Peptide Nucleic Acid Clamping Versus Direct Sequencing for the Detection of EGFR Gene Mutation in Patients with Non-small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Direct sequencing (DS) is the standard method for detection of epidermal growth factor receptor (EGFR) gene mutation in non-small cell lung cancer (NSCLC); however, low detection sensitivity is a problem. The aim of this study is to demonstrate higher detection rate of EGFR gene mutation with peptide nucleic acid (PNA) clamping compared with DS. MATERIALS AND METHODS: This is a single arm, prospective study for patients with stage IIIB/IV or relapsed NSCLC. Using tumor DNA from 138 patients, both DS and PNA clamping for EGFR gene in exon 18, 19, 20, and 21 were performed. Discrepant results between the two methods were verified using Cobas and a mutant enrichment based next generation sequencing (NGS). Patients with activating mutations were treated with EGFR tyrosine kinase inhibitor (EGFR-TKI, gefitinib, or erlotinib) as first line treatment. RESULTS: Of 138 paired test sets, 24 (17.4%) and 45 (32.6%) cases with activating mutations were detected by DS and PNA clamping, respectively. The difference of detection rate between the two methods was 15.2% (95% confidence interval, 8.7% to 17.8%; p < 0.001). Between the two methods, 25 cases showed discrepant results (n=23, PNA+/DS-; n=2, PNA-/DS+). Mutations were confirmed by Cobas or NGS in 22 of 23 PNA+/DS- cases. The response rates to EGFR-TKI were 72.2% in the PNA+/DS+ group and 85.0% in the PNA+/DS- group. CONCLUSION: PNA clamping showed a significantly higher detection rate of EGFR gene mutation compared with DS. Higher sensitivity of PNA clamping was not compromised by the loss of predictive power of response to EGFR-TKI.

Usefulness of Rigid Bronchoscopic Intervention Using Argon Plasma Coagulation for Central Airway Tumors

OBJECTIVES: Argon plasma coagulation (APC) is a noncontact form of electrocautery that utilizes ionized argon as the electrical current. A rigid bronchoscopic use of APC for the management of central airway obstruction could be safe and rapidly effective. This study evaluated the usefulness of rigid bronchoscopy with APC for the management of central airway obstructions due to benign or malignant tumors. METHODS: Twenty patients with obstructing central airway tumors were retrospectively reviewed from February 2008 to February 2013 at Chonnam National University Hospital. All patients received rigid bronchoscopic tumor removal under general anesthesia. APC was applied before and after tumor removal. RESULTS: The median age of patients was 59 years (interquartile range [IQR], 51 to 67 years) and 70% were female. The causes of airway obstruction included malignancy (n=8) and benign tumor (n=12). Airway tumors comprised intraluminal lesions (n=11, 55%) and mixed intraluminal/extraluminal lesions (n=9, 45%). The median tumor size was 15 mm (IQR, 10 to 18 mm). The median degree of airway obstruction was significantly reduced after intervention (90% [IQR, 88% to 96%] vs. 10% [IQR, 0% to 20%], P<0.001). The median American Thoracic Society dyspnea grade (3 [IQR, 1 to 4] vs. 1 [IQR, 0 to 1], P<0.001) and forced expiratory volume in one second (1.03 L [IQR, 0.52 to 1.36 L] vs. 1.98 L [IQR, 1.57 to 2.64 L], P=0.004) were significantly improved after intervention. There were no procedure-related acute complications and deaths. CONCLUSION: Rigid bronchoscopy with APC is an effective and safe procedure to alleviate central airway obstruction caused by tumors.

Prevalence of Chronic Sputum and Associated Factors in Korean Adults

Chronic sputum is a troublesome symptom in many respiratory diseases. The prevalence of chronic sputum varies from 1.2% to 13% according to the country. The purpose of this study was to estimate the prevalence of chronic sputum and to find its associated factors in a general Korean population. We analyzed the data of the Korea National Health and Nutrition Examination Survey 2010 and 2011. A total number of 6,783 subjects aged 40 yr or more were enrolled in this study with 3,002 men and 3,781 women. As a result, the prevalence of chronic sputum was 6.3% (n=430). Significant risk factors for chronic sputum by multivariate analysis were: age (> or =70 yr) (odds ratio [OR], 1.954; 95% confidence interval [CI], 1.308-2.917), current smoking (OR, 4.496; 95% CI, 3.001-6.734), chronic obstructive pulmonary disease (COPD) (OR, 1.483; 95% CI, 1.090-2.018), and tuberculosis (OR, 1.959; 95% CI, 1.307-2.938). In conclusion, the prevalence of chronic sputum in Korea was in the intermediate range compared with other countries. Smoking is a preventable risk factor identified in this study, and major respiratory diseases, such as COPD and tuberculosis, should be considered in subjects with chronic sputum.

Successful Treatment of Crizotinib-Associated Severe Hepatotoxicity in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

Crizotinib-associated severe hepatotoxicity has been rarely reported and experts recommended stopping crizotinib treatment in patients with grade 3/4 transaminase elevation. We experienced a case of anaplastic lymphoma kinase-positive non-small cell lung cancer occurring as a result of severe hepatotoxicity due to crizotinib-associated hepatitis, accompanied by the reactivation of chronic hepatitis B, which was reversed with dose reduction and anti-viral therapy. Our case highlights the possibility that crizotinib might induce hepatitis and this might be associated with the underlying presence of chronic hepatitis B. In addition, crizotinib could be continued with reduced unless there are any other therapeutic options.

Repeated Favorable Responses to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in a Case of Advanced Lung Adenocarcinoma / 결핵및호흡기질환

The presence of epidermal growth factor receptor (EGFR) mutation is a prognostic and predictive marker for EGFR-tyrosine kinase inhibitor (TKI) therapy. However, inevitably, relapse occurs due to the development of acquired resistance, such as T790M mutation. We report a case of repeated responses to EGFR-TKIs in a never-smoked woman with adenocarcinoma. After six cycles of gemcitabine and cisplatin, the patient was treated by gefitinib for 4 months until progression. Following the six cycles of third-line pemetrexed, gefitinib retreatment was initiated and continued with a partial response for 6 months. After progression, she was recruited for an irreversible EGFR inhibitor trial, and the time to progression was 11 months. Although EGFR direct sequencing on the initial diagnostic specimen revealed a wild-type, we performed a rebiopsy from the progressed subcarinal node at the end of the trial. The result of peptide nucleic acid clamping showed L858R/L861Q.

A Case of Candida glabrata Pneumonia in a Patient with Diabetes Mellitus / 대한내과학회지

Despite the increasing frequency of non-albicans candidemia, reported pneumonia cases due to Candida glabrata are rare. A 50-year-old diabetic woman developed cough and pleuritic chest pain, which were refractory to empirical antibiotics and anti-tuberculosis treatment for several months. The causative organism of the pneumonia was C. glabrata, which was cultured in bronchoalveolar lavage and blood culture specimens. Amphotericin therapy resulted in successful resolution of the pneumonia and candidemia. This is the first proven case of C. glabrata pneumonia in Korea.

Never-Smoker Lung Cancer Is Increasing

PURPOSE: Lung cancer has been the leading cause of death in South Korea since the year 2000. Adenocarcinoma became the most frequent type in the national survey of lung cancer since year 2005. MATERIALS AND METHODS: We analyzed 5,456 cases with lung cancer from 2004 to 2012 in a community cancer center. The mean age was 69.9 years, and 78.9% was male. RESULTS: Adenocarcinoma (ADC, 40.8%) was the most frequent type, followed by squamous cell carcinoma (SQC, 36.4%), small cell carcinoma (SCC, 14.8%) and non-small cell lung cancer (NSCLC) not otherwise specified (8.1%). In male patients, SQC was the most frequent type (43.5%), while ADC showed highest incidence in females (72.6%). Anatomic stage at diagnosis in NSCLC was I (10.3%), II (5.8%), IIIA (15.7%), IIIB (19.2%), and IV (49.0%). In SCC, 41.7% was in limited stage and 58.3% was diagnosed in extensive stage. The proportion of never smoker has been increased from 19.1% in 2004~2008 to 25.4% in 2009~2012. Never-smokers are more likely to be female (68.2% vs. 4.0%, p<0.001), have ADC (69.9% vs. 31.3%, p<0.001), and manifest as stage IV disease (58.5% vs. 45.2%, p<0.001), compared to smokers. Among 1,908 cases whose initial treatment was recorded, 42.5% received chemotherapy, 25.7% received radiation treatment, 20.5% received surgery and the remaining 11.3% received supportive cares only or transferred to other health care facilities. CONCLUSION: In conclusion, proportion of lung cancer in never-smoker is increasing. As screening for smokers will miss this growing population, we need to discover biomarkers to find high risk population of lung cancer.

Analysis of Patients with Hemoptysis in a Tertiary Referral Hospital / 결핵및호흡기질환

BACKGROUND: This study attempted to investigate the main causes of hemoptysis, the type of examinations used for diagnosis, the treatment modalities and outcomes. METHODS: A retrospective study was conducted on the medical records of 221 patients admitted to the Chonnam National University Hospital, between January 2005 and February 2010, with hemoptysis. RESULTS: Bronchiectasis (32.6%), active pulmonary tuberculosis (18.5%), fungus ball (10.8%), and lung cancer (5.9%) accounted for most causes of hemoptysis. Computed tomography scan was the most sensitive diagnostic test when employed alone, with positive yield of 93.2%. There were 161 cases of conservative treatment (72.9%), 42 cases of bronchial artery embolization (BAE) (19.0%), and 18 cases of surgery (8.1%). Regarding the amount of hemoptysis, 70 cases, out of 221 cases, were mild (31.5%), 36 cases moderate (16.2%), and 115 cases massive hemoptysis (52.0%). Most of the patients were treated conservatively, but if there was more bleeding present, BAE or surgery was more commonly performed than the conservative treatment (p< or =0.0001). In the multivariate model, severe hemoptysis and lung cancer were independently associated with short-term recurrence. BAE was independently associated with long-term recurrence, and lung cancer was associated with in-hospital mortality. The overall in-hospital mortality rate was 11.3%. CONCLUSION: Hemoptysis is a common symptom with a good prognosis in most cases. However, patients exhibiting massive bleeding or those with malignancy had a poorer prognosis. In-hospital mortality was strongly related to the cause, especially in lung cancer.

Temozolomide-Associated Bronchiolitis Obliterans Organizing Pneumonia Successfully Treated with High-Dose Corticosteroid

Temozolomide is an oral alkylating agent with clinical activity against glioblastoma multiforme (GM). It is generally well-tolerated and has few pulmonary side effects. We report a case of temozolomide-associated brochiolitis obliterans organizing pneumonia (BOOP) requiring very high-dose corticosteroid treatment. A 56-yr-old woman presented with a 2-week history of exertional dyspnea. For the treatment of GM diagnosed 4 months previously, she had undergone surgery followed by chemoradiotherapy, and then planned adjuvant chemotherapy with temozolomide. After the 1st cycle, progressive dyspnea was gradually developed. Chest radiograph showed diffuse patchy peribronchovascular ground-glass opacities in both lungs. Conventional dose of methylprednisolone (1 mg/kg/day) was begun for the possibility of BOOP. Although transbronchial lung biopsy findings were compatible with BOOP, the patient's clinical course was more aggravated until hospital day 5. After the dose of methylprednisolone was increased (500 mg/day for 5 days) radiologic findings were improved dramatically.

Apoptosis of T Lymphocytes Isolated from Peripheral Blood of Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease

PURPOSE: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways and progressive destruction of lung parenchyma. Apoptosis is critical for the maintenance of normal tissue homeostasis and is in equilibrium with proliferation and differentiation. This study was undertaken to investigate relationship between apoptosis of peripheral blood lymphocytes during exacerbation of COPD and inflammatory response that characterizes this condition. MATERIALS AND METHODS: Seventeen patients with COPD exacerbation, 21 stable COPD, and 12 control subjects were included. T lymphocytes were isolated from peripheral blood using MACS. Apoptosis of T lymphocytes was assessed with FACS using annexin V and 7-aminoactinomycin. Serum levels of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha were determined by an immunoassay technique. RESULTS: There was significantly increased percentage of apoptotic lymphocytes, CD 4+, and CD 8+ T cells in the peripheral blood of patients with exacerbation of COPD compared with stable COPD. Serum levels of IL-6, IL-8, and TNF-alpha were significantly increased in patients with exacerbation of COPD compared with stable COPD. Only TNF-alpha presented a positive correlation with apoptotic lymphocytes in patients with exacerbation of COPD. CONCLUSION: Increased apoptotic lymphocytes may be associated with upregulation of TNF-alpha in the peripheral blood of patients with acute exacerbation of COPD.

Mortality and Prognostic Factors in Acute Respiratory Distress Syndrome due to Tuberculosis / 대한내과학회지

BACKGROUND/AIMS: Acute respiratory distress syndrome (ARDS) due to tuberculosis (TB) is a rare disease, but its mortality is believed to be high. The aim of this study was to evaluate the mortality rate and prognostic factors of ARDS. METHODS: We retrospectively reviewed the demographic, clinical, radiologic, and laboratory data of 19 patients with ARDS due to active pulmonary TB at Chonnam National University Hospital between January 2000 and December 2010. RESULTS: The median age of patients was 71.1 (interquartile range [IQR] 51-74) years. None had a history of TB treatment. The most common symptoms were dyspnea (90%), fever (68%), and cough (53%). The overall in-hospital mortality was 73%. The median acute physiologic assessment and chronic health evaluation (APACHE) III score and pneumonia severity index (PSI) were 81.9 (IQR 59.0-92.0) and 111.0 (IQR 77.0-131.0), respectively. The PSI was significantly higher in non-survivors than in survivors (55.0 vs. 122.0; p = 0.016). The rate of TB treatment before admission was significantly higher in survivors than in non-survivors (75% vs. 13%; p = 0.037). The time from admission to treatment initiation was significantly longer in non-survivors than in survivors (3 vs. 0 days; p = 0.049). The median duration of mechanical ventilation was 11 days (IQR 5-16 days). The most common cause of death was a refractory shock (53%). CONCLUSIONS: The overall mortality rate of ARDS due to pulmonary TB was high. A high PSI score and delay of TB treatment may be risk factors for a poor outcome of ARDS due to pulmonary TB.

Treatment Outcome of Combination Therapy Including Clarithromycin for Mycobacterium avium Complex Pulmonary Disease

BACKGROUND/AIMS: The frequency of nontuberculous mycobacteria pulmonary disease in HIV-negative patients is increasing; the most common pathogen in Korea is the Mycobacterium avium complex (MAC). However, few studies have evaluated the treatment outcome of MAC pulmonary disease in Korea. METHODS: The efficacy of a clarithromycin-containing regimen for MAC pulmonary disease was studied in 42 patients treated for more than 6 months between January 2005 and December 2008. All patients were treated with a regimen consisting of clarithromycin, rifampin, and ethambutol. Streptomycin was added in 10 patients. RESULTS: Among the 42 patients, a negative culture conversion was achieved in 33 (78.6%), and the median duration of treatment in these patients was 19 months (interquartile range [IQR], 16 to 22). Of the 33 patients with a negative culture conversion, 14 completed treatment. During the follow-up period (median, 10 months; IQR, 4 to 20) for the 14 patients, one relapsed at 24 months after treatment completion. The culture conversion rate was significantly higher in patients who were treated with more than 500 mg/day clarithromycin (87.1% vs. 54.5%, p = 0.038). CONCLUSIONS: The combined regimen including clarithromycin was effective against MAC pulmonary disease. High-dose clarithromycin of more than 500 mg/day may improve the outcome of patients with MAC pulmonary disease.

Plasma proGRP Concentration is Sensitive and Specific for Discriminating Small Cell Lung Cancer from Nonmalignant Conditions or Non-small Cell Lung Cancer

To date, most clinical data on pro-gastrin-releasing peptide (proGRP) have been based on serum concentrations. This study evaluated the agreement between proGRP levels in fresh serum and plasma in patients with various lung diseases. Pairs of serum and EDTA plasma were collected from 49 healthy individuals. At the same time, EDTA plasma of 118 lung cancer patients and 23 patients with benign pulmonary diseases were prospectively collected. Compared to serum, plasma proGRP concentrations were higher by an average of 103.3%. Plasma proGRP was higher in malignancy (336.4 +/- 925.4 pg/mL) than in benign conditions (40.1 +/- 11.5 pg/mL). Small cell lung cancer (SCLC) patients showed higher levels of proGRP (1,256.3 +/- 1,605.6 pg/mL) compared to other types of lung cancer. Based on the ROC curve analyses at a specificity of 95%, the diagnostic sensitivity of plasma proGRP was estimated to be 83.8% in distinguishing SCLC from all the other conditions, and 86.5% for discriminating SCLC from the nonmalignant cases. Among the SCLC cases, limited stage disease had lower levels of plasma proGRP than extensive disease. When measuring circulating levels of proGRP, the use of plasma is preferred over serum. Plasma proGRP has a potential marker for discriminating SCLC from nonmalignant conditions or non-small cell lung cancer.

Comparison of Therapeutic Efficacy of Gefitinib and Erlotinib in Patients with Squamous Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: Gefitinib and erlotinib are useful, molecular targeted agents in patients with non-small-cell lung cancer (NSCLC) who failed previous chemotherapy. We compared the efficacy and toxicity of two drugs in patients with squamous cell lung cancer, most of whom are male smokers. METHODS: We retrospectively reviewed the clinical information on patients with NSCLC who were treated with gefitinib or erlotinib treatment at Chonnam National University Hwasun Hospital between July 2002 and November 2009. The overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) were compared between the two drugs. RESULTS: A total of 182 (100 gefitinib vs. 82 erlotinib) of 584 patients treated by targeted agents had squamous histology. Of the 182 patients, 167 (91.7%) were male and 159 (87.4%) were smokers. The ORR and disease control rate (DCR) were 4.9% and 40.6%, and there was no significant difference between gefitinib and erlotinib (ORR, 5.0% vs 4.8%; p=0.970; DCR, 40.0% vs 41.4%; p=0.439). The median OS in the gefitinib group was 12.1 months, and that in the erlotinib was 12.7 months (hazard ratio [HR], 1.282; 95% confidence interval [CI], 0.771~2.134; p=0.339). The median PFS for the gefitinib group was 1.40 months, compared with 1.37 months for the erlotinib group (HR, 1.092; 95% CI, 0.809~1.474; p=0.564). Skin rash > or =grade 3 was more common in erlotinib (12.2%) than gefitinib (1.0%, p=0.003) groups. CONCLUSION: This retrospective study showed that the two drugs appear to have similar antitumor efficacy and toxicity except for skin rash.

Influence of Diaphragmatic Mobility on Hypercapnia in Patients with Chronic Obstructive Pulmonary Disease

A reduction in diaphragm mobility has been identified in patients with chronic obstructive pulmonary disease (COPD) and has been associated with a decline in pulmonary function parameters. However, little information exists regarding the potential role of diaphragm mobility on hypercapnia in COPD. A new method of assessing the mobility of the diaphragm, using ultrasound, has recently been validated. The purpose of the present study was to investigate the relationship between diaphragm mobility and pulmonary function parameters, as well as that between arterial blood gas values and diaphragm mobility, in COPD patients. Thirty seven COPD patients were recruited for pulmonary function test, arterial blood gas analysis and diaphragm mobility using ultrasound to measure the craniocaudal displacement of the left branch of the portal vein. There were significant negative correlations between diaphragmatic mobility and PaCO2 (r = -0.373, P = 0.030). Diaphragmatic mobility correlated with airway obstruction (FEV1, r = 0.415, P = 0.011) and with ventilatory capacity (FVC, r = 0.302, P = 0.029; MVV, r = 0.481, P = 0.003). Diaphragmatic mobility also correlated significantly with pulmonary hyperinflation. No relationship was observed between diaphragm mobility and PaO2 (r = -0.028, P = 0.873). These findings support a possibility that the reduction in diaphragm mobility relates to hypercapnia in COPD patients.

A Case of Peripheral T Cell Lymphoma Presenting as Severe Hypoxic Respiratory Failure: A Case Report / 대한구급학회지

We describe here the first known case in Korea of pulmonary involvement with peripheral T cell lymphoma and the patient presented with severe hypoxic respiratory failure. A 57-yr-old man was admitted to our hospital with rapid progression of dyspnea and bilateral diffuse infiltration on a chest radiograph. He received mechanical ventilation and low dose corticosteroid treatment under the suspicion of critical illness-related corticosteroid insufficiency. Transbronchial lung biopsy revealed large atypical lymphoid cells with positivity for CD3+. We diagnosed this patient as having a peripheral T cell lymphoma and we treated him with high dose corticosteroid. His clinical and radiologic findings rapidly improved and then he received a full dose of chemotherapy for the peripheral T cell lymphoma.

A Case of Rectus Sheath Hematoma Complicated with Hypovolemic Shock in a Critically-Ill Patient / 결핵및호흡기질환

Rectus sheath hematoma (RSH) is a rare condition caused by hemorrhage into the rectus sheath. It is usually associated with severe cough, abdominal surgery, coagulopathy, and anticoagulation treatment. RSH can be difficult to diagnose and can be misdiagnosed as acute appendicitis, as diverticulitis, or as an ovarian mass. Although RSH usually presents as a benign condition, it can be life threatening, especially in the critically-ill patient. Here, we report a case of fatal RSH due to hypovolemic shock in a critically-ill 73-year-old woman, who had received heparin treatment due to acute myocardial infarction in the intensive care unit and who had been successfully treated by conservative management.

Bronchopathia Osteochodroplastica Mimicking Lung Malignancy / 대한흉부외과학회지

Tracheobronchopathia osteochondroplastica (TO) is an uncommon benign disease of an unknown etiology and it affects the cartilaginous walls of large airways. Most cases of TO have been reported to involve the lower two-thirds of the trachea and the proximal bronchi. Unlike the usual cases of TO, exclusive bronchial involvement and the formation of a solitary mass are very rare. We experienced an unusual case that had exclusive bronchial involvement and the formation of a solitary mass and this all mimicked lung malignancy. After surgical resection, we were finally able to diagnose the mass as bronchopathia osteochondroplastica.

Female Lung Cancer: Re-Analysis of National Survey of Lung Cancer in Korea, 2005

PURPOSE: Female lung cancers have different clinical features and therapeutic results as compared to those of male lung cancers. The aim of this study was to analyze the differences of Korean men and women with lung cancer. MATERIALS AND METHODS: We re-analyzed the results of a national survey of lung cancer conducted by the Korean Association for the Study of Lung Cancer in 2005. RESULTS: Of the 8,788 patients, 2,124 (24.2%) were female. The mean age at the diagnosis was 62.5 years for the females and 64.8 years for the males and the difference was significant (p<0.001). An age <50 years was more frequent for the women than for the men (16.2% vs. 7.9%, respectively; p=0.001). The stages between genders were different for the patients with non-small cell carcinoma (NSCLC) (p<0.001), but not for the patients with small cell carcinoma. The overall survival time was longer for woman than that for the man (p<0.001). However, the male patients had longer survival for the smokers with adenocarcinoma and the smokers with squamous cell carcinoma. The never smoker female patients had a better survival time than did the smoking female patients, but the male patient' survival was not influenced by the smoking status. The stage-specific survival rates were better for the women at all stages of NSCLC (p<0.001). The women who received chemotherapy had a longer survival time did the men who received chemotherapy (p<0.001). CONCLUSION: Women with lung cancer were relatively overrepresented among the younger patients and they smoked less intensively, raising the question of gender- specific differences in the carcinogenesis of lung cancer. Over-representation of adenocarcinoma was observed in the women regardless of their smoking status. Women with lung cancer had a better prognosis than men; however, the smoking females showed the worst prognosis. Gender and the smoking status are clearly important factors in the therapeutic approach to lung cancer.