Oncogene-driven non-small cell lung cancers in patients with a history of smoking lack smoking-induced mutations.

Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET and fusions involving ALK and RET. In addition to occurring in non-smokers, alterations in these "non-smoking-related oncogenes" (NSROs) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared to typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients. NSRO-driven NSCLCs in smokers and non-smokers had similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs, which was confirmed in two large NSCLC datasets from other geographic regions. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to regulation of the cell cycle. These findings suggest that, while the genomic landscape is similar between NSRO-driven NSCLC in smokers and non-smokers, smoking still affects the tumor phenotype independently of genomic alterations.

Airway interventions for tracheobronchial involvement in esophageal carcinoma: a retrospective cohort outcome study and algorithmic approach.

Background: In advanced esophageal carcinoma (EC), there is limited data on risk factors predicting tracheobronchoesophageal fistula (TEF) formation and survival among patients who required airway interventions. Methods: A retrospective analysis of consecutive patients with EC, who had airway involvement requiring intervention, was conducted from 1998 to 2018. Demographics, clinical progress, disease stage, treatment and survival outcomes were recorded. Patients were followed up till death or until completion of the study. Survival was estimated with the Kaplan-Meier method and curves compared by log-rank test. Multivariate analyses of risk factors were performed using Cox proportional hazard regression. Results: A total of 122 patients were included. The median (IQR) survival from time of airway intervention was 3.30 (1.57-6.88) months, while the median (IQR) survival from time of histological diagnosis was 8.90 (4.91-14.45) months. Tumour location within 20 mm of the carina, prior radiotherapy and/or esophageal stenting were significantly associated with formation of TEF. Mid EC [adjusted hazard ratio (HR) 1.9; 95% confidence interval (CI): 1.1-3.2] or presence of TEF (adjusted HR 1.8; 95% CI: 1.0-3.2) were associated with lower survival. Patients receiving chemotherapy (adjusted HR 0.46; 95% CI: 0.25-0.84), or esophageal stenting whether before or after airway intervention (adjusted HR 0.32; 95% CI: 0.15-0.68 and adjusted HR 0.51; 95% CI: 0.29-0.90) were associated with increased survival. Conclusions: Factors associated with TEF formation include airway location, radiotherapy and prior esophageal stenting, and the development of TEF was associated with poorer survival. An algorithmic approach towards tracheobronchial involvement in EC is proposed based on these findings and a review of the literature.

Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities.

PURPOSE: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFR T790M-negative resistance. EXPERIMENTAL DESIGN: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M-) disease. RESULTS: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M- tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M- tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M- and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. CONCLUSIONS: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.

Malignant pleural effusion survival prognostication in an Asian population.

BACKGROUND AND OBJECTIVE: LENT and PROMISE scores prognosticate survival in patients with MPE. Prognostication guides the selection of interventions and management. However, the predictive value of these scores and their refinements (modified-LENT) in Asians remain unclear. We aim to evaluate the performance of LENT, modified-LENT and clinical PROMISE scores; identify predictors of survival; and develop an alternative prognostication tool should current scores lack accuracy. METHODS: Retrospective medical record review of an Asian pleuroscopy database from 2011 to 2018 of patients with MPE was conducted. The prognostic capability of current available scores were evaluated using C-statistics. Demographic and clinical variables as predictors of survival were assessed, and an alternative model was developed using logistic regression. RESULTS: In 130 patients, the C-statistics for modified-LENT was not significantly different from LENT (0.59 (95% CI: 0.52-0.67) vs 0.56 (95% CI: 0.49-0.63); P = 0.403). In 57 patients, the PROMISE C-statistics was 0.72 (95% CI: 0.53-0.91). In our alternative prognostication model (n = 147), Sex, Eastern Cooperative Oncology Group status, Leukocyte count, EGFR mutation, Chemotherapy and primary Tumour type (SELECT) were predictors of 90-day mortality (C-statistic = 0.87 (95% CI: 0.79-0.95)). SELECT sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios using a predicted probability of 90-day mortality cut-off point of 10% were 0.91, 0.68, 0.34, 0.98, 2.83 and 0.13, respectively. CONCLUSION: The LENT, modified-LENT and PROMISE scores have poor accuracy of survival prognostication in Asian patients with MPE undergoing pleuroscopy. The proposed SELECT prognostication model is accurate at identifying patients with high probability of survival at 90 days.

Genomic landscape of lung adenocarcinoma in East Asians.

Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.

Role of bronchoalveolar lavage in the management of immunocompromised patients with pulmonary infiltrates.

Pulmonary infiltrates are a significant cause of morbidity and mortality in immunocompromised patients and remain a diagnostic challenge due to the broad range of etiologies that include infection and malignancy. Empiric therapy may be sub-optimal and can adversely impact outcome. Therefore, a confirmed diagnosis is necessary and flexible bronchoscopy with bronchoalveolar lavage (BAL) may be a useful diagnostic tool. Samples are obtained for microbiological and cytological testing, but the procedure carries risk of complications including the adverse events related to moderate sedation. A review of published literature on BAL in immunocompromised patients from the year 2000 was undertaken focusing on diagnostic yield, complication rate, mortality as well as factors impacting these outcomes. Studies in which the majority of patients were supported on mechanical ventilation were excluded. A total of 23 studies (7 prospective and 16 retrospective) met inclusion criteria. This covered 3,395 procedures in 3,192 patients with a mean age of 47.4 years; 60.3% male gender. Diagnostic yield ranged from 26% to 69% with no clear association between diagnostic yield and etiology of immunosuppression or clinical/radiological presentation. Post BAL modification of treatment as an indicator for clinical utility ranged from 11% to 84%; and complication rate ranged from 1% to 52%. No specific factors were associated with increased adverse event rate. This review provides a summary of the data on the use of BAL for diagnosis of pulmonary infiltrates in immunocompromised patients, highlighting the heterogeneity of patients, significant variation in findings reported and the need for more data to optimize patient selection.

Utility of bronchoalveolar lavage in the management of immunocompromised patients presenting with lung infiltrates.

BACKGROUND: Bronchoalveolar lavage (BAL) is utilized for diagnosing lung infiltrates in immunocompromised. There is heterogeneity in the data and reported diagnostic yields range from 26 to 69%. Therefore, selection criteria for BAL to maximize yield and minimize complications are unclear. Objectives of this study were to determine the diagnostic yield and complication rate of BAL in immunocompromised patients presenting with lung infiltrates, and identify factors impacting these outcomes. Exploratory aims included characterization of pathogens, rate of treatment modification and mortality. METHODS: Retrospective study from January 2012 to December 2016. Patients on mechanical ventilation were excluded. Positive diagnostic yield was defined as confirmed microbiological or cytological diagnosis. RESULTS: A total of 217 patients were recruited (70.1% male and mean age: 51.7 ± 14.6 years). Diagnostic yield was 60.8% and complication rate 14.7%. Complications (hypoxemia and endobronchial bleeding) were all sell-limiting. Treatment modification based on BAL results was 63.3%. In 97.0% an infectious aetiology was identified. HIV infection (OR 5.304, 95% CI 1.611-17.458, p = 0.006) and severe neutropenia (OR 4.253, 95% CI 1.288-14.045, p = 0.018) were associated with positive yield. Leukemia (OR 0.317, 95% CI 0.102-0.982, p = 0.047) was associated with lower yield. No factors impacted complication rate. Overall mortality (90-day) was 17.5% and in those with hematologic malignancy, it was 28.3%. CONCLUSION: BAL retains utility in diagnosis of immunocompromised patients with lung infiltrates. However, patients with hematologic malignancy have a high mortality and alternative sampling should be considered because of poor results with BAL. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01374542 . Registered June 16, 2011.

Impact of simulation training on performance and outcomes of endobronchial ultrasound-guided transbronchial needle aspiration performed by trainees in a tertiary academic hospital.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic yield and low complication rate. Whilst it has been included in international guidelines for the diagnosis and staging of lung cancer, current results are mostly based on EBUS experts performing EBUS-TBNA in centres of excellence. The impact of simulation training on diagnostic yield, complications, scope damage and repair cost in a real-world teaching hospital is unclear. METHODS: A review of our hospital EBUS-TBNA registry from August 2008 to December 2016 was performed. A positive diagnosis was defined as a confirmed histological or microbiological diagnosis based on EBUS sampling. Complications were classified as major or minor according to the British Thoracic Society guidelines. In addition, we assessed the cost of repairs for scope damage before and after simulation training was implemented. Using CUSUM analysis, the learning curves of individual trainees and the institution were plotted. RESULTS: There were 608 EBUS-TBNA procedures included in the study. The number of procedures performed by trainees who underwent conventional training was 331 and those who underwent simulation training performed 277 procedures. Diagnostic yield for trainees without simulation training was 88.2% vs. 84.5% for trainees with simulation training (P=0.179). There was no statistical difference in the diagnostic yield between the groups of trainees (OR: 0.781, 95% CI: 0.418-1.460, P=0.438) after adjusting for risk factors. There was an increase in overall complications from 13.6% to 16.6% (OR: 2.247, 95% CI: 1.297-3.891, P=0.004) after introduction of the simulation training, but a trend to decrease in major complications 3.6% to 0.7% (P=0.112). The cost for scope repairs for the trainees without simulation training was SGD 413.88 per procedure vs. SGD 182.79 per procedure for the trainees with simulation training, with the mean difference being SGD 231.09 per procedure (95% CI: 178.40-640.60, P=0.268). CUSUM analysis showed an increasing learning curve for the trainees with simulation training after an initial competency period. CONCLUSIONS: There was no statistical difference in diagnostic yield from EBUS-TBNA and cost of scope damage after simulation training was introduced into our training program. Interestingly, there was an increase in minor complications. CUSUM analysis can provide additional information on institutional learning curves. The value of simulation training in EBUS-TBNA remains uncertain.

Diagnosis of Peripheral Lung Lesions via Conventional Flexible Bronchoscopy with Multiplanar CT Planning.

Background. Conventional flexible bronchoscopy has limited sensitivity in the diagnosis of peripheral lung lesions and is dependent on lesion size. However, advancement of CT imaging offers multiplanar reconstruction facilitating enhanced preprocedure planning. This study aims to report efficacy and safety while considering the impact of patient selection and multiplanar CT planning. Method. Prospective case series of patients with peripheral lung lesions suspected of having lung cancer who underwent flexible bronchoscopy (forceps biopsy and lavage). Endobronchial lesions were excluded. Patients with negative results underwent CT-guided transthoracic needle aspiration, surgical biopsy, or clinical-radiological surveillance to establish the final diagnosis. Results. 226 patients were analysed. The diagnostic yield of bronchoscopy was 80.1% (181/226) with a sensitivity of 84.2% and specificity of 100%. In patients with a positive CT-Bronchus sign, the diagnostic yield was 82.4% compared to 72.8% with negative CT-Bronchus sign (p = 0.116). Diagnostic yield was 84.9% in lesions > 20 mm and 63.0% in lesions ≤ 20 mm (p = 0.001). Six (2.7%) patients had transient hypoxia and 2 (0.9%) had pneumothorax. There were no serious adverse events. Conclusion. Flexible bronchoscopy with appropriate patient selection and preprocedure planning is more efficacious in obtaining a diagnosis in peripheral lung lesions compared to historical data. This trial is registered with ClinicalTrials.gov Identifier: NCT01374542.

Desensitisation to cigarette package graphic health warnings: a cohort comparison between London and Singapore.

OBJECTIVES: We compared 2 sociocultural cohorts with different duration of exposure to graphic health warning labels (GHWL), to investigate a possible desensitisation to their use. We further studied how a differing awareness and emotional impact of smoking-associated risks could be used to prevent this. SETTING: Structured interviews of patients from the general respiratory department were undertaken between 2012 and 2013 in 2 tertiary hospitals in Singapore and London. PARTICIPANTS: 266 participants were studied, 163 Londoners (35% smokers, 54% male, age 52±18 years) and 103 Singaporeans (53% smokers, p=0.003; 78% male, p<0.001; age 58±15 years, p=0.012). MAIN OUTCOMES AND MEASURES: 50 items assessed demographics, smoking history, knowledge and the deterring impact of smoking-associated risks. After showing 10 GHWL, the impact on emotional response, cognitive processing and intended smoking behaviour was recorded. RESULTS: Singaporeans scored lower than the Londoners across all label processing constructs, and this was consistent for the smoking and non-smoking groups. Londoners experienced more 'disgust' and felt GHWL were more effective at preventing initiation of, or quitting, smoking. Singaporeans had a lower awareness of lung cancer (82% vs 96%, p<0.001), despite ranking it as the most deterring consequence of smoking. Overall, 'blindness' was the least known potential risk (28%), despite being ranked as more deterring than 'stroke' and 'oral cancer' in all participants. CONCLUSIONS: The length of exposure to GHWL impacts on the effectiveness. However, acknowledging the different levels of awareness and emotional impact of smoking-associated risks within different sociocultural cohorts could be used to maintain their impact.

Evaluation of Pulmonary Nodules: Clinical Practice Consensus Guidelines for Asia.

BACKGROUND: American College of Chest Physicians (CHEST) clinical practice guidelines on the evaluation of pulmonary nodules may have low adoption among clinicians in Asian countries. Unique patient characteristics of Asian patients affect the diagnostic evaluation of pulmonary nodules. The objective of these clinical practice guidelines was to adapt those of CHEST to provide consensus-based recommendations relevant to practitioners in Asia. METHODS: A modified ADAPTE process was used by a multidisciplinary group of pulmonologists and thoracic surgeons in Asia. An initial panel meeting analyzed all CHEST recommendations to achieve consensus on recommendations and identify areas that required further investigation before consensus could be achieved. Revised recommendations were circulated to panel members for iterative review and redrafting to develop the final guidelines. RESULTS: Evaluation of pulmonary nodules in Asia broadly follows those of the CHEST guidelines with important caveats. Practitioners should be aware of the risk of lung cancer caused by high levels of indoor and outdoor air pollution, as well as the high incidence of adenocarcinoma in female nonsmokers. Furthermore, the high prevalence of granulomatous disease and other infectious causes of pulmonary nodules need to be considered. Therefore, diagnostic risk calculators developed in non-Asian patients may not be applicable. Overall, longer surveillance of nodules than those recommended by CHEST should be considered. CONCLUSIONS: TB in Asia favors lesser reliance on PET scanning and greater use of nonsurgical biopsy over surgical diagnosis or surveillance. Practitioners in Asia are encouraged to use these adapted consensus guidelines to facilitate consistent evaluation of pulmonary nodules.

Use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of granulomatous mediastinal lymphadenopathy.

INTRODUCTION: This study assessed the clinical utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnosis of suspected granulomatous mediastinal lymphadenopathy. MATERIALS AND METHODS: Retrospective chart review of all patients who underwent EBUS-TBNA for suspected granulomatous mediastinal lymphadenopathy at Singapore General Hospital between December 2008 and December 2011 inclusive. RESULTS: Over a period of 3 years, a total of 371 patients underwent EBUS-TBNA of whom 33 (9%) had the procedure performed for evaluation of suspected granulomatous mediastinal lymphadenopathy - 18 for suspected tuberculosis (TB) and non-tuberculous mycobacterial (NTM) lymphadenitis, and 15 for suspected sarcoidosis. EBUS-TBNA was diagnostic in 9 of the 13 patients with a final diagnosis of TB/NTM. EBUS-TBNA cultures were positive in 6 of them (46%), 1 showed acid-fast bacilli (AFB) although cultures were negative, and 2 had necrotising granulomatous inflammation from EBUS-TBNA biopsies and sputum cultures grew TB. EBUS-TBNA was diagnostic in 9 of the 14 patients with a final diagnosis of sarcoidosis through histology showing non-caseating granulomatous inflammation. The sensitivities of EBUS-TBNA for diagnosis of TB/NTM, sarcoidosis and overall granulomatous mediastinal lymphadenopathy were 69%, 64%, 64%; the negative predictive values were 56%, 17%, 33%; and accuracies were 78%, 67%, 70%, respectively. CONCLUSION: EBUS-TBNA can be useful in the diagnosis of suspected granulomatous mediastinal lymphadenopathy with sensitivities and accuracies of >60%.

Update on interventional bronchoscopy for the thoracic radiologist.

Interventional bronchoscopy, together with other domains of interventional pulmonology, has experienced tremendous technological advances. Diagnostic applications include endobronchial ultrasound, which enables endoscopists to see through airway walls. White light videobronchoscopy, autofluorescence imaging, and narrow band imaging have enhanced the ability to detect early lung cancer at a preinvasive stage. Electromagnetic navigational bronchoscopy, ultrathin bronchoscopy, and virtual bronchoscopy increase the diagnostic yield of biopsy of small peripheral lung lesions. The options that are currently available for the relief of central airway obstruction are also numerous, with both flexible and rigid bronchoscopic applications. Stents, although dichotomized to silicone and metal, come in various sizes and shapes to suit the requirements of the pathology being treated. Ablative techniques are categorized into those with an immediate effect and those with a delayed effect. Laser, electrocautery, and argon plasma coagulation can immediately relieve obstruction and control hemoptysis, whereas cryosurgery, brachytherapy, and photodynamic therapy have established roles in subacute airway obstruction and in the treatment of early lung cancer. Microdebriders have recently been added to the armamentarium of modalities for mechanical debulking of tumor. Distal airway obstruction has also been targeted with bronchial thermoplasty treatment of refractory asthma and with bronchoscopic lung volume reduction for the management of severe emphysema. This array of new technology has fostered collaborative work with a wide range of other medical specialties to deliver safer, more effective, minimally invasive treatment.

Bronchoscopic lung volume reduction.

The application of lung volume reduction surgery in clinical practice is limited by high postoperative morbidity and stringent selection criteria. This has been the impetus for the development of bronchoscopic approaches to lung volume reduction. A range of different techniques such as endobronchial blockers, airway bypass, endobronchial valves, thermal vapor ablation, biological sealants, and airway implants have been employed on both homogeneous as well as heterogeneous emphysema. The currently available data on efficacy of bronchoscopic lung volume reduction are not conclusive and subjective benefit in dyspnoea scores is a more frequent finding than improvements on spirometry or exercise tolerance. Safety data are more promising with rare procedure-related mortality, few serious complications, and short hospital length of stay. The field of bronchoscopic lung volume reduction continues to evolve as ongoing prospective randomized trials build on earlier feasibility data to clarify the true efficacy of such techniques.

Role of endobronchial ultrasound in the diagnosis of bronchogenic cysts.

Diagnosis of bronchogenic cysts is possible with computed tomography, but half of all cases present as soft tissue densities. Two such cases are highlighted where asymptomatic bronchogenic cysts that presented as soft tissue masses were evaluated by endobronchial ultrasound (EBUS). After studying the ultrasound image characteristics, the diagnosis was confirmed using EBUS-guided transbronchial needle aspiration (EBUS-TBNA). The first case had ultrasound findings of an anechoic collection, and the aspirate was serous with negative microbiologic cultures. The second was an echogenic collection within a hyperechoic wall. Needle aspirate was purulent and cultured Haemophilus influenza. The diagnosis of a bronchogenic cyst complicated by infection was made, and the lesion was surgically resected. This potential for EBUS in the diagnosis of bronchogenic cysts and in identifying complications such as infection should be considered in the management of such cases.

Bronchoscopic management of sarcoidosis related bronchial stenosis with adjunctive topical mitomycin C.

A 58-year-old woman with multiple proximal airway stenoses due to sarcoidosis failed to improve with steroid therapy. After bronchoscopic balloon dilation with adjunctive topical mitomycin C, there was symptomatic improvement and preserved patency of the airways one month later. However, the patient's effort tolerance gradually deteriorated subsequently, and a repeat bronchoscopy one year later showed recurrence of airway stenosis.