Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study.

PURPOSE: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study. METHODS: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0-2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety. RESULTS: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53-0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1-12.5) and 13.9 months (95% CI 13.1-15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively. CONCLUSION: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified. CLINICAL TRIAL NUMBER: NCT02474355.

Identifying differentially expressed genes and screening small molecule drugs for lapatinib-resistance of breast cancer by a bioinformatics strategy.

BACKGROUND: Lapatinib, a dual tyrosine kinase inhibitor that interrupts the epidermal growth factor receptor (EGFR) and HER2/neu pathways, has been indicated to have significant efficacy in treating HER2-positive breast cancer. However, acquired drug resistance has become a very serious clinical problem that hampers the use of this agent. In this study, we aimed to screen small molecule drugs that might reverse lapatinib-resistance of breast cancer by exploring differentially expressed genes (DEGs) via a bioinformatics method. MATERIALS AND METHODS: We downloaded the gene expression profile of BT474-J4 (acquired lapatinib-resistant) and BT474 (lapatinib-sensitive) cell lines from the Gene Expression Omnibus (GEO) database and selected differentially expressed genes (DEGs) using dChip software. Then, gene ontology and pathway enrichment analyses were performed with the DAVID database. Finally, a connectivity map was utilized for predicting potential chemicals that reverse lapatinib-resistance. RESULTS: A total of 1, 657 DEGs were obtained. These DEGs were enriched in 10 pathways, including cell cycling, regulation of actin cytoskeleton and focal adhesion associate examples. In addition, several small molecules were screened as the potential therapeutic agents capable of overcoming lapatinib-resistance. CONCLUSIONS: The results of our analysis provided a novel strategy for investigating the mechanism of lapatinib-resistance and identifying potential small molecule drugs for breast cancer treatment.

CCND1 G870A polymorphism interaction with cigarette smoking increases lung cancer risk: meta-analyses based on 5008 cases and 5214 controls.

Evidence indicates CCND1 G870A polymorphisms as a risk factor for a number of cancers. Increasing studies have been conducted on the association of CCND1 G870A polymorphism with lung cancer risk. However, the results were controversial. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses examining the association between CCND1 G870A polymorphism and lung cancer were performed. Subgroup analyses regarding ethnicity, smoking status, histological types and source of controls were also implemented. All eligible studies for the period up to May 2012 were identified. The overall data from ten case-control studies including 5,008 cases and 5,214 controls indicated that variant A allele may have an association with increased lung cancer risk (AA vs GG: OR = 1.21; 95 % CI = 1.08-1.36, dominant model: OR = 1.09; 95 % CI = 1.00-1.19, recessive model: OR = 1.23; 95 % CI = 1.01-1.49). In the subgroup analysis by ethnicity, A allele may elevate lung cancer risk among Asians but not Caucasians or Mixed ethnicities. In smoking status subgroup, A allele was shown to associate with increased lung cancer risk among smokers but not non-smokers. In the subgroup analysis by histological types, increased cancer risks were shown in adenocarcinoma but not squamous cell carcinoma, under the homozygote comparison and recessive models. Collectively, the results of the present study suggest that CCND1 G870A polymorphism might be a low-penetrant risk factor for lung cancer, particularly among Asians and smokers. Moreover, homozygous AA alleles might have a correlation with increased lung adenocarcinoma susceptibility.

MTHFR C677T and A1298C polymorphisms and cervical carcinoma susceptibility: meta-analyses based on 4,421 individuals.

MTHFR polymorphisms have been implicated as risk factors for several cancers. Studies have conducted on the associations of MTHFR polymorphisms with cervical carcinoma risk and have generated inconclusive results. The aim of the present study was to increase power demonstrating the possible relations. Meta-analyses examining the association between MTHFR C677T and A1298C polymorphisms and cervical carcinoma risk were performed. Separate analyses on ethnicity and source of controls were also implemented. Eligible studies were identified for the period up to Dec 2011. Eleven case-control studies containing 1859 cases and 2562 controls regarding MTHFR C677T polymorphisms were selected, of which four studies containing 461 cases and 832 controls described A1298C polymorphisms. For the overall data, no associations of MTHFR C677T polymorphisms with cervical carcinoma were observed (TT vs CC: OR = 1.07; 95 %CI = 0.73-1.58; dominant model: OR = 0.89; 95 %CI = 0.66-1.18; recessive model: OR = 1.13; 95 %CI = 0.84-1.52). In the subgroup analysis by ethnicity, MTHFR 677T allele was associated with decreased cervical cancer susceptibility among Caucasians (TT vs CC: OR = 0.65; 95 %CI = 0.45-0.93; dominant model: OR = 0.70; 95 %CI = 0.58-0.86) but not Asians. As for A1298C polymorphism, no marked associations of A1298C genetic variation with cervical cancer risk were observed (CC vs AA: OR = 1.01; 95 %CI = 0.60-1.73; dominant model: OR = 1.17; 95 %CI = 0.91-1.49; recessive model: OR = 0.99; 95 %CI = 0.60-1.63). Collectively, the results of the present study suggest that MTHFR 677T allele might play a preventive role for cervical carcinoma among Caucasians. A1298C polymorphisms might exert little effect on cervical cancerigenesis.

Role of inhibitor of apoptosis protein Livin in radiation resistance in nonsmall cell lung cancer.

OBJECTIVE: The objective of the present study was to explore the role of the inhibitor of apoptosis protein (IAP) Livin in radioresistance in nonsmall cell lung cancer (NSCLC). METHODS: Lung adenocarcinoma cell lines A549 and SPC-A1 were used for this study. Using the technique of molecular cloning and gene transfection, two Livin isoforms, Livinα and ß, respectively, were expressed in A549 cells with the purpose of exploring the role of Livin in radiation resistance of A549 cells. Moreover, a Livin-specific gene-silencing system was developed using SPC-A1 cell line with the purpose of increasing radiosensitivity of SPC-A1 cells. RESULTS: A549 cells were induced by radiation to express Livin isoforms, Livinα and ß. A549 cells expressed Livin isoforms stably after gene transfection and the transfected cells demonstrated characteristics of antiradiation. However, Livin gene-silenced SPC-A1 cells exhibited remarkably enhanced radiation sensitivity. CONCLUSION: The IAP Livin is an important molecule in antiradiotherapy of NSCLC. Livin-specific gene silencing is likely to be an effective means to enhance radiation sensitivity of lung cancer.

Polymorphisms of TP53 codon 72 with prostate carcinoma risk: a meta-analysis.

Previous published data indicated TP53 codon 72 polymorphisms as risk factors for various cancers. A large number of studies have been conducted on the association of TP53 codon 72 polymorphisms with susceptibility to prostate carcinoma and have yielded inconclusive results. The aim of the present study is to derive a more precise estimation of the relationship. We conducted a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to Feb 2009. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. A total of six case-control studies, including 582 cases and 1075 controls, met the included criteria and thus were selected. Consequently, the relevant data were extracted and further analyzed using systematic meta-analyses. For the overall data, no associations of TP53 codon 72 polymorphisms with prostate carcinoma were observed (for Arg/Arg versus Pro/Pro: OR = 0.88; 95%CI = 0.62-1.25; for dominant model: OR = 1.05; 95%CI = 0.78-1.43; for recessive model: OR = 0.85; 95%CI = 0.67-1.06). In the subgroup analysis by ethnicity, individuals carrying Arg allele may have an increased susceptibility to prostate cancer compared with those carrying Pro allele in Caucasians. While for Asians, TP53 codon 72 polymorphism was unlikely to be a risk factor for prostate cancer. Moreover, TP53 codon 72 polymorphism seems to exert little effect on the metastasis and differentiation status of developing prostate carcinoma. Collectively, the results of the present study suggest that TP53 codon 72 polymorphism might be a low-penetrant risk factor for developing prostate carcinoma in Caucasians but not in Asians.

Assessment of the relationship between Helicobacter pylori and lung cancer: a meta-analysis.

BACKGROUND AND AIMS: Helicobacter pylori infection has been thought to play a critical role in gastric carcinoma tumorigenesis and progression. Several studies have been devoted to the relationship between H. pylori infection and lung cancer risk and have generated inconclusive results. In this study we aimed to evaluate the potential association of H. pylori infection with lung cancer risk. METHODS: We conducted a search in Medline, OVID, EMBASE and CNKI, covering all published papers until October 2008. The relevant published papers were deliberately selected according to the established inclusion criteria for publications. Essential data were then extracted from the included studies and further analyzed by a systematic meta-analysis. RESULTS: A total of 98 papers were identified. Of these, four case-control studies met the inclusion criteria and thus were finally selected. Lung cancer risk for H. pylori infection was 3.24-fold (95% CI=1.11-9.47) (Z=2.15, p<0.05) compared with the controls. CONCLUSIONS: The pooled data suggest infection of H. pylori as a potential risk factor for lung cancer.

TP53 codon 72 polymorphism contributes to nasopharyngeal cancer susceptibility: a meta-analysis.

BACKGROUND AND AIMS: Previously, TP53 codon 72 polymorphisms have been implicated as risk factors for various cancers. Several studies have been conducted on the association of TP53 codon 72 polymorphisms with susceptibility to nasopharyngeal carcinoma (NPC) and have yielded inconclusive results. The aim of the present study was to assess possible associations of NPC risk with TP53 codon 72 polymorphisms. METHODS: We conducted a search in Medline, EMBASE, OVID, ScienceDirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published until November 2008. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. RESULTS: Consequently, five studies including 394 cases and 606 controls met the included criteria and thus were selected. Ultimately, relevant data were extracted and further analyzed using systematic meta-analyses. The results showed that individuals carrying wild homozygote Arg/Arg genotype have a decreased risk of NPC compared with those carrying Pro/Pro genotype (OR: 0.46, 95% CI: 0.30-0.70). For Pro allele, no evidence indicated that individuals with a combined Pro genotype (Arg/Pro+Pro/Pro) have a significant risk of NPC compared with those with Arg/Arg genotype (OR: 0.81, 95% CI: 0.62-1.07). For Arg allele, individuals with a combined Arg genotype (Arg/Pro+Arg/Arg) have a marked decreased susceptibility to NPC relative to those with homozygote Pro/Pro genotype. CONCLUSIONS: Results of the present study suggest that TP53 codon 72 polymorphisms may be a risk factor for NPC. Homozygote Pro/Pro genotype could significantly increase susceptibility to NPC, whereas Arg allele markedly decreases NPC risk.

Association studies of CYP1A1 and GSTM1 polymorphisms with esophageal cancer risk: evidence-based meta-analyses.

BACKGROUND AND AIMS: Previous studies have implicated cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) polymorphisms as risk factors for various cancers. A number of studies have been devoted to the association of CYP1A1 or GSTM1 polymorphism with susceptibility to esophageal carcinoma and have yielded conflicting results. We undertook this study to assess possible associations of esophageal cancer risk with CYP1A1 genetic variation and GSTM1 null genotype, respectively. METHODS: We conducted a search in MEDLINE, EMBASE and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published until May 2008. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. RESULTS: Ultimately, 26 studies met the included criteria and thus were selected. Relevant data were extracted and further analyzed using systematic meta-analyses. Results showed that the overall OR for CYP1A1 Msp1 polymorphism was 1.24 (95% CI = 0.84-1.83). Restricting analyses to ethnic groups and histological groups, data failed to show a correlation between CYP1A1 Msp1 polymorphism and esophageal cancer risk. Overall OR for CYP1A1 exon7 polymorphism was 1.37 (95% CI = 1.06-1.77), and subgroup analyses showed that CYP1A1 exon7 polymorphism increases esophageal cancer risk in Asians but not in Caucasians. As for GSTM1 deficiency, the overall OR was 1.20 (95% CI = 0.96-1.49), and further subgroup analyses failed to show a marked association of GSTM1 deletion with esophageal cancer. CONCLUSIONS: Results of the present study suggest that CYP1A1 exon7 polymorphisms may be a risk factor for esophageal cancer in Asians but not in Caucasians, whereas neither CYP1A1 Msp1 nor GSTM1 polymorphism was associated with increased susceptibility to esophageal cancer.

Polymorphisms of CYP1A1 and GSTM1 and laryngeal cancer risk: evidence-based meta-analyses.

PURPOSE: Previous evidence implicates CYP1A1 and GSTM1 polymorphisms as risk factors for various cancers. A number of studies have been devoted to the association of CYP1A1 or GSTM1 polymorphism with susceptibility to laryngeal carcinoma, with the results inconsistent and inconclusive. The aim of the present study was to assess the possible associations of laryngeal cancer risk with CYP1A1 genetic variation and GSTM1 null genotype respectively. METHODS: The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications, then the extracted data were further analyzed using systematic meta-analyses. RESULTS: The results showed that the overall odds ratio (OR) was 1.32 (95% CI = 1.08-1.61) for CYP1A1 Mspl polymorphism. Using subgroup analysis, the pooled ORs were 1.38 (95% CI = 0.98-1.95) in Asians and 1.29 (95% CI = 1.01-1.65) in Caucasians. For CYP1A1 exon7 polymorphism, the overall OR was 1.38 (95% CI = 0.98-1.95). The overall OR was 1.24 (95% CI = 1.03-1.49) for GSTM1 polymorphism and the pooled ORs were 1.36 (95% CI = 0.75-2.48) in Asians, 1.16 (95% CI = 0.94-1.44) in Caucasians and 1.52 (95% CI = 1.05-2.19) in Turkey population. CONCLUSIONS: The data suggest CPY1A1 MspI polymorphism as a risk factor for laryngeal cancer in Caucasians but not in Asians. However, the results suggest a marked correlation of GSTM1 polymorphism with laryngeal cancer risk in Turkey population but not Caucasians and Asians.

Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value.

BACKGROUND: Our aim was to detect lymphatic endothelial marker podoplanin, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and vascular endothelial growth factor receptor-3 (VEGFR)-3 and study the prognostic relevance of lymphangiogenesis in non-small cell lung cancer (NSCLC). MATERIALS: 82 paraffin-embedded tissues and 40 fresh frozen tissues from patients with NSCLC were studied. Tumor samples were immunostained for the lymphatic endothelial markers. Lymphangiogenesis was assessed by immunohistochemical double stains for Podoplanin and Ki-67. The prognostic relevance of lymphangiogenesis-related clinicopathological parameters in NSCLC was evaluated. RESULTS: We found that the number of podoplanin positive vessels was correlated positively with the number of LYVE-1 positive vessels. Most of VEGFR-3 positive, few of LYVE-1 positive and none of podoplanin positive vessels were blood vessels. Peritumoral lymphatic vessel density (ptLVD), pathologic stage, lymph node status, lymphatic vessel invasion (LVI), vascular endothelial growth factor-C (VEGF-C) expression and Ki-67 index of the endothelium cells of the micro lymphatic vessels (Ki67%) were associated significantly with a higher risk of tumor progress. ptLVD, pathologic stage, lymph-node metastasis and Ki67% were independent prognostic parameters for overall survival. CONCLUSION: Podoplanin positive ptLVD might play important roles in the lymphangiogenesis and progression of NSCLC. Patients with high podoplanin+ ptLVD have a poor prognosis.

Possible association of Helicobacter pylori infection with laryngeal cancer risk: an evidence-based meta-analysis.

BACKGROUND: Infection with Helicobacter pylori (H. pylori) is a major cause of various gastric diseases and has been reported to play a role in the process of tumorigenesis and progression of gastric carcinoma. However, whether H. pylori infection increases susceptibilities to other cancers is not fully understood. Several studies have been devoted to the relationship between H. pylori infection and laryngeal cancer risk and have yielded conflicting results. In this study, we aimed to evaluate the possible association of H. pylori infection with laryngeal cancer risk. METHODS: The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. Extracted data were further analyzed by a systematic meta-analysis. RESULTS: A total of 15 papers were identified. Of these, five case-control studies were selected. Laryngeal cancer risk for H. pylori infection was 2.03-fold (95% CI=1.28-3.23) (Z=3.00, p<0.01) compared with the controls. CONCLUSIONS: The pooled data suggest infection with H. pylori as a possible risk factor for laryngeal cancer.

Is the application of prostaglandin E1 effective for the treatment of sudden hearing loss? An evidence-based meta-analysis.

Microvascular dysfunction in the cochlea has been considered the major cause of sudden hearing loss (SHL). For some time, prostaglandin E(1) (PGE(1)), an effective vasodilator, has been used to treat patients with SHL, however the benefits of this therapy remain unclear. The present study assessed the efficacy of PGE(1) on SHL via a quantitative meta-analysis of 13 randomized controlled studies. The pooled odds ratio was 1.95 (95% confidence interval: 1.53, 2.50) and the test for overall effect (Z-value) was 5.31 (P < 0.00001), suggesting that PGE(1) is an effective and promising strategy for the treatment of SHL.

Adenoviral-mediated up-regulation of Otos, a novel specific cochlear gene, decreases cisplatin-induced apoptosis of cultured spiral ligament fibrocytes via MAPK/mitochondrial pathway.

Previous reports have implicated Otos, a novel specific gene expressed by spiral ligament fibrocytes (SLFs) with unclear functions, as a protective gene for cochlea. However, whether Otos gene could protect SLFs against cisplatin (DDP)-induced apoptosis remains largely unknown. In the present study, we utilized Adenoviral-mediated gene transfection to up-regulate Otos expression in cultured SLFs and further assessed the cell viability and apoptosis as well as possible MAPK and mitochondrial pathways. As expected, the data showed that Otos up-regulation significantly decreased apoptosis of SLFs induced by DDP possibly through activation of ERK and partial inhibition of JNK and mitochondrial pathway but not p-38 pathway, suggesting Otos as a potential protective gene for cochlea and raising the possibility of Otos up-regulation as a promising approach to DDP-induced deafness therapy.

Short interfering RNA directed against TWIST, a novel zinc finger transcription factor, increases A549 cell sensitivity to cisplatin via MAPK/mitochondrial pathway.

Previous reports have implicated epithelial-mesenchymal transition (EMT) as a major cause of cancer. TWIST, a novel zinc finger transcription factor, was suggested to be an important inducer of EMT and therefore be involved in different phases of tumorigenicity. However, whether TWIST suppression could increase chemosensitivity of cancer cells to chemotherapeutic agent remains unclear. In the present study, we utilized RNA interference to knockdown TWIST expression in A549 cells and further assessed the cell viability and apoptosis as well as possible MAPKs and mitochondrial pathways. The data showed that TWIST depletion significantly sensitized A549 cells to cisplatin by inducing activation of JNK/mitochondrial pathway but not ERK and p-38 pathways, suggesting critical roles of TWIST in A549 cell chemoresistance to cisplatin and raising the possibility of TWIST depletion as a promising approach to lung cancer therapy.

[Effects of house dust mite allergen DNA vaccines on the allergic airway inflammation in murine models].

OBJECTIVE: To investigate the effects of allergen DNA vaccines on the airway allergic inflammation in C57BL/6 mouse models sensitized and challenged with house dust mite extracts. METHODS: C57BL/6 mice were sensitized and challenged with house dust mite extract (HDME). After vaccinated with Der p1 or Der p2 DNA vaccine or both, the mice were rechallenged with HDME. All mice underwent pulmonary lavage in 24h after the last time of rechallenge, and the pathological manifestations of the lung, cell counts and differentials, and IL-4, IL-5, IL-10, IFNgamma, IgE and IgG1 in broncho-alveolar fluid (BALF) and serum were detected. RESULTS: Airway eosinophilic inflammation was evident in mice sensitized/challenged with HDME. Total cell count, eosinophil count and the levels of IL-4, IL-5, IgE and IgG1 in BALF increased, and IL-10 decreased significantly, while the IFNgamma level showed no change, as compared with the control group. In the Der p1 group, the Der p2 group, and the Der p1 and p2 group, the infiltration of inflammatory cells and the levels of IL-4, IL-5, IgE and IgG1 decreased; the Der p1 and p2 group showed no significant difference compared with the control group. The effect was more significant in the Der p1 and p2 group compared to the Der p1 group and the Der p2. IFNgamma level showed no significant change in three DNA vaccine groups. CONCLUSION: Der p1 and p2 DNA vaccine, Der p1 DNA vaccine, and Der p2 DNA vaccine could efficiently reverse established allergic inflammation. Der p1 and p2 DNA vaccine was more effective than Der p1 DNA vaccine and Der p2 DNA vaccine.

Comparison of inhaled corticosteroid combined with theophylline and double-dose inhaled corticosteroid in moderate to severe asthma.

OBJECTIVE: Recent studies have found that theophylline exerts anti-inflammatory and immunomodulatory effects. This study was performed to compare the efficacy of inhaled corticosteroids (ICS) combined with slow-release theophylline (SRT) with that of double-dose ICS in asthma control, anti-inflammatory activity and safety. METHODOLOGY: In a randomized, open, parallel, control trial, 41 patients with asthma were randomly treated with either beclomethasone dipropionate 500 microg b.i.d. (BDP group) or a combination of BDP 250 microg b.i.d and SRT 0.2 g b.i.d. (SRT/BDP group) for 6 weeks. At the start and at the end of treatment, lung function testing and sputum induction were performed, and plasma cortisol levels were measured. Sputum was analyzed for cell differential counts and the interleukin (IL)-5 level. Patients kept a record of peak expiratory flow (PEF), symptom score, and beta2-agonist use. RESULTS: Significant increases in the morning and the evening PEF and FEV1 were observed (P < 0.05), together with an obvious reduction in symptom score and beta2-agonist use (P < 0.01). Significant decreases in the percentage eosinophils and IL-5 level in induced sputum also occurred (P < 0.05). However, there was no difference between the two groups for all these parameters. There was no significant change in the plasma cortisol level for either group. CONCLUSIONS: Both ICS combined with SRT and double-dose ICS had the same effect on asthma control, improving symptoms and ameliorating lung function. Both therapies had similar anti-airway inflammatory effects and therapeutic safety. Combining SRT with ICS may allow a reduction in ICS dose when treating asthma.