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.

Empathy Levels Among Healthcare Professionals: An Asian Multi-professional Cross-Sectional Study.

BACKGROUND: The aim of the study was to measure empathy in healthcare professionals in Singapore and to compare the scores between the different professions: doctors, nurses, and allied health professionals. METHODS: An online survey questionnaire was conducted using the Jefferson Scale of Empathy (JSE) from July 2019 to January 2020. The total JSE score was calculated and compared among the different groups. Multiple linear regression was performed to assess predictors of total empathy scores for groups with statistically lower scores. RESULTS: The survey was completed by 4,188 healthcare professionals (doctors (n=569, 13.6%), nurses (n=3032, 72.4%), and allied health professionals (n=587, 14.0%)) out of the 9,348-strong survey population, with a response rate of 44.8%. The study revealed a mean empathy score (SD) of 103.6 (15.6) for the cohort. The mean empathy score (SD) was 112.3 (14.7), 101.3 (15.2), and 107.0 (15.0), respectively for doctors, nurses, and allied health professionals. These were statistically significantly different among the groups (p< 0.0001), with nurses scoring significantly lower than either doctors (p< 0.0001) or allied health professionals (p< 0.0001). Multiple linear regression showed that age < 30 years old, male gender, Malay ethnicity, and working in a hospital setting were associated with significantly lower empathy scores in the nursing group. CONCLUSION: Nurses in Singapore had significantly lower empathy scores compared to doctors and allied health professionals. Further research on the underlying causes should be undertaken and measures to improve empathy among Singapore nursing staff should be explored and implemented.

A Retrospective Cohort Study Evaluating the Safety and Efficacy of Sequential versus Concurrent Intrapleural Instillation of Tissue Plasminogen Activator and DNase for Pleural Infection.

Methods: We conducted a retrospective review of patients with pleural infection requiring intrapleural therapy at two tertiary referral centres. Results: We included 84 (62.2%) and 51 (37.8%) patients who received sequential and concurrent intrapleural therapy, respectively. Patient demographics and clinical characteristics, including age, RAPID score, and percentage of pleural opacity on radiographs before intrapleural therapy, were similar in both groups. Treatment failure rates (defined by either in-hospital mortality, surgical intervention, or 30-day readmission for pleural infection) were 9.5% and 5.9% with sequential and concurrent intrapleural therapy, respectively (p = 0.534). This translates to a treatment success rate of 90.5% and 94.1% for sequential and concurrent intrapleural therapy, respectively. There was no significant difference in the decrease in percentage of pleural effusion size on chest radiographs (15.1% [IQR 6-35.7] versus 26.6% [IQR 9.9-38.7], p = 0.143) between sequential and concurrent therapy, respectively. There were also no significant differences in the rate of pleural bleeding (4.8% versus 9.8%, p = 0.298) and chest pain (13.1% versus 9.8%, p = 0.566) between sequential and concurrent therapy, respectively. Conclusion: Our study adds to the growing literature on the safety and efficacy of concurrent intrapleural therapy in pleural infection.

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.

Operationalization of critical care triage during a pandemic surge using protocolized communication and integrated supportive care.

Triage becomes necessary when demand for intensive care unit (ICU) resources exceeds supply. Without triage, there is a risk that patients will be admitted to the ICU in the sequence that they present, disadvantaging those who either present later or have poorer access to healthcare. Moreover, if the patients with the best prognosis are not allocated life support, there is the possibility that overall mortality will increase. Before formulating criteria, principles such as maximizing lives saved and fairness ought to have been agreed upon to guide decision-making. The triage process is subdivided into three parts, i.e., having explicit inclusion/exclusion criteria for ICU admission, prioritization of patients for allocation to available beds, and periodic reassessment of all patients already admitted to the ICU. Multi-dimensional criteria offer more holistic prognostication than only using age cutoffs. Appointed triage officers should also be enabled to make data-driven decisions. However, the process does not merely end with an allocation decision being made. Any decision has to be sensitively and transparently communicated to the patient and family. With infection control measures, there are challenges in managing communication and the psychosocial distress of dying alone. Therefore, explicit video call protocols and social services expertise will be necessary to mitigate these challenges. Besides symptom management and psychosocial management, supportive care teams play an integral role in coordination of complex cases. This scoping review found support for the three-pronged, triage-communication-supportive care approach to facilitate the smooth operationalization of the triage process in a pandemic.

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.

Is bronchial thermoplasty cost-effective as treatment for problematic asthma patients? Singapore's perspective on a global model.

BACKGROUND AND OBJECTIVE: Bronchial thermoplasty (BT) has been shown to be effective at reducing asthma exacerbations and improving asthma control for patients with severe persistent asthma but it is also expensive. Evidence on its cost-effectiveness is limited and inconclusive. In this study, we aim to evaluate the incremental cost-effectiveness of BT combined with optimized asthma therapy (BT-OAT) relative to OAT for difficult-to-treat and severe asthma patients in Singapore, and to provide a general framework for determining BT's cost-effectiveness in other healthcare settings. METHODS: We developed a Markov model to estimate the costs and quality-adjusted life years (QALYs) gained with BT-OAT versus OAT from the societal and health system perspectives. The model was populated using Singapore-specific costs and transition probabilities and utilities from the literature. Sensitivity analyses were conducted to identify the main factors determining cost-effectiveness of BT-OAT. RESULTS: BT-OAT is not cost-effective relative to OAT over a 5-year time horizon with an incremental cost-effectiveness ratio (ICER) of $US138 889 per QALY from the societal perspective and $US139 041 per QALY from the health system perspective. The cost-effectiveness of BT-OAT largely depends on a combination of the cost of the BT procedure and the cost of asthma-related hospitalizations and emergency department (ED) visits. CONCLUSION: Based on established thresholds for cost-effectiveness, BT-OAT is not cost-effective compared with OAT in Singapore. Given its current clinical efficacy, BT-OAT is most likely to be cost-effective in a setting where the cost of BT procedure is low and costs of hospitalization and ED visits are high.

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.