Background: With the need for "actionable histology" in the current era of targeted cancer treatment, and the increasing practice of upfront thoracoscopy (without a prior diagnostic thoracentesis) or a "biopsy first" approach in suspected malignant pleural effusions (MPEs), we sought to prospectively evaluate the diagnostic accuracy, including full molecular profiling of cancer, and safety of medical thoracoscopy (MT) at a tertiary referral hospital. Methods: Patients with MT performed for an undiagnosed pleural effusion between January 2020 and December 2022 were included in this observational cohort study. All procedures were performed with a semirigid thoracoscope under conscious sedation. Clinical outcomes and adverse events were recorded prospectively. Results: We evaluated 141 patients, with a mean age of 67 +/- 12 years. Talc poudrage was performed in 67 (47.5%) patients with a median of 2 [interquartile range (IQR), 1-4] hospitalisation days after MT. Upfront thoracoscopy was performed in approximately half (55.3%) of patients. The overall diagnostic accuracy of MT was 95.7% in our cohort. A final diagnosis of cancer was made in 116 (82.3%) patients, with lung (67.2%) and breast cancer (8.6%) the most common. The diagnostic sensitivity of MT for malignancy was 94.8%, and molecular profiling of relevant cancer types for oncogenic mutations was achieved in all patients with malignancy seen on histopathology. The most common non-malignant diagnosis was tuberculous pleuritis in 14 patients (9.9%). Major complications occurred in 3 (2.1%) patients. Two patients had re-expansion pulmonary edema that resolved with low flow oxygen supplementation in the general ward, and one patient required intensive care unit admission for cardiac tamponade from a malignant pericardial effusion. There were no cases of mortality, bleeding complications or persistent air leaks. Conclusions: MT is a well-tolerated and effective option for the evaluation of undiagnosed pleural effusions. With expanding utility and expertise with MT and other pleural interventions, the challenge for respiratory physicians is integrating these into expeditious diagnostic and effective therapeutic pathways, individualised to patients' needs.

Abstract 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. We term these “non-smoking-related oncogenes” (NSROs). NSRO-driven tumors account for approximately half of NSCLCs in East Asia, and, alarmingly, their age-adjusted incidence is increasing for unknown reasons. In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers. However, the clonal architecture and genomic landscape of these tumors remain largely unexplored. Here, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. Overall, NSRO-driven NSCLCs in smokers and non-smokers had similar genomic landscapes and clonal architectures that were distinct from those in typical-smoking NSCLCs. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs. We confirmed this unexpected finding in two large NSCLC data sets from other geographic regions. However, we observed differences in the tumor transcriptomes of NSRO-driven NSCLCs in smokers and non-smokers, with tumors in smokers displaying higher transcriptomic activities related to regulation of the cell cycle. This suggested that smoking does have an impact on tumor phenotype in NSCRO-driven NSCLC, likely through non-genetic mechanisms. We concluded that NSRO-driven NSCLCs, whether in non-smokers or smokers, constitute an important disease entity that is very different from typical-smoking NSCLC. Citation Format: Chen-Yang Huang, Nanhai Jiang, Meixin Shen, Gillianne Lai, Aaron C. Tan, Amit Jain, Stephanie P. Saw, Mei-Kim Ang, Quan Sing Ng, Darren Wan-Teck Lim, Ravindran Kanesvaran, Eng-Huat Tan, Wan Ling Tan, Boon-Hean Ong, Kevin L. Chua, Devanand Anantham, Angela Takano, Tony KH Lim, Wai Leong Tam, Ngak Leng Sim, Anders J. Skanderup, Daniel S.W. Tan, Steven G. Rozen. Dearth of smoking-induced mutations in oncogene-driven NSCLCs despite smoking exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1748.

Abstract Non–small cell lung cancers (NSCLC) in nonsmokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET and fusions involving ALK and RET. In addition to occurring in nonsmokers, alterations in these “nonsmoking-related oncogenes” (NSRO) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared with typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients. NSRO-driven NSCLCs in smokers and nonsmokers 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 data sets from other geographic regions. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to the regulation of the cell cycle. These findings suggest that, whereas the genomic landscape is similar between NSRO-driven NSCLC in smokers and nonsmokers, smoking still affects the tumor phenotype independently of genomic alterations. Significance: Non-small cell lung cancers driven by nonsmoking-related oncogenes do not harbor genomic scars caused by smoking regardless of smoking history, indicating that the impact of smoking on these tumors is mainly nongenomic.

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.

Background and Objective. Intrapleural tissue plasminogen activator/deoxyribonuclease (tPA/DNase) is increasingly being used for pleural infections. Compared to sequential instillation of tPA/DNase, concurrent instillation considerably reduces the complexity of the administration process and reduces workload and the number of times the chest drain is accessed. However, it remains unclear if concurrent intrapleural therapy is as efficacious or safe as sequential intrapleural therapy. 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.

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

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 . We term these “non-smoking-related oncogenes” (NSROs). In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers, and the clonal architecture and genomic landscape of these tumors remain unknown. We investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. NSRO-driven NSCLCs in smokers and non-smokers have 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. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to regulation of the cell cycle, suggesting that smoking still affects tumor phenotype independently of genomic alterations. Statement of significance This study highlights the lack of genomic scars caused by smoking in NSCLCs driven by non-smoking-related oncogenes regardless of smoking history. The impact of smoking on these tumors is mainly non-genomic. The transcriptomic features of NSCLCs associated with smoking may help in the development of therapeutic approaches.

SESSION TITLE: Complicated Pleural Effusions SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/10/2023 12:55 pm - 01:44 pm PURPOSE: There is insufficient data to support the routine use of concurrent vs sequential administration of IET with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) for pleural infection despite an increasing trend of physician preference for concurrent administration. METHODS: A retrospective review of patients in two tertiary institutions who received IET for pleural infection from 2017-2022 was conducted. Pleural infection was defined as a compatible clinical history with at least one of the following pleural fluid characteristics: i) purulent macroscopically, ii) positive gram stain or culture, iii) pH ≤ 7.20, glucose ≤ 3.0 mmol/L or lactate dehydrogenase (LDH) > 1,000 IU/L, iv) complex pleural effusion defined by ultrasonographic (or radiographic) evidence of loculations or septations. RESULTS: 135 patients (77.8% male, median age 64 years) were recruited. 84 (62.2%) patients received sequential, and 51 (37.8%) patients received concurrent IET. Median RAPID score was 3 (IQR 2-4). IET initiation occurred at a median of 2 (IQR 1-4) days after chest tube insertion. There were no significant differences in demographic and RAPID scores between both groups. 29.6% of patients received 1-2 doses, 39.3% received 3-4 doses, and 31.1% received 5-6 doses of IET. 20.7% of patients received once daily IET dosing and 11.1% received reduced dose tPA (5mg). Compared to sequential IET, the concurrent IET group received fewer doses (3 (IQR 2-3) vs 4 (IQR 3-6), p<0.001), but fewer received a reduced tPA (5mg) dose (3.9% vs 15.5%, p=0.038). Following the first dose, length of stay was 6 (IQR 4-11) days and duration of chest tube drainage was 4 (IQR 3-6) days. Treatment success was 93.3%. Treatment failure, defined by in-hospital mortality attributed to pleural infection, or the need for surgical intervention within 30 days following the initial dose of tPA/DNase, occurred in 9 (6.7%) patients – 3 (surgery for empyema), 6 (in-hospital mortality from pleural infection). Adverse events occurred in 34 (25.2%) patients – 5.9% had pleural bleeding (bloody pleural fluid with acute drop in haemoglobin, requiring blood transfusion or surgery), 11.9% had chest pain requiring escalation in analgesia, and 2.2% had 30-day readmission related to unresolved pleural infection. There were no significant differences in treatment failure (8.3% vs 3.9%, p=0.482) and adverse event rates (26.2% vs 25.5%, p=0.928) for sequential vs concurrent IET. No significant differences in pleural bleeding (4.8% vs 9.8%, p=0.298) and significant chest pain (13.1% vs 9.8%, p=0.566) were observed. CONCLUSIONS: Our study demonstrates the feasibility of concurrent IET, with similar efficacy and safety compared to sequential IET. CLINICAL IMPLICATIONS: Further studies to validate the benefits of concurrent IET and optimal dosing should be performed, including the impact on overall cost. DISCLOSURES: No relevant relationships by Devanand Anantham No relevant relationships by Imran Bin Mohamed Noor No relevant relationships by Wui Mei Chew No relevant relationships by Eugene Gan No relevant relationships by Ken Junyang Goh No relevant relationships by Marnie Tamayo Gutierrez No relevant relationships by Sandra Hui No relevant relationships by Carrie Leong No relevant relationships by Wen Ting Lim No relevant relationships by Jasmine Ong No relevant relationships by Ivana Phua No relevant relationships by Aza Taha No relevant relationships by Qiao Li Tan No relevant relationships by Kah Yee Tham No relevant relationships by Jane Wong

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% 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.

Singapore is a small island city-state in Southeast Asia (Fig. 1), with a multiracial population of 5.7 million people, comprising 76% Chinese, 15% Malays, and 9% Indians and other races.1 Lung cancer presents a significant health challenge to our aging population.

Pulmonary alveolar proteinosis (PAP) can be due to primary autoimmune and secondary causes, including e-cigarette, or vaping, product use-associated lung injury. We present a 33-year-old male presenting with PAP and a history of vaping. Serum anti-granulocyte-macrophage colony-stimulating factor antibodies were present. Vitamin E (VE), but not VE acetate, was detected in bronchoalveolar lavage. This is the first report of potential association between vaping and autoimmune PAP.

Abstract 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 EGFRT790M-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.

The pace of the COVID-19 pandemic has overwhelmed some of the best resourced health systems in the world and has made the need for triage of ICU resources a real possibility.In response, several substantive values have been articulated to serve as guiding principles.The decision to not provide a patient with necessary intensive care unit (ICU) treatment is quite literally a life and death judgement, and excluded patients will almost immediately require some measures of palliation.Examples of substantive values include the statement of the UNESCO International Bioethics Committee, "Macro-and micro-allocation of healthcare resources are ethically justified only when they are based on the principle of justice, beneficence, and equity."In March 2019, the New England Journal of Medicine carried a paper that espoused four values: (1) maximise benefits, (2) treat people equally, (3) promote and reward instrumental value and (4) give priority to the worst off first.Although there is likely to be broad agreement with such values, limited guidance is available when deciding on a particular course of action if there is a direct clash between values.In the context of resource constraints, how should we respond when forced to decide between beneficence and equity?To operationalise ethical values, consensus statements have been developed to offer a blueprint.The triage process can be divided into three parts: (1) explicit inclusion and exclusion criteria for ICU entry, (2) prioritisation based on mortality prediction and (3) reassessment of patients after an appropriate duration of ICU care to identify those who should have life support discontinued.Crisis standards of care require that these processes be conducted with consistency, transparency and accountability.Such blueprint is a tremendous resource to institutions when confronted with an unanticipated pandemic.However, COVID-19 is in truth a rolling pandemic (i.e.,

OBJECTIVES:There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients.MATERIALS AND METHODS:We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted.RESULTS:A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time.CONCLUSIONS:This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.

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.

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. Genomic and transcriptomic analysis of lung adenocarcinoma (LUAD) in Asia indicates that Asian LUADs have fewer mutations, lower driver prevalence and fewer copy number alterations than European LUADs.