Frequency and clinical features of BRAF mutations among patients with stage III/IV lung adenocarcinoma without EGFR/ALK aberrations.

PURPOSE: BRAF mutations are found in 1-5% of non-small cell lung cancers, particularly adenocarcinomas. However, information regarding this mutation is limited in patients without EGFR/ALK aberrations, who have limited treatment options. PATIENTS AND METHODS: The medical records of 224 stage III/IV adenocarcinoma patients without EGFR/ALK aberrations and with available pathologic tissue, were retrospectively reviewed. BRAF mutations were evaluated using a PNAClampTM BRAF mutation detection kit (Panagene, Daejeon, Korea). The outcomes in the study population were compared with stage III/IV adenocarcinoma patients harboring an EGFR mutation. A case report of targeted therapy against BRAF mutations was also presented. RESULTS: A cohort of 222 adenocarcinoma patients with adequate pathologic tissue samples was analyzed. The median patient age was 63 years, 68.8% of the patients were male and 68.7% were ever-smokers. The V600E BRAF mutation was detected in 4 patients (1.8%). The 222 study patients had a poorer survival outcome compared to stage III/IV adenocarcinoma patients with an EGFR mutation (median, 12 vs 67 months, P<0.001) from a recent previous study. Moreover, a 47-year-old female with a recurrent adenocarcinoma and a BRAF V600E mutation exhibited tumor regression after a fourth line therapy with dabrafenib and trametinib, targeting agents against BRAF mutations. CONCLUSION: Although BRAF mutations are found in 1.8% of advanced adenocarcinoma patients without EGFR/ALK aberration, they may be able to serve as a treatment target in those patients.

EGFR and KRAS mutation analyses from specimens obtained by bronchoscopy and EBUS-TBNA.

BACKGROUD: Procurement of tumor tissue is mandatory for a mutation analysis in patients with non-small cell lung cancer. The purpose of this study was to evaluate the usefulness of bronchoscopic biopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy for detecting epidermal growth factor receptor (EGFR) and KRAS mutations in routine practice. METHODS: Tumor DNA was extracted from formalin-fixed paraffin-embedded tissues, and amplifications of exons 18-21 of EGFR and codons 12, 13 and 61 of KRAS were performed using polymerase chain reaction (PCR). PCR products were subjected to direct sequencing in both directions. RESULTS: Of 211 consecutive specimens, 201 (95.3%) were available for EGFR mutation analysis, and 196 (92.9%) were adequate for KRAS mutation analysis. EGFR and KRAS mutations were detected in 14.9% and 5.4%, respectively. A median of 16 days was spent from biopsy to the final report for either EGFR or KRAS mutation status. The detection rates for both mutations were similar between bronchoscopic biopsy and EBUS-TBNA (P > 0.05). Female gender (53.3%), never smoker (63.3%), and adenocarcinoma (96.7%) were predominant in patients with EGFR mutations. Among patients with adenocarcinoma (n = 104), the frequencies of EGFR and KRAS mutations were 27.9% and 10.6%, respectively. CONCLUSIONS: Small tissue samples obtained by bronchoscopic biopsy and EBUS-TBNA are sufficient for detecting EGFR and KRAS mutations in routine practice. Therefore, concurrent mutational analyses of small tissue samples should be considered at the time of initial diagnosis.

Early intervention on the outcomes in critically ill cancer patients admitted to intensive care units.

PURPOSE: To determine whether earlier intervention was associated with decreased mortality in critically ill cancer patients admitted to an intensive care unit (ICU). METHODS: A retrospective observational study was performed of 199 critically ill cancer patients admitted to the ICU from the general ward between January 2010 and December 2010. A logistic regression model was used to adjust for potential confounding factors in the association between time to intervention and in-hospital mortality. RESULTS: In-hospital mortality was 52 %, with a median Simplified Acute Physiology Score 3 (SAPS 3) of 80 [interquartile range (IQR) 67-93], and a median Sequential Organ Failure Assessment (SOFA) score of 8 (IQR 5-11). Median time from physiological derangement to intervention (time to intervention) prior to ICU admission was 1.5 (IQR 0.6-4.3) h. Median time to intervention was significantly shorter in survivors than in non-survivors (0.9 vs. 3.0 h; p < 0.001). Additionally, the mortality rates increased significantly with increasing quartiles of time to intervention (p < 0.001, test for trend). Other factors associated with in-hospital mortality were severity of illness, performance status, hematologic malignancy, stem-cell transplantation, presence of three or more abnormal physiological variables, time from derangement to ICU admission, presence of infection, need for mechanical ventilation and vasopressor, and low PaO(2)/FiO(2) ratio. Even after adjusting for potential confounding factors, time to intervention was still significantly associated with hospital mortality (adjusted odds ratio 1.445, 95 % confidence interval 1.217-1.717). CONCLUSIONS: Early intervention before ICU admission was independently associated with decreased in-hospital mortality in critically ill cancer patients admitted to the ICU.

Daily 300 mg dose of linezolid for multidrug-resistant and extensively drug-resistant tuberculosis: updated analysis of 51 patients.

OBJECTIVES: Linezolid may be an effective treatment for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). The objective was to evaluate the efficacy, tolerability and adverse events of a 300 mg daily dose of linezolid in the treatment of MDR/XDR-TB. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 51 MDR-TB patients, including 26 patients (51%) with XDR-TB, to evaluate the safety, tolerability and efficacy of therapy with 300 mg/day linezolid. All patients had failed previous treatments with second-line anti-TB drugs. RESULTS: Patients were treated with linezolid for a median of 413 days (IQR 237-622 days). Favourable treatment outcome (treatment success or still on treatment after culture conversion) was achieved in 40 patients (78%) with culture conversion at a median of 55 days (IQR 41-91 days) from the start of linezolid therapy. Eleven patients (22%) had unfavourable outcomes (treatment failure or death) and 14 (27%) discontinued treatment due to neurotoxicity (peripheral or optic neuropathy) after a median of 278 days (IQR 174-412 days). CONCLUSIONS: Our findings suggest that linezolid at a daily dose of 300 mg is effective against intractable MDR/XDR-TB, and may be associated with fewer neuropathic side effects than a daily dose of 600 or 1200 mg.

Ultrasound guided fine needle aspiration of a lung mass via a transesophageal approach using endobronchial ultrasound bronchoscope.

Diagnostic accuracy, safety and minimal invasiveness are well established advantages of the endobronchial ultrasound (EBUS) technique when used for lung cancer staging. Combining it with transesophageal ultrasound can offer complete mediastinal staging, extending the reach of this technique to lymph node stations that are inaccessible even by mediastinoscopy. Traditionally this has been achieved by arranging a bronchoscopist and gastroenterologist to perform the procedure on two separate occasions using two separate expensive systems. Performing the procedure with a single physician (pulmonologist) using a single scope offers logistical advantages. For this reason, the practice of fine needle aspiration (FNA) via both the transbronchial and transesophageal approach by a pulmonologist using the single EBUS scope has emerged and is likely to grow and become widely accepted in future. The present case reports illustrate the additional applicability of allowing direct puncture of a lung mass using transesophageal FNA done by a pulmonologist using a single EBUS scope as a part of the combined approach.

Polymorphisms in interleukin-1B and its receptor antagonist genes and the risk of chronic obstructive pulmonary disease in a Korean population: a case-control study.

BACKGROUND: Although several studies have evaluated the association between interleukin-1B (IL1B) polymorphisms and the risk of chronic obstructive pulmonary disease (COPD), most of these studies have focused on -511C-->T and -31T-->C polymorphisms, and the results of these studies have been inconsistent. This study was conducted to investigate the association between four potentially functional polymorphisms of the IL1B gene (-3737C-->T, -1464G-->C, -511C-->T, and -31T-->C) and the risk of COPD. In addition, we examined a potential interaction of the IL1B polymorphisms with the VNTR polymorphism of the IL-1 receptor antagonist (IL1RN) gene in determining the risk of COPD. METHODS: The IL1B and IL1RN genotypes were determined in 311 COPD patients and 386 healthy controls. RESULTS: Individuals with at least one variant allele of the -511C-->T and -31T-->C polymorphisms were at a significantly increased risk for COPD when compared to carriers with each homozygous wild-type allele [adjusted odds ratio (OR) 1.53, 95% confidence interval (CI) 1.03-2.26, P=0.03; and adjusted OR 1.50, 95% CI 1.02-2.24, P=0.04, respectively]. When the COPD cases were stratified according to disease severity, the presence of at least one -511T and -31C alleles was significantly associated with severe COPD (adjusted OR 2.80, 95% CI 1.47-5.33, P=0.002; and adjusted OR 2.33, 95% CI 1.24-4.40, P=0.01, respectively), however, there was no significant association between the -511C-->T and -31T-->C genotypes and mild-to-moderate COPD. In addition, individuals carrying at least one IL1RN*2 allele were at a significantly lower risk for COPD compared to subjects carrying no IL1RN*2 allele (adjusted OR 0.51, 95% CI 0.26-0.98, P=0.04). In haplotype/diplotype analyses, individuals with one or two copies of the IL1B CCTC haplotype that carried the risk allele at all of the -3737C-->T, -1464G-->C, -511C-->T, and -31T-->C loci, were at a significantly increased risk of severe COPD when compared with subjects with zero copy of the CCTC haplotype (adjusted OR 1.96, 95% CI 1.16-3.29, P=0.01). CONCLUSION: These findings suggest that polymorphisms in the IL1B and IL1RN genes might be useful markers for determining genetic susceptibility to COPD in a Korean population.