Yu-Hsiu Chung

Endobronchial Ultrasonography-Guided Transbronchial Needle Aspiration Increases the Diagnostic Yield of Peripheral Pulmonary Lesions: A Randomized Trial

BACKGROUND The diagnostic yield of endobronchial ultrasonography (EBUS)-guided transbronchial needle aspiration (TBNA) for peripheral pulmonary lesions (PPLs) has not been evaluated. The diagnostic impact of TBNA when the EBUS probe is adjacent to lesions remains to be determined. DESIGN A prospective, randomized trial. METHODS Two hundred two patients with PPLs and positive EBUS findings were enrolled. They were randomly classified into two groups. In the EBUS conventional diagnostic procedures (CDPs) group (103 patients), both transbronchial biopsy (TBB) and bronchial washing (BW) were performed. In the EBUS-TBNA plus CDPs group (99 patients), TBNA, TBB, and BW were performed. The diagnostic yield in each group was compared. RESULTS A total of 182 patients (94 in the EBUS CDPs group and 88 in the EBUS-TBNA plus CDPs group) were analyzed. The yield in the EBUS-TBNA plus CDPs group (78.4%) was significantly higher than the EBUS CDPs group (60.6%, p = 0.015). Cases in which the EBUS probe was located within the lesions had a significantly higher diagnostic yield (78.3%) than when the EBUS probe was adjacent to them (47.2%, p < 0.001). Concerning the three different techniques, TBNA showed the highest diagnostic yield (62.5%) in comparison to TBB (48.9%) and to BW (19.8%). The diagnostic yield of TBNA remained unchanged even when the EBUS probe was adjacent to the lesions (p = 0.89). No additional adverse effects were observed in the EBUS-TBNA plus CDPs group. CONCLUSIONS Applying TBNA to EBUS-guided CDPs further increased the diagnostic yield of PPLs without additional risk. The diagnostic advantage of TBNA became more obvious if the EBUS probe was adjacent to the lesions. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00626587.

Impact of clinical severity index, infective pathogens, and initial empiric antibiotic use on hospital mortality in patients with ventilator-associated pneumonia

BACKGROUND The prompt initial use of appropriate antibiotics should improve mortality rates in adults with ventilator-associated pneumonia (VAP). However, the incidence of multidrug-resistant (MDR) pathogen infections is on the rise, and the choice of the initial empiric antibiotic may be challenging. We investigated whether appropriate initial antibiotic therapy, infective pathogens, and the clinical severity index influence hospital mortality in patients with VAP and determined independent risk factors for the same. METHODS This study evaluated 163 adult patients (aged ≥ 18 years) at Chang Gung Memorial Hospital, Kaohsiung, Taiwan, from January 1, 2007, to January 31, 2008. Eligibility was evaluated based on criteria for VAP. Sequential Organ Failure Assessment (SOFA) scores, Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) scores, oxygenation index, underlying comorbidities, septic shock status, previous tracheostomy status, and factors related to pneumonia were collected for analysis. RESULTS Ninety-two patients survived from a total 163 patients with VAP during the course of their confinement in the intensive care unit. Multivariable logistic regression analysis identified that a pre-existing Charlson Comorbidity Index score (P = .011), initial oxygenation index (P = .025), SOFA score (P = .043), VAP caused by Acinetobacter baumanii (P = .030), and infection with MDR pathogens (P = .003) were independent risk factors for hospital mortality in patients with VAP. CONCLUSION High Charlson Comorbidity Index score, high initial oxygenation index, high SOFA score, and infection with Acinetobacter baumannii or MDR pathogens significantly affect hospital mortality in patients with VAP.

Baseline and Trend of Lymphocyte-to-Monocyte Ratio as Prognostic Factors in Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer Patients Treated with First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

Background Patients with early-stage lung cancer who have a high baseline lymphocyte-to-monocyte ratio (LMR) have a favorable prognosis. However, the prognostic significance of LMR in patients with advanced-stage EGFR-mutant non-small cell lung cancer (NSCLC) receiving first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has not been established. We conducted a retrospective analysis to investigate the influence of LMR on clinical outcomes including progression-free survival (PFS) and overall survival (OS) in EGFR-mutant patients with NSCLC. Materials and Methods Of 1310 lung cancer patients diagnosed between January 2011 and October 2013, 253 patients receiving first-line EGFR-TKIs for EGFR-mutant NSCLC were included. The cut-off values for baseline and the 1-month-to-baseline ratio of LMR (MBR), determined by using receiver operating characteristic curves, were 3.29 and 0.63, respectively. Patients were divided into 3 prognostic groups: high LMR and MBR, high LMR or MBR, and low LMR and MBR. Results The mean patient age was 65.2 years, and 41% were men. The median PFS and OS were 10.3 and 22.0 months, respectively. The PFS in patients with high LMR and MBR, high LMR or MBR, and low LMR and MBR were 15.4, 7.1, and 2.0 months, respectively (p < 0.001), whereas the OS were 32.6, 13.7, and 5.1 months, respectively (p < 0.001). Conclusion A combination of baseline and trend of LMR can be used to identify patients with a high mortality risk in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs.

Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy

Introduction Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy. Methods To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment. Results Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality. Conclusions Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.

NEW IMAGE CHARACTERISTICS IN ENDOBRONCHIAL ULTRASONOGRAPHY FOR DIFFERENTIATING PERIPHERAL PULMONARY LESIONS

Endobronchial ultrasonography (EBUS) rapidly and accurately localizes peripheral pulmonary lesions. It can aid differential diagnosis by characterizing lesions and discriminating between neoplastic and non-neoplastic disease. From July 2005 through December 2006, patients with peripheral lesions underwent EBUS examination in a tertiary-referral teaching hospital. Image characteristics were subsequently correlated with definite histopathologic diagnosis. Three current-issued image patterns of EBUS were assayed from 40 initial patients, including (a) hypoechoic areas, (b) anechoic areas and (c) luminant areas around the probe. Excluding 22 cases because of inconsistent typing, 193 patients possessing definite diagnoses were enrolled in the investigation, of which 107 cases (55.4%) were neoplastic diseases. Hypoechoic areas appeared to be unrelated to the nature of the lesions (p = 0.288). Most lesions with anechoic areas were neoplasms (18 of 21 cases, 85.7%) and lesions without luminant areas suggested non-neoplastic disease (19 of 24 cases, 79.2%). Anechoic and luminant areas were significantly different between neoplasm and non-neoplasm groups (p = 0.003 and p < 0.001, respectively). The average additional time for EBUS required was 3.85 +/- 2.36 min (range 1 to 13 min). In conclusion, this uncomplicated and time-saving method of using EBUS image patterns could provide additional information to facilitate differential diagnoses.

Factors Predicting Ventilator Dependence in Patients with Ventilator-Associated Pneumonia

Objectives. To determine risk factors associated with ventilator dependence in patients with ventilator-associated pneumonia (VAP). Study Design. A retrospective study was conducted at Chang Gung Memorial Hospital, Kaohsiung, from January 1, 2007 to January 31, 2008. Methods. This study evaluated 163 adult patients (aged ≥18 years). Eligibility was evaluated according to the criterion for VAP, Sequential Organ Failure Assessment (SOFA) score, Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) score. Oxygenation index, underlying comorbidities, septic shock status, previous tracheostomy status, and factors related to pneumonia were collected for analysis. Results. Of the 163 VAP patients in the study, 90 patients survived, yielding a mortality rate of 44.8%. Among the 90 surviving patients, only 36 (40%) had been weaned off ventilators at the time of discharge. Multivariate logistic regression analysis was used to identify underlying factors such as congestive cardiac failure (P = 0.009), initial high oxygenation index value (P = 0.04), increased SOFA scores (P = 0.01), and increased APACHE II scores (P = 0.02) as independent predictors of ventilator dependence. Results from the Kaplan-Meier method indicate that initial therapy with antibiotics could increase the ventilator weaning rate (log Rank test, P < 0.001). Conclusions. Preexisting cardiopulmonary function, high APACHE II and SOFA scores, and high oxygenation index were the strongest predictors of ventilator dependence. Initial empiric antibiotic treatment can improve ventilator weaning rates at the time of discharge.

First- or Second-line Gefitinib Therapy in Unknown Epidermal Growth Factor Receptor Mutants of Non-Small-Cell Lung Cancer Patients Treated in Taiwan

Gefitinib is effective in treating patients with non-small-cell lung cancer (NSCLC). The response rate and improvement in survival are related to several aspects, including race, gender, smoking status, and histology; however, little is known about the relationship between survival and length of gefitinib treatment. We conducted this retrospective study to examine this relationship and identify the predictive factors influencing survival and tumor response in chemonaive and chemotherapy patients who had stage IIIb or IV NSCLC with unknown epidermal growth factor receptor mutants. This analysis was aimed to clarify the difference between first- and second-line gefitinib therapy. Among the 918 newly diagnosed, inoperable NSCLC patients from March 2003 to December 2006, 437 (47.6%) had ever received gefitinib therapy. One hundred forty-nine patients (34.0%) who selected gefitinib as first- or second-line therapy were included in the analysis. The overall survival rates of first- and second-line gefitinib therapy were 12.8 months and 20.7 months, respectively (P = .110). The shorter overall survival may be caused by the omission of platinum-based doublet chemotherapy in 37 patients from the first-line group (39.4%). There was also no significant difference in progression-free survival (6.8 months versus 4.9 months; P = .415), and the objective tumor response and disease control rates were similar. Better prognosis and tumor response was associated with female gender, adenocarcinoma, nonsmokers, and good performance status. The difference in overall survival between patients undergoing second-line treatment compared with those undergoing first-line treatment preceding chemotherapy was significant (P = .041). The overall survival, progression-free survival, and tumor response rates were similar in the patients who received gefitinib as initial therapy or after conventional chemotherapy.

Antacid Use and De Novo Brain Metastases in Patients with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Were Treated Using First-Line First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Background Antacid treatments decrease the serum concentrations of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), although it is unknown whether antacids affect clinical outcomes. As cerebrospinal fluid concentrations of TKIs are much lower than serum concentrations, we hypothesized that this drug-drug interaction might affect the prognosis of patients with de novo brain metastases. Materials and Methods This retrospective study evaluated 269 patients with EGFR-mutant non-small cell lung cancer (NSCLC) who had been diagnosed between December 2010 and December 2013, and had been treated using first-line first-generation EGFR-TKIs. Among these patients, we identified patients who concurrently used H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) as antacids. Patients who exhibited >30% overlap between the use of TKIs and antacids were considered antacid users. Results Fifty-seven patients (57/269, 21.2%) were antacid users, and antacid use did not significantly affect progression-free survival (PFS; no antacids: 11.2 months, H2RAs: 9.4 months, PPIs: 6.7 months; p = 0.234). However, antacid use significantly reduced overall survival (OS; no antacids: 25.0 months, H2RAs: 15.5 months, PPIs: 11.3 months; p = 0.002). Antacid use did not affect PFS for various metastasis sites, although antacid users with de novo brain metastases exhibited significantly shorter OS, compared to non-users (11.8 vs. 16.3 months, respectively; p = 0.041). Antacid use did not significantly affect OS in patients with bone, liver, or pleural metastases. Conclusion Antacid use reduced OS among patients with EGFR-mutant NSCLC who were treated using first-line first-generation EGFR-TKIs, and especially among patients with de novo brain metastases.

Baseline, Trend, and Normalization of Carcinoembryonic Antigen as Prognostic Factors in Epidermal Growth Factor Receptor-Mutant Nonsmall Cell Lung Cancer Patients Treated With First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

AbstractAmong epidermal growth factor receptor (EGFR) mutation status unknown nonsmall cell lung cancer (NSCLC) patients, those with higher carcinoembryonic antigen (CEA) level are more likely to response to EGFR-tyrosine kinase inhibitors (TKIs) because they tend to have mutant epidermal growth factor receptor (EGFR). However, patients with higher CEA also have more tumor burden. With the above paradoxical evidence, it is prudent to understand the prognostic significance of baseline CEA in patients with EGFR-mutant NSCLC treated with first-line EGFR-TKIs. The clinical significance of the trend in CEA after treatment and the impact of CEA normalization during EGFR-TKI therapy are also unknown and potentially important.A total of 241 patients who received first-line EGFR-TKIs were included. As to baseline CEA, patients were divided into normal, low, and high baseline CEA by cut point determined by receiver operating characteristic curves. As to CEA responses, patients were divided into 3 groups accordingly to their amount of CEA change after taking TKIs. In group A, 1-month follow-up CEA level decreased more than 35% with nadir CEA normalization; in group B, 1-month follow-up CEA level decreased more than 35% without nadir CEA normalization; and in group C, 1-month follow-up CEA level decreased less than 35% or increased.Patients with higher baseline CEA levels had shorter progression-free survival (PFS) and overall survival (OS) (CEA > 32 vs 5–32 vs <5 ng/mL, PFS = 8.8 vs 11.3 vs 14.4 months, respectively, P < 0.001; OS = 17.8 vs 22.0 vs 27.9 months, respectively, P = 0.01). For trend and CEA normalization in groups A, B, and C, PFS was 14.3, 10.6, and 7.1 months, respectively (P < 0.001); OS was 29.7, 20.0, and 16.2 months, respectively (P < 0.001).Baseline, trend, and normalization of CEA levels are potential prognostic markers for patients with EGFR-mutant advanced NSCLC treated with first line EGFR-TKIs.

a randomized clinical trial of neurally adjusted ventilatory assist versus conventional weaning mode in patients with COPD and prolonged mechanical ventilation

Background Patient-ventilator asynchrony is a common problem in mechanically ventilated patients; the problem is especially obvious in COPD. Neutrally adjusted ventilatory assist (NAVA) can improve patient-ventilator asynchrony; however, the effect in COPD patients with prolonged mechanical ventilation is still unknown. The goals of this study are to evaluate the effect of NAVA and conventional weaning mode in patients with COPD during prolonged mechanical ventilation. Methods The study enrolled a total of 33 COPD patients with ventilator dependency for more than 21 days in the weaning center. A diaphragm electrical activity (Edi) catheter was inserted in patients within 24 hours after admission to the respiratory care center, and patients were randomly allocated to NAVA or conventional group. A spontaneous breathing trial was performed every 24 hours. The results correlated with the clinical parameters. Results There were significantly higher asynchrony incidence rates in the whole group after using Edi catheter (before vs post-Edi catheter insertion =60.6% vs 87.9%, P<0.001). Asynchrony index: before vs post-Edi catheter insertion =7.4%±8.5% vs 13.2%±13.5%, P<0.01. Asynchrony incidence: NAVA vs conventional =0% vs 84.2%, P<0.001. Asynchrony index: NAVA vs conventional =0 vs 11.9±11.2 (breath %), P<0.001. The most common asynchrony events were ineffective trigger and delayed trigger. Conclusion Compared to conventional mode, NAVA mode can significantly enhance respiratory monitoring and improve patient-ventilator interaction in COPD patients with prolonged mechanical ventilation in respiratory care center.