Sung Chul Hwang

Expression of peroxiredoxin and thioredoxin in human lung cancer and paired normal lung

Background:  Peroxiredoxins (Prxs) have been implicated in regulating many cellular processes including cell proliferation, differentiation and apoptosis. However, the pathophysiological significance of Prx proteins, especially in lung disease, has not been defined. Therefore, the authors investigated the distribution and expression of various Prx isoforms in lung cancer and compared this with normal lung from human and mouse.

Expression of excision repair cross-complementation group 1 protein predicts poor outcome in advanced non-small cell lung cancer patients treated with platinum-based doublet chemotherapy

BACKGROUND Alterations in apoptosis and DNA damage repair related proteins are associated with resistance to chemotherapy, which is the most important cause of treatment failure in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Pretreatment tumor biopsy specimens from 50 patients with NSCLC including stage IIIB with malignant pleural effusion or stage IV or recurrent disease were analyzed for p53, Bcl-2, Bax, and ERCC1 expression by immunohistochemistry. All patients were treated with platinum-based third-generation doublet chemotherapy, in which gemcitabine and cisplatin was the most commonly administered regimen (17 patients). RESULTS High expression of p53, Bcl-2, Bax, and ERCC1 was observed in 24 (48%), 8 (16%), 32 (63%), and 28 (55%) patients, respectively. In univariate analysis, high expression of ERCC1 demonstrated a trend of association with poor overall survival (OS) (median, 8 months vs. 11 months; P=0.055). High expression of p53, Bcl-2, Bax was not correlated with patient outcome. High expression of ERCC1 was an independent prognostic factor for poor OS (P=0.002) along with poor performance status (P=0.028) and lack of disease control (P=0.001) in multivariate analysis. CONCLUSIONS High expression of ERCC1 may be a useful prognostic factor for poor outcome in advanced NSCLC patients treated with platinum and third-generation doublet chemotherapy.

Vascular endothelial growth factor in the serum of patients with non-small cell lung cancer: correlation with platelet and leukocyte counts.

BACKGROUND Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide expressed in a wide variety of tumors, and it stimulates angiogenesis and increases vascular permeability. Increased expression of VEGF may be associated with advanced stage and poor prognosis in patients with non-small cell lung cancer (NSCLC). METHODS Using enzyme-linked immunosorbent assay, the levels of VEGF were determined in serum from 41 patients with untreated NSCLC (Stage: IIB, 3; IIIA, 6; IIIB, 17; IV, 15; HISTOLOGY squamous cell carcinoma, 18; adenocarcinoma. 14; undetermined, 9). RESULTS The median VEGF level was 312 pg/ml, ranging from 70 to 1440 pg/ml. Patients were divided into high VEGF (>312 pg/ml) and low VEGF (< or =312 pg/ml) groups using the median value as a cut-off. There were no significant associations between the serum VEGF levels and various clinicopathologic characteristics including age, gender, histologic type, stage and treatment. A significant positive correlation was found between serum VEGF levels and platelet counts (r=0.495; P=0.001). In addition, serum VEGF levels also correlated with leukocyte counts (r=0.478; P=0.002). In seven patients with measurement of follow-up serum VEGF levels at the end of treatment (chemotherapy and/or radiotherapy), the median serum VEGF level significantly decreased after the treatment (416 pg/ml; range, 96-812 pg/ml vs. 185 pg/ml; range, 49-487 pg/ml; P=0.028). However, the median platelet count (317,000/microl; range, 190,000-395,000/microl vs. 246,000/microl; range, 72,000-271,000/microl; P=0.028) and leukocyte count (10,000/microl; range, 8700-17,200/microl vs. 5100/microl; range, 3900-9500/microl; P=0.018) also decreased after the treatment. There was no statistically significant difference in the median survival of the patients between high VEGF group and low VEGF group (8 months vs. 9 months, P=0.647). CONCLUSIONS Although serum VEGF level was significantly associated with platelet and leukocyte counts in NSCLC patients, it did not correlate with tumor burden and prognosis of the patients.

Nuclear factor E2-related factor 2 Dependent Overexpression of Sulfiredoxin and Peroxiredoxin III in Human Lung Cancer

Background/Aims Oxidative stress results in protein oxidation and is implicated in carcinogenesis. Sulfiredoxin (Srx) is responsible for the enzymatic reversal of inactivated peroxiredoxin (Prx). Nuclear factor E2-related factor 2 (Nrf2) binds to antioxidant responsive elements and upregulates the expression of Srx and Prx during oxidative stress. We aimed to elucidate the biological functions and potential roles of Srx in lung cancer. Methods To study the roles of Srx and Prx III in lung cancer, we compared the protein levels of Nrf2, Prxs, thioredoxin, and Srx in 40 surgically resected human lung cancer tissues using immunoblot and immunohistochemical analyses. Transforming growth factor-β1, tumor necrosis factor-α, and camptothecin treatment were used to examine Prx III inactivation in Mv1Lu mink lung epithelial cells and A549 lung cancer cells. Results Prx I and Prx III proteins were markedly overexpressed in lung cancer tissues. A significant increase in the oxidized form of a cysteine sulfhydryl at the catalytic site of Prxs was found in carcinogenic lung tissue compared to normal lung tissue. Densitometric analyses of immunoblot data revealed significant Srx expression, which was higher in squamous cell carcinoma tissue (60%, 12/20) than in adenocarcinoma (20%, 4/20). Also, Nrf2 was present in the nuclear compartment of cancer cells. Conclusions Srx and Prx III proteins were markedly overexpressed in human squamous cell carcinoma, suggesting that these proteins may play a protective role against oxidative injury and compensate for the high rate of mitochondrial metabolism in lung cancer.

Clinical usefulness of the fluorodeoxyglucose (FDG)-PET maximal standardized uptake value (SUV) in combination with CT features for the differentiation of adenocarcinoma with a bronchioloalveolar carcinoma from other subtypes of non-small cell lung cancers

PURPOSE To evaluate the clinical usefulness of fluorodeoxyglucose (FDG)-PET maximal SUV in combination with CT features for differentiation of adenocarcinoma with bronchioloalveolar carcinoma (BAC) from other subtypes of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS This retrospective study included 125 patients (104 men and 21 women; mean age, 64 years) who underwent CT and subsequent FDG-PET examinations for preoperative evaluation and underwent curative intent operation with the final diagnoses of NSCLC made by surgical histopathology. We categorized NSCLC into adenocarcinoma with BAC feature and other subtypes. Finally, there were 16 cases of adenocarcinoma with BAC and 109 cases of other NSCLC subtypes included in the study. Several CT features of lung cancer were analyzed, including tumor size, presence of spiculation, margin (irregular or smooth), pattern of the mass (pure solid, pure ground glass opacity and mixed), associated pleural effusion and location (center, mid and periphery). Maximal SUV and visual scores of FDG uptakes of primary NSCLC were evaluated. The diagnostic performances of CT alone, PET alone, and combination of two modalities to predict adenocarcinoma with BAC from other subtypes of NSCLC were calculated. RESULTS A nodule with a mixed pattern with partly solid and ground glass opacity was significantly more frequent CT feature of an adenocarcinoma with BAC (8/16, 50%) as compared with the other subtypes (2/109, 1.8%) (p<0.0001). Maximal SUV of adenocarcinoma with BAC (mean=7.2) was significantly lower than that of other subtypes of NSCLC (mean=13.33) (p<0.0001). Sensitivity, specificity, PPV, and NPV of CT for differentiating adenocarcinoma with BAC from other subtypes was 50% (8/16), 98.2% (107/109), 80% (8/10), and 93% (107/115), respectively. Sensitivity, specificity, PPV, and NPV of FDG-PET was 68.8% (11/16), 86.2% (94/109), 42.3% (11/26), and 94.9% (94/99), respectively. Sensitivity, specificity, PPV, and NPV of combination of two modalities was 81.3% (13/16), 85.3% (93/109), 44.8% (13/29), 96.9% (93/96), respectively. CONCLUSION Careful combined assessment of the FDG-PET maximal SUV and CT findings have the potential to differentiate an adenocarcinoma with BAC from other NSCLC subtypes, such as a pure BAC. These findings might be useful for imaging interpretations and will help initial planning of NSCLC management.

Computerized Physician Order Entry and Electronic Medical Record Systems in Korean Teaching and General Hospitals: Results of a 2004 Survey

OBJECTIVE To determine the availability of computerized physician order entry (CPOE) and electronic medical record (EMR) systems in teaching and general hospitals in the Republic of Korea. DESIGN A combined mail and telephone survey of 283 hospitals. MEASUREMENTS The surveys assessed the availability of CPOE and EMRs in the hospitals, as well as inducement, participation, and saturation regarding CPOE use by physicians. RESULTS A total of 122 (43.1%) hospitals responded to the survey. The complete form of CPOE was available in 98 (80.3%) hospitals. The use of CPOE was mandatory in 92 (86.0%) of the 107 hospitals that responded to the questions regarding the requirement of CPOE use. In 85 (79.4%) of the hospitals in which CPOE was in use, more than 90% of physicians used the system. In addition, physicians entered more than 90% of their total orders through CPOE in 87 (81.3%) hospitals. In contrast, a complete EMR system was available in only 11 (9.0%) of the hospitals. CONCLUSION Of the teaching and general hospitals in the Republic of Korea that responded to the survey, the majority (80.3%) have CPOE systems, and a complete EMR system is available in only 9%.

Expression of Bcl-2 predicts outcome in locally advanced non-small cell lung cancer patients treated with cisplatin-based concurrent chemoradiotherapy

BACKGROUND Platinum-based concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced unresectable non-small cell lung cancer (NSCLC). The determination of parameters that may predict the result of the treatment has strong clinical implications. PATIENTS AND METHODS Pretreatment tumor biopsy specimens from 39 patients with locally advanced NSCLC (stage IIIA: 5, stage IIIB: 34) were analyzed for p53, Bcl-2, Bax and ERCC1 expression by immunohistochemistry. All patients were treated with cisplatin-based CCRT. Twenty-four patients received induction chemotherapy followed by CCRT (60Gy/30 fractions, 6mg/m(2) of cisplatin daily). The most commonly administered induction chemotherapy regimen was VIP (etoposide, ifosfamide, cisplatin; 20 patients). Fifteen patients received the same CCRT without induction chemotherapy. RESULTS High expression of p53, Bcl-2, Bax and ERCC1 was observed in 15 (38%), 19 (49%), 17 (44%) and 12 (31%) patients, respectively. High expression of Bcl-2 was significantly associated with longer survival duration (20 months vs. 9 months, P=0.008) and better response to the treatment (74% vs. 30%, P=0.01). In multivariate analysis, Bcl-2 expression was the only significant independent prognostic factor of overall survival (P=0.007) among the pretreatment patients characteristics. CONCLUSIONS High expression of Bcl-2 may be a useful prognostic factor in locally advanced NSCLC patients treated with cisplatin-based CCRT.

Low expression of Bax predicts poor prognosis in resected non-small cell lung cancer patients with non-squamous histology.

Objective The present study evaluated the prognostic significance of apoptosis-related proteins p53, Bax and galectin-3 in patients with non-small cell lung cancer (NSCLC) treated with surgical resection. Methods We investigated the expression of these proteins and their association with clinicopathologic characteristics including disease-free survival (DFS) and overall survival (OS) in 205 NSCLC patients who underwent surgical resection (Stage I, 97; II, 46; IIIA, 45; IIIB, 17) using immunohistochemistry. Eighty-eight patients (43%) received adjuvant treatment (chemotherapy: 8, radiotherapy: 24, both: 56). Results High expressions of Bax, p53 and galectin-3 were observed in 48 (23%), 81 (40%) and 105 (51%) patients, respectively. Low expression of Bax was significantly associated with male gender, squamous cell histology and low expression of galectin-3. Five-year DFS and OS of total patients were 37 and 46%, respectively. High expressions of p53 and galectin-3 were not associated with poor DFS or OS, and no significant correlation existed between low expression of Bax and outcome of patients. However, in patients with non-squamous histology (108 patients), low expression of Bax was a significant independent predictor of poor DFS (P = 0.017) and OS (P = 0.037). In addition, in patients with Stage II or III disease, low expression of Bax significantly correlated with poor DFS (P = 0.004). It was also the most significant independent poor prognostic factor second only to a large primary tumor size in Stage II or III patients with non-squamous histology. Conclusions Low expression of Bax was significantly associated with poor prognosis in resected NSCLC patients with non-squamous histology.

Serum angiopoietin-1 as a prognostic marker in resected early stage lung cancer

PURPOSE We evaluated the clinical significance of angiopoietins and vascular endothelial growth factor (VEGF) in patients with resected early stage lung cancer. PATIENTS AND METHODS The study enrolled 101 patients with completely resected non-small cell lung cancer (NSCLC) of stage I or II, along with 70 healthy volunteers. Serum concentrations of angiopoietin-1, angiopoietin-2, and VEGF were measured with an ELISA. Immunohistochemical expression of angiopoietin-1 was compared with the microvessel density on the lung cancer tissues. RESULTS The patients had lower serum angiopoietin-1 (32.1+/-9.9 ng/mL vs. 39.0+/-10.8 ng/mL, p<0.001), higher angiopoietin-2 (1949.2+/-1099.4 pg/mL vs. 1498.6+/-650.0 pg/mL, p<0.01), and higher VEGF (565.1+/-406.3 pg/mL vs. 404.6+/-254.8 pg/mL, p<0.01) levels than the controls. The angiopoietin-2 level was higher in stage II than in stage I patients (p<0.05). The levels of angiopoietin-1 (r=0.28) and angiopoietin-2 (r=0.36) each correlated with the VEGF level. Patients with a higher level of angiopoietin-1 (> or =31.2 ng/mL) had better disease-specific and relapse-free survival than those with a lower angiopoietin-1 level (<31.2 ng/mL). Angiopoietin-1 expression negatively correlated with the microvessel density. CONCLUSION Serum angiopoietin-1 is a potential marker for predicting postoperative survival and recurrence in patients with early stage NSCLC.

Emphysema as a risk factor for the outcome of surgical resection of lung cancer.

It is unclear whether emphysema, regardless of airflow limitation, is a predictive factor associated with survival after lung cancer resection. Therefore, we investigated whether emphysema was a risk factor associated with the outcome after resection for lung cancer. This study enrolled 237 patients with non small cell lung cancer with stage I or II who had surgical removal. Patient outcome was analyzed based on emphysema. Emphysema was found in 43.4% of all patients. Patients with emphysema were predominantly men and smokers, and had a lower body mass index than the patients without emphysema. The patients without emphysema (n=133) survived longer (mean 51.2±3.0 vs. 40.6±3.1 months, P=0.042) than those with emphysema (n=104). The univariate analysis showed a younger age, higher FEV1/FVC, higher body mass index, cancer stage I, and a lower emphysema score were significant predictors of better survival. The multivariate analysis revealed a younger age, higher body mass index, and cancer stage I were independent parameters associated with better survival, however, emphysema was not. This study suggests that unfavorable outcomes after surgical resection of lung cancer should not be attributed to emphysema itself.