Autoimmune pulmonary alveolar proteinosis with a history of vaping and vitamin E-positive bronchoalveolar lavage.

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.

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis.

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.

Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.

PURPOSE: Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC. PATIENTS AND METHODS: MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG. RESULTS: Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154). CONCLUSION: Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC.

Lipidomic Profiling of Lung Pleural Effusion Identifies Unique Metabotype for EGFR Mutants in Non-Small Cell Lung Cancer.

Cytology and histology forms the cornerstone for the diagnosis of non-small cell lung cancer (NSCLC) but obtaining sufficient tumour cells or tissue biopsies for these tests remains a challenge. We investigate the lipidome of lung pleural effusion (PE) for unique metabolic signatures to discriminate benign versus malignant PE and EGFR versus non-EGFR malignant subgroups to identify novel diagnostic markers that is independent of tumour cell availability. Using liquid chromatography mass spectrometry, we profiled the lipidomes of the PE of 30 benign and 41 malignant cases with or without EGFR mutation. Unsupervised principal component analysis revealed distinctive differences between the lipidomes of benign and malignant PE as well as between EGFR mutants and non-EGFR mutants. Docosapentaenoic acid and Docosahexaenoic acid gave superior sensitivity and specificity for detecting NSCLC when used singly. Additionally, several 20- and 22- carbon polyunsaturated fatty acids and phospholipid species were significantly elevated in the EGFR mutants compared to non-EGFR mutants. A 7-lipid panel showed great promise in the stratification of EGFR from non-EGFR malignant PE. Our data revealed novel lipid candidate markers in the non-cellular fraction of PE that holds potential to aid the diagnosis of benign, EGFR mutation positive and negative NSCLC.

Radial endobronchial ultrasound in diagnosing peripheral lung lesions in a high tuberculosis setting.

BACKGROUND: Current data for the utility of radial endobronchial ultrasound (EBUS) in investigating peripheral lung lesions (PLLs) has been restricted to populations with low pulmonary tuberculosis (TB) incidence. The aim of this study was to assess the diagnostic utility of radial EBUS with guide sheath in the diagnosis of peripheral lung lesions in Singapore, a high TB incidence setting. METHODS: A post-hoc database analysis was performed. 123 consecutive patients with computed tomographic evidence of PLLs who underwent radial EBUS guided bronchoscopy were included. RESULTS: The final diagnosis was malignancy in 76 cases and benign in 44 cases. Radial EBUS guided bronchoscopy had a sensitivity of 65.8 % for malignancy, positive predictive value of 100 %, negative predictive value of 62.9 %, and a diagnostic accuracy of 82.5 %. 22 patients had a final diagnosis of pulmonary TB. The diagnostic sensitivity for pulmonary TB was 77.3 %, with a positive predictive value of 100 %, negative predictive value of 95.2 % and a diagnostic accuracy of 95.8 %. Overall, 58.8 % of pulmonary TB cases relied on histology to make an early diagnosis. CONCLUSION: Radial EBUS guided bronchosopy is useful in investigating PLLs in a high TB incidence setting. Our data also suggests that radial EBUS is a more rapid diagnosis technique for tuberculous lesions.

Impact of Smoking and Brain Metastasis on Outcomes of Advanced EGFR Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

OBJECTIVES: This purpose of this study was to examine clinical-pathologic factors--particularly smoking and brain metastases--in EGFR mutation positive (M(+)) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI. METHODS: A retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M(+) ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival. RESULTS: 444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M(+.) Amongst never-smokers (n=468), EGFR M(+) were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson's chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival. CONCLUSIONS: The high prevalence of EGFR M(+) in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.

Oesophageal Doppler ultrasound in the assessment of haemodynamic status of patients admitted to the medical intensive care unit with septic shock.

INTRODUCTION: Haemodynamic monitoring is an essential element in the management of critically ill patients in the intensive care unit (ICU). However, there have been increasing concerns about the clinical utility and safety profile of the invasive pulmonary artery catheter (PAC). Oesophageal Doppler (ED) monitoring has emerged recently as a safer and less invasive tool which can be used by the intensivist to estimate cardiac output in the critically ill patient. Validation studies have thus far only been performed in surgical patients perioperatively and in mixed surgical/medical ICU patients. Currently, minimal data are available in any sizeable Asian population or in patients with severe sepsis. The assumption that these normograms and data hold true for our local medical ICU patients may not be valid due to differences in body habitus. MATERIALS AND METHODS: Our primary aim is to validate the oesophageal Doppler as a reliable measure of cardiac index, systemic vascular resistance (SVR) and preload in our local Asian population of patients with severe sepsis and septic shock in the medical ICU. This was a prospective pilot study on 12 consecutive mechanically ventilated patients in our medical ICU with the diagnosis of septic shock as defined by SCCM/ESICM/ACCP/ATS/SIS International Sepsis definitions Conference-Critical Care Medicine 2003 and required PAC haemodynamic monitoring as indicated by Medical Intensive Care Unit attending. RESULTS: Ninety-seven paired cardiac output measurements were made. Cardiac output ranged from 2.87 to 11.0 L/ min (calculated cardiac index ranging from 1.73 to 6.36 L/min/m2) when measured using the PAC with thermodilution technique and from 2.0 to 12.1 L/min (calculated cardiac index of 1.2 to 7.2 L/min/m2) using the trans-oesophageal Doppler. There was moderately good correlation between CIpac and CIed (correlation coefficient, r = 0.762 with PCA = 58%). The mean bias was 0.26 L/min/m2 (P <0.07), while the limit of agreement was +/- 1.44 L/min/m2. CONCLUSION: ED has good correlation with PAC in measuring cardiac index in Asians with septic shock but is an unreliable measure of both pre-load and SVR.

Use of molecular adsorbent recirculating system in acute liver failure attributable to dengue hemorrhagic fever.

Fulminant liver failure is an uncommon but life-threatening complication of severe dengue infection. Molecular adsorbent recirculating system (MARS), which reverses hepatic encephalopathy, is an emerging important element in the armamentarium of organ support in the intensive care unit in patients suffering from acute liver failure. We report an intensive care unit case of fulminant liver failure secondary to dengue hemorrhagic fever, which was supported with MARS. MARS led to rapid reversal of biochemical profile and encephalopathy, resulting in early extubation and intensive care unit discharge.

Acute exacerbation of COPD requiring admission to the intensive care unit.

OBJECTIVE: The aim of this study was to summarize experiences of patients admitted to the intensive care unit (ICU) for an acute exacerbation of COPD and to identify factors associated with a poor outcome. METHODOLOGY: An observational case series of 102 consecutive admissions to the ICU for acute exacerbation of COPD between January 1998 and December 2002 were studied. RESULTS: In total, 102 admissions to the ICU were reviewed. There were no ICU deaths but there were 18 hospital deaths (18%). A total of 28 patients were treated with non-invasive positive pressure ventilation (NIPPV), of whom four (14% failure rate) subsequently required intubation and mechanical ventilation (MV). Another 16 patients (16%) were successfully weaned from MV with NIPPV. Nine patients (9%), who had more than one episode of re-intubation after weaning (RAW), were from the mechanically ventilated group. Tracheostomy was performed for four patients (3.9%). The median duration of both NIPPV and MV was 1 day. The median length of stay in the ICU and hospital were 2 days (SD, 7.2) and 8 days (SD, 9.6), respectively. Univariate analysis identified serum total protein to be associated with hospital mortality (P = 0.004) CONCLUSION: For patients with acute exacerbations of COPD in the ICU, serum total protein, a surrogate marker for nutrition, was significantly associated with hospital mortality.