Chung-Ping Hsu

Surgical–pathologic factors affect long-term outcomes in stage IB (pT2 N0 M0) non–small cell lung cancer: A heterogeneous disease

OBJECTIVES Our objective was to identify surgical-pathologic factors affecting prognosis in stage IB non-small cell lung cancers. METHODS Between 1997 and 2006, a cohort of 272 cases of pT2 N0 M0 stage lung cancer were retrospectively analyzed. The patients included 70 women and 202 men with a mean age of 67.0 years. The surgical resections included pneumonectomy in 4, bilobectomy or lobectomy in 217, and limited resections in another 51. The impact of surgical-pathologic characteristics on survival, including cell type, tumor differentiation, tumor size, depth of visceral pleural invasion, type of surgical resection, and extent of lymphadenectomy on patient survival, was compared accordingly. RESULTS Tumor types included adenocarcinoma/bronchioloalveolar carcinoma in 142, squamous cell carcinoma in 100, and others in 30. Cell differentiations were classified as well, moderately, and poorly differentiated in 23, 151, and 92 cases, respectively. The mean tumor size was 3.9 cm in diameter, and the average resected lymph node number was 14.3. Direct visceral pleural or subpleural invasions (<1 mm) were found in 134 and 42 cases, respectively. Angiolymphatic invasions were seen in 26 cases, and positive tumor margins were found in 14 cases. The overall 5-year and 10-year survivals were 59.5% and 41.3%, respectively. Good prognostic factors using univariate analysis included female gender, nonlimited resection, well-differentiated tumor, no angiolymphatic invasion, smaller size (<or=3 cm), and numbers of nodes retrieved (>14 nodes). However, the Cox proportional hazard model revealed female gender, well-differentiated tumor, no pleural involvement, no angiolymphatic invasion, and more than 14 nodes retrieved as independent good prognostic factors. CONCLUSIONS Stage IB lung cancer can be treated by standard pulmonary resection accompanied by adequate mediastinal lymphadenectomy. Owing to the heterogeneity of stage IB lung cancer and the fact that prognosis can be affected by many surgical-pathologic factors, refinement of the current TNM staging criteria may be needed.

N-acetyl cysteine mitigates curcumin-mediated telomerase inhibition through rescuing of Sp1 reduction in A549 cells

Curcumin is a natural compound that has been extensively observed due to its potential as an anticancer drug. Curcumin restrains cancer cell progression via telomerase activity suppression. However, the exact mechanism is still unknown. In this study, we demonstrate that the effects of curcumin on cell viability and telomerase activity can be blunted by reactive oxygen species (ROS) inhibitor N-acetyl cysteine (NAC). The ROS induced by curcumin in A549 cells was detected by flow cytometry. Using Western blot and RT-PCR, human telomerase reverse transcriptase (hTERT) decreased in the presence of curcumin. Sp1 is one of the important transcription factors in hTERT expression. Our data showed that curcumin decreases the expression of Sp1 through proteasome pathway. In addition, NAC blunted the Sp1 reduction and hTERT downregulation by curcumin. Further, reporter assay and DNA affinity precipitation assay confirmed the influence of curcumin on Sp1 in hTERT regulation. This is the first study to demonstrate that curcumin induces ROS production resulting in Sp1 binding activity inhibition and hTERT downregulation.

Clinical experience in radical lymphadenectomy for adenocarcinoma of the gastric cardia

OBJECTIVES We evaluated the pattern of nodal metastasis and its prognosis after radical lymphadenectomy in adenocarcinoma of the gastric cardia. METHODS We conducted a retrospective cohort study of 70 patients (52 men and 18 women; mean age 63.6 years) with adenocarcinomas of the gastric cardia who underwent extended gastrectomy (65 total gastrectomies and 5 proximal gastrectomies) and radical lymphadenectomy (D2 to D4) at Taichung Veterans General Hospital between 1989 and 1995. RESULTS Twenty-four complications developed in 22 (31.4%) patients, and seven (10.0%) hospital deaths occurred. An overall 5-year cumulative survival of 37.6% was obtained. Lymph node metastases were identified in 53 (75.7%) patients. Nodal involvement was closely related to the depth of tumor invasion (p = 0.005). When the gastric wall invasion was limited to the subserosal layer (T1 and T2, n = 15), no patient had N4 group nodal metastasis. Once the serosal layer had been involved (beyond T3), N4 group nodal metastasis was frequently seen (30.9%, 17 of 55 patients). A multivariable analysis revealed that the level of nodal involvement, the depth of tumor invasion, and the presence of complications were independent prognostic factors. Cumulative 5-year survivals of curability A (n = 12), B (n = 19), and C (n = 32) resections were 100%, 21.2%, and 27.5%, respectively (p = 0.0001). The long-term survival of the patients after resection was also closely related to their pTNM stages (p = 0.0004). CONCLUSIONS We conclude that gastrectomy accompanied by radical lymphadenectomy provides a reasonable long-term survival expectancy that is closely related to the stage of the disease and the curability of resection.

Epigenetic mechanisms for silencing glutathione S‐transferase m2 expression by hypermethylated specificity protein 1 binding in lung cancer

Glutathione S‐transferases M2 (GST‐M2) is a detoxifying enzyme. Low expression levels of GST‐M2 have been detected in lung cancer cells. However, little is known about the regulation of GST‐M2 in lung cancer cells. In this study, the authors investigated the epigenetic regulatory mechanisms of GST‐M2 in lung cancer cells.

Lipocalin 2, a new GADD153 target gene, as an apoptosis inducer of endoplasmic reticulum stress in lung cancer cells.

Endoplasmic reticulum (ER) stress is activated under severe cellular conditions. GADD153, a member of the C/EBP family, is an unfolded protein response (UPR) responsive transcription factor. Increased levels of lipocalin 2, an acute phase protein, have been found in several epithelial cancers. The aim of this study is to investigate the function of lipocalin 2 in lung cancer cells under ER stress. Treatment with thapsigargin, an ER stress activator, led to increases in cytotoxicity, ER stress, apoptosis, and lipocalin 2 expression in A549 cells. GADD153 silencing decreased lipocalin 2 expression in A549 cells. On chromatin immunoprecipitation assay, ER stress increased GADD153 DNA binding to lipocalin 2 promoter. Furthermore, silencing of lipocalin 2 mitigated ER stress-mediated apoptosis in A549 cells. Our findings demonstrated that lipocalin 2 is a new GADD153 target gene that mediates ER stress-induced apoptosis.

Expression of glutathione S-transferase M2 in stage I/II non-small cell lung cancer and alleviation of DNA damage exposure to benzo(a)pyrene

Glutathione S-transferases (GSTs) are a family of inducible enzymes that are important in carcinogen detoxification. GST-Mu class is showing the high activity towards most polycyclic aromatic hydrocarbon (PAH) epoxide. Our objective is to clarify the expression of GST-M2 in non-small-cell lung carcinoma (NSCLC) patients and to determine the role of GST-M2 in protecting against DNA damage. We detected changes in GST-M2 expression at mRNA levels with a panel of lung cell lines and clinical samples of malignant and paired adjacent non-malignant tissues from 50 patients with stage I or II non-small-cell lung carcinoma using real-time RT-PCR. Comet assay and gamma-H2AX were used to clarify whether DNA damaged was protected by GST-M2. Our data demonstrate that the expression of GST-M2 in tumor tissues is significantly lower than in paired adjacent non-malignant tissues (p=0.016). Loss of GST-M2 is closely associated with age, gender, T value, N value and cell differentiation (p<0.05) in early stage I/II patients. Downregulation of GST-M2 is mediated through aberrant hypermethylation in lung cancer cell lines. Protection against B[a]P-induced DNA damage by GST-M2 in lung cancer cells was detected by Comet assay and gamma-H2AX. In conclusion, DNA hypermethylation altered and reduced GST-M2 expression that resulted in susceptible to benzo[a]pyrene (B[a]P) induced DNA damage. It implies that GST-M2 reduction occurs prior to tumorigenesis.

Pulmonary sequestration-differences in diagnosis and treatment in a single institution.

Background: Pulmonary sequestration (PS) is a rare congenital lung malformation. In this study, we evaluated the diagnosis and treatment of PS in 31 adult patients at a single institution. Methods: A retrospective review of all patients 16 years of age and older with PS in a single institution between January 1985 and January 2011 was conducted. The following data were analyzed for all patients: major symptoms, diagnostic procedures, operative findings, operative techniques, postoperative complications, and outcome. Results: Our study involved 31 patients, 17 male and 14 female, with an average age of 32.1 (17–57) years, who underwent surgical intervention for PS. The preoperative symptoms of these patients included cough, hemoptysis, fever, pneumonia, and chest pain. Thirty (96.8%) patients were diagnosed by thoracic computed tomography. Of the 31 patients, 29 were diagnosed with intralobar pulmonary sequestration and two had extralobar pulmonary sequestration. Surgical procedures for intralobar pulmonary sequestration included lobectomy in 22 patients (including one thoracoscopic lobectomy), segmentectomy in six, and wedge resection in one of the patients. Thoracoscopic simple mass excision was performed on the two patients with extralobar pulmonary sequestration. Two patients had a postoperative complication (prolonged air leak in 1 patient and postoperative hemothorax in the other). The average hospital stay for all study patients was 6.4 (4–18) days, and there was no mortality. Conclusion: Diagnostic tools may enable the clinician to obtain a definitive diagnosis in patients where there is a strong suspicion of PS via a noninvasive procedure. Computed tomography angiography may be the diagnostic imaging method of choice for optimal evaluation of the sequestrated lung and its vascular supply.

GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer

Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of total lung cancers; 40% to 60% of NSCLC patients die of cancer recurrence after cancer resection. Since GLK (also named MAP4K3) induces activation of NF-κB, which contributes to tumor progression, we investigated the role of GLK in NSCLC. GLK protein levels of 190 samples from pulmonary tissue arrays and 58 pulmonary resection samples from stage I to stage III NSCLC patients were studied using immunohistochemistry or immunoblotting. High levels of GLK proteins were detected in pulmonary tissues from NSCLC patients. Elevated GLK protein levels were correlated with increased recurrence risks and poor recurrence-free survival rates in NSCLC patients after adjusting for pathologic stage, smoking status, alcohol status, and EGFR levels. Thus, GLK is a novel prognostic biomarker for NSCLC recurrence.

EGFR-activating mutations, DNA copy number abundance of ErbB family, and prognosis in lung adenocarcinoma.

In this study, EGFR-activating mutation status and DNA copy number abundances of members of ErbB family were measured in 261 lung adenocarcinomas. The associations between DNA copy number abundances of ErbB family, EGFR-activating mutation status, and prognosis were explored. Results showed that DNA copy number abundances of EGFR, ERBB2, ERBB3, and ERBB4 had associations with overall survival in lung adenocarcinoma with EGFR-activating mutations. In the stratification analysis, only ERBB2 showed significant discrepancy in patients carrying wild type EGFR and other members of ErbB family in patients carrying EGFR-activating mutation. This indicated that CNAs of ErbB family had effect modifications of EGFR-activating mutation status. Findings of this study demonstrate potential molecular guidance of patient management of lung adenocarcinoma with or without EGFR-activating mutations.

Glutathione S-Transferase Mu2 Suppresses Cancer Cell Metastasis in Non-Small Cell Lung Cancer

Glutathione S-transferase mu2 (GST-M2) is a phase II detoxification enzyme. Low expression of GST-M2 in lung cancers is due to hypermethylation of its promoter. Lung cancer with the GST mu-null genotype is associated with shorter survival. However, a correlation between GST-M2 and important clinical parameters, as well as the migration of GST-M2–defective cells in lung cancer, has not been established. In the present study, we investigate the role of GST-M2 in cell migration and actin disassembly in lung cancer cells. GST-M2 and CCN2 mRNA levels were significantly reduced in non–small cell lung cancer (NSCLC) tumors when compared with matched normal lung tissues in 82 patients with NSCLC. We found that high expressions of both GST-M2 and CCN2 are correlated with favorable survival of patients with lung cancer when compared with similar patients without GST-M2 or CCN2 expression. GST-M2 can induce CCN2 expression by driving the CCN2 proximal promoter. Overexpression of GST-M2 decreases the formation of filopodia, resulting in remodeling of the reorganized cytoskeletons. Overexpression of GST-M2 significantly suppressed cancer cell migration on wound-healing assay. In addition, overexpression of GST-M2 dramatically reduced tumor growth and metastasis in a xenograft mouse model. These data highlight the potential of GST-M2 as a novel tumor suppressor. GST-M2 increases the expression of CCN2 in lung cancer cells, which inhibits cancer cell migration in lung cancer and animal models. Mol Cancer Res; 11(5); 518–29. ©2013 AACR.