Kyeong Cheol Shin

Detection and comparison of peptide nucleic acid-mediated real-time polymerase chain reaction clamping and direct gene sequencing for epidermal growth factor receptor mutations in patients with non-small cell lung cancer

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are recommended as first-line therapy in patients with advanced, recurrent, or metastatic non-squamous non-small cell lung cancer (NSCLC) that have active EGFR mutations. The importance of rapid and sensitive methods for the detection of EGFR mutations is emphasized. The aim of this study is to examine the EGFR mutational status by both direct DNA sequencing and peptide nucleic acid (PNA)-mediated real-time PCR clamping and to evaluate the correlation between the EGFR mutational status and the clinical response to EGFR-tyrosine kinase inhibitors. Clinical specimens from 240 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20 and 21. All clinical data and tumor specimens were obtained from 8 centers of the Korean Molecular Lung Cancer Group (KMLCG). After genomic DNA was extracted from paraffin-embedded tissue specimens, we performed PNA-mediated real-time PCR clamping and direct DNA sequencing for the detection of EGFR mutations. Of 240 tumor samples, PNA-mediated PCR clamping was used to detect genomic alterations in 83 (34.6%) samples, including 61 identified by sequencing and 22 additional samples (10 in exon 19, 9 in exon 21, and 3 in both exons); direct DNA sequencing was used to identify a total of 63 (26.3%) mutations that contained 40 deletion mutations in exon 19 (63.5%) and 18 substitution mutations (28.6%) in exon 21. PNA-mediated PCR clamping was used to identify more mutations than clinical direct sequencing, whereas clinical outcomes were not significantly different between the groups harboring activating mutations detected by each method. These data suggest that PNA-mediated real-time PCR clamping exhibits high sensitivity and is a simple procedure relative to direct DNA sequencing that is a useful screening tool for the detection of EGFR mutations in clinical settings.

Best immunohistochemical panel in distinguishing adenocarcinoma from squamous cell carcinoma of lung: tissue microarray assay in resected lung cancer specimens

The emergence of the targeted therapies for non-small cell lung carcinoma (NSCLC) has generated a need for accurate histologic subtyping of NSCLC. In this study, we assessed the utility of immunohistochemical markers that could be helpful in distinction between adenocarcinoma (ADC) and squamous cell carcinoma (SCC). We performed a battery of immunohistochemistry using tissue microarray for napsin-A, Thyroid transcription factor 1 (TTF-1), p63, cytokeratin (CK) 5/6, thrombomodulin (CD141), Epithelial-related antigen (MOC-31), carcinoembryonic antigen (CEA), Cyclooxygenase 2 (COX-2), high-molecular-weight CK (HMWCK), p27kip1 (p27), and Rb protein in 129 resected primary NSCLC with 81 ADCs and 48 SCCs and 10 metastatic ADC to the lung (primary in colon, 7 cases; stomach, 2 cases; vagina, 1 case). Cases of ADC and SCC were morphologically unequivocal and solid tumors with no definite squamous or glandular differentiation were excluded for this analysis. Napsin-A and TTF-1 were positive in 81% and 70% of ADC and in 0% and 2% of SCC, respectively, whereas P63 and CK5/6 were positive in 91% and 90% of SCC and in 9% and 4% of ADC, respectively (P < .001). CD141 stained significantly higher in SCC over ADC (positive in 2% of ADC and 46% of SCC. MOC-31, CEA, COX-2, HMWCK, p27, and Rb appeared to be not useful markers in distinction between ADC and SCC because of their low specificity. None of metastatic ADC to the lung showed positive for napsin-A and TTF-1. It was evident that combination of napsin-A, TTF-1, CK5/6, and p63 was the best immunohistochemical panel in differentiating ADC from SCC of the lung in this study. CD141 appeared to be a potential new marker for SCC with high specificity. Cyclooxygenase 2, MOC-31, CEA, HMWCK, p27, and Rb showed less specificity for differentiation ADC from SCC.

The Effect of Body Composition on Pulmonary Function

Background The pulmonary function test is the most basic test method to diagnosis lung disease. The purpose of this study was to research the correlation of the body mass index (BMI), the fat percentage of the body mass (fat%), the muscle mass, the fat-free mass (FFM) and the fat-free mass index (FFMI), waist-hip ratio (WHR), on the forced expiratory volume curve. Methods Between March and April 2009, a total of 291 subjects were enrolled. There were 152 men and 139 female (mean age, 46.3±9.92 years), and they were measured for the following: forced vital capacity (FVC), forced expiratory volume at 1 second (FEV1), and forced expiratory flow during the middle half of the FVC (FEF25-75) from the forced expiratory volume curve by the spirometry, and the body composition by the bioelectrical impedance method. Correlation and a multiple linear regression, between the body composition and pulmonary function, were used. Results BMI and fat% had no correlation with FVC, FEV1 in male, but FFMI showed a positive correlation. In contrast, BMI and fat% had correlation with FVC, FEV1 in female, but FFMI showed no correlation. Both male and female, FVC and FEV1 had a negative correlation with WHR (male, FVC r=-0.327, FEV1 r=-0.36; p<0.05; female, FVC r=-0.175, FEV1 r=-0.213; p<0.05). In a multiple linear regression of considering the body composition of the total group, FVC explained FFM, BMI, and FFMI in order (r2=0.579, 0.657, 0.663). FEV1 was explained only fat% (r2=0.011), and FEF25-75 was explained muscle mass, FFMI, FFM (r2=0.126, 0.138, 0.148). Conclusion The BMI, fat%, muscle mass, FFM, FFMI, WHR have significant association with pulmonary function but r2 (adjusted coefficient of determination) were not high enough for explaining lung function.

Therapeutic Experience of Bing-Neel Syndrome Associated with Waldenstrom's Macroglobulinemia

Waldenstroms macroglobulinemia is an uncommon low-grade B-cell lymphoproliferative disorder in which monoclonal immunoglobulin M is produced. Neurological symptoms due to hyperviscosity are frequent manifestations of Waldenstroms macroglobulinemia. However, central nervous system infiltration by plasmacytoid lymphocytes (Bing-Neel syndrome) has only rarely been reported. We report a case of a 51-yr-old woman suffering from Waldenstroms macroglobulinemia who complained of persistant headache. Brain magnetic resonance imaging revealed an extra-axial soft tissue mass along the left cavernous sinus, left tentorium, right tentorium, and falx cerebri. A stereotactic biopsy of dural tissue from the falx was performed and showed plasmacytoid lymphocyte infiltration. The patient became symptom- free with irradiation of the whole brain followed by chemotherapy with fludarabine.

Clinical and Bronchoscopic Findings in Ugandans with Pulmonary Kaposi's Sarcoma

Background Pulmonary Kaposis sarcoma (PKS) directly affects the life expectancy of those infected and yet the clinical and radiographic features of Kaposis sarcoma (KS) with pulmonary involvement are nonspecific, which makes diagnosis difficult. In Uganda, pulmonary tuberculosis, which has clinical features that closely resemble those of PKS, also occurs commonly and thus confusion is bound to arise. Bronchoscopy is a recognized diagnostic investigatory modality for PKS. The aim of present study was to identify unique or useful points for the differential diagnosis of PKS and other opportunistic infections. Methods The clinical, radiologic, and bronchoscopic findings in thirty-five Ugandan patients (age 20-50, median 32) with PKS were analyzed. Results Cough and weight loss were most common and occurred in 97.1%, whereas fever occurred in 62.9%, and breathlessness in 57.1%. Thirty-four patients (97.1%) showed mucocutaneous KS, and palatal KS was most frequent and was observed in 74.3%. In addition, 25 patients (71.4%) showed the characteristic endobronchial plaques of KS. The most frequently observed radiographic abnormality was bilateral reticulonodular density. Histological examinations of bronchoscopic biopsies revealed KS in 7 (36.6%) cases. Five PFS patients (25%) also had co-existent tuberculosis. Conclusions The majority of patients with PKS showed no specific findings on physical examination, apart from mucocutaneous KS. Our findings indicate that palatal KS may be a strong predictor of PKS. In Uganda, pulmonary tuberculosis may be the most common concomitant pulmonary infection in PKS patients.

Clinical characteristics of non-small cell lung cancer patients who experienced acquired resistance during gefitinib treatment

BACKGROUND The NSCLC patients who experienced good clinical responses to an EGFR-TKI will inevitably develop acquired resistance. A great deal of research is being carried out to discover the molecular mechanisms underlying this resistance. In comparison, few studies have been conducted to find out about the clinical characteristics of acquired resistance in the patients who had responded to an EGFR-TKI. Herein we investigated clinical characteristics of NSCLC patients who experienced acquired resistance during gefitinib therapy. PATIENTS AND METHODS We reviewed NSCLC patients who showed a clinical benefit from initial gefitinib therapy. All clinical data were obtained from 11 centers of Korean Molecular Lung Cancer Group (KMLCG). The clinical manifestations of acquired resistance, time to progression (TTP), and post-progression survival (PPS) after gefitinib failure were analyzed retrospectively. RESULTS A total of 417 patients were recruited. Median TTP was 10.2 months (95% CI, 9.5-10.9). TTP showed a significant longer duration in female, non-smoker, and patients with adenocarcinoma. At the time of acquired resistance, 63.3% of the patients showed symptomatic deterioration. Sites of disease progression were as follows: primary lung lesion in 58.4%, previous metastasis in 38.3%, and new metastasis in 54.2%. Patients with EGFR wild type showed a tendency of higher frequency in symptomatic deterioration and newly development of CNS metastasis compared with patients with EGFR mutation. There was a significant difference in newly development of lung metastasis between patients with exon 19 deletion and those with L858R mutation (41.4% vs. 6.3%, p=0.02). PPS was 8.9 months (95% CI, 7.4-10.4). Smoking history, PS, new CNS lesion and subsequent chemotherapy were independent factors for PPS. CONCLUSION This study suggests that clinical manifestations of acquired resistance may be different according to EGFR mutation status and EGFR mutation genotype. In addition, subsequent chemotherapy confers clinical benefit in terms of PPS in NSCLC patients who experienced acquired resistance after gefitinib therapy.

A Case of Solitary Fibrous Pleura Tumor Associated with Severe Hypoglycemia: Doege-Potter Syndrome

Solitary fibrous tumor of the pleura (SFTP) is a rare primary intrathoracic tumor that arises from mesenchymal tissue underlying the mesothelial layer of the pleura. It usually has an indolent clinical course. The hypoglycemia that accompanies SFTP was first described by Doege and Potter independently in 1930, hence the eponym Doege-Potter syndrome (DPS). The incidence of DPS is reported to be ~4%. In this report, we present a typical case of DPS that was cured through complete surgical resection.

Safety and Effectiveness of Indacaterol in Chronic Obstructive Pulmonary Disease Patients in South Korea

Background Inhaled indacaterol (Onbrez Breezhaler), a long-acting β2-agonist, is approved in over 100 countries, including South Korea, as a once-daily bronchodilator for maintenance and treatment of chronic obstructive pulmonary disease (COPD). Here, we present an interim analysis of a post-marketing surveillance study conducted to evaluate the real-world safety and effectiveness of indacaterol in the Korean population. Methods This was an open-label, observational, prospective study in which COPD patients, who were newly prescribed with indacaterol (150 or 300 µg), were evaluated for 12 or 24 weeks. Safety was assessed based on the incidence rates of adverse events (AEs) and serious adverse events (SAEs). Effectiveness was evaluated based on physicians assessment by considering changes in symptoms and lung function, if the values of forced expiratory volume in 1 second were available. Results Safety data were analyzed in 1,016 patients of the 1,043 enrolled COPD patients receiving indacaterol, and 784 patients were included for the effectiveness analysis. AEs were reported in 228 (22.44%) patients, while 98 (9.65%) patients reported SAEs. The COPD condition improved in 348 patients (44.4%), while the condition was maintained in 396 patients (50.5%), and only 40 patients (5.1%) exhibited worsening of ailment as compared with baseline. During the treatment period, 90 patients were hospitalized while nine patients died. All deaths were assessed to be not related to the study drug by the investigator. Conclusion In real-life clinical practice in South Korea, indacaterol was well tolerated in COPD patients, and can be regarded as an effective option for their maintenance treatment.

Randomized Phase III Study of Docetaxel Plus Cisplatin Versus Pemetrexed Plus Cisplatin as First-line Treatment of Nonsquamous Non-Small-cell Lung Cancer: A TRAIL Trial.

Introduction To date, no prospective phase III trials have directly compared the efficacy of pemetrexed plus cisplatin (Pem‐Cis) with docetaxel plus cisplatin (Doc‐Cis) in patients with nonsquamous non–small‐cell lung cancer. Materials and Methods A total of 148 chemotherapy‐naive patients lacking driver mutations were randomized into 21‐day regimens of cisplatin 70 mg/m2 with either docetaxel 60 mg/m2 (n = 71) or pemetrexed 500 mg/m2 (n = 77) for ≤ 4 cycles. The primary objective was to assess the noninferiority of progression‐free survival (PFS) for patients receiving the Doc‐Cis regimen. The secondary endpoints were the response rates, overall survival, and toxicity profiles. Results Partial remission was observed in 24 (31.2%) and 24 (33.8%) patients in the Pem‐Cis and Doc‐Cis groups, respectively. The median PFS was 4.7 months (95% confidence interval [CI], 4.4‐5.0) in the Pem‐Cis arm and 4.4 months (95% CI, 3.7‐5.1) in the Doc‐Cis arm (P > .05). The median overall survival was longer in the Doc‐Cis arm (13.3 months; 95% CI, 8.1‐18.5) than in the Pem‐Cis arm (11.7 months; 95% CI, 8.6‐14.8; P > .05). Between the 2 arms, no significant difference was found in the subsequent treatments after failure of first‐line treatment. The rate of grade 3 or 4 neutropenia and febrile neutropenia was greater in the Doc‐Cis arm than in the Pem‐Cis arm. Conclusion In nonsquamous non–small‐cell lung cancer patients lacking driver mutations, the PFS and response rates were similar between the 2 arms, and toxicity was tolerable, although adverse events and more severe toxicities were observed more frequently in the Doc‐Cis arm. Micro‐Abstract No prospective phase III trials have directly compared the efficacy of pemetrexed plus cisplatin (Pem‐Cis) with docetaxel plus cisplatin (Doc‐Cis) in nonsquamous non–small‐cell lung cancer. A total of 148 chemotherapy‐naive patients lacking driver mutations were randomized to the Pem‐Cis or Doc‐Cis arm. The progression‐free survival and response rate was similar between the 2 arms, although adverse events and more severe toxicities were observed more frequently in the Doc‐Cis arm.

Asthma-COPD Overlap Shows Favorable Clinical Outcomes Compared to Pure COPD in a Korean COPD Cohort

Purpose Comparisons of the characteristics of chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap syndrome (ACOS) have been the focus of several studies since the diseases were defined by the Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease guidelines. However, no consensus is available yet. In this study, we aimed to compare the characteristics of asthma-COPD overlap (ACO) and COPD. Methods We retrospectively reviewed 1,504 patients with COPD in a Korean COPD Subtype Study cohort. The occurrence of ACO was defined as a positive response to a bronchodilator (an increase in forced expiratory volume in 1 second [FEV1] of 12% and 200 mL). Results Among 1,504 patients with COPD, 223 (14.8%) were diagnosed with ACO. Men (95.5%) and current smokers (32.9%) were more prevalent in the ACO group compared with the pure COPD group (90.5% and 25.3%, respectively; P=0.015 and P=0.026, respectively). Patients with ACO had a better quality of life (St. Georges Respiratory Questionnaire for COPD score=31.0±18.0 [mean±standard deviation]) than those with pure COPD (35.3±19.1) (P=0.002). Although the prevalence of acute exacerbation was not different between the 2 groups, patients with severe exacerbation required hospital admission significantly more frequently in the pure COPD group than in the ACO group. Patients with ACO showed a higher likelihood of FEV1 recovery than those with pure COPD (P<0.001). Conclusions We suggest that ACO is characterized by less severe symptoms, and therefore it might lead to rare severe exacerbation and the possibility of lung function recovery.