect HER2, EGFR, KRAS, ALK, and ROS1 mutations. The demographic data and treatment outcomes of HER2 mutation-positive lung ADC patients were analyzed and compared to those with HER2 mutation-negative tumors. HER2 mutation was identified in 40 (4.5%) lung ADC patients. HER2 mutations tended to occur in male patients with advanced-stage disease and never-smokers. A775_G776insYVMA (n = 22, 55%) was the most prevalent HER2 mutation, followed by P780_Y781insGSP (n = 4, 10%). For patients diagnosed with stage-IIIB/IV disease, HER2-mutant patients showed clinical outcomes comparable to EGFR-mutant patients (P = 0.721, log-rank test) and a better overall survival (OS) compared to patients lacking driver mutations in the investigated genes (P = 0.033, Breslow test). Specifically, lung ADC patients with stage-IV HER2-mutant tumors treated with chemotherapy or targeted agents, even without afatinib or anti-HER2 targeted therapy, showed similar clinical outcomes to lung ADC patients harboring EGFR exon 19 deletion or L858R mutations (P = 0.870). In addition, multivariate analysis indicated that HER2 mutation status was not a major risk factor for diminished OS in stage-IV lung cancer. In conclusion, lung ADC harboring HER2 mutations showed distinct characteristics from other driver mutations, including increased chemosensitivity with in advanced stage disease.

Transthoracic Ultrasound Elastography in Pulmonary Lesions and Diseases.

Ultrasound elastography has shown promising result in the diagnosis of various diseases; however, its application for pulmonary diseases has yet to be clarified. This study aimed to assess the application and feasibility of ultrasound elastography in various pulmonary lesions and diseases. We enrolled 45 patients with radiographic evidence of pneumonia, tumors or obstructive pneumonitis, and 70 ultrasonic lesions were identified (eight necrosis, 17 atelectasis, seven consolidation and 38 tumors). Ultrasound elastography was performed and the strain ratio, which is the ratio of strain of the reference tissue to an equally measuring region of interest of a lesion, was measured. The strain ratio was significantly different among lesions with different ultrasound morphologies (1.03 ± 0.71 [necrosis] vs. 2.51 ± 1.14 [atelectasis] vs. 19.98 ± 15.59 [consolidation] vs. 36.19 ± 20.18 [tumor]; p < 0.05). The strain ratio of primary lung cancer was also significantly different from pneumonia (p = 0.023) and metastatic lung cancer (p = 0.015). In conclusion, transthoracic ultrasound elastography can differentiate pulmonary lesions with different ultrasound morphologies. ClinicalTrials.gov Identifier: NCT02636985.

Effect of Tracheostomy on Weaning Parameters in Difficult-to-Wean Mechanically Ventilated Patients: A Prospective Observational Study.

BACKGROUND AND OBJECTIVE: Weaning parameters are commonly measured through an endotracheal tube in mechanically ventilated patients recovering from acute respiratory failure, however this practice has rarely been evaluated in tracheostomized patients. This study aimed to investigate changes in weaning parameters measured before and after tracheostomy, and to explore whether the data measured after tracheostomy were associated with weaning outcomes in difficult-to-wean patients. METHODS: In a two-year study period, we enrolled orotracheally intubated patients who were prepared for tracheostomy due to difficult weaning. Weaning parameters were measured before and after the conversion to tracheostomy and compared, and the post-tracheostomy data were tested for associations with weaning outcomes. RESULTS: A total of 86 patients were included. After tracheostomy, maximum inspiratory pressure (mean difference (Δ) = 4.4, 95% CI, 2.7 to 6.1, P<0.001), maximum expiratory pressure (Δ = 5.4, 95% CI, 2.9 to 8.0, P<0.001) and tidal volume (Δ = 33.7, 95% CI, 9.0 to 58.5, P<0.008) significantly increased, and rapid shallow breathing index (Δ = -14.6, 95% CI, -25.4 to -3.7, P<0.009) and airway resistance (Δ = -4.9, 95% CI, -5.8 to -4.0, P<0.001) significantly decreased. The patients who were successfully weaned within 90 days of the initiation of mechanical ventilation had greater increments in maximum inspiratory pressure (5.9 vs. 2.4, P = 0.04) and maximum expiratory pressure (8.0 vs. 2.0, P = 0.02) after tracheostomy than those who were unsuccessfully weaned. CONCLUSIONS: In conclusion, the conversion from endotracheal tube to tracheostomy significantly improved the measured values of weaning parameters in difficult-to-wean patients who subsequently weaned successfully from the mechanical ventilator. The change was significant only for airway resistance in patients who failed weaning. TRIAL REGISTRATION: ClinicalTrials.gov NCT01312142.