JSI-124 inhibits cell proliferation and tumor growth by inducing autophagy and apoptosis in murine malignant mesothelioma.

Malignant pleural mesothelioma (MPM), mainly caused by asbestos exposure, has a poor prognosis and lacks effective treatment compared with other cancer types. The intracellular transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed and hyperactivated in most human cancers. In this study, the role of STAT3 in murine MPM was examined. Inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway with the selective inhibitor JSI-124 has an antitumor effect in murine MPM. Specifically, we demonstrated that JSI-124 inhibits murine MPM cell growth and induces apoptotic and autophagic cell death. Exposure of RN5 and AB12 cells to JSI-124 resulted in apoptosis via the Bcl-2 family of proteins. JSI-124 triggered autophagosome formation, accumulation, and conversion of LC3I to LC3II. Autophagy inhibitors, Chloroquine (CQ) and Bafilomycin A1 (Baf-A1), inhibited autophagy and sensitized RN5 and AB12 cells to JSI-124-induced apoptosis. Our data indicate that JSI-124 is a promising therapeutic agent for MPM treatment.

A Propensity Score-Matching Analysis: Robotic Thymectomy Through the Subxiphoid Has Advantages Over Video-Assisted Thymectomy Surgery.

Objective: The purpose of this article is to evaluate the security and effectiveness of subxiphoid and subcostal robot-assisted thoracoscopic thymectomy (S-RATT) and compare it with subxiphoid and subcostal video-assisted thoracoscopic thymectomy (S-VATT) in terms of short-term perioperative results and costs. Methods: A retrospective study was carried out on 62 individuals who had undergone successful complete thymectomy for anterior mediastinal disease using subxiphoid and subcostal arch approaches. Propensity score-matching analysis was utilized between the two groups, and the perioperative outcomes were compared. Results: The S-RATT group exhibited less intraoperative blood loss (20 ± 15.35 versus 69.55 ± 69.54, P < .001), lower levels of C-reactive protein (112.38 ± 68.08 versus 72.58 ± 42.62, P = .027), and lower postoperative pain scores (2.09 ± 1.54 versus 4.27 ± 1.28, P < .001). However, the hospitalization costs of patients in the S-VATT group were found to be lower than those in the S-RATT group (33,802.41 ± 8785.05 versus 49,977.53 ± 20,221.79, P < .001). Conclusions: S-RATT appears to be a viable and secure method for managing anterior mediastinal tumors.

Laparoscopic Nissen Versus Toupet Fundoplication for Short- and Long-Term Treatment of Gastroesophageal Reflux Disease: A Meta-Analysis and Systematic Review.

BACKGROUND: Laparoscopic Nissen fundoplication (LNF) is the most common standard technique worldwidely for Gastroesophageal reflux disease (GERD). Another type of fundoplication, laparoscopic Toupet fundoplication (LTF), intends to reduce incidence of postoperative complications. A systematic review and meta-analysis are required on short- and long-term outcomes based on randomized controlled trials (RCTs) between LNF and LTF. METHODS: We searched databases including PubMed, Cochrane, Embase, and Web of Knowledge for RCTs comparing LNF and LTF. Outcomes included postoperative reflux recurrence, postoperative heartburn, dysphagia and postoperative chest pain, inability to belch, gas bloating, satisfaction with intervention, postoperative esophagitis, postoperative DeMeester scores, operating time (min), in-hospital complications, postoperative use of proton pump inhibitors, reoperation rate, postoperative lower oesophageal sphincter (LOS) pressure (mmHg). We assessed data using risk ratios and weighted mean differences in meta-analyses. RESULTS: Eight eligible RCTs comparing LNF (n = 605) and LTF (n = 607) were identified. There were no significant differences between the LNF and LTF in terms of postoperative reflux recurrence, postoperative heartburn, postoperative chest pain, satisfaction with intervention, reoperation rate in short and long term, in-hospital complications, esophagitis in short term, and gas bloating, postoperative DeMeester scores, postoperative use of proton pump inhibitors, reoperation rate in long term. LTF had lower LOS pressure (mmHg), fewer postoperative dysphagia and inability to belch in short and long term and gas bloating in short term compared to LNF. CONCLUSION: LTF were equally effective at controlling reflux symptoms and improving the quality of life, but with lower rate of complications compared to LNF. We concluded that LTF surgical treatment was superior for over 16 years old patients with typical symptoms of GERD and without upper abdominal surgical history upon high-level evidence of evidence-based medicine.

SMAC exhibits anti-tumor effects in ECA109 cells by regulating expression of inhibitor of apoptosis protein family.

BACKGROUND: The poor prognosis and rising incidence of esophageal cancer highlight the need for improved therapeutics that are essential prior to treatment. LCL161 is an SMAC (second mitochondrial activator of caspases) mimic and inhibitor of apoptosis protein (IAP) antagonist which exhibits anti-tumor effects and improves the chemical sensitivity of many cancers. AIM: To ascertain the effects and mechanisms of the SMAC analog LCL161 on esophageal cancer cells. METHODS: MTT assay and TUNEL assay were used to detect cell proliferation and apoptosis, respectively. Western blot analysis was used to study the molecular mechanisms of LCL161-induced death of ECA109 cells. RESULTS: LCL161 decreased ECA109 cell proliferation in dose- and time-dependent manner and induced apoptosis of ECA109 cells in a dose-dependent manner. Also, LCL161 induced a significant decrease in the expression of the XIAP and significant increase in the expression of Caspase-3. In addition, Bax increased significantly with increasing concentrations of LCL161, and the relative expression of Bax was significantly different between groups. CONCLUSION: These findings support the hypothesis that LCL161 can inhibit proliferation and induce apoptosis in esophageal cancer cells by regulating the expression of IAP family members, suggesting that it has potential to be an effective treatment for esophageal squamous cell carcinoma.

RNF213 gene mutation in circulating tumor DNA detected by targeted next-generation sequencing in the assisted discrimination of early-stage lung cancer from pulmonary nodules.

BACKGROUND: To distinguish early-stage lung cancer from benign disease in pulmonary nodules, especially lesions with ground-glass opacity (GGO), we assessed gene mutations of ctDNA in peripheral blood using targeted next-generation sequencing (NGS). METHODS: Single pulmonary nodule patients without mediastinal lymph nodes and symptoms that were hard to diagnose by chest CT and lung cancer biomarker measurement in multiple medical centers were enrolled into the study. All patients accepted minimally invasive surgery but refused preoperative biopsy. Gene mutations in preoperative blood samples were detected by targeted NGS. Mutations with significant differences between lung tumors and benign lesions, as grouped by postoperative pathology, were screened. Protein expression was determined by immunohistochemistry. Highly expressed genes were selected as biomarkers to verify the mutations in peripheral blood. RESULTS: In the training set, the RNF213, KMT2D, CSMD3 and LRP1B genes were mutated more frequently in early-stage lung cancer (27 cases) than in benign nodules (15 cases) (P < 0.05). High expression of the RNF213 gene in lung cancers and low expression in benign diseases were seen by immunohistochemistry. The RNF213 gene was mutated in 25% of lung cancer samples in the validation set of 28 samples and showed high specificity (100%). In GGO patients, RNF213 was mutated more frequently in early-stage lung cancer compared to benign diseases (P < 0.05). CONCLUSIONS: RNF213 gene mutations were observed more frequently in early-stage lung cancer, but not in benign nodules. Mutation of the RNF213 gene in peripheral blood may be a high specificity biomarker for the assisted early diagnosis of lung cancer in pulmonary nodules. KEY POINTS: Significant findings of the study: In peripheral venous blood and tumor tissue, RNF213 gene mutated more frequently in lung cancer than benign pulmonary nodules. WHAT THIS STUDY ADDS: Detection mutation of the RNF213 gene in peripheral blood may be a high specificity method for the assisted early diagnosis of lung cancer in pulmonary nodules.

Combination of electromagnetic navigation bronchoscopy-guided microwave ablation and thoracoscopic resection: An alternative for treatment of multiple pulmonary nodules.

Here, we describe a novel method using microwave ablation (MWA) guided by electromagnetic navigation bronchoscopy (ENB) and video-assisted thoracoscopic surgery (VATS) for simultaneous treatment of multiple high-risk pulmonary nodules in a 47-year-old woman. After the ENB registration process, the operator delivered the locatable electromagnetic probe to the target in the right upper lobe following the navigational route. MWA was performed after an antenna was passed into the lesion through the working channel. The wedge resection of the left upper lobe and lower lobe and the lingual segment resection were performed by VATS. The pathological diagnoses was adenocarcinoma in situ (AIS) of the right upper lobe lesion, AIS of the left upper lobe, minimally invasive adenocarcinoma of the left lower lobe lesion and chronic inflammation of the lingular segment. MWA guided by ENB combined with VATS is an alternative treatment strategy to deal with multiple pulmonary nodules at the same stage of the operation.

Salivary Microbial Dysbiosis is Associated with Systemic Inflammatory Markers and Predicted Oral Metabolites in Non-Small Cell Lung Cancer Patients.

An increasing number of studies have suggested the dysbiosis of salivary microbiome has been linked to the advancement of multiple diseases and proved to be helpful for the diagnosis of them. Although epidemiological studies of salivary microbiota in carcinogenesis are mounting, no systemic study exists regarding the oral microbiota of non-small cell lung cancer (NSCLC) patients. In this study, we presented the characteristics of the salivary microbiota in patients from NSCLC and healthy controls by sequencing of the 16S rRNA microbial genes. Our result revealed distinct salivary microbiota composition in patients from NSCLC compared to the healthy controls. As principal co-ordinates analysis (PCoA) showed, saliva samples clearly differed between the two groups, considering the weighted (p = 0.001, R2 = 0.17), and unweighted (p = 0.001, R2 = 0.25) UniFrac distance. Phylum Firmicutes (31.69% vs 24.25%, p < 0.05) and its two genera Veillonella (15.51%% vs 9.35%, p < 0.05) and Streptococcus (9.96% vs 6.83%, p < 0.05) were strongly increased in NSCLC group compared to the controls. Additionally, the relative abundances of Fusobacterium (3.06% vs 4.92%, p = 0.08), Prevotella (1.45% vs 3.52%, p < 0.001), Bacteroides (0.56% vs 2.24%, p < 0.001), and Faecalibacterium (0.21% vs 1.00%, p < 0.001) in NSCLC group were generally decreased. Furthermore, we investigated the correlations between systemic inflammation markers and salivary microbiota. Neutrophil-lymphocyte ratio (NLR) positively correlated with the Veillonella (r =0.350, p = 0.007) and lymphocyte-monocyte ratio (LMR) negatively correlated with Streptococcus (r =-0.340, p = 0.008). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways inferred by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) showed that pathways related to xenobiotics biodegradation and metabolism (p < 0.05) and amino acid metabolism (p < 0.05) were enriched in the NSCLC group. Folate biosynthesis (p < 0.05) significantly decreased in NSCLC group. The specific correlations of clinical systemic inflammation markers and predicted KEGG pathways also could pronounce a broad understanding of salivary microbiota in patients with NSCLC. Moreover, our study extended the new sight into salivary microbiota-targeted interventions to clinically improve the therapeutic strategies for salivary dysbiosis in NSCLC patients. Further investigations of the potential mechanism of salivary microbiota in the progression of NSCLC are still in demand.

Rapamycin may inhibit murine S180 sarcoma growth by regulating the pathways associated with autophagy and cancer stem cells.

OBJECTIVE: The objective of this study was to investigate the molecular mechanisms involved in rapamycin-induced inhibition of tumor growth. MATERIALS AND METHODS: Murine S180 sarcoma cells were subcutaneously injected into mice, and the tumor-bearing mice were randomly divided into three groups (vehicle control, 2 mg/kg rapamycin, and 4 mg/kg rapamycin). The effect of rapamycin on tumor growth was determined by measuring tumor volume. Mammalian target of rapamycin (mTOR), Beclin1, ULK1, LC3, Notch1, CD133, and CD90 expressions was confirmed using confocal microscopy and Western blotting. RESULTS: The tumor growth inhibition rates induced by high-dose and low-dose rapamycin were 48.8% and 30.1%, respectively. Beclin1 and ULK1 expressions and the LC3-II/LC3-I ratio in tumor tissues were altered by rapamycin, whereas mTOR, Notch1, CD133, and CD90 expressions were significantly inhibited by rapamycin in immunofluorescence assays. Western blotting also showed similar results. CONCLUSION: Tumor growth delay induced by rapamycin may be associated with the suppression of the cancer stem cell phenotype (Notch1, CD133, and CD90) and promotion of autophagy (mTOR, Beclin1, ULK1, and LC3-II/LC3-I ratio) in the murine S180 sarcoma model.

Alterations of fecal bacterial communities in patients with lung cancer.

Emerging evidence suggests the microbiome may affect a number of diseases, including lung cancer. However, the direct relationship between gut bacteria and lung cancer remains uncharacterized. In this study, we directly sequenced the hypervariable V1-V2 regions of the 16S rRNA gene in fecal samples from patients with lung cancer and healthy volunteers. Unweighted principal coordinate analysis (PCoA) revealed a clear difference in the bacterial community membership between the lung cancer group and the healthy control group. The lung cancer group had remarkably higher levels of Bacteroidetes, Fusobacteria, Cyanobacteria, Spirochaetes, and Lentisphaerae but dramatically lower levels of Firmicutes and Verrucomicrobia than the healthy control group (P < 0.05). Despite significant interindividual variation, eight predominant genera were significantly different between the two groups. The lung cancer group had higher levels of Bacteroides, Veillonella, and Fusobacterium but lower levels of Escherichia-Shigella, Kluyvera, Fecalibacterium, Enterobacter, and Dialister than the healthy control group (P < 0.05). Most notably, correlations between certain specific bacteria and serum inflammatory biomarkers were identified. Our findings demonstrated an altered bacterial community in patients with lung cancer, providing a significant step in understanding the relationship between gut bacteria and lung cancer. To our knowledge, this is the first study to evaluate the correlations between certain specific bacteria and inflammatory indicators. To better understand this relationship, further studies should investigate the underlying mechanisms of gut bacteria in lung cancer animal models.

Curcumin induces apoptosis and inhibits angiogenesis in murine malignant mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare form of cancer that is associated with asbestos exposure. Unfortunately, current therapies have limited efficacy. Previous studies have indicated that curcumin exerts antiproliferative and antitumor effects, and has low toxicity. The present study aimed to evaluate the anticancer effects of curcumin on the RN5 MPM cell line. The inhibitory effects of curcumin on cell viability were determined using the sulforhodamine B assay. In addition, cell cycle progression was analyzed by propidium iodide (PI) staining and flow cytometry, and curcumin­induced apoptosis was measured by Annexin V/PI double staining. The translocation of apoptosis-inducing factor (AIF) was assessed by western blotting and immunofluorescence, and the expression levels of the phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase (Akt)­mammalian target of rapamycin (mTOR) signaling pathway proteins and mitochondria-associated proteins were evaluated by western blotting. In vivo antitumor effects were evaluated in a subcutaneous murine model. Briefly, tumors were harvested from the mice, and immunohistochemistry was conducted to evaluate cell proliferation, apoptosis and angiogenesis. The results indicated that curcumin inhibited RN5 cell viability and induced apoptotic cell death. In addition the findings suggested that curcumin-induced cell apoptosis occurred via the mitochondrial pathway, and caspase­independent and AIF-dependent pathways. Further analysis revealed that curcumin may act as a PI3K-Akt-mTOR signaling pathway inhibitor by downregulating PI3K, p-Akt, p-mTOR and p-p70 ribosomal protein S6 kinase. Furthermore, curcumin inhibited tumor angiogenesis in vivo. In conclusion, curcumin may be potent enough to be developed as a novel therapeutic agent for the treatment of MPM.

A case report of cardia cancer complicated with idiopathic muscular hypertrophy of the oesophagus treated with thoracoscopic surgery.

The incidence of idiopathic muscular hypertrophy of oesophagus (IMHE) is low, and <100 cases of IMHE have been reported. IMHE is a benign oesophageal disease, characterised by hyperplasia of all layers of the wall and in particular, muscle layer. Only a few cases have been reported regarding its clinical symptoms and images. In this present case, we report a cardia cancer with IMHE, showing significant hypertrophy of muscular layer of middle part of the oesophagus and successfully treated with minimally invasive thoracoscopic surgery.

Involvement of syk and VEGF-C in invasion of lung adenocarcinoma A549 cells.

BACKGROUND AND AIMS: Lung cancer has become one of the most dangerous malignant tumors in the world nowadays, whose pathogenesis is complex involving multi-genes and multi-elements. This study aims to investigate the values of spleen tyrosine kinase (Syk) and vascular endothelial growth factor-C (VEGF-C) in lymphangiogenesis and metastasis of lung adenocarcinoma A549 cells. MATERIALS AND METHODS: The pcDNA3.1-VEGF-C and pLNCX-syk were constructed and transfected into A549 cells. After cells with stable expression were sorted, the level of VEGF-C was tested by RT-PCR and immunohistochemistry and the mRNA of syk was tested by RT-PCR. The cell invasion assay was investigated by transwell chamber in vitro. Restriction enzyme digestion and gel electrophoresis demonstrated successful construction of the pcDNA3.1-VEGF-C. RESULTS: RT-PCR and immunohistochemistry revealed higher expression of VEGF-C in VEGFC-construct-transfected A549 cells than that in controls (P < 0.05). Successful construction of the pLNCX-syk was demonstrated by restriction enzyme electrophoresis and sequencing. RT-PCR revealed Syk expression higher in syk-construct-transfected cells than in controls (P < 0.05). CONCLUSIONS: The results indicate a potential link between the upregulation of Syk and VEGF-C expression and lung adenocarcinoma.

Development Pattern on Lymph Node Resection in Minimally Invasive Esophagectomy and 2-year Survival Analysis.

Background Thoracoscopic-laparoscopic procedures have been used more in the operations of esophagus cancer; in most times we call it minimally invasive esophagectomy, which is becoming mature. However, the efficacy of minimally invasive esophagectomy is still unclear, especially about the dissection of lymph nodes and survival. Methods A retrospective review was performed. The development process of minimally invasive esophagectomy for esophageal cancer was divided into three stages: the first stage 20, the second stage 37, the third stage 50. Result Total 107 patients underwent minimally invasive esophagectomy between July 2010 and May 2015. The number of lymph node resected during the three stages increased significantly, with a mean of 12.65, 15.91, and 20.16 nodes, respectively (p = 0.0075). The number of lymph nodes dissection greater than or equal to 12 or 18 increased significantly (p = 0.000). The patients from the first and the second stages had the similar 2-year survival rate (p = 0.8618). There is no significant difference in the 2-year disease-free survival rate (p = 0.606). Conclusion Surgeons accumulate experience on lymphadenectomy during minimally invasive esophagectomy as time goes by, and experience on 50 to 60 cases is essential and necessary to accomplish an apparent progress.

Clinical Study of Allogeneic Graft Reconstruction for Sternum Tumor.

OBJECTIVES: This paper aimed to study the feasibility, the surgical methodology, and technique for reconstruction using allogeneic sternal graft after sternum tumor resection. MATERIALS AND METHODS: Three patients (2 men and 1 woman, aged 19, 44, and 52) with primary sternum malignant tumor were admitted from January 2008 to December 2010 to the Second Hospital of Shandong University, Jinan, China. We conducted subtotal resection of the sternum and simultaneous reconstruction with allogeneic sternal graft. Allogeneic sternum was frozen beforehand; the scope of removal was 2 cm away from the lesion. Transplanted allogeneic sternum was fixed using steel wire and residual cavity was filled with the greater omentum. RESULTS: Three patients recovered without major complication and were discharged from the hospital with successful operation and satisfactory results. They were followed-up for 6 months to 2 years, no tumor relapse or any obvious rejection were found. CONCLUSIONS: The freezing allogeneic sternum can be used as a substitute for reconstruction after sternum tumor resection.

Role of Smac in apoptosis of lung cancer cells A549 induced by Taxol.

BACKGROUND: A series of structurally unique second mitochondria-derived activators of caspase (Smac) that act as antagonists of inhibitor of apoptosis proteins (IAPs) directly have been discovered and have been shown to promote chemotherapy-induced apoptosis. In this study, we investigate the role of Smac in Taxol-induced apoptosis of lung cancer cell in vitro. METHODS: PcDNA3.1/Smac recombinants were transfected into the non-small cell lung cancer cell line A549. Smac expression was detected by RT-PCR and Western blot. The invasive ability of cells was examined. Flow cytometry was used to analyze apoptosis of cells induced by Taxol with Annexin V/PI double staining technique. RESULTS: Smac expression was significantly higher in the PcDNA3.1/Smac recombinant group than in the untransfected group at mRNA and protein level (p < 0.05) and lower invasion through a basal membrane was apparent after transfection (p < 0.05). A small number of cells were promoted to apoptosis in the PcDNA3.1/Smac group. There were significant differences compared to the empty vector group and control group. The apoptosis rate was significantly higher in PcDNA3.1/Smac + Taxol group than in other groups (p < 0.05). CONCLUSIONS: Transfected Smac can enhance the chemosensitivity of the non-small cell lung cancer cell line A549 to Taxol.

Effect of Smac in combination with cisplatin on esophageal cancer cell line ECA109.

OBJECTIVE: This study was to investigate inhibiting effect of structurally unique Second mitochondria-derived activator of caspase (Smac) in combination with cisplatin on esophageal cancer cell line ECA109. METHODS: PcDNA3.1-Smac (ECA109/Smac group), pcDNA3.1 (ECA109/neo group) and PBS (ECA109 or control group) were transfected into ECA109 cells respectively, and transfected cells which expressed Smac stably were got. Smac protein expression was analyzed by Western blot. The invasive ability of cells was examined. Flow cytometry was used to analyze apoptosis induced by cisplatin with Annexin V/PI double staining technique. RESULTS: Smac gene was successfully transfected into ECA109 cell, over-expression of Smac could decrease cell invasive ability obviously compared to control group (P<0.05). Apoptosis rate of cells induced by cisplatin in ECA109/Smac group was significant higher than that in ECA109/neo and ECA109 group (P<0.05). CONCLUSION: It indicated that over-expression of Smac increases the sensitivity of esophageal cancer ECA109 cells to cisplatin treatment, combination of conventional anticancer drug with Smac may be beneficial for the treatment of esophageal cancer.

Application of a bioengineered composite neotrachea in a dog model.

BACKGROUND: Surgical treatment of extensive tracheal lesions remains a major challenge because of lack of an ideal airway substitute that is well vascularized, rigid, and autologous. We describe a novel surgical technique of tracheal reconstruction using a combination of a polypropylene mesh material and anterior cervical myocutaneous flap in a dog model. MATERIALS AND METHODS: A 3.5-4 cm length of cervical trachea was resected in 16 dogs and replaced with a myocutaneous cervical neck flap wrapped around the plain polypropylene tube (group 1, n = 7) or wrapped around a composite of polypropylene tube with an implanted Z-type metallic-covered stent (group 2, n = 9). The cervical tracheal defect was repaired with the previously mentioned substitute that was directly sutured to the remaining tracheal ends. Dogs were followed up using bronchoscopy and x-rays and euthanized at predetermined times for histologic examination. RESULTS: In group 1, four dogs died within 2 wk from respiratory failure with varying degrees of airway collapse and difficulties in expectoration. In group 2, eight dogs survived, whereas one died of anastomotic dehiscence 1 wk after surgery. Necropsy and histologic examination of the anastomotic sites revealed good healing tissue. Pathologic examination also revealed excellent healing of the squamous epithelium of the neotrachea and the columnar epithelium of the native tracheal mucosa. CONCLUSIONS: The tissue compatibility of the polypropylene mesh material and anterior cervical myocutaneous skin flap makes this a promising therapeutic substitute for treatment of patients with extensive tracheal lesions.

Effect of Smac and Taxol on non-small-cell lung cancer.

A series of structurally unique second mitochondria-derived activator of caspases (Smacs) that act as antagonists of the inhibitor of apoptosis proteins (IAPs) directly have been discovered. They play crucial roles in mitochondrial apoptosis pathways and promote chemotherapy-induced apoptosis. In this study, we constructed a eukaryotic expression vector pcDNA3.1/Smac and transfected it into A549 human lung cancer cells. Then we analyzed the cell invasive and cloning ability, as well as cell apoptosis induced by Taxol. The results showed that over-expressed Smac significantly inhibited A549 cell invasive and cloning ability and promoted apoptosis following Taxol treatment. This finding provides a potential approach for the biological therapy of lung cancer.

Response to first-line chemotherapy in patients with non-small cell lung cancer according to RRM1 expression.

BACKGROUND: The response to cytotoxic chemotherapy varies greatly in patients with advanced non-small cell lung cancer (NSCLC), and molecular markers may be useful in determining a preferable therapeutic approach for individual patients. This retrospective study was performed to evaluate the predictive value of ribonucleotide reductase regulatory subunit M1 (RRM1) on the therapeutic efficacy of platinum-based chemotherapy in patients with NSCLC. METHODS: Patients with advanced NSCLC who received platinum doublet chemotherapy (n = 229) were included in this retrospective study, and their clinical outcomes were analyzed according to RRM1 expression. RESULTS: In patients receiving gemcitabine-based therapy, the disease control rate (DCR) and progression-free survival (PFS) of patients with RRM1-negative tumors were significantly higher than in patients with RRMI-positive tumors (P = 0.041 and P = 0.01, respectively), and multivariate analysis showed that RRM1 expression was an independent prognostic factor (P = 0.013). No similar differences were found in patients receiving docetaxel- or vinorelbine-based therapy. In RRM1-positive patients, the DCRs for docetaxel and vinorelbine were higher than for gemcitabine (P = 0.047 and P = 0.047, respectively), and docetaxel and vinorelbine showed a longer PFS than gemcitabine-based chemotherapy (P = 0.012 and P = 0.007). No similar differences were found among patients with RRM1-negative tumors. CONCLUSIONS: Negative RRM1 expression in advanced NSCLC is associated with a higher response rate to gemcitabine-based chemotherapy. In patients with RRM1-positive tumors, docetaxel and vinorelbine showed a higher therapeutic efficacy than gemcitabine-based therapy. Additional prospective studies are needed to investigate the predictive meaning of RRM1 in the response to chemotherapy.

Response to first-line chemotherapy in patients with non-small-cell lung cancer according to epidermal growth factor receptor and K-RAS mutation status.

BACKGROUND: Epidermal growth factor receptor (EGFR)-targeted therapy has shown a favorable efficacy in patients with non-small-cell lung cancer (NSCLC). Conversely, K-RAS mutations were reported to have an adverse effect on the survival of patients with NSCLC. These studies suggest that the tumor biology of patients with EGFR or K-RAS mutations is different from that of patients with wild-type mutations. Therefore, we hypothesized that the response to cytotoxic chemotherapy may differ among patients with and without EGFR or K-RAS mutations. METHODS: A total of 229 patients with advanced NSCLC who received platinum doublet chemotherapy were included in this retrospective study, and their clinical outcomes were analyzed according to EGFR and K-RAS mutation status. RESULTS: EGFR and K-RAS mutations were found in 52.4% and 27.9% of patients, respectively. Progression-free survival (PFS) was significantly higher in patients with EGFR mutations than in patients with wild-type EGFR (P = .008), and multivariate analysis showed that EGFR mutation was an independent factor to chemotherapy (P = .01). Among the patients with EGFR mutations, the disease control rate for docetaxel was higher than for gemcitabine-based therapy (P = .031). In addition, docetaxel or vinorelbine showed a longer PFS than gemcitabine-based chemotherapy in patients with EGFR mutations (P = .033 and P = .028). However, no similar differences were found according to the K-RAS mutations. CONCLUSIONS: EGFR, but not K-RAS mutation, is associated with improved survival time to platinum-based chemotherapy. In patients with EGFR mutations, PFS for docetaxel and gemcitabine was higher than for vinorelbine-based chemotherapies. The predictive meaning of EGFR mutation for chemotherapy should be further investigated.