Albert Y.H. Lim

Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite–Induced Asthma

Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform γ-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of γ-tocotrienol in a house dust mite (HDM) experimental asthma model. BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory biomarkers. Sera were assayed for IgE and γ-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. γ-Tocotrienol displayed better free radical–neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including α-tocopherol. Besides, γ-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mechanistically, γ-tocotrienol was found to block nuclear NF-κB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did α-tocopherol and prednisolone. More importantly, γ-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform γ-tocotrienol in allergic asthma.

Timeliness of diagnosing lung cancer: Number of procedures and time needed to establish diagnosis

Abstract To study number of procedures and time to diagnose lung cancer and factors affecting the timeliness of clinching this diagnosis. Retrospective cohort study of lung cancer patients who consecutively underwent diagnostic bronchoscopy in 1 year (October 2013 to September 2014). Out of 101 patients diagnosed with lung cancer from bronchoscopy, average time interval between first abnormal computed tomogram (CT) scan-to-1st procedure, 1st procedure-to-diagnosis, and 1st abnormal CT scan-to-diagnosis was 16 ± 26, 11 ± 19, and 27 ± 33 days, respectively. These intervals were significantly longer in those requiring repeat procedures. Multivariate analysis revealed inconclusive 1st procedure to be the predictor of prolonged (>30 days) CT scan to diagnosis time (P = 0.04). Twenty-nine patients (28.7%) required repeat procedures (n = 63). Reasons behind repeating the procedures were inadequate procedure (n = 14), inaccessibility of lesion (n = 9), inappropriate procedure (n = 5), mutation analysis (n = 2), and others (n = 2). Fifty had visible endo-bronchial lesion, 20 had positive bronchus sign, and 83 had enlarged mediastinal/hilar lymph-nodes or central masses adjacent to the airways. Fewer procedures, and shorter procedure to diagnosis time, were observed in those undergoing convex probe endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) (P = 0.04). Most patients exhibit enlarged mediastinal lymph node or mass adjacent to the central airway accessible by convex probe EBUS-TBNA. Hence, combining it with conventional bronchoscopic techniques such as bronchoalveolar lavage, brush, and forceps biopsy increases detection rate, and reduces number of procedures and time to establish diagnosis. This may translate into cost and resource savings, timeliness of diagnosis, greater patient satisfaction, and conceivably better outcomes.

Pleural LDH as a prognostic marker in adenocarcinoma lung with malignant pleural effusion

AbstractTo study the performance of serum and pleural lactate dehydrogenase (LDH) level in predicting survival in patients with adenocarcinoma lung presenting with malignant pleural effusions (MPE) at initial diagnosis.Retrospective cohort study of the patient hospitalized for adenocarcinoma lung with MPE in year 2012.Univariate analyses showed lower pleural fluid LDH 667 (313–967) versus 971 (214–3800), P = 0.04, female gender 9 (100%) versus 27 (41.5%), P = 0.009, never smoking status 9 (100%) versus 36 (55.3%), P = 0.009, and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy 8 (89%) versus 26 (40%), P = 0.009 to correlate with survival of more than 1.7 year versus less than 1.7 year. In multivariate analysis, low pleural fluid LDH and female gender maintained significance. The pleural LDH level of ⩽1500 and >1500 U/L discriminated significantly (P = 0.009) between survival.High pleural LDH (>1500 IU/L) predicts shorter survival (less than a year) in patients with adenocarcinoma lung presenting with MPE at the time of initial diagnosis. This marker may be clinically applied for selecting therapeutic modality directed at prevention of reaccumulation of MPE. Patients with low pleural LDH may be considered suitable for measures that provide more sustained effect on prevention of reaccumulation such as chemical pleurodesis or tunneled pleural catheter.

Can EGFR-Tyrosine Kinase Inhibitors (TKI) Alone Without Talc Pleurodesis Prevent Recurrence of Malignant Pleural Effusion (MPE) in Lung Adenocarcinoma

Abstract: Background and Objective: Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) are effective against lung adenocarcinoma. However, limited data is available assessing the effectiveness of EGFR-TKI use in preventing re-accumulation of MPE. To our knowledge, there is no literature on comparison of talc pleurodesis with EGFR-TKIs alone on re-accumulation of MPE in Asian population. We investigated if EGFR-TKI therapy for advanced lung adenocarcinoma with malignant pleural effusion (MPE) is also successful in preventing pleural fluid re-accumulation following initial drainage. Methods: An observational cohort study of patients with lung adenocarcinoma and MPE in the year 2012 was conducted. Results: 70 patients presented with MPE from lung adenocarcinoma. Fifty six underwent EGFR mutation testing of which 39 (69.6%) had activating EGFR mutation and 34 (87.1%) received TKI. 20 were managed by pleural fluid drainage only whereas 14 underwent talc pleurodesis following pleural fluid drainage. Time taken for the pleural effusion to re-accumulate in those with and without pleurodesis was 9.9 vs. 11.7 months, p=0.59 respectively. More patients (n=10, 25.6%) with activating EGFR mutation presented with complete opacification (white-out) of the hemithorax compared to none without activating EGFR mutation (p=0.02). Conclusion: In TKI eligible patients, early talc pleurodesis may not confer additional benefit in preventing re-accumulation of pleural effusion and may be reserved for non-adenocarcinoma histology, or EGFR negative adenocarcinoma. Complete opacification of the hemithorax on presentation may serve as an early radiographic signal of positive EGFR mutation status.

IMMUNOLOGICAL COROLLARY OF THE PULMONARY MYCOBIOME IN BRONCHIECTASIS: THE CAMEB STUDY

Understanding the composition and clinical importance of the fungal mycobiome was recently identified as a key topic in a “research priorities” consensus statement for bronchiectasis. Patients were recruited as part of the CAMEB study: an international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis patients. The mycobiome was determined in 238 patients by targeted amplicon shotgun sequencing of the 18S–28S rRNA internally transcribed spacer regions ITS1 and ITS2. Specific quantitative PCR for detection of and conidial quantification for a range of airway Aspergillus species was performed. Sputum galactomannan, Aspergillus specific IgE, IgG and TARC (thymus and activation regulated chemokine) levels were measured systemically and associated to clinical outcomes. The bronchiectasis mycobiome is distinct and characterised by specific fungal genera, including Aspergillus, Cryptococcus and Clavispora. Aspergillus fumigatus (in Singapore/Kuala Lumpur) and Aspergillus terreus (in Dundee) dominated profiles, the latter associating with exacerbations. High frequencies of Aspergillus-associated disease including sensitisation and allergic bronchopulmonary aspergillosis were detected. Each revealed distinct mycobiome profiles, and associated with more severe disease, poorer pulmonary function and increased exacerbations. The pulmonary mycobiome is of clinical relevance in bronchiectasis. Screening for Aspergillus-associated disease should be considered even in apparently stable patients. The airway mycobiome in bronchiectasis is associated with clinically significant disease http://ow.ly/MCKj30knVrn

Experience With the Use of Single-Use Disposable Bronchoscope in the ICU in a Tertiary Referral Center of Singapore

Background: Flexible bronchoscopy is performed frequently in intensive care units (ICUs) for various indications using the reusable conventional bronchoscope (CB). Recently, “single-use disposable bronchoscope” (SB) was introduced into the health care industry. The purpose of this study was to compare the utility of SB with CB in ICU. Methods: A retrospective review of medical records of patients undergoing flexible bronchoscopy in the ICUs in the year 2015. Results: Ninety-three patients undergoing flexible bronchoscopy in the ICU were studied. Eighty-three bronchoscopies were performed using SB in 71 patients, and 24 using CB in 22 patients. The most common indications for using the SB were percutaneous tracheostomy [n=37 (44.6%)] in neuro-ICU, followed by collecting specimens for microbiological evaluation [n=20 (24.1%)] in the medical ICU. Airway inspection [8 (9.6%)], bronchial toilet [8 (9.6%)], hemoptysis [5 (6%)], and intubation [3 (3.6%)] were other indications for which SB was used. Microbiological yield of SB was 70% (14/20) versus 70% (7/10) for CB (P=1.0). The median interval between identification of the need-to-start of the procedure was shorter with SB (10 min) versus CB (66 min, P=0.01), whereas the cost was similar, SGD450 versus SGD472, respectively. In addition, less (3 personnel) were needed to perform bronchoscopy with SB versus 5 with CB with additional resource sparing effect in terms of nursing personnel having to wheel the CB equipment to ICU. Conclusions: SB is equivalent in performance to CB in ICU. In addition, the SB may confer clinical, economic, and logistical advantages over the CB.

Significance of coexistent granulomatous inflammation and lung cancer

Aims Coexistence of lung cancer and granulomatous inflammation in the same patient confuses clinicians. We aimed to document the prevalence, clinicopathological features, treatment outcomes and prognosis in patients with coexisting granulomatous inflammation undergoing curative lung resection for lung cancer, in a tuberculosis (TB)-endemic country. Methods An observational cohort study of patients with lung cancer undergoing curative resection between 2012 and 2015 in a tertiary centre in Singapore. Results One hundred and twenty-seven patients underwent lung resection for cancer, out of which 19 (14.9%) had coexistent granulomatous inflammation in the resected specimen. Median age was 68 years and 58.2% were males. Overall median (range) survival was 451 (22–2452) days. Eighteen (14%) patients died at median duration of 271 days after surgery. The postsurgery median survival for those alive was 494 (29–2452) days in the whole group. Subgroup analysis did not reveal any differences in age, gender, location of cancer, radiological features, type of cancer, chemotherapy, history of TB or survival in patients with or without coexistent granulomatous inflammation. Conclusions Incidental detection of granulomatous inflammation in patients undergoing lung resection for cancer, even in a TB-endemic country, may not require any intervention. Such findings may be due to either mycobacterial infection in the past or ‘sarcoid reaction’ to cancer. Although all patients should have their resected specimen sent for acid-fast bacilli culture and followed up until the culture results are reported, the initiation of the management of such patients as per existing lung cancer management guidelines does not affect their outcome adversely.

Role of Bronchoscopy in Prompt Discharge From the Intensive Care Unit.

Background:Intensive care unit (ICU) stays are 2.5 times more costly than other hospital stays, and 93.3% of ICU use is for respiratory disease with ventilator support. The aim of this study was to assess the role of bronchoscopy on discontinuation of mechanical ventilation, and prompt discharge from ICU in our institution. Methods:Retrospective review of medical records of patients referred for bronchoscopic intervention for acute respiratory failure from malignant or benign central airway diseases requiring ICU admission. Results:Twelve critically ill patients were studied. Median (range) age was 63 years (range, 35 to 85 y). Nine (75%) had endotracheal tube, and 3 (25%) had tracheostomy tube. Nine (75%) of 12 patients admitted to ICU could be transferred to general ward after median (range) interval of 2 days (range, 1 to 7 d) after the day of intervention. Median (range) prebronchoscopy and postbronchoscopy PaO2/FiO2 ratio was 102.8 (range, 99.2 to 328) and 180 (range, 129 to 380), respectively, with significant improvement postintervention (P=0.002). Radiologically, all 8 patients with lung atelectasis on presentation experienced complete reexpansion of the lung on the day after bronchoscopic intervention. Conclusion:The majority of patients in our cohort (75%) of benign and malignant etiology could be promptly (within 2 d postbronchoscopy) transferred out from ICU to general ward after successful discontinuation of mechanical ventilation and extubation after bronchoscopic intervention. We advocate early recognition and bronchoscopic intervention in suitable patients.

A new therapeutic avenue for bronchiectasis: Dry powder inhaler of ciprofloxacin nanoplex exhibits superior ex vivo mucus permeability and antibacterial efficacy to its native ciprofloxacin counterpart

Graphical abstract Figure. No caption available. ABSTRACT Non‐cystic fibrosis bronchiectasis (NCFB) characterized by permanent bronchial dilatation and recurrent infections has been clinically managed by long‐term intermittent inhaled antibiotic therapy among other treatments. Herein we investigated dry powder inhaler (DPI) formulation of ciprofloxacin (CIP) nanoplex with mannitol/lactose as the excipient for NCFB therapy. The DPI of CIP nanoplex was evaluated against DPI of native CIP in terms of their (1) dissolution characteristics in artificial sputum medium, (2) ex vivo mucus permeability in sputum from NCFB and healthy individuals, (3) antibacterial efficacy in the presence of sputum against clinical Pseudomonas aeruginosa strains (planktonic and biofilm), and (4) cytotoxicity towards human lung epithelial cells. Despite their similarly fast dissolution rates in sputum, the DPI of CIP nanoplex exhibited superior mucus permeability to the native CIP (5–7 times higher) attributed to its built‐in ability to generate highly supersaturated CIP concentration in the sputum. The superior mucus permeability led to the CIP nanoplexs higher antibacterial efficacy (>3 log10 CFU/mL). The DPI of CIP nanoplex exhibited similar cytotoxicity towards the lung epithelial cells as the native CIP indicating its low risk of toxicity. These results established the promising potential of DPI of CIP nanoplex as a new therapeutic avenue for NCFB.

Our Clinical Experience of Self-Expanding Metal Stent for Malignant Central Airway Obstruction

Background We studied the safety, effectiveness, and limitations of airway stenting using self-expanding metal stent (SEMS) in patients with malignant central airway obstruction (CAO). Methods A retrospective review of records of patients undergoing SEMS placement for malignant CAO during year 2013 - 2014 was done. Results Sixteen patients (11 males and five females) underwent SEMS placement for malignant CAO. Median (range) age was 66 (54 - 78) years. No perioperative or immediate postoperative complications were seen except acute myocardial infarction (AMI) in one patient. Three patients were transferred to intensive care unit (ICU) for closer monitoring after the procedure and were discharged the next day. All four patients with lung atelectasis on presentation experienced complete re-expansion of the lung post-stenting. The dyspnea was substantially relieved in 14 (87.5%) patients. Two of the three patients who had been intubated were weaned off from the ventilator following stent insertion. Stent patency was maintained until death in all patients except one. Median survival from the date of diagnosis and the date of stent placement in lung cancer, esophageal cancer, and thyroid cancer were 140 (21 - 564) and 85 (15 - 361), 288 (80 - 419) and 61 (60 - 171), and 129 (71 - 187) and 67 (16 - 118) days, respectively. This survival was similar to reported expected survival associated with the underlying malignancy. During follow-up, granulation tissue (n = 1), mucostasis (n = 1), and tumor ingrowth (n = 2) were the most frequently encountered complications. Conclusion SEMSs are safe and effective in reversing respiratory failure caused by malignant CAO, averting premature death, allowing application of cancer targeted therapy, and restoring impending shortened survival to expected life expectancy associated with the underlying malignancy.