Causal associations between gut microbiota, metabolites and asthma: a two-sample Mendelian randomization study.

BACKGROUND: While several traditional observational studies have suggested associations between gut microbiota and asthma, these studies are limited by factors such as participant selection bias, confounders, and reverse causality. Therefore, the causal relationship between gut microbiota and asthma remains uncertain. METHODS: We performed two-sample bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationships between gut microbiota and asthma as well as its phenotypes. We also conducted MR analysis to evaluate the causal effect of gut metabolites on asthma. Genetic variants for gut microbiota were obtained from the MiBioGen consortium, GWAS summary statistics for metabolites from the TwinsUK study and KORA study, and GWAS summary statistics for asthma from the FinnGen consortium. The causal associations between gut microbiota, gut metabolites and asthma were examined using inverse variance weighted, maximum likelihood, MR-Egger, weighted median, and weighted model and further validated by MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis. RESULTS: We identified nine gut microbes whose genetically predicted relative abundance causally impacted asthma risk. After FDR correction, significant causal relationships were observed for two of these microbes, namely the class Bacilli (OR = 0.84, 95%CI = 0.76-0.94, p = 1.98 × 10-3) and the order Lactobacillales (OR = 0.83, 95%CI = 0.74-0.94, p = 1.92 × 10-3). Additionally, in a reverse MR analysis, we observed a causal effect of genetically predicted asthma risk on the abundance of nine gut microbes, but these associations were no longer significant after FDR correction. No significant causal effect of gut metabolites was found on asthma. CONCLUSIONS: Our study provides insights into the development mechanism of microbiota-mediated asthma, as well as into the prevention and treatment of asthma through targeting specific gut microbiota.

Circle-seq based method for eccDNA synthesis and its application as a canonical promoter independent vector for robust microRNA overexpression.

Extrachromosomal circular DNA (eccDNA) has recently gained increasing attention due to its significant role in cancer and other pathophysiologic states. The majority of circular DNAs detected by Circle-seq are small-size eccDNAs with enigmatic functions. One major technical hurdle is to synthesize eccDNA for functional identification. Here, we describe CAES (Circle-seq based Artificial EccDNA Synthesis), a promising and reliable method for artificial eccDNA synthesis. Eight eccDNAs carrying different microRNA genes (eccMIR) found in gastric cancer tissues, ranging from 329 bp to 2189 bp in size, were created utilizing the CAES method. Exonuclease V and single restriction-endonuclease digestion identified the circular structure of synthetic eccDNAs. The DNA circularization efficiency afforded by CAES ranged from 15.6% to 31.1%, which was negatively correlated with the eccDNA length. In addition, we demonstrated that CAES-synthesized eccMIRs can express both miRNA-3p and - 5p molecules efficiently independent of a canonical promoter in human cell lines. Further assays proved that these eccMIRs were functional as they were able to repress the luciferase gene containing a miRNA-target sequence in the 3'UTR as well as the endogenous mRNA targets. Finally, kinetics study revealed that eccDNA exhibited a decay rate similar to the standard plasmids and linear DNA in cultured cells. Together, this study offers a rapid and convenient method for Circle-seq users to synthesize artificial eccDNAs. It also demonstrates the promising potential of eccMIR as a bacterial DNA-free vector for safe and robust miRNA overexpression in both basic research and therapeutic applications.

ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the most common and fatal diffuse fibrotic lung disease accompanied by macrophage M2 activation. ErbB4 is involved in and affects the process of inflammation. In this study, we determined that the mRNA level and protein expression of ErbB4 and M2 cytokine members were increased in the serum of IPF patients. In mouse alveolar macrophage MH-S cells, after knocking down ErbB4 by siRNA, the mRNA level and protein expression of M2 activator induced by interleukin (IL)-4 were decreased compared with the control group. Activating by ErbB4 agonist neuromodulatory protein (NRG)-1, IL-4-induced M2 program was promoted. Mechanistically, treated with NRG-1 in MH-S cells, the phosphorylation level of Akt did not change, while the phosphorylation level of ERK increased. Using SCH772984 to inhibit ERK pathway, the increasing IL-4-induced M2 activation by NRG-1 was inhibited, and the high level of M2 activator protein expression and mRNA expression was restored. Collectively, our data support that ErbB4 and M2 programs are implicated in IPF, and ErbB4 participates in the regulation of M2 activation induced by IL-4 through the ERK pathway.

miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3' untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML.

Sunitinib selectively targets leukemogenic signaling of mutant SHP2 in juvenile myelomonocytic leukemia.

Leukemogenic SHP2 mutations occur in 35% of patients with juvenile myelomonocytic leukemia (JMML), a hematopoietic malignancy with poor response to cytotoxic chemotherapy. Novel therapeutic strategies are urgently needed for patients with JMML. Previously, we established a novel cell model of JMML with HCD-57, a murine erythroleukemia cell line that depends on EPO for survival. SHP2-D61Y or -E76K drove the survival and proliferation of HCD-57 in absence of EPO. In this study, we identified sunitinib as a potent compound to inhibit SHP2-mutant cells by screening a kinase inhibitor library with our model. We used cell viability assay, colony formation assay, flow cytometry, immunoblotting, and a xenograft model to evaluate the effect of sunitinib against SHP2-mutant leukemia cells in vitro and in vivo. The treatment of sunitinib selectively induced apoptosis and cell cycle arrest in mutant SHP2-transformed HCD-57, but not parental cells. It also inhibited cell viability and colony formation of primary JMML cells with mutant SHP2, but not bone marrow mononuclear cells from healthy donors. Immunoblotting showed that the treatment of sunitinib blocked the aberrantly activated signals of mutant SHP2 with deceased phosphorylation levels of SHP2, ERK, and AKT. Furthermore, sunitinib effectively reduced tumor burdens of immune-deficient mice engrafted with mutant-SHP2 transformed HCD-57. Our data demonstrated that sunitinib selectively inhibited SHP2-mutant leukemia cells, which could serve as an effective therapeutic strategy for SHP2-mutant JMML in the future.

Transcriptome analysis reveals effects of leukemogenic SHP2 mutations in biosynthesis of amino acids signaling.

Gain-of-function mutations of SHP2, especially D61Y and E76K, lead to the development of neoplasms in hematopoietic cells. Previously, we found that SHP2-D61Y and -E76K confer HCD-57 cells cytokine-independent survival and proliferation via activation of MAPK pathway. Metabolic reprogramming is likely to be involved in leukemogenesis led by mutant SHP2. However, detailed pathways or key genes of altered metabolisms are unknown in leukemia cells expressing mutant SHP2. In this study, we performed transcriptome analysis to identify dysregulated metabolic pathways and key genes using HCD-57 transformed by mutant SHP2. A total of 2443 and 2273 significant differentially expressed genes (DEGs) were identified in HCD-57 expressing SHP2-D61Y and -E76K compared with parental cells as the control, respectively. Gene ontology (GO) and Reactome enrichment analysis showed that a large proportion of DEGs were involved in the metabolism process. Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis showed that DEGs were the mostly enriched in glutathione metabolism and biosynthesis of amino acids in metabolic pathways. Gene Set Enrichment Analysis (GSEA) revealed that the expression of mutant SHP2 led to a significant activation of biosynthesis of amino acids pathway in HCD-57 expressing mutant SHP2 compared with the control. Particularly, we found that ASNS, PHGDH, PSAT1, and SHMT2 involved in the biosynthesis of asparagine, serine, and glycine were remarkably up-regulated. Together, these transcriptome profiling data provided new insights into the metabolic mechanisms underlying mutant SHP2-driven leukemogenesis.

Leukemogenic SHP2 mutations lead to erythropoietin independency of HCD-57 cells: a novel model for preclinical research of SHP2-mutant JMML.

Leukemogenic SHP2 mutations occur in 35% of patients with juvenile myelomonocytic leukemia (JMML), a rare but fatal hematopoietic malignancy without representative cell models, which are urgently needed to investigate the pathogenesis and to develop novel therapeutic strategies. In this study, we established stable cell lines with aberrant signaling resembling SHP2-mutant JMML through retroviral expression of SHP2-D61Y/E76K in HCD-57 cells, a murine erythroleukemia cell line that depends on erythropoietin (EPO) for survival. SHP2-D61Y/E76K drives the survival and proliferation of HCD-57 cells in the absence of EPO, but not in Ba/F3 cells in the absence of IL-3. Transformed HCD-57 cells showed activated MAPK signaling that is consistent with SHP2-mutant JMML. Transformed HCD-57 cells were sensitive to dasatinib and trametinib, two targeted drugs previously reported to inhibit SHP2-mutant JMML cells. Furthermore, we injected mutant SHP2-transformed HCD-57 cells into immune-deficient mice intravenously and found that these cells rapidly proliferated in the spleen and bone marrow, providing an excellent model for in vivo testing of drugs targeting the aberrant signaling of mutant SHP2. In conclusion, we established the novel cell lines HCD-57/SHP2-E76K and -D61Y that depended on signaling of mutant SHP2 for survival, thus resembling SHP2-mutant JMML. Our model is a valuable tool to investigate the pathogenic mechanisms of mutant SHP2 and targeted drugs for SHP2-mutant JMML.

Loss of MLL Induces Epigenetic Dysregulation of Rasgrf1 to Attenuate Kras-Driven Lung Tumorigenesis.

Menin is necessary for the formation of the menin/mixed lineage leukemia (MLL) complex and is recruited directly to chromatin. Menin is an important tumor suppressor in several cancer types, including lung cancer. Here, we investigated the role of MLL in menin-regulated lung tumorigenesis. Ablation of MLL suppressed KrasG12D-induced lung tumorigenesis in a genetically engineered mouse model. MLL deficiency decreased histone H3 lysine 4 trimethylation (H3K4me3) and subsequently suppressed expression of the Ras protein-specific guanine nucleotide-releasing factor 1 (Rasgrf1) gene. Rasgrf1 was essential for the GTP-bound active state of Kras and the activation of Kras downstream pathways as well as their cancer-promoting activities. MI-3, a small-molecule inhibitor targeting MLL, specifically inhibited the growth of Kras-mutated lung cancer cells in vitro and in vivo with minimal effect on wild-type Kras lung cancer growth. Together, these results demonstrate a novel tumor promoter function of MLL in mutant Kras-induced lung tumorigenesis and further indicate that specific blockade of the MLL-Rasgrf1 pathway may be a potential therapeutic strategy for the treatment of tumors containing Kras mutations. SIGNIFICANCE: Activation of mutant Kras is dependent on MLL-mediated epigenetic regulation of Rasgrf1, conferring sensitivity to small-molecule inhibition of MLL in Kras-driven lung cancer.

Efficacy of SCF drug conjugate targeting c-KIT in gastrointestinal stromal tumor.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a rare type of cancer that occurs in the gastrointestinal tract. The majority of GIST cases carry oncogenic forms of KIT, the receptor for stem cell factor (SCF). Small molecule kinase inhibitor imatinib is effective in prolonging the survival of GIST patients by targeting KIT. However, drug resistance often develops during the therapeutic treatment. Here, we produced a SCF-emtansine drug conjugate (SCF-DM1) with favorable drug efficacy towards GIST cells. METHODS: Recombinant human SCF (rhSCF) was expressed in E. coli cells and further purified with Ni-NTA Sepharose and Phenyl Sepharose. It was then conjugated with DM1, and the conjugated product SCF-DM1 was evaluated using in vitro cell-based assays and in vivo xenograft mouse model. RESULTS: SCF-DM1 was effective in inhibiting imatinib-sensitive and -resistant GIST cell lines and primary tumor cells, with IC50 values of < 30 nM. It induced apoptosis and cell cycle arrest in GIST cells. In xenograft mouse model, SCF-DM1 showed favorable efficacy and safety profiles. CONCLUSIONS: rhSCF is a convenient and effective vector for drug delivery to KIT positive GIST cells. SCF-DM1 is an effective drug candidate to treat imatinib-sensitive and -resistant GIST.

The Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia.

Gain-of-function mutations of isocitrate dehydrogenases 1/2 (IDH1/2) play crucial roles in the development and progression of acute myeloid leukemia (AML), which provide promising therapeutic targets. Two small molecular inhibitors, ivosidenib and enasidenib have been approved for the treatment of IDH1- and IDH2-mutant AML, respectively. Although these inhibitors benefit patients with AML clinically, drug resistance still occurs and have become a major problem for targeted therapies of IDH-mutant AML. A number of up-to-date studies have demonstrated molecular mechanisms of resistance, providing rationales of novel therapeutic strategies targeting mutant IDH1/2. In this review, we discuss mechanisms of resistance to ivosidenib and enasidenib in patients with AML.

The effect of quercetin on cervical cancer cells as determined by inducing tumor endoplasmic reticulum stress and apoptosis and its mechanism of action.

OBJECTIVE: This study aimed to explore the effect of quercetin on cervical cancer cells by inducing tumor endoplasmic reticulum stress (ERS) and apoptosis and its mechanism of action. METHODS: HeLa cells were treated with different concentrations of quercetin, and the cell viability was measured using methyl thiazolyl tetrazolium (MTT) colorimetric assays. The apoptosis rate was measured using flow cytometry. The changes in the related protein X (Bax), B-cell lymphoma/leukemia-2 (Bcl-2), and G1/S-specific cyclin-D1 (Cyclin D1) levels after the HeLe apoptosis were determined using Western blot, and the changes in the human cystinase-3 (Caspase-3), glucoprotein 78 (GRP78), and enhancer-binding protein homologous protein (CHOP) levels, and the receptor-related protein levels in the ERS pathway/endoribonuclease inositol requiring enzyme 1 (IRE1), and the phosphorylated pancreatic endoplasmic reticulum stress kinase (p-Perk), and the activated transcription factor-6 (ATF6) levels were also quantified. RESULTS: After treating the HeLa cells with different concentrations of quercetin, the cell viability was inhibited to varying degrees, showing a significant time and concentration dependence. The apoptosis rate in the quercetin group increased significantly in comparison with the blank control group, and the apoptosis rate also showed a tendency to increase progressively with an increasing concentration of the quercetin (P<0.05). The Bax and Bcl-2 levels in the quercetin intervention group showed a tendency to increase progressively in comparison with the blank control group, and Cyclin D1 showed a tendency to decrease progressively (P<0.05). The of Caspase-3, GRP78, and CHOP expression levels in the quercetin intervention group rose significantly in comparison with the blank control group (P<0.05). The IRE1, p-Perk, and c-ATF6 levels in the quercetin intervention group showed a tendency to rise gradually in comparison with the blank control group (P<0.05). CONCLUSION: Quercetin may promote the apoptosis of cervical cancer HeLe cells by inducing the tumor ERS pathway.

Determining optimal gestational weight gain (GWG) in a northwest Chinese population: A CONSORT.

ABSTRACT: To determine optimal gestational weight gain (GWG) for the Chinese population.Live singleton deliveries at the largest maternal & childcare hospital in northwest China from 2010 to 2012 were analyzed retrospectively. Multivariable logistic regression analysis was conducted to determine the lowest aggregated risk of interested perinatal outcomes based on Chinese adult body mass index (BMI) categories.Eight thousand eight hundred seventy enrolled parturients were divided into 4 groups according to their prepregnancy BMI: underweight (21.31%, BMI < 18.5 kg/m2), normal weight (67.81%, 18.5 kg/m2 ≤ BMI < 24 kg/m2), overweight (8.99%, 24 kg/m2 ≤ BMI < 28 kg/m2 and obese (1.89%, BMI ≥ 28 kg/m2). The optimal GWG values for the above 4 groups were 16.7 kg (GWG range, 12.0-21.5), 14.5 kg (9.5-19.5), 11.5 kg (7.0-16.5), and 8.0 kg (5.0-13.0). The rates of inadequate, optimal and excessive GWG in present study were 6.14% (545), 62.34% (5529), and 31.52% (2796) respectively, which were significantly different from those of the 2009 Institute of Medicine recommendation (χ2 = 1416.05, Pinteraction < 0.0001).Wider optimal GWG ranges than those recommended by Institute of Medicine were found in our study, and our proposed criteria seems to be practical to the Chinese population.

Support Vector Machine for Lung Adenocarcinoma Staging Through Variant Pathways.

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors. How to effectively diagnose LUAD at an early stage and make an accurate judgement of the occurrence and progression of LUAD are still the focus of current research. Support vector machine (SVM) is one of the most effective methods for diagnosing LUAD of different stages. The study aimed to explore the dynamic change of differentially expressed genes (DEGs) in different stages of LUAD, and to assess the risk of LUAD through DEGs enriched pathways and establish a diagnostic model based on SVM method. Based on TMN stages and gene expression profiles of 517 samples in TCGA-LUAD database, coefficient of variation (CV) combined with one-way analysis of variance (ANOVA) were used to screen out feature genes in different TMN stages after data standardization. Unsupervised clustering analysis was conducted on samples and feature genes. The feature genes were analyzed by Pearson correlation coefficient to construct a co-expression network. Fisher exact test was conducted to verify the most enriched pathways, and the variation of each pathway in different stages was analyzed. SVM networks were trained and ROC curves were drawn based on the predicted results so as to evaluate the predictive effectiveness of the SVM model. Unsupervised hierarchical clustering analysis results showed that almost all the samples in stage III/IV were clustered together, while samples in stage I/II were clustered together. The correlation of feature genes in different stages was different. In addition, with the increase of malignant degree of lung cancer, the average shortest path of the network gradually increased, while the closeness centrality gradually decreased. Finally, four feature pathways that could distinguish different stages of LUAD were obtained and the ability was tested by the SVM model with an accuracy of 91%. Functional level differences were quantified based on the expression of feature genes in lung cancer patients of different stages, so as to help the diagnosis and prediction of lung cancer. The accuracy of our model in differentiating between stage I/II and stage III/IV could reach 91%.

Biodegradable nanoparticles as siRNA carriers for in vivo gene silencing and pancreatic cancer therapy.

The clinical application of RNA interference (RNAi)-based cancer gene therapy has been hampered by the lack of efficient delivery of short interfering RNA (siRNA). In this context, the use of biodegradable charged polyester-based vectors (BCPVs) for delivering mutated K-Ras-targeting siRNA in a pancreatic xenograft model was investigated in vivo. Using mice bearing pancreatic xenografts as an animal model, results show that fluorescently labeled TRAMA (carboxytetramethylrhodamine) K-Ras siRNA continuously accumulated in the xenograft via BCPVs for at least 72 h. After the treatment, the level of the targeted mRNA and protein reduced to 50% of their original level. As a consequence, significant suppression in tumor growth, decreased tumor local infiltration, and increased cell apoptosis were observed in the xenograft model after the siRNA treatment. More importantly, physiological analysis results reveal that an excessive amount of BCPV (10 times higher than the commonly treated amount) will not have a significant influence on the status of the blood stream, blood stream components, and organ tissue, suggesting that BCPVs have very low in vivo toxicity. Our results indicate that the delivery of K-Ras-targeting siRNA via BCPV nanoparticles may be a promising strategy for pancreatic cancer therapy.

Pretreatment neutrophil-to-lymphocyte ratio as predictor of survival for patients with metastatic nasopharyngeal carcinoma.

BACKGROUND: The outcomes of patients with metastatic nasopharyngeal carcinoma (NPC) differ between individuals. The purpose of this study was to examine the impact of neutrophil-to-lymphocyte ratio (NLR) on survival in patients with metastatic NPC. METHODS: A total of 229 patients with disseminated NPC were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte, and NLR on survival were examined using the proportional hazards regression model to estimate hazard ratio (HR). The relationship between short-term treatment efficacy and pretreatment NLR was analyzed using the chi-square test. RESULTS: The pretreatment elevated neutrophil count (p = .020), percentage of neutrophil (p < .001), and NLR (p = .002) were statistically significantly associated with a poor prognosis. The cutoff value selected for NLR was 3.6. The median survival time was 15.3 months for the high-NLR group and was 23.5 months for the low-NLR group (p < .001). CONCLUSION: NLR is a prognosticator in patients with metastatic NPC.

[Joint serum tumor markers serve as survival predictive model of erlotinib in the treatment of recurrent non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: Molecular targeting therapy is the direction of individualized treatment of lung cancer, scholars has been established targeted therapy prediction models which provide more guidance for clinical individual therapy. This study investigated the relationship among pulmonary surfactant-associated protein D (SP-D), transforming growth factor α (TGF-α), matrix metalloproteinase 9 (MMP-9), tissue polypeptide specific antigen (TPS), and Krebs von den Lungen-6 (KL-6) and response as well as survival in the patients with recurrent non-small cell lung cancer, which Erlotinib was as second line treatment after failure to chemotherapy. This study also established a predictive prognostic model. METHODS: Serum levels of SP-D, TGF-α, MMP-9, TPS, and KL-6 in 114 patients before erlotinib treatment were detected by ELISA method. Combined with clinical factors, these levels were used to investigate the relationship with efficacy in erlotinib treatment and construct a predicted prognostic model by Kaplan-Meier curve and Cox proportional hazard model multivariate analysis. RESULTS: The objective response rate (ORR) and disease control rate (DCR) in the 114 patients, were 22.8% (26/114) and 72.8% (83/114), to Erlotinib treatment respectively. The median progression-free survival (PFS) and one year survival rate with Erlotinib treatment were 5.13 months and 69.3%, respectively. Patients in the SP-D>110 ng/mL group exhibited more ORR (33.3% vs 13.3%, P=0.011) and DCR (83.3% vs 63.3%, P=0.017) than those in the ≤110 ng/mL group. Patients in the MMP-9≤535 ng/mL group showed more DCR (83.9%) than those in the >535 ng/mL group (62.1%) (P=0.009). Patients in the TPS<80 U/L group showed more DCR (82.4%) than those in the ≥80 U/L group (55.0%) (P=0.002). The SP-D>110 ng/mL (5.95 months vs 3.25 months, P=0.009), MMP-9≤535 ng/mL (5.83 months vs 3.47 months, P=0.046), KL-6<500 U/mL (6.03 months vs 3.40 months, P=0.040), and TPS<80 U/L (6.15 months vs 2.42 months, P=0.014) groups showed better PFS. Multivariate analysis showed that current or ever-smoker, wild style of EGFR status, progression after prior chemotherapy, absence of skin rash, elevated serum LDH level, and TPS≥80 U/L were independent adverse prognostic factors for PFS. These six factors were used in the prognostic model. Patients were categorized into four prognosis risk groups based on the prognostic index from the model, namely, low risk, intermediate low risk, intermediate risk, and high risk groups. The median PFS of good, intermediate, poor, and very poor prognosis groups were 9.12, 6.88, 3.52, and 0.93 months (P<0.001), respectively. CONCLUSIONS: The prognostic model based on clinical parameters with TPS will be useful in identifying patients who might be most likely to benefit from Erlotinib therapy in the patients with recurrent non-small cell lung cancer.

Efficacy and safety of icotinib in Chinese patients with advanced non-small cell lung cancer after failure of chemotherapy.

BACKGROUND: The preclinical experiments and several clinical studies showed icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in Chinese patients with advanced non-small cell lung cancer (NSCLC) who failed previous chemotherapy. We performed a retrospective study of the efficacy and safety of icotinib monotherapy in a different and more recent sample of Chinese patients. METHODS: The clinical data of 149 patients with advanced NSCLC who were admitted to Zhejiang Cancer Hospital from August 1, 2011 to July 31, 2012 were retrospectively analyzed. All patients were given icotinib treatment after the failure of previous chemotherapy. Univariate and multivariate analyses were conducted based on the Kaplan Meier method and Cox proportional hazards model. RESULTS: The objective response rate was 33/149 and disease control rate was 105/149. No complete response occurred. Median progression free survival (PFS) with icotinib treatment was 5.03 months (95% CI: 3.51 to 6.55). Median overall survival was 12.3 months (95% CI: 10.68 to 13.92). Multivariate analysis showed that the mutation of EGFR and one regimen of prior chemotherapy were significantly associated with longer PFS. At least one drug related adverse event was observed in 65.8% (98/149) of patients, but mostly grade 1 or 2 and reversible and none grade 4 toxicity. CONCLUSIONS: Icotinib monotherapy is an effective and well tolerated regimen for Chinese patients with NSCLC after the failure of chemotherapy. It is a promising agent and further study with icotinib in properly conducted trials with larger patient samples and other ethnic groups is warranted.

Docetaxel-based chemotherapy as second-line regimen for advanced thymic carcinoma.

Thymic carcinoma is an uncommon neoplasm. The efficacy of second-line treatment with docetaxel in advanced thymic carcinoma has not been well studied. Therefore, we conducted a review of the efficacy of docetaxel-based chemotherapy as a second-line regimen for advanced thymic carcinoma. Fifteen patients with advanced thymic carcinoma who received second-line chemotherapy with docetaxel singlet or docetaxel/platinum combination chemotherapy regimens were retrospectively reviewed. There were 11 males and four females, with a median age of 53 years. Squamous cell carcinoma was most common (n = 10), followed by undifferentiated carcinoma (n = 4), and small cell carcinoma (n = 1). Eight patients received docetaxel/platinum combination chemotherapy and seven docetaxel mono-therapy. Four patients showed partial responses, representing a response rate of 26.7%. The median progression-free survival and overall survival in the 15 patients were 4.0 (2.8-5.2) and 22.0 (14.6-29.4) months, respectively. There was no difference in progression-free survival between the docetaxel singlet or docetaxel/platinum combination chemotherapy (3.5 months vs. 4.0 months, P = 0.889). A docetaxel-based regimen could be a potential therapeutic option as a second-line chemotherapy for advanced thymic carcinoma.

Preoperative elevation of serum C-reactive protein as an indicator of poor prognosis for early-stage esophageal squamous cell carcinoma.

Preoperative elevation of serum C-reactive protein (CRP) is reportedly associated with poor prognosis in several types of cancer. This study investigated the role of serum CRP as a prognostic factor in early-stage esophageal squamous cell carcinoma (ESCC). The preoperative serum CRP levels were measured in 156 newly diagnosed pT1-2N0M0 patients using an enzyme-linked immunosorbent assay. Correlations between serum CRP levels and other clinical parameters were analyzed. Multivariate analyses were performed to find prognostic markers using Cox's proportional hazards model. CRP concentrations were within the normal range in 117 (75%) individuals, but were elevated in 39 (25%) patients. Serum CRP levels were significantly correlated with the tumor length (p = 0.032), depth (T classification, p = 0.0157), or histologic grade (p = 0.034). The overall 5-year survival rates were 76.3% and 50.2% in the low- and high-CRP groups, respectively (p = 0.005). By multivariate analyses, the elevated serum CRP level was found to be an independent prognostic factor for poor survival (hazard ratio = 2.131; p = 0.007), regardless of tumor classification or other prognostic factors. In conclusion, preoperative, high serum CRP is an independent determinant of poor prognosis in early-stage ESCC.

Re-administration after the failure of gefitinib or erlotinib in patients with advanced non-small cell lung cancer.

OBJECTIVE: Few treatment options are available for advanced non-small cell lung cancer (NSCLC) patients who have failed of gefitinib or erlotinib treatment in second/third-line treatment. The aim of this study was to investigate the efficacy of re-administration of the same TKI after failure of gefitinib or erlotinib. PATIENTS AND METHODS: The clinical data of 33 patients with advanced NSCLC were retrospectively analyzed. All of the patients were given the same TKI treatment after the failure of gefitinib or erlotinib. Survival analysis was evaluated by Kaplan-Meier method. RESULTS: Twenty patients (60.6%) were re-administration with gefitinib as the 2(nd) EGFR-TKI, and thirteen patients (39.4%) received erlotinib. One patient (3.0%) showed partial response (PR), 14 (42.4%) achieved stable disease (SD), and 18 (54.5%) had progressive disease (PD). The disease control rate was 45.5% and the median progression-free survival was 1.5 months (95% CI: 0.6-2.3 months). The PFS in patients who got disease control in the prior TKI was 2.2 and 1.2 months in the progression disease cases (P=0.29), the DCR was 54.5% and 27.3% in two group, respectively (P=0.26). CONCLUSIONS: Re-administration of TKI seems to be a potential therapeutic option for treatment of selected advanced NSCLC patients after failure of gefitinib or erlotinib, especially for the patients with NSCLC who once responded from the prior TKI treatment.