Prevention and management of lung cancer in China.

Lung cancer is the leading cause of cancer-related death worldwide. In China, the incidence of lung cancer has grown rapidly, resulting in a large social and economic burden. Several researchers have devoted their studies to lung cancer and have demonstrated that there are many risk factors for lung cancer in China, including tobacco use, environmental pollution, food, genetics, and chronic obstructive pulmonary disease. However, the lung cancer incidence is still growing rapidly in China, and there is an even higher incidence among the younger generation. One explanation may be the triple-neglect situation, in which medical policies that neglect prevention, diagnosis, and supportive care have increased patients' mortality and reduced their quality of life. Therefore, it is necessary to enhance the efficiency of prevention and early diagnosis not only by focusing more attention on treatment but also by drawing more attention to supportive care for patients with lung cancer.

Role of a serum-based biomarker panel in the early diagnosis of lung cancer for a cohort of high-risk patients.

BACKGROUND: This study applied a combined cancer biomarker panel to clinically identify small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) in a high-risk population. METHODS: The serum levels of 4 biomarkers (progastrin-releasing peptide [ProGRP], carcinoembryonic antigen [CEA], squamous cell carcinoma antigen [SCC], and cytokeratin 19 fragment [CYFRA21-1]) were determined in 153 patients with a high risk of lung cancer (12 with a new diagnosis of SCLC, 52 with NSCLC, and 89 without lung cancer). Information about diagnosis delays was collected through interviews of all participants. RESULTS: Significantly higher serum levels of ProGRP (P < .0001) were found among the SCLC patients versus the rest of the population. A receiver operating characteristic curve analysis established the cutoff values of ProGRP, CEA, SCC, and CYFRA21-1 as 300 pg/mL, 7.3 ng/mL, 3 ng/mL, and 6.5 ng/mL, respectively. The sensitivity and specificity of ProGRP in diagnosing SCLC were 75% and 100%, respectively. Among the 14 lung cancer patients with a false-negative computed tomography (CT) result, the diagnostic panel detected 8 additional cancers. CONCLUSIONS: This panel increased the diagnostic specificity for high-risk subjects (those with renal failure being excluded), and auxiliary to a CT scan, it increased the sensitivity for patients with lung cancer. These results might be applied to shorten the diagnosis delay at health care institutions in China.

Prevalence of undiagnosed and undertreated chronic obstructive pulmonary disease in lung cancer population.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a risk factor and important coexisting disease for lung cancer; however, the current status of management of COPD in lung cancer patients is not fully described. This study addressed this issue in a general teaching hospital in China. METHODS: Medical records of hospitalized lung cancer patients in Zhongshan Hospital, Fudan University, between January 2006 and December 2010 were reviewed. The definition of COPD was according to the spirometric criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document. The diagnostic rate (COPD recorded as a discharge diagnosis/spirometry-defined percentage) and conformity to GOLD treatment guidelines were investigated. The factors influencing diagnosis were analysed. RESULTS: During the study period, the prevalence of spirometry-defined COPD in hospitalized lung cancer patients was 21.6% (705/3263). The overall diagnostic rate of COPD was 7.1%, and the treatment conformity for stable and acute exacerbation of COPD was 27.1% and 46.8%, respectively. Respiratory physicians had a higher diagnostic rate than non-respiratory doctors (34.8% vs 2.9%, P < 0.001) and a better treatment conformity for acute exacerbation of COPD (63.6% vs 37.5%, P = 0.048). Patients with COPD as a discharge diagnosis had more chance to receive guideline-consistent treatment. The diagnostic rate of COPD was higher among patients with a history of smoking, respiratory diseases or symptoms. CONCLUSIONS: COPD is substantially underdiagnosed and undertreated in a hospitalized lung cancer population. History of smoking, respiratory diseases and symptoms promotes diagnosis. Education of COPD knowledge among patients and doctors is urgently required in this special population.

[Value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in early diagnosis of lung cancer].

OBJECTIVE: To evaluate the application value of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in early diagnosis of lung cancer. METHODS: Retrospective analyses were conducted for 347 cases of pulmonary space-occupying lesions at Zhongshan Hospital from June 2010 to October 2012. The diagnostic validity of PET/CT and fluorodeoxyglucose maximum standardized uptake value (SUVmax) of lesions were compared respectively. Among different morphological characteristics, pathologic types and levels of tumor markers. The diagnostic value of PET/CT was also evaluated along with serum tumor markers for lung cancer. RESULTS: SUVmax was positively correlated with lesion size (r = 0.484, P < 0.05) and negatively with tumor differentiation degree (r = -0.232, P < 0.01). It was significantly higher in tumor marker positive group than the negative group (10.6 ± 5.5 vs 7.6 ± 5.4, P < 0.05). The diagnostic specificity, sensitivity and accuracy of PET/CT were 50.0%, 96.6% and 89.3% in lung cancer. And the greater the lesion, the higher the diagnostic accuracy (P < 0.05). PET/CT plus serum tumor markers could boost the diagnostic specificity of lung cancer by 30% (P < 0.01). CONCLUSIONS: (18)F-FDG PET/CT has high diagnostic values for early stage pulmonary nodules. It can also suggest the differentiation degree of lung cancer. Combined use of serum tumor markers and (18)F-FDG PET/CT increases the early diagnostic specificity of lung cancer.

[Value of low-dose spiral computed tomography in lung cancer screening].

OBJECTIVE: To explore the application value of low-dose spiral computed tomography (LDCT) in lung cancer screening. METHODS: A total of 2251 asymptomatic subjects undergoing chest LDCT scan at Center of Physical Examination, Affiliated Zhongshan Hospital, Fudan University between June 2011 and December 2012 were prospectively enrolled. The incidence rates of lung nodule and lung cancer were analyzed to compare the value of LDCT screening in subjects with smoking-related high, medium and low risks of lung cancer. The value of serum tumor biomarker in the reduction of false positive of LDCT was also discussed. RESULTS: Among all subjects, 9.9% (222/2251) displayed at least 1 non-calcified nodule with a diameter ≥ 4 mm. Two subjects were diagnosed with lung cancer and 1 of them received surgical resection. Other subjects with lung nodules were followed. There was no statistical difference in the incidence rates of lung nodule between the high, medium and low-risk groups of lung cancer associated with smoking (8.8%, 9.5% and 10.1%, P = 0.864). The incidence rates of lung nodule in subjects ≥ 55 years old were higher than that of those <55 years old (12.7% vs 9.1%, P = 0.034). Female gender had a high risk of ground glass opacity (GGO) or ground glass nodule (GGN) (P = 0.015). The independent or combined increase of serum tumor biomarkers of carcinoembryonic antigen (CEA), neuron specific enolase (NSE), cytokeratin fragment 21-1 (Cyfra211) and squamous cell carcinoma antigen (SCC) might not predicate the incidence of lung nodule. CONCLUSION: LDCT screening is highly valuable in lung cancer screening.

[Evaluation of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of hilar and mediastinal masses of unknown etiologies].

OBJECTIVE: To explore the diagnostic values of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the patients with hilar and mediastinal masses. METHODS: A total of 91 patients with mediastinal/hilar masses undergoing EBUS-TBNA in Zhongshan Hospital between September 2009 and March 2011 were retrospectively enrolled. Their unknown etiologies were difficult to be assessed by a traditional biopsy. The association of pathologic examinations and clinical data were analyzed. RESULTS: Among them, 61 patients had malignant lesions while 30 patients were diagnosed with benign diseases. In the cases with malignant lesions, the diagnostic sensitivity, specificity and accordance rate were 91.67%, 100% and 91.80% respectively. The diagnostic accordance rate of benign lesions was 60%. And 36.9% (24/65) of the samples were small-sized so as to improve the diagnostic accuracy. The combination of cytology and histology significantly increased the diagnostic accordance versus cytology alone in all cases (P < 0.01). But there was no statistically significant difference in the malignant lesion subgroup with a better tendency (P > 0.05). No severe complication occurred. CONCLUSION: With a high diagnostic accuracy and a low complication rate for the patients with hilar and mediastinal masses of unknown etiologies, EBUS-TBNA has different values for diagnosing malignant and benign lesions.

[A retrospective study of diagnosis and treatment of chronic obstructive pulmonary disease in patients with lung cancer].

OBJECTIVE: To assess the diagnostic and therapeutic status of non-respiratory physicians managing chronic obstructive pulmonary disease (COPD) for patients with lung cancer at general hospitals to promote a standardized regimen. METHODS: Through a retrospective survey from January 2009 to December 2010 at our hospital, the data of clinical features, pulmonary function test results and information of therapy for lung cancer patients with COPD admitted at non-respiratory departments (mostly of thoracic surgery) were collected. RESULTS: A total of 240 lung cancer patients with COPD were admitted. Five patients were diagnosed as COPD with a diagnostic rate of 2.1%. And 210 cases of patients were stable. According to GOLD guidelines in 2010, only 50 cases were treated with adequate drugs (23.8%). Among another 30 patients with acute exacerbation, the following therapies were administrated: selective bronchodilator (n = 13, 43.3%), antibiotics (n = 26, 86.7%) and glucocorticoids (n = 1, 3.3%). CONCLUSION: Underdiagnosis and inadequate treatment of COPD in lung cancer patients by non-respiratory physicians are too serious to be neglected.

Prolonged progression-free survival and overall survival are associated with diabetes mellitus but inversely associated with levels of blood glucose in patients with lung cancer.

BACKGROUND: Previous studies have provided conflicting evidence about the increased overall survival (OS) in lung cancer patients with diabetes mellitus (DM) compared with those without DM. This study assessed progression-free survival (PFS)/OS in lung cancer patients with or without DM and tentatively analyzed the impact of blood glucose levels on PFS/OS in lung cancer patients. METHODS: Data were collected from lung cancer patients based upon admission records from January 2010 to January 2012 and follow-up records from January 2010 to January 2015 in the Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai. The data included patient sex, age, body mass index (BMI), smoking status, history of DM, level of blood glucose, pathological type, clinical stage of cancer, chemotherapy regimen, and history of anti-DM drugs. The Cox regression model and Kaplan-Meier method were used for the analysis of hazard factors and PFS/OS. For comparison of PFS/OS in lung cancer with or without DM, patients were divided into three groups: lung cancer with DM, lung cancer without DM but with elevated level of blood glucose, lung cancer without DM or elevated level of blood glucose. RESULTS: In total, the data from 200 lung cancer patients (138 males/62 females, aged 29.0 to 78.0 years, mean 60.0 ±â€Š8.6 years) were collected. For the comparison of PFS/OS in lung cancer patients with or without DM, patients were divided into three groups: lung cancer with DM (n = 31); lung cancer without DM but with elevated levels of blood glucose (n = 40); and lung cancer without both DM and elevated levels of blood glucose (n = 128), whereas 1 patient dropped out of the study. All the patients underwent complete chemotherapy and were followed up for 36.0 to 60.0 months. Kaplan-Meier survival analysis showed that lung cancer patients with DM had increased PFS and OS compared with those without DM (log-rank, P < 0.05, P < 0.01); the median PFS in lung cancer with DM was 12.0 months (95% confidence interval [CI], 4.0-16.0) vs. 6.0 months in those without DM (95% CI, 5.8-6.3); and the median OS in lung cancer patients with DM was 37.0 months (95% CI, 29.0-46.6) vs. 12.0 months in those without DM (95% CI, 10.9-13.1). For the other two groups of patients without DM, there was a trend toward a shorter PFS and OS in patients with elevated blood glucose compared with those without elevated blood glucose. Cox regression showed that PFS in lung cancer patients was favorably associated with the usage of anti-DM drugs, BMI, clinical stage of cancer, and chemotherapy regimen (all P < 0.05) but was inversely associated with the level of blood glucose (P < 0.05). CONCLUSIONS: Lung cancer patients with DM have prolonged PFS and OS compared with those without DM, and the level of blood glucose was inversely associated with PFS. The current results indicate that PFS may be a meaningful intermediate endpoint for OS and that the levels of blood glucose hopefully represent a prognostic factor in lung cancer patients.

Silencing the epidermal growth factor receptor gene with RNAi may be developed as a potential therapy for non small cell lung cancer.

Lung cancer has emerged as a leading cause of cancer death in the world. Non-small cell lung cancer (NSCLC) accounts for 75-80% of all lung cancers. Current therapies are ineffective, thus new approaches are needed to improve the therapeutic ratio. Double stranded RNA (dsRNA)-mediated RNA interference (RNAi) has shown promise in gene silencing, the potential of which in developing new methods for the therapy of NSCLC needs to be tested. We report here RNAi induced effective silencing of the epidermal growth factor receptor (EGFR) gene, which is over expressed in NSCLC. NSCLC cell lines A549 and SPC-A1 were transfected with sequence- specific dsRNA as well as various controls. Immune fluorescent labeling and flow cytometry were used to monitor the reduction in the production of EGFR protein. Quantitative reverse-transcriptase PCR was used to detect the level of EGFR mRNA. Cell count, colony assay, scratch assay, MTT assay in vitro and tumor growth assay in athymic nude mice in vivo were used to assess the functional effects of EGFR silencing on tumor cell growth and proliferation. Our data showed transfection of NSCLC cells with dsRNA resulted in sequence specific silencing of EGFR with 71.31% and 71.78 % decreases in EGFR protein production and 37.04% and 54.92% in mRNA transcription in A549 and SPC-A1 cells respectively. The decrease in EGFR protein production caused significant growth inhibition, i.e.: reducing the total cell numbers by 85.0% and 78.3%, and colony forming numbers by 63.3% and 66.8%. These effects greatly retarded the migration of NSCLC cells by more than 80% both at 24 h and at 48 h, and enhanced chemo-sensitivity to cisplatin by four-fold in A549 cells and seven-fold in SPC-A1. Furthermore, dsRNA specific for EGFR inhibited tumor growth in vivo both in size by 75.06% and in weight by 73.08%. Our data demonstrate a new therapeutic effect of sequence specific suppression of EGFR gene expression by RNAi, enabling inhibition of tumor proliferation and growth. However, in vivo use of dsRNA for gene transfer to tumor cells would be limited because dsRNA would be quickly degraded once delivered in vivo. We thus tested a new bovine lentiviral vector and showed lentivector-mediated RNAi effects were efficient and specific. Combining RNAi with this gene delivery system may enable us to develop RNAi for silencing EGFR into an effective therapy for NSCLC.

[Effect of aquaporin-1 and sodium channel on pleural fluid transport in mice].

OBJECTIVE: To investigate the effect of sodium channel and aquaporin-1 on pleural fluid transport. METHODS: Mice were briefly anesthetized, and the pleural space was infused with 0.25 ml of hyperosmolar or isosmolar solution, with terbutaline or amiloride in instilled solution. The mice were treated with either intraperitoneal dexamethasone or intravenous HgCl(2). Mice were euthanized at specified times for measurement of pleural fluid osmolality, volume and (125)I-album in concentration. The rate of pleural fluid filtration and clearance was calculated, which was used to indicate the effect of sodium channel regulator (amiloride and terbutaline) and aquaporin regulator (dexamethasone and HgCl(2)) on pleural fluid transport. RESULTS: Amiloride decreased the osmotically driven water transport and isosmolar fluid clearance in pleural space (P < 0.05). Terbutaline increased osmotically driven water transport and isosmolar fluid clearance in pleural space (P < 0.05). HgCl(2) decreased, while dexamethasone increased, the osmotically driven water transport in pleural space (P < 0.05). HgCl(2) and dexamethasone had no effect on pleural isosmolar fluid clearance (P > 0.05). CONCLUSIONS: Sodium channel may play a role in osmotic and isosmolar fluid transport in pleural space. Aquaporin-1 may play a role in osmotic fluid transport in pleural space, while having no effect on isosmolar fluid clearance.

Anti-inflammatory effect of methoxyphenamine compound in rat model of chronic obstructive pulmonary disease.

AIM: To evaluate the anti-inflammatory effect of methoxyphenamine compound (MC) on chronic obstructive pulmonary disease (COPD) in rats by measurement of proinflammatory cytokines, total and differential white cell counts (WCC) of bronchroalveolar lavage fluid (BALF). METHODS: Adult rat model of COPD (COPD group) was induced by intratracheal instillation of lipopolysaccharides and exposure to cigarette smoke. Treatment groups received different dosage of MC (3, 9, and 27 mg daily, MC group) or prednisone (0.25 mg daily, P group) respectively. Tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), interleukin-6 (IL-6), transforming growth factor beta (TGF-beta) of BALF were determined by ELISA. Total and differential WCC were performed after Giemsa staining. RESULTS: The levels of TNF-alpha, IL-1beta, IL-6, TGF-beta, total and differential WCC in BALF of MC groups were significantly decreased than that of COPD group (P<0.01), and there was no significant difference among MC groups. There was no significant decrease in the levels of TNF-alpha, IL-1beta and count of alveolar macrophages in P group compared to those of COPD group. More significant decrease in total WCC and neutrophils was found in P than in COPD group (P<0.01). CONCLUSION: MC has anti-inflammmatory effect in the rats with COPD.

Effect of aquaporin-1 deletion on pleural fluid transport.

AIM: To investigate the role of aquaporin-1 (AQP1) and sodium channel on pleural fluid transport. METHODS: Wild-type and AQP1 null mice were used in this study. After the mice were briefly anesthetized, 0.25 mL of hyperosmolar or isosmolar solution (containing terbutaline, amiloride or saline only) was infused into the pleural space. Then mice were sacrificed at scheduled times for measurement of pleural fluid osmolality or volume. RESULTS: After instillation of hyperosmolar fluid into the pleural space, the osmolality of pleural fluid in wild-type mice was higher than that in AQP1 null mice killed at the same time (1, 2, 5 min). There was no difference in the isosmolar clearance between the wild-type and AQP1 null mice after injection of 0.25 mL isosmolar fluid into the pleural space. Terbutaline increased the osmotic and isosmolar fluid transport across pleura, but these effects were not influenced by AQP1 deletion. In contrast, amiloride reduced osmotic and isosmolar pleural fluid transport, and these effects were not influenced by AQP1 deletion. CONCLUSION: AQP1 water channels facilitated osmotic fluid transport across the pleural surface. However, AQP1 did not play an important role in pleural isosmolar fluid clearance. Sodium channel may play a role in osmotic and isosmolar pleural fluid transport. The effects of sodium channel on fluid transport across pleural space were not influenced by aquaporin-1 deletion.