Inverted Placement of Endoscopic One-Way Endobronchial Valve Combined with Gelfoam in the Closure of Bronchopleural Fistula with Empyema in a Mechanically Ventilated Patient: A Case Report.

Bronchopleural fistula (BPF) with empyema caused by severe necrotizing pulmonary infection is a complicated clinical problem that is often associated with poor general condition so surgical interventions cannot be tolerated in most cases. Here, we present the successful management of multiple BPF with empyema in a mechanically ventilated patient with aspiration lung abscess. Occlusion utilizing Gelfoam followed by endobronchial valves (EBVs) implanted inverted via bronchoscope decreased the air leaking significantly and made intrapleural irrigation for empyema achievable and safe. This is the first report of a novel way of EBV placement and the combination use with other occlusive substances in BPF with empyema in a patient on mechanical ventilation. This method may be an option for refractory BPF cases with pleural infection.

Probability of cancer in high-risk patients predicted by the protein-based lung cancer biomarker panel in China: LCBP study.

BACKGROUND: The authors built a model for lung cancer diagnosis previously based on the blood biomarkers progastrin-releasing peptide (ProGRP), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and cytokeratin 19 fragment (CYFRA21-1). In the current study, they examined whether modification of the model to include relevant clinical information, risk factors, and low-dose chest computed tomography screening would improve the performance of the biomarker panel in large cohorts of Chinese adults. METHODS: The current study was a large-scale multicenter study (ClinicalTrials.gov identifier NCT01928836) performed in a Chinese population. A total of 715 participants were enrolled from 5 regional centers in Beijing, Henan, Nanjing, Shanghai, and Chongqing between October 2012 and February 2014. Serum biomarkers ProGRP, CEA, SCC, and CYFRA21-1 were analyzed on the ARCHITECT i2000SR. Relevant clinical information was collected and used to develop a patient risk model and a nodule risk model. RESULTS: The resulting patient risk model had an area under the receiver operating characteristic (ROC) curve of 0.7037 in the training data set and 0.7190 in the validation data set. The resulting nodule risk model had an area under the ROC curve of 0.9151 in the training data set and 0.5836 in the validation data set. Moreover, the nodule risk model had a relatively higher area under the ROC curve (0.9151 vs 0.8360; P = 0.001) compared with the American College of Chest Physician model in patients with lung nodules. CONCLUSIONS: Both the patient risk model and the nodule risk model, developed for the early diagnosis of lung cancer, demonstrated excellent discrimination, allowing for the stratification of patients with different levels of lung cancer risk. These new models are applicable in high-risk Chinese populations. Cancer 2018;124:262-70. © 2017 American Cancer Society.

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.

[Therapeutic efficacy and safety of chemotherapy subsequent EGFR-TKI in advanced non-small cell lung cancer patients with EGFR-TKI acquired resistance].

OBJECTIVE: To explore the therapeutic efficacy and safety of chemotherapy subsequent epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in advanced non-small cell lung cancer (NSCLC) patients with EGFR-TKI acquired resistance. METHODS: The clinical features of 36 advanced NSCLC patients with EGFR-TKI acquired resistance from Affiliated Zhongshan Hospital, Fudan University between May 2006 and April 2014 were retrospectively reviewed. Twenty-seven of them received chemotherapy subsequent EGFR-TKI and another 9 chemotherapy alone. The short-term response, progression-free survival and side effects of two groups were compared. RESULTS: The objective response rates of chemotherapy subsequent EGFR-TKI and chemotherapy alone groups were 7.4% and 0 (P = 0.557), disease control rates 81.5% and 44.4% (P = 0.046) and median progression-free survival 3.3 and 2.5 months, respectively (P = 0.587). No significant differences existed in the rates of side effects between two groups (P > 0.05). CONCLUSIONS: The disease control rates of chemotherapy subsequent EGFR-TKI group are higher than chemotherapy alone group, but there is no survival benefit. And the side effects of subsequent therapy are tolerable.

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.

Tumor mutational burden and efficacy of chemotherapy in lung cancer.

PURPOSE: TMB is one of the potent biomarkers of response to immune checkpoint blockade. The association between TMB and efficacy of chemotherapy in advanced lung cancer has not been comprehensively explored. METHODS: Ninety lung cancer patients receiving first-line chemotherapy with large panel next-generation sequencing data of pre-treatment tumor tissue were identified. The effect of TMB on PFS of chemotherapy were evaluated in univariate and multivariate analyses. RESULTS: The median TMB level of lung cancer patients enrolled in this study was 9.4 mutations/Mb, with TMB levels in smokers significantly higher than those in non-smokers. All patients were divided into high TMB and low TMB groups with the cutoff of the median TMB. The patients with low TMB had longer PFS of first-line chemotherapy (median PFS 9.77 vs 6.33 months, HR = 0.523, 95% CI 0.32-0.852, log-rank P = 0.009). Subgroup analysis showed that PFS of chemotherapy favored low TMB than high TMB among subgroups of male, age < 60, NSCLC, adenocarcinoma, stage IV, ECOG PS 0, driver mutation positive, TP53 wild type and patients not receiving bevacizumab. In multivariate analysis, PFS of chemotherapy remained significantly longer in low TMB group (HR = 0.554, p = 0.036). In those patients received immunotherapy upon unsatisfactory chemotherapy, PFS of immunotherapy was much longer in high TMB group (median PFS 32.88 vs 6.62 months, HR = 0.2426, 95% CI 0.06-0.977, log-rank P = 0.04). CONCLUSIONS: TMB level of tumor tissue is a potent biomarker for efficacy of chemotherapy and immunotherapy in lung cancer. It may provide some clues for the decision of treatment strategy.

International expert consensus on diagnosis and treatment of lung cancer complicated by chronic obstructive pulmonary disease.

Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.

[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.

Safety and Efficacy of Epitinib for EGFR-Mutant Non-Small Cell Lung Cancer With Brain Metastases: Open-Label Multicentre Dose-Expansion Phase Ib Study.

BACKGROUND: Non-small-cell lung cancer (NSCLC) had poor prognosis in patients with brain metastasis. The trial evaluated the safety and efficacy of epitinib (HMPL-813), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), for EGFR-mutant NSCLC with brain metastasis. PATIENTS AND METHODS: This open-label, dose-expansion phase Ib study (ClinicalTrials.gov: NCT02590952) was conducted at 7 Chinese centers and enrolled patients with EGFR-mutant advanced NSCLC with brain metastasis. Epitinib was administered at 120 mg or 160 mg, orally QD. The primary endpoint was safety and tolerability. RESULTS: Between April 2015 and April 2019, 72 patients were enrolled and received epitinib at 120 mg (n = 30) or 160 mg (n = 42). Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 13 (43.3%) patients in 120 mg group and 21 (50.0%) in 160 mg group. The objective response rate (ORR) was 53.6% (95% CI 33.9%-72.5%) in 120 mg group and 40.5% (25.6%-56.7%) in 160 mg group. The median duration of response in the 120 mg and 160 mg groups were 7.40 months (95% CI 3.70-7.40) and 9.10 months (6.50-12.00), respectively. The median progression-free survival were 7.40 months (95% CI 5.40-9.20) and 7.40 months (5.50-10.00), respectively. CONCLUSION: In patients with EGFR-mutant NSCLC with brain metastasis, epitinib was well tolerable with a promising efficacy. According to the comprehensive assessment on safety and efficacy, 160 mg QD could be the recommended phase 2 dose.

Expert consensus on multi-disciplinary treatment, whole-course pulmonary rehabilitation management in patients with lung cancer and chronic obstructive lung disease.

Comorbidity of lung cancer and chronic obstructive pulmonary disease (COPD) is very common. Surgical operation is the initial treatment of lung cancer. But surgery operation will aggravate the symptoms of COPD, such as shortness of breath, chest tightness. On the other side, the COPD also increase the perioperative complications. Besides, the COPD may also influence the anti-cancer treatment and long-term survival of lung cancer patients. At present, there are guidelines for pulmonary rehabilitation (PR) of COPD or lung cancer respectively, but there is no reference expert consensus on the PR of patients with lung cancer who are comorbidity of COPD. Primary care has to satisfy the patient's complex needs holistically, and single-disease guidelines are unsuitable. In view of this, we organized experts from respiratory department, thoracic surgery department, oncology department, nursing department, etc., to write the expert consensus. We discussed the contents of the expert consensus through literature review, expert correspondence, expert meeting and discussion. This expert consensus contain five parts: introduction, respiratory assessment, timing of PR, PR strategies, perioperative PR management strategies in lung cancer patients with COPD. This expert consensus focuses on patients with COPD comorbid lung cancer and undergoing surgery operation, highlighting the concept of whole process management. For clinical medical staff, this expert consensus will promote the practice of PR in and out the hospital for this specific patient; for patients, this expert consensus is helpful to better understand PR and improve the enthusiasm of participating in PR in the whole process.

Characteristics of Chinese patients with cough in primary care centre.

BACKGROUND: Cough is one of the most common respiratory symptoms and is well characterized in specialized cough clinics with high success rates of diagnosis and treatment. However, there is a paucity of data regarding cough in primary care settings. The present study aimed at investigating clinical epidemiology of cough through a national study of two questionnaire surveys sent to primary care physicians in China. METHODS: Approximately 18,000 subjects recruited were having daytime or night symptoms of cough and diagnoses of respiratory disease from February 2005 to April 2006 as Survey 1 and from June 2007 to December 2007 as Survey 2. Patients suffering from respiratory malignancy, hyperthyroidism, hypertension, heart disease, diabetes, severe hypohepatia or renal dysfunction, pregnancy, possible pregnancy or lactation, neutropenia were not eligible. Information regarding demography, history of allergies, symptomatic profile, treatment and curative effects for cough was elicited. RESULTS: 8216 questionnaires were collected in Survey 1 and 9711 in Survey 2. The mean values of ages were 25.7 and 22.3 years old, respectively. Symptoms included expectoration (74% and 76%), wheeze (59% and 74%), breathlessness (22% and 26%), chest pain (9% and 13%) and fever (15% and 18%). About 15% and 23% patients had hypersusceptibility, of whom 6% to 17% had a family history. More than 50% of the cases had histories of allergic rhinitis, asthma, conjunctivitis or atopic dermatitis. Asthma, COPD, and bronchitis were dominant etiologies of cough. Procaterol or the combination of antibiotics and steroids were used as the treatment. CONCLUSION: Causes and outcomes of cough differed with ages and time in this particular national study, while successful and precise diagnosis and management of cough in primary care settings need to be further improved in China.

[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.

Rapid discrimination between tuberculosis and sarcoidosis using next-generation sequencing.

OBJECTIVES: Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (MTB), has similar clinical, radiological, and histopathological characteristics to sarcoidosis (SA). Accurately distinguishing SA from TB remains a clinical challenge. METHODS: A total of 44 TB patients and 47 SA patients who were clinically diagnosed using chest radiography, pathological examination, routine smear microscopy, and microbial culture were enrolled in this study. The MTB genome was captured and sequenced directly from tissue specimens obtained upon operation or biopsy, and the feasibility of next-generation sequencing (NGS) for the MTB genome in the differential diagnosis of TB from SA was evaluated. RESULTS: Using a depth >10× and coverage >15% of the sequencing data, TB patients were identified via the NGS approach directly using operation or biopsy specimens without clinical pretreatment. The sensitivity, specificity, and concordance of the NGS method were 81.8% (36/44), 95.7% (45/47), and 89.0% (81/91), respectively (kappa = 0.78, 95% confidence interval 0.65-0.91; P<0.001). CONCLUSIONS: This study established an improved NGS strategy for rapidly distinguishing patients with TB from those with SA and has potential clinical benefits.

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.

Zfra is an inhibitor of Bcl-2 expression and cytochrome c release from the mitochondria.

Zfra is a small size 31-amino-acid C2H2 zinc finger-like protein, which is known to interact with c-Jun N-terminal kinase 1 (JNK1), WW domain-containing oxidoreductase (WWOX, FOR or WOX1), TNF receptor-associated death domain protein (TRADD) and nuclear factor kappaB (NF-kappaB) during stress response. Here, we show that Zfra became phosphorylated at Ser8 (as determined by specific antibody) and translocated to the mitochondria in response to inducers of mitochondrial permeability transition (MPT) (e.g. staurosporine and betulinic acid). Overexpressed Zfra induced cell death. This event is associated, in part, with increased dissipation of mitochondrial membrane potential (MMP) and increased chromosomal DNA fragmentation. Intriguingly, Zfra significantly downregulated Bcl-2 and yet blocked cytochrome c release from the mitochondria. Overexpression of an S8G-Zfra mutant (Ser8 to Gly8 alteration) could not induce cell death, probably due to its failure of translocating to the mitochondria and causing MMP dissipation. Over-expressed proapoptotic WOX1 induced cytochrome c release from the mitochondria. Zfra bound and blocked the effect of WOX1. Taken together, Ser8 is essential for overexpressed Zfra to exert cell death via the mitochondrial pathway. Zfra downregulates Bcl-2 and induces MMP dissipation but causes no cytochrome c release, indicating a novel death pathway from the mitochondria.

Tumor-derived DNA from pleural effusion supernatant as a promising alternative to tumor tissue in genomic profiling of advanced lung cancer.

Pleural effusion (PE) is commonly observed in advanced lung cancer and was suggested to contain both cell-free tumor DNA and tumor cells. Molecular profiling of PE represents a minimally invasive approach of detecting tumor driver mutations for clinical decision making, especially when tumor tissues are not available. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples to address the feasibility in clinical use. Methods: Sixty-three metastatic lung cancer patients with (n=30, cohort 1) or without (n=33, cohort 2) matched tumor tissues were enrolled in this study. PE and plasma samples of each patient were collected simultaneously. Supernatant and cell precipitate of PE were processed separately to extract cfDNA (PE-cfDNA) and sediment DNA (sDNA). All samples were subjected to targeted next-generation sequencing (NGS) of 416 cancer-related genes. Results: PE supernatants contain more abundant tumor DNA than PE sediments and plasma samples, suggested by higher mutant allele frequencies (MAF) and elevated mutation detection rate in PE-cfDNA (98.4% vs. 90.5% in PE sDNA vs. 87% in plasma cfDNA). In Cohort 1 with matched tumor tissue, tumor mutational burden (TMB) of PE-cfDNA was similar as tumor tissues (6.4 vs. 5.6), but significantly higher than PE sDNA (median TMB: 3.3) and plasma cfDNA (median TMB: 3.4). Ninety-three percent (27 out of 29) of tissue-determined driver mutations were detected in PE-cfDNA, including alterations in ALK, BRAF, EGFR, ERBB2, KRAS, NF1, PIK3CA, and RET, while only 62% were captured in plasma cfDNA. PE-cfDNA also has the highest detection rate of EGFR driver mutations in the full cohort (71% vs. 68% in PE sDNA vs. 59% in plasma cfDNA). Mutation detection from cytological negative and hemorrhagic PE is challenging. Comparatively, PE-cfDNA demonstrated absolute superiority than PE sDNA in such a scenario, suggesting that it is an independent source of tumor DNA and therefore less influenced by the abundance of tumor cells. Conclusion: Genomic profiling of PE-cfDNA offers an alternative, and potentially more meticulous approach in assessing tumor genomics in advanced lung cancer when tumor tissue is not available. Our data further demonstrate that in hemorrhagic or cytologically negative PE samples, PE-cfDNA has higher mutation detection sensitivity than sDNA and plasma cfDNA, and therefore is a more reliable source for genetic testing.

Calpain 2 knockdown promotes cell apoptosis and restores gefitinib sensitivity through epidermal growth factor receptor/protein kinase B/survivin signaling.

Gefitinib, an epidermal growth factor receptor (EGFR)­specific drug, is effective for ~1 year, after which resistance is inevitable. Calpain 2 (CAPN2) is known to serve a role in the drug response and resistance in certain cancer therapies. However, the full function of CAPN2, particularly in non­small cell lung cancer, has not yet been elucidated. In the present study, CAPN2 expression in gefitinib­resistant lung adenocarcinoma cells was investigated. CAPN2 function in these cells was further evaluated using gene knockdown both in vitro and in vivo. The results demonstrated that CAPN2 was strongly associated with gefitinib­resistance, and CAPN2 mRNA and protein expression levels were significantly increased in gefitinib­resistant cell lines. Furthermore, CAPN2 knockdown inhibited gefitinib­resistant cell proliferation in vitro and in vivo. CAPN2 conferred gefitinib­resistance by inhibiting cell apoptosis and arresting the cell cycle. CAPN2 knockdown also induced caspase activation and mitochondrial dysfunction, and its function in gefitinib resistance appeared to be largely mediated by EGFR/protein kinase B/survivin signaling pathway activation. These results suggest that CAPN2 is responsible for EGFR­tyrosine kinase inhibitor resistance, and CAPN2 inhibition may be used to provide therapeutic benefits in the treatment of gefitinib resistance.