Whole genome gene expression changes and hematological effects of rikkunshito in patients with advanced non-small cell lung cancer receiving first line chemotherapy.

It has been demonstrated that the traditional Chinese medicine rikkunshito, ameliorates anorexia in several types of human cancer and attenuates lung injury by inhibiting neutrophil infiltration. The current study investigated the clinical and hematological effects of rikkunshito and its underlying mechanisms of action in the treatment of advanced non-small cell lung cancer (NSCLC). The Illumina microarray BeadChip was used to analyze the whole-genome expression profiles of peripheral blood mononuclear cells in 17 patients with advanced NSCLC. These patients were randomized to receive combination chemotherapy (cisplatin and gemcitabine) with (n=9, CTH+R group) or without (n=8, CTH group) rikkunshito. The primary endpoint was the treatment response and the categories of the scales of anorexia, nausea, vomiting and fatigue; secondary endpoints included the hematological effect and whole genome gene expression changes. The results of the current study indicated that there were no significant differences in clinical outcomes, including treatment response and toxicity events, between the two groups. Median one-year overall survival (OS) was 12 months in the CTH group and 11 months in the CTH+R group (P=0.058 by log-rank test), while old age (>60 years old) was the only independent factor associated with one-year OS (hazard ratio 1.095, 95% confidence interval, 1.09-1.189, P=0.030). Patients in the CTH+R group experienced significantly greater maximum decreases in both white cell count (P=0.034) and absolute neutrophil count (P=0.030) from the baseline. A total of 111 genes associated with neutrophil apoptosis, the cell-killing ability of neutrophils, natural killer cell activation and B cell proliferation were up-regulated following rikkunshito treatment. A total of 48 genes associated with neutrophil migration, coagulation, thrombosis and type I interferon signaling were down-regulated following rikkunshito treatment. Rikkunshito may therefore affect the blood neutrophil count when used with combination chemotherapy in patients with NSCLC, potentially by down-regulating prostaglandin-endoperoxidase synthase 1, MPL, AMICA1 and junctional adhesion molecule 3, while up-regulating elastase, neutrophil expressed, proteinase 3, cathepsin G and cluster of differentiation 24.

A Survival Scoring System for Non-Small Cell Lung Cancer Patients with De Novo Bone Metastases.

In the pre-tyrosine kinase inhibitors (TKIs) era, non-small cell lung cancer (NSCLC) patients with de novo bone metastases had a worse prognosis than those without. However, whether epidermal growth factor receptor (EGFR)-TKIs affect the outcomes of EGFR mutant NSCLC patients with de novo bone metastases has not been well studied thus far. We retrospectively studied the effect of EGFR mutation status and first-line EGFR-TKIs on patient outcomes and created a survival scoring system for NSCLC patients with de novo bone metastases. This retrospective study evaluated 1510 NSCLC patients diagnosed between November 2010 and March 2014. Among these patients, 234 patients had de novo bone metastases. We found that 121 of these 234 patients (51.7%) had positive EGFR mutation tests, and a positive EGFR mutation test significantly affected overall survival (OS) (EGFR mutant: 15.2 months, EGFR wild type: 6.5 months; p < 0.001). Other prognostic factors significant in the multivariable analysis for NSCLC with de novo bone metastases included Eastern Cooperative Oncology Group performance status (PS) (OS; PS 0-2: 11.2 months, PS 3-4: 4.9 months; p = 0.002), presence of extraosseous metastases (OS; with extraosseous metastases: 8.8 months, without extraosseous metastases: 14.0 months; p = 0.008), blood lymphocyte-to-monocyte ratio (LMR) (OS; LMR > 3.1: 17.1months, LMR ≤ 3.1: 6.9months; p < 0.001). A positive EGFR mutation status reversed the poor outcomes of NSCLC patients with de novo bone metastases. A simple and useful survival scoring system including the above clinical parameters was thus created for NSCLC patients with de novo bone metastases.

Impact of clinical parameters and systemic inflammatory status on epidermal growth factor receptor-mutant non-small cell lung cancer patients readministration with epidermal growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration to lung cancer patients is common owing to the few options available. Impact of clinical factors on prognosis of EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKI readministration after first-line EGFR-TKI failure and a period of TKI holiday remains unclear. Through this retrospective study, we aimed to understand the impact of clinical factors in such patients. METHODS: Of 1386 cases diagnosed between December 2010 and December 2013, 80 EGFR-mutant NSCLC patients who were readministered TKIs after failure of first-line TKIs and intercalated with at least one cycle of cytotoxic agent were included. We evaluated clinical factors that may influence prognosis of TKI readministration as well as systemic inflammatory status in terms of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR). Baseline NLR and LMR were estimated at the beginning of TKI readministration and trends of NLR and LMR were change amount from patients receiving first-Line TKIs to TKIs readministration. RESULTS: Median survival time since TKI readministration was 7.0 months. In the univariable analysis, progression free survival (PFS) of first-line TKIs, baseline NLR and LMR, and trend of LMR were prognostic factors in patients receiving TKIs readministration. In the multivariate analysis, only PFS of first-line TKIs (p < 0.001), baseline NLR (p = 0.037), and trend of LMR (p = 0.004) were prognostic factors. CONCLUSION: Longer PFS of first-line TKIs, low baseline NLR, and high trend of LMR were good prognostic factors in EGFR-mutant NSCLC patients receiving TKI readministration.

Advanced non-Small cell lung cancer patients at the extremes of age in the era of epidermal growth factor receptor tyrosine kinase inhibitors.

OBJECTIVES: The clinical characteristics and survival of very young (≤40 years) and very old (>80years) patients with advanced non-small cell lung cancer (NSCLC) are distinct. However, the benefits of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) to patients at the extremes of age with NSCLC harboring EGFR mutation have not been well studied. We retrospectively studied the effect of extreme age on patients' clinical characteristics and prognosis. MATERIALS AND METHODS: Of 1510 lung cancer patients diagnosed between November 2010 and March 2014, 555 patients who were tested for EGFR mutations were included. Patients were divided into the following groups according to age: young (≤40 years), lower medium (41-60 years), higher medium (61-80years), and very old (>80years). RESULTS: Of the 555 patients, 20 (3.6%) patients were aged ≤40 years and 60 (10.8%) patients were aged >80years. Young NSCLC patients had a lower BMI (p=0.003), more brain (p=0.016) and bone metastases (p=0.002) Very young lung cancer patients still have poor prognosis even they were EGFR mutant. (EGFR mutant vs. wild type patients, OS: 12 vs. 7.3 months, p=0.215) Very old NSCLC patients had a lower BMI (p=0.003) and poor ECOG PS (p=0.028). Positive EGFR mutation test reverses poor prognosis of elderly NSCLC patients. (EGFR mutant vs. wild type patients, OS: 13.2 vs. 4.9 months, p=0.003) CONCLUSION: We observed EGFR mutations reverse the poor prognosis of old patients with NSCLC. However, young patients with lung cancer have a poor prognosis even if they harbor EGFR mutations.

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.

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.

The impact of clinical parameters on progression-free survival of non-small cell lung cancer patients harboring EGFR-mutations receiving first-line EGFR-tyrosine kinase inhibitors.

OBJECTIVES: In daily practice, some patients with certain clinical characteristics may have better responses to the administration of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). It is therefore reasonable to stratify and weigh the importance of these clinical parameters which may not only affect patients' responses to TKIs but also progression-free survival (PFS) other than the impact of EGFR mutation status per se. MATERIALS AND METHODS: This retrospective study evaluated EGFR-mutant, non-small cell lung cancer patients who received EGFR-TKIs as a first-line therapy between January 2011 and December 2013. Several potential prognostic factors were analyzed with respect to PFS, and the results of this analysis were validated in another time cohort. RESULTS: A total of 262 patients were included in the study. Age ≤ 40 years, uncommon EGFR mutations, poor performance status, more sites of distal metastasis, and blood lymphocyte to monocyte ratio ≤ 3 were independently associated with poor PFS. These five factors were included in a scoring system and three prognostic groups A, B, and C, were formed based on total scores of 0-1, 2, and ≥ 3, respectively. In the test group, the PFS was 15.7 month, 9.3 month, and 4.0 month in groups A, B, and C, respectively (p<0.001). Between the test and validation groups, no significant differences were found in each one of the three prognostic groups. CONCLUSIONS: The scoring system appears valid and reproducible for PFS prognosis in EGFR-mutant patients who received first-line EGFR-TKIs.

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.

Among 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.

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.

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.

Higher levels of soluble Fas ligand and transforming growth factor-ß after omalizumab treatment: a case report.

A skewed T-helper (T(h))1/T(h)2 immune response is considered to be the major cause of allergic disorders. Overproduction of T(h)2 cytokines, which promote recruitment and activation of mast cells and eosinophils, plays a key part in the pathogenesis of allergic asthma. The mechanisms by which omalizumab is effective in asthma treatment are not yet fully understood. A 16-year-old girl who was experiencing frequent asthma attacks in spite of daily administration of budesonide (640 µg) and montelukast (10mg) was given omalizumab (375 mg) at intervals of 2 weeks, to prevent a visit to the emergency room. Plasma levels of T(h)1 cytokines [interferon (IFN)-γ and interleukin (IL)-12p70], T(h)2 cytokines (IL-4 and IL-13), other proinflammatory and regulatory cytokines [IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß], chemokines [monocyte chemotactic protein (MCP)-1, chemokine ligand (CCL)7, and CCL17], and soluble Fas ligand (sFasL) were measured before treatment and after treatment for 8 weeks. She showed a good clinical response to omalizumab: her lung function parameters improved and the use of ß2-agonist decreased. No emergency room visits were required after omalizumab treatment for 8 weeks. Plasma levels of sFasL and TGF-ß showed obvious increases after omalizumab therapy. IL-12p70 levels were decreased as compared to the corresponding baseline levels. These findings suggest that the effects of omalizumab in asthma treatment are not restricted to the regulation of the skewed T(h)1/T(h)2 cytokine immune response, and sFasL-mediated apoptosis and regulatory T-cell (Treg)-mediated TGF-ß seem to have important roles in the therapeutic effects of omalizumab.

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.

Mortality risk factors in patients with Acinetobacter baumannii ventilator: associated pneumonia.

BACKGROUND/PURPOSE: Ventilator-associated pneumonia (VAP) caused by Acinetobacter baumannii has contributed to high mortality rate, prolonged stays in the intensive care unit, and the rapid development of antimicrobial resistance to commonly used antimicrobials. This study sought to determine predictors of mortality and carbapenem resistance for patients with A baumannii VAP. METHODS: We retrospectively reviewed 541 adult patients with A baumannii pneumonia, who were admitted to a medical center between 2005 and 2007; of which 180 (33.3%) had been treated with mechanical ventilation. Of the 180 patients, 98 (54.4%) who survived were categorized as the survivor group, and 82 (45.6%) who died as the mortality group. Eighty-seven (48.3%) with imipenem-sensitive A baumannii VAP were categorized as the IS-AB group, and the remaining 93 (51.7%) with imipenem-resistant VAP as the IR-AB group. RESULTS: Compared with the survivor group, the mortality group had significantly higher Charlson comorbidity index scores, and more neoplastic disease, other sites of infection, bloodstream infections, altered mental status, confusion, urea >7 mmol/L, respiratory rate >30/min, low blood pressure (systolic <90 mmHg or diastolic <60 mmHg), age >65 years (CURB-65) ≥ 3, creatinine > 1.6 mg/dL, C-reactive protein ≥ 100 mg/L, and imipenem resistance. The survivor group had more cases of tracheostomy and diabetes mellitus than the mortality group had. Compared with the IS-AB group, the IR-AB group had higher Charlson comorbidity index scores, longer stays before VAP onset, an increase in other sites of infection, white blood cell count <4/µL or >1.1 × 10(4)/µL, and higher hospital mortality rates. CONCLUSION: Inadequate initial empiric antimicrobial therapy and higher disease severity scores, including CURB ≥ 3 and C-reactive protein ≥ 120 mg/L, were independent risk factors associated with higher mortality rates for A baumannii pneumonia. Length of stay before VAP and white blood cell count <4/µL or >1.1 × 10(4)/µL were independent risk factors for carbapenem resistance.

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.

Association of tumor necrosis factor-alpha-863C/A gene polymorphism with chronic obstructive pulmonary disease.

The aim of this study was to investigate genetic effects on the pathogenesis of chronic obstructive pulmonary disease (COPD). The study was conducted as a prospective case-control study in a medical center in southern Taiwan. The patient group consisted of 145 male patients with smoking-related COPD and a control group of 139 resistant smokers from July 2004 to September 2009. We compared allele and genotype frequencies of three tag single nucleotide polymorphisms (SNP) of the TNF-alpha gene promoter region at -308, -863, and -1031 in all subjects. We also analyzed the influence of each genetic variant on pulmonary function parameters, body mass index (BMI), serum TNF-alpha levels, and outcomes among heavy smokers with or without COPD. COPD patients had a significantly lower A allele frequency (9.7 vs. 15.1%, OR = 0.6, p = 0.048, false discovery rate q = 0.144) and a significantly lower A carrier genotype frequency (19.3 vs. 30.2%, OR = 0.52, p = 0.042, q = 0.135) than resistant smokers. The -863 CA genotype was associated with a better FEV(1)/FVC ratio (79 vs. 71.5%, p = 0.034), and higher BMI (24.9 vs. 23.6 kg/m(2), p = 0.048). In addition, COPD patients with the -1031 C carrier genotype had higher serum TNF-alpha levels (20.9 vs. 16.2 pg/ml, p = 0.01). BMI (hazard ratio = 0.84, 95% CI = 0.74-0.96, p = 0.008) was the only independent predictor for mortality. The TNF-alpha -863 A allele may confer a degree of resistance to the susceptibility to and muscle wasting of COPD among heavy smokers.

Clinical outcomes in patients with ICU-related pancreatitis.

AIM: To identify risk factors predictive of intensive care unit (ICU) mortality in patients with ventilator-related pancreatitis. The clinical outcomes of patients with ventilator-related pancreatitis were compared with those of patients with pancreatitis-related respiratory failure as well as controls. METHODS: One hundred and forty-eight patients with respiratory failure requiring mechanical ventilation and concomitant acute pancreatitis were identified from a prospectively collected dataset of 9108 consecutive patients admitted with respiratory failure over a period of five years. Sixty patients met the criteria for ventilator-related pancreatitis, and 88 (control patients), for pancreatitis-related respiratory failure. RESULTS: Mortality rate in ventilator-related pancreatitis was comparable to that in ICU patients without pancreatitis by case-control methodology (P = 0.544). Multivariate logistic regression analysis identified low PaO(2)/FiO(2) (OR: 1.032, 95% CI: 1.006-1.059, P = 0.016) as an independent risk factor for mortality in patients with ventilator-related pancreatitis. The mortality rate in patients with ventilator-related pancreatitis was lower than that in patients with acute pancreatitis-related respiratory failure (P < 0.001). CONCLUSION: We found that low PaO(2)/FiO(2) was an independent clinical parameter predictive of ICU mortality in patients with ventilator-related pancreatitis.

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.

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.