Diagnosis of primary lung cancer and benign pulmonary nodules: a comparison of the breath test and 18F-FDG PET-CT.

With the application of low-dose computed tomography in lung cancer screening, pulmonary nodules have become increasingly detected. Accurate discrimination between primary lung cancer and benign nodules poses a significant clinical challenge. This study aimed to investigate the viability of exhaled breath as a diagnostic tool for pulmonary nodules and compare the breath test with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computed tomography (CT). Exhaled breath was collected by Tedlar bags and analyzed by high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). A retrospective cohort (n = 100) and a prospective cohort (n = 63) of patients with pulmonary nodules were established. In the validation cohort, the breath test achieved an area under the receiver operating characteristic curve (AUC) of 0.872 (95% CI 0.760-0.983) and a combination of 16 volatile organic compounds achieved an AUC of 0.744 (95% CI 0.7586-0.901). For PET-CT, the SUVmax alone had an AUC of 0.608 (95% CI 0.433-0.784) while after combining with CT image features, 18F-FDG PET-CT had an AUC of 0.821 (95% CI 0.662-0.979). Overall, the study demonstrated the efficacy of a breath test utilizing HPPI-TOFMS for discriminating lung cancer from benign pulmonary nodules. Furthermore, the accuracy achieved by the exhaled breath test was comparable with 18F-FDG PET-CT.

Long noncoding RNA AFAP1-AS1 is upregulated in NSCLC and associated with lymph node metastasis and poor prognosis.

Long noncoding RNA (lncRNA) has been indicated to have an important role in various types of malignant tumors; however, only a small number of lncRNAs have been entirely elucidated. In the present study, a novel lncRNA, actin filament associated protein 1 antisense RNA 1 (AFAP1-AS1), was investigated, which is highly expressed in non-small cell lung cancer (NSCLC). Reverse transcription-quantitative polymerase chain reaction and in situ hybridization were performed to detect AFAP1-AS1 expression in frozen tissues and tissue microarrays, respectively. The results revealed that the expression level of AFAP1-AS1 was significantly increased in tumor tissues, compared with the paired non-cancerous tissues. It was also determined that the AFAP1-AS1 expression level was higher in patients with lymph node metastasis than those without lymph node metastasis (P=0.014). Kaplan-Meier analysis was conducted to evaluate the overall survival of patients with NSCLC and different expression levels of AFAP1-AS1, and the results indicated that patients with high AFAP1-AS1 expression had a reduced survival time, compared with those with low AFAP1-AS1 expression (P=0.011). Cox regression analysis was also performed to analyze the prognostic value of lncRNA AFAP1-AS1. The obtained data demonstrated that lncRNA AFAP1-AS1 was an unfavorable prognostic biomarker for NSCLC (HR: 3.12, 95% CI (1.05-9.25), P=0.040). In conclusion, it was demonstrated that lncRNA AFAP1-AS1 is overexpressed in NSCLC and an unfavorable biomarker for patients with NSCLC.

Profiling expression of coding genes, long noncoding RNA, and circular RNA in lung adenocarcinoma by ribosomal RNA-depleted RNA sequencing.

Noncoding RNA play important roles in various biological processes and diseases, including cancer. The expression profile of circular RNA (circRNA) has not been systematically investigated in lung adenocarcinoma (LUAD). In this study, we performed genomewide transcriptome profiling of coding genes, long noncoding RNA (lncRNA), and circRNA in paired LUAD and nontumor tissues by ribosomal RNA-depleted RNA sequencing. The detected reads were first mapped to the human genome to analyze expression of coding genes and lncRNA, while the unmapped reads were subjected to a circRNA prediction algorithm to identify circRNA candidates. We identified 1282 differentially expressed coding genes in LUAD. Expression of 19 023 lncRNA was detected, of which 244 lncRNAs were differentially expressed in LUAD. AFAP1-AS1, BLACAT1, LOC101928245, and FENDRR were most differentially expressed lncRNAs in LUAD. Also identified were 9340 circRNA candidates with ≥ 2 backspliced, including 3590 novel circRNA transcripts. The median length of circRNA was ~ 530 nt. CircRNA are often of low abundance, and more than half of circRNAs we identified had < 10 reads. Agarose electrophoresis and Sanger sequencing were used to confirm that four candidate circRNA were truly circular. Our results characterized the expression profile of coding genes, lncRNA, and circRNA in LUAD; 9340 circRNAs were detected, demonstrating that circRNA are widely expressed in LUAD. Database: The raw RNA sequencing data have been submitted to Gene Expression Omnibus (GEO) database and can be accessed with the ID GEO: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104854.

Integrative analysis of gene expression in response to low-dose ionizing radiation in a human skin model.

The advance in medical imaging and utilization has raised the concern about exposure to low-dose ionizing radiation (LDIR). Cellular and molecular responses to high-dose ionizing radiation have been characterized, but in the range of low dose, these responses are poorly understood. Here, we investigate the gene expression in response to LDIR (10 cGy) in the EpiDermFT human skin model. We identified 3299 differentially expressed genes (DEGs) in response to LDIR. Among these DEGs, we noted several well-characterized long noncoding RNAs. Gene Ontology and KEGG pathway analysis were performed to detect altered molecular response. GO and KEGG pathway results showed that genes corresponding to "regulation of cell proliferation" were enriched. Gene set enrichment analysis showed that KRAS signaling pathway was enriched in response to LDIR and transcription targets of NF-κB were also enriched when exposed to LDIR.

Cytidine deaminase polymorphism predicts toxicity of gemcitabine-based chemotherapy.

BACKGROUND: The aim of this study was to ascertain whether single nucleotide polymorphisms of cytidine deaminase (CDA), a key enzyme in the metabolism pathway of gemcitabine, could predict clinical outcomes of cancer patients with gemcitabine-based chemotherapy. METHODS: We searched MEDLINE and EMBASE up to January 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according to the Newcastle-Ottawa Quality Assessment Scale. For each included study, the overall survival (OS), overall response rate (ORR) and toxicities were extracted and pooled using random-effects model. RESULTS: In total, data from 13 studies were included. CDA 208A>G and CDA 435C>T were not included in quantified synthesis due to limited data. CDA 79A>C polymorphism was not significantly associated with OS; however, patients carrying the variant CDA 79C allele were likely to have a poor survival, hazard ratio (HR)=1.03, 95% CI 0.957-1.27 (AC+CC vs. AA). CDA 79A>C polymorphism did not correlated with ORR, odds ratio (OR)=0.719, 95% CI 0.363-1.425 (AC+CC vs. AA). However, patients with the variant CDA 79C allele would experience more grade ≥ 3 leucopenia (OR=2.933, 95% CI 1.357-6.605) and tended to have more severe neutropenia (OR=1.313, 95% CI 0.157-10.981). CONCLUSIONS: These results suggest that CDA 79A>C polymorphisms is a potential biomarker for toxicity of gemcitabine-based chemotherapy and a CDA testing before gemcitabine administration is preferred.

Circulating tumor DNA is effective for the detection of EGFR mutation in non-small cell lung cancer: a meta-analysis.

BACKGROUND: Circulating tumor DNA (ctDNA) has offered a minimally invasive and feasible approach for detection of EGFR mutation for non-small cell lung cancer (NSCLC). This meta-analysis was designed to investigate the diagnostic value of ctDNA, compared with current "gold standard," tumor tissues. METHODS: We searched PubMed, EMBASE, Cochrane Library, and Web of Science to identify eligible studies that reported the sensitivity and specificity of ctDNA for detection of EGFR mutation status in NSCLC. Eligible studies were pooled to calculate the pooled sensitivity, specificity, and diagnostic odds ratio (DOR). The summary ROC curve (SROC) and area under SROC (AUSROC) were used to evaluate the overall diagnostic performance. RESULTS: Twenty-seven eligible studies involving 3,110 participants were included and analyzed in our meta-analysis, and most studies were conducted among Asian population. The pooled sensitivity, specificity, and DOR were 0.620 [95% confidence intervals (CI), 0.513-0.716), 0.959 (95% CI, 0.929-0.977), and 38.270 (95% CI, 21.090-69.444), respectively. The AUSROC was 0.91 (95% CI, 0.89-0.94), indicating the high diagnostic performance of ctDNA. CONCLUSION: ctDNA is a highly specific and effective biomarker for the detection of EGFR mutation status. IMPACT: ctDNA analysis will be a key part of personalized cancer therapy of NSCLC.

XRCC3 Thr241Met is associated with response to platinum-based chemotherapy but not survival in advanced non-small cell lung cancer.

BACKGROUND: A lot of studies have investigated the correlation between x-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism and clinical outcomes in non-small cell cancer (NSCLC), while the conclusion is still conflicting. MATERIALS AND METHODS: We conducted this meta-analysis to evaluate the predictive value of XRCC3 Thr241Met polymorphism on response and overall survival of patients with NSCLC. Pooled odds ratios (ORs) and hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) were used to estimate the association strength. RESULTS: A total of 14 eligible studies with 2828 patients were identified according to our inclusion criteria. Meta-analysis results showed that carriers of the variant 241Met allele were significantly associated with good response, compared with those harboring the wild 241Thr allele (Met vs. Thr, OR = 1.453, 95% CI: 1.116-1.892, Pheterogeneity = 0.968 and ThrMet+MetMet vs. ThrThr, OR = 1.476, 95% CI: 1.087-2.004, Pheterogeneity = 0.696). This significant association was observed in Caucasian population but not in Asian population. On the other hand, there was no significant association of XRCC3 Thr241Met polymorphism with survival (ThrMet+MetMet vs. ThrThr, HR = 1.082, 95% CI: 0.929-1.261, Pheterogeneity = 0.564), and there was no difference between Asian and Caucasian population. CONCLUSIONS: These findings suggest a predictive role of XRCC3 Thr241Met polymorphism on response to platinum-based chemotherapy in patients with advanced NSCLC. Additionally, we first report that the XRCC3 Thr241Met polymorphism is associated with response to platinum-based chemotherapy and highlights the prognostic value of the XRCC3 Thr241Met polymorphism.

Predictive value of XPD polymorphisms on platinum-based chemotherapy in non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The correlation between xeroderma pigmentosum group D (XPD) polymorphisms (Lys751Gln and Asp312Asn) and clinical outcomes of non-small cell lung cancer (NSCLC) patients, who received platinum-based chemotherapy (Pt-chemotherapy), is still inconclusive. This meta-analysis was aimed to systematically review published evidence and ascertain the exact role of XPD polymorphisms. METHODS: Databases of MEDLINE and EMBASE were searched up to April 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according the Newcastle-Ottawa Quality Assessment Scales. The relationship between XPD polymorphisms and response to Pt-chemotherapy and survival was analyzed. RESULTS: A total of 22 eligible studies were included and analyzed in this meta-analysis. The overall analysis suggested that the XPD Lys751Gln polymorphism was not associated with response to Pt-chemotherapy or survival. However, the XPD 312Asn allele was significantly associated with poor response to Pt-chemotherapy compared with the Asp312 allele (Asn vs. Asp: OR = 0.435, 95% CI: 0.261-0.726). Additionally, the variant genotype of XPD Asp312Asn polymorphism was associated with favorable survival in Caucasian (AspAsn vs. AspAsp: HR = 0.781, 95% CI: 0.619-0.986) but unfavorable survival in Asian (AspAsn+AsnAsn vs. AspAsp: HR = 1.550, 95% CI: 1.038-2.315). CONCLUSIONS: These results suggest that XPD Asp312Asn polymorphism may function as a predictive biomarker on platinum-based chemotherapy in NSCLC and further studies are warranted.

Genetic polymorphisms of xeroderma pigmentosum group D and prostate cancer risk: a meta-analysis.

INTRODUCTION: The Xeroderma pigmentosum group D (XPD, also referred to as excision repair cross complementing gene 2, ERCC2) is one of key genes involved in nucleotide excision repair and two potentially functional polymorphisms of XPD (Asp312Asn and Lys751Gln) have been widely investigated in various cancers including prostate cancer. However, the results were conflicting rather than conclusive. AIMS: Thus, we conducted a meta-analysis to evaluate the associations between these two polymorphisms of XPD and the risk of prostate cancer. MATERIALS AND METHODS: An electronic search of PubMed and Embase was conducted to select relevant studies. Studies containing available genotype frequencies of XPD Asp312Asn and Lys751Gln were chosen, and the associations were assessed by pooled odds ratios with 95% confidence intervals. RESULTS: According to PubMed and Embase databases, we identified seven eligible studies from six articles, including 2641 cases and 3259 controls for Asp312Asn and nine eligible studies from eight articles, including 3255 cases and 3654 controls for Lys751Gln. The meta-analysis showed that no overall association was observed between XPD Asp312Asn and prostate cancer risk. However, the significantly increased risk of 312Asp allele was found among Asians and Africans, but it seemed to be protective in Caucasians when stratified by ethnicity. For XPD Lys751Gln, overall findings had implicated null effects. CONCLUSION: These findings indicated that the Asn allele of XPD Asp312Asn might be a risk-factor for developing prostate cancer among Asian and African men but protective for Caucasian population.

Hsa-miR-499 rs3746444 polymorphism contributes to cancer risk: a meta-analysis of 12 studies.

BACKGROUND: Single nucleotide polymorphisms (SNPs) occurred in pre-microRNAs or targets of microRNAs (miRs) may contribute to cancer risks. Since 2007, many studies have investigated the association between common SNPs located on hsa-miR-499 (rs3746444) and cancer risks; however, the results were inconclusive. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a meta-analysis of 12 studies that included 5765 cases and 7076 controls to identify the strength of association. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, individuals with the variant AG (OR = 1.215, 95% CI: 1.027, 1.437; P(heterogeneity)<0.01) and AG/GG (OR = 1.227, 95% CI: 1.046, 1.439; P(heterogeneity)<0.01) genotypes were associated with a significantly increased risk of cancer than those with wild AA genotype. Sub-group analysis revealed that the variant AG (OR = 1.411, 95% CI: 1.142, 1.745; P(heterogeneity) = 0.01) and AG/GG (OR = 1.413, 95% CI: 1.163, 1.717, P(heterogeneity) = 0.01) genotypes still showed an increased risk of cancer in Asians; however, a trend of reduced risk of cancer was observed in Caucasians (AG vs. AA: OR = 0.948, 955 CI: 0.851, 1.057, P(heterogeneity) = 0.12; AG/GG vs. AA: OR = 0.959, 95% CI: 0.865, 1.064; P(heterogeneity) = 0.19). Meta-regression showed that ethnicity (p = 0.048) and sample size (p = 0.02) but not cancer types (p = 0.89) or source of control (p = 0.97) were the sources of heterogeneity. CONCLUSIONS: These meta-analysis results suggest that hsa-miR-499 polymorphism rs3746444 is associated with a significantly increased risk of cancer, especially in Asian populations.

Fixed-dose rate infusion and standard rate infusion of gemcitabine in patients with advanced non-small-cell lung cancer: a meta-analysis of six trials.

PURPOSE: To compare the response, survival, hematological and non-hematological toxicities of gemcitabine administrated at fixed-dose rate infusion (10 mg/m(2)/min, FDR) and standard 30 min infusion in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Electronic databases of MEDLINE, EMBASE and Cochrane Library were searched using key words of "gemcitabine," "fixed-dose rate," "non-small-cell lung cancer" and their alternative spellings. An expanded search of references of relative articles was also performed. The last search was performed on September 10, 2012. Primary endpoints were overall survival rate (ORR) and 1-year survival rate (1-year SR); hematological and non-hematological toxicities were secondary endpoints. RESULTS: Six randomized controlled trials, involving 867 patients, met our inclusion criteria and were analyzed. Pooled results showed that FDR infusion of gemcitabine had an equal ORR (RR = 0.91, 95 % CI: 0.74-1.13; heterogeneity p = 0.39) and 1-year SR (RR = 1.09, 95 % CI: 0.93-1.29; heterogeneity p = 0.75) compared with standard infusion. Subgroup analysis found that chemotherapy drug combinations do not affect the results of ORR or 1-year SR. Patients received FDR infusion, however, experienced more grade 3/4 hematological (neutropenia, leukopenia and anemia) and non-hematological (diarrhea and fatigue) toxicities. CONCLUSION: This meta-analysis found that FDR infusion of gemcitabine had equal ORR and 1-year SR with standard infusion in patients with advanced NSCLC, while FDR infusion was associated with more grade 3/4 hematological and non-hematological toxicities.