SBF2-AS1: An oncogenic lncRNA in small-cell lung cancer

The long noncoding RNAs (lncRNAs) SBF2 antisense RNA 1 (SBF2-AS1) was found to act as an oncogenic lncRNA in non–small-cell lung cancer (NSCLC), but the role of SBF2-AS1 in small-cell lung cancer (SCLC) was still unclear. The purpose of this study was to provide the clinical significance and biological function of SBF2-AS1 in SCLC. In our results, SBF2-AS1 was found to be upregulated in SCLC tissues compared with NSCLC tissues or adjacent normal lung tissues. Besides, SBF2-AS1 expression was also elevated in SCLC cell lines compared with the normal bronchial epithelial cell line or NSCLC lines. Moreover, high expression of SBF2-AS1 was associated with clinical stage, tumor size, lymph node metastasis and distant metastasis in SCLC patients. Survival analysis showed SCLC patients with high expression of SBF2-AS1 had shorter overall survival than patients with low expression of SBF2-AS1, and high expression of SBF2-AS1 acted as an independent poor prognostic factor for overall survival in SCLC patients. The study in vitro suggested inhibition of SBF2-AS1 obviously depressed cell proliferation, migration, and invasion in SCLC. In conclusion, SBF2-AS1 acts as a novel oncogenic lncRNA in SCLC.     

Small-cell lung cancer brain metastasis: From molecular mechanisms to diagnosis and treatment

Lung cancer is the most malignant human cancer worldwide, also with the highest incidence rate. However, small-cell lung cancer (SCLC) accounts for 14 % of all lung cancer cases. Approximately 10 % of patients with SCLC have brain metastasis at the time of diagnosis, which is the leading cause of death of patients with SCLC worldwide. The median overall survival is only 4.9 months, and a long-tern cure exists for patients with SCLC brain metastasis due to limited common therapeutic options. Recent studies have enhanced our understanding of the molecular mechanisms leading to meningeal metastasis, and multimodality treatments have brought new hopes for a better cure for the disease. This review aimed to offer an insight into the cellular processes of different metastatic stages of SCLC revealed by the established animal models, and into the major diagnostic methods of SCLC. Additionally, it provided in-depth information on the recent advances in SCLC treatments, and highlighted several new models and biomarkers with promises to improve the prognosis of SCLC.     

Neuron-specific enolase in the diagnosis and therapy monitoring of lung cancer: a comparison with CEA, TPA, ferritin and calcitonin

The significance of neuron-specific enolase (NSE) in the diagnosis and treatment monitoring of lung cancer was investigated in comparison with such established tumour markers as carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), ferritin and calcitonin. We determined the serum concentrations of these tumour markers in 25 patients with small cell lung cancer (SCLC), 30 patients with non small cell lung cancer (NSCLC), and 38 patients with benign pulmonary diseases (BPD). In 14 patients with lung cancer, it was possible to follow up the behaviour of the tumour markers under treatment for up to 16 months. Calcitonin proved to have a surprisingly low sensitivity for SCLC. The utility of TPA and of ferritin was restricted, although the sensitivity was comparably high, by the high rate of false positive results. For NSCLC, CEA proved to be the best tumour marker. At present, NSE appears to be the tumour marker with the greatest specificity and sensitivity for SCLC. Its determination in the diagnosis, treatment and follow-up of SCLC makes good sense.     

Serum pleiotrophin as a diagnostic and prognostic marker for small cell lung cancer

Pleiotrophin (PTN) is involved in tumour progression, angiogenesis and metastasis. The purpose of this study was to investigate the expression level of PTN in the serum of patients with small cell lung cancer (SCLC) and to explore the clinical significance of PTN. Serum samples from 128 patients with SCLC, 120 healthy volunteers (HV) and 60 patients with benign lung disease (BLD) were collected. The levels of serum PTN were determined with ELISA and its correlation with the clinical data was examined. The serum PTN levels in SCLC patients were significantly higher than that in BLD patients (P < 0.05) or HV (P < 0.05). With a cutoff value of 258.18 ng/mL, the sensitivity and specificity of PTN to SCLC patients and BLD patients, SCLC patients and HV were 79.2% and 91.7%, 86.7% and 95.8% respectively. An area under the curve for all stages of SCLC resulting from PTN, which was significantly better than the other tumour markers tested including progastrin‐releasing peptide and neuron‐specific enolase. High serum PTN levels appear to correlate with poor survival in patients with SCLC. These results suggest that PTN levels in the serum could be a new effective biomarker for the diagnosis and prognosis of SCLC.     

Serum NSE, CEA, CT, CA 15-3 levels in human lung cancer

The significance of neuron specific enolase (NSE) was investigated in comparison with other tumor markers (CEA, CT, CA 15-3) used in the diagnosis and treatment monitoring of lung cancer. As previously described, the calcitonin assay proved to have very low sensitivity for small cell lung cancer (SCLC). The serum NSE assay was, however, shown to be a useful diagnostic aid for discrimination between histologically different lung cancers, and therefore this assay may be a valuable tool for treatment monitoring in SCLC patients. CA 15-3, also an unspecific marker, showed similar sensitivity to the NSE assay in SCLC patients, the sensitivity being higher than CEA in non small cell lung cancer (NSCLC).     

Preoperative carbohydrate antigen 195 (CA195) and CEA serum levels as prognostic factors in patients with colorectal cancer

We evaluated in 214 patients with primary colorectal cancer the prognostic value of the preoperative serum levels of CEA and CA195. For CEA these levels were above the cutoff of 6 ng/ml in 31.3% of patients, whereas for CA195 they were higher than 12 U/ml in 35.9% of patients. The simultaneous use of both antigens increased the sensitivity to 49%, which was significantly higher than that of CEA (p < 0.001) and CA195 (p < 0.01) taken singly. The mean preoperative CEA levels were significantly (p < 0.001) correlated with Dukes' stage only, while there was a significant correlation between preoperative serum levels of CA195 and Dukes' stage (p < 0.001), grade of differentiation (p < 0.01) and tumor location (p < 0.05). The results indicated that high preoperative serum levels of CEA and CA195 were associated with a shorter overall survival (p < 0.0001). In addition, separate Cox multivariate analysis showed that preoperative CA195 was, after Dukes' stage, the strongest factor to predict overall survival (p < 0.0001).     

Association of GWAS-Identified Lung Cancer Susceptibility Loci with Survival Length in Patients with Small-Cell Lung Cancer Treated with Platinum-Based Chemotherapy

Genetic variants have been shown to affect length of survival in cancer patients. This study explored the association between lung cancer susceptibility loci tagged by single-nucleotide polymorphisms (SNPs) identified in the genome-wide association studies and length of survival in small-cell lung cancer (SCLC). Eighteen SNPs were genotyped among 874 SCLC patients and Cox proportional hazards regression was used to examine the effects of genotype on survival length under an additive model with age, sex, smoking status and clinical stage as covariates. We identified 3 loci, 20q13.2 (rs4809957G >A), 22q12.2 (rs36600C >T) and 5p15.33 (rs401681C >T), significantly associated with the survival time of SCLC patients. The adjusted hazard ratio (HR) for patients with the rs4809957 GA or AA genotype was 0.80 (95% CI, 0.66–0.96; P = 0.0187) and 0.73 (95% CI, 0.55–0.96; P = 0.0263) compared with the GG genotype. Using the dominant model, the adjusted HR for patients carrying at least one T allele at rs36600 or rs401681 was 0.78 (95% CI, 0.63–0.96; P = 0.0199) and 1.29 (95% CI, 1.08–1.55; P = 0.0047), respectively, compared with the CC genotype. Stratification analyses showed that the significant associations of these 3 loci were only seen in smokers and male patients. The rs4809957 SNP was only significantly associated with length of survival of patients with extensive-stage but not limited-stage tumor. These results suggest that some of the lung cancer susceptibility loci might also affect the prognosis of SCLC.     

Onconeural antibodies in sera from patients with various types of tumours

Purpose  We assessed the frequency and levels of onconeural antibodies in 974 patients with various types of tumours, but without apparent paraneoplastic neurological syndromes (PNS). Patients and methods  We included patients with the following tumours: 200 small-cell lung cancer (SCLC) patients, 253 breast cancer patients, 182 ovarian cancer patients, 266 uterine cancer patients and 73 thymoma patients, as well as 52 patients with PNS and cancer and 300 healthy blood donors. Sera were screened for amphiphysin, CRMP5, Hu, Ma2, Ri and Yo antibodies using a multi-well immunoprecipitation technique. Results  The most frequently detected antibodies were Hu followed by CRMP5. Ma2, Yo, amphiphysin and Ri antibodies were less common, but each was found at similar frequencies. Onconeural antibodies were present at similar levels in sera from the PNS control group and from cancer patients. Hu antibodies were rare in cancers other than SCLC. CRMP5 was the only antibody found in patients with thymoma and this antibody was more common among patients with thymoma than in other tumour patients. With one exception, coexisting antibodies were only found in patients with SCLC. The presence of onconeural antibodies in SCLC patients was not associated with prolonged survival. Conclusion  Onconeural antibodies are associated with various types of tumours suggesting that all antibodies should be included in the serological screening for possible PNS. The levels of onconeural antibody are not sufficiently sensitive to discriminate between cancer patients with PNS and those without.     

VEGF and IL-18 in induced sputum of lung cancer patients

Cytokines are key players in the biological processes of malignant tumors and special interest has been focused on cytokines exerting tumor and anti-tumor properties, such as vascular endothelial growth factor (VEGF) and Interleukin-18 (IL-18). Aim of this study was to assess IL-18 and VEGF levels in induced sputum of lung cancer patients at diagnosis, and assess their possible association with the histological type of cancer, the stage and the overall patient survival. Seventy six patients with a diagnosis of lung cancer were recruited and were followed up for 48months. Thirteen healthy smokers and 16 healthy non-smokers were used as control groups. VEGF and IL-18 were measured by ELISA in sputum supernatants at the time of diagnosis. Lung cancer patients had significantly higher baseline IL-18 and VEGF levels compared to healthy controls (p<0.001). No difference was found in IL-18 and VEGF levels between the various stages in non-small cell lung cancer (NSCLC) and between limited and extended small cell lung cancer (SCLC). However, the ratio of VEGF/IL-18 was significantly higher in NSCLC compared to SCLC patients (p=0.018). In extended SCLC overall survival was inversely associated with baseline sputum VEGF levels (p=0.034) and estimated mortality risk was 1.14 (95% CI 1.006-1.283) for an increase of 100pg/ml in VEGF levels. Such association was not found regarding baseline IL-18 levels. VEGF levels in induced sputum may have a prognostic role in the survival of SCLC. The ratio VEGF/IL-18 in induced sputum differs between NSCLC and SCLC, indicating differences in angiogenesis mechanisms and/or immunological response in these two major histological types of lung cancer.     

Distinct mutational backgrounds and clonal architectures implicated prognostic discrepancies in small-cell carcinomas of the esophagus and lung

Small-cell carcinoma of the esophagus (SCCE) is a rare and aggressive cancer. Although several consistent genomic changes were observed previously between SCCE and small-cell lung cancer (SCLC), detailed mutational landscapes revealing discrepancies in genetic underpinnings of tumorigenesis between these two cancers are scarce, and little attention has been paid to answer whether these genetic alterations were related to the prognosis. Herein by performing whole-exome sequencing of 48 SCCE and 64 SCLC tumor samples, respectively we have shown that the number of driver mutations in SCCE was significantly lower than in SCLC (p = 0.0042). In SCCE, 46% of recurrent driver mutations were clonal, which occurred at an early stage during tumorigenesis, while 16 driver mutations were found clonal in SCLC. NOTCH1/3, PIK3CA, and ATM were specifically clonal in SCCE, while TP53 was clonal in SCLC. The total number of clonal mutations differed between two cancers and presented lower in SCCE compared to SCLC (p = 0.0036). Moreover, overall survival (OS) was shorter in patients with higher numbers of clonal mutations for both cancers. In summary, SCCE showed distinct mutational background and clonal architecture compared with SCLC. Organ-specific clonal events revealed different molecular mechanisms underlying tumorigenesis, tumor development, patients’ prognosis, and possible variations in therapeutic outcomes to candidate treatments.Subject terms: Oesophageal cancer, Small-cell lung cancer     

Serum Level of CC-Chemokine Ligand 18 Is Increased in Patients with Non-Small-Cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas

CC-chemokine ligand 18 (CCL18) is mainly expressed by alternatively activated macrophages and DCs and plays an important role in lung fibrosis, arthritis and other diseases. Here CCL18 was measured in sera of 31 healthy volunteers and 170 patients with lung cancer and correlated these data with histology, tumor stage and clinical parameters. Mean CCL18 serum level of the patients with non-small-cell lung cancer was 150(857) ng/ml vs. 32(61) ng/ml in the healthy control group. Patient groups differ significantly according their histology (adenocarcinoma 143(528) ng/ml vs squamous cell carcinoma 187(857) ng/ml, p<0.02). In addition, we found a significant difference between patients with lower versus higher T-stage (p<0.003). Receiver operating characteristic (ROC) analyses revealed a cutoff point of 83 ng/ml (area under the curve (AUC): 0.968; p<0.0001) to discriminate between healthy controls and non-small-cell lung cancer patients. ROC analyses to discriminate between patients, who died because of cancer related death and those who died for other reasons did not lead to a valid AUC. To stratify the tumor patients, a criterion value plot was performed leading to a point of equal sensitivity and specificity (54%) of 162 ng/ml. Patients with a CCL18 serum level higher than 160 ng/ml had a mean survival time of 623 days. In contrast, those in patients with a baseline level between 83 ng/ml and 160 ng/ml the mean survival time was 984 days (p<0.005). Survival-analysis revealed in adenocarcinoma a mean survival of 1152 days in the group below 83 ng/ml. In the median group the mean survival time was 788 days and in the group with the highest levels the mean survival time was 388 days (p<0.001). In contrast, we found no correlation between the FEV1 and the CCL18 baseline level. In conclusion, in patients suffering from adenocarcinoma increased serum CCL18 levels predict a diminished survival time.     

The correlation between pre-operative serum tumor markers and lymph node metastasis in gastric cancer patients undergoing curative treatment

Abstract

Background: There was few study concentrated on the correlation between the evaluated tumor markers and lymph node metastasis. In this study, we aimed to evaluate the correlation between the CA724, CA242, CA199, CEA and the lymph node metastasis of gastric cancer and assess the prognostic value of them in different N stage patients.

Methods: We analyzed the correlation between serum level of CA724, CA242, CA199, CEA and lymph node metastasis in 1501 gastric cancer patients.

Results: Lymph node metastasis of gastric cancer was related with tumor location, Bormann type, tumor size, histological type, depth of invasion and TNM stage (p?<?0.05). The values of CA724, CA242, CA199 and CEA were positively correlated with the metastatic lymph node counts and the N stage (p?<?0.05). The later the N stage was, the levels of CA724, CA242 and CA199 were higher. The later the N stage was, the positive rates of tumor markers were higher (p?<?0.05). In comparing with single tumor markers, the positive rates of tumor markers combination were higher. The combination of CA724?+?CA242?+?CA199?+?CEA had highest positive rate. The higher CEA level related to N1 stage patients while higher CA199 was related with poor prognosis for N1 stage patients. For N0 and N2 stage patients, evaluation of CA724 indicated poorer prognosis. For N1 and N2 stage gastric patients, the patients with increased CA242 inclined to have shorter survival time.

Conclusions: The tumor makers CA724, CA242, CA199 and CEA were evaluated significantly in the gastric patients with later N stage. The combination of these four tumor markers maybe prefer diagnostic index of gastric cancer and its lymph node metastasis. These tumor markers can be a possible indicator of poorer prognosis in different N stage patients.     

Preoperative albumin-to-globulin ratio predicts survival in patients with non-small-cell lung cancer after surgery

The prognostic value of the preoperative albumin-to-globulin ratio (AGR) has not been investigated in non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the clinical applicability of the preoperative AGR to predict the prognosis in patients with NSCLC. We retrospectively enrolled 545 patients with stage I/II/III NSCLC who underwent surgery at our institution. The cutoff value for preoperative AGR was calculated by using a receiver operating characteristic curve analysis. A low AGR was associated with several clinicopathological variables related to tumor progression. In the multivariate analyses, the preoperative AGR was identified as an independent prognostic factor for disease-free survival (DFS; P = 0.003) and overall survival (OS; P = 0.005). For patients with stage II and III with a preoperative AGR ≤ 1.43, the surgery plus chemotherapy group had a significantly longer DFS and OS than the surgery alone group (P = 0.002 and P = 0.001, respectively); however, a significant difference in DFS and OS between these two groups was not observed in patients with stage II and III with an AGR > 1.43 (P = 0.808 and P = 0.842, respectively). The preoperative AGR is an independent, significant predictor of DFS and OS in patients with NSCLC. Our results also demonstrate that the preoperative AGR might be a predictive marker of the therapeutic effect of postoperative chemotherapy in patients with stage II and III NSCLC.     

Serum cathepsin H as a potential prognostic marker in patients with colorectal cancer

Cathepsin H is a lysosomal cysteine protease that may participate in tumor progression. In order to evaluate its potential as a prognostic marker, its protein levels were measured by ELISA in preoperative sera from 324 patients with colorectal cancer. The level of cathepsin H was significantly increased in patient sera, the median level was 8.4 ng/mL versus 2.1 ng/mL in 90 healthy blood donors (p < 0.0001). A weak association of cathepsin H levels was found with patient age (p = 0.02) but not with Dukes' stage, sex, or the level of carcinoembryonic antigen (CEA). In survival analysis a significant difference was found between the group of patients with low cathepsin H (first tertile) who had a poor prognosis and the remaining patients (p = 0.03). The risk of patients was further stratified when cathepsin H levels were combined with CEA. Patients with high CEA and low cathepsin H had the highest risk of death with a hazard ratio of 2.72 (95% CI 1.73-4.28), p < 0.0001. Our results show that the prognostic information of cathepsin H differs from that of the related cathepsins B and L and suggest different roles during the progression of malignant disease.     

Combination of Circulating Tumor Cells with Serum Carcinoembryonic Antigen Enhances Clinical Prediction of Non-Small Cell Lung Cancer

Circulating tumor cells (CTCs) have emerged as a potential biomarker in the diagnosis, prognosis, treatment, and surveillance of lung cancer. However, CTC detection is not only costly, but its sensitivity is also low, thus limiting its usage and the collection of robust data regarding the significance of CTCs in lung cancer. We aimed to seek clinical variables that enhance the prediction of CTCs in patients with non-small cell lung cancer (NSCLC). Clinical samples and pathological data were collected from 169 NSCLC patients. CTCs were detected by CellSearch and tumor markers were detected using the Luminex xMAP assay. Univariate analyses revealed that histology, tumor stage, tumor size, invasiveness, tumor grade and carcinoembryonic antigen (CEA) were associated with the presence of CTCs. However, the level of CTCs was not associated with the degree of nodal involvement (N) or tumor prognostic markers Ki-67, CA125, CA199, Cyfra21-1, and SCCA. Using logistic regression analysis, we found that the combination of CTCs with tumor marker CEA has a better disease prediction. Advanced stage NSCLC patients with elevated CEA had higher numbers of CTCs. These data suggest a useful prediction model by combining CTCs with serum CEA in NSCLC patients.     

Increased CYFRA 21-1, CEA and NSE are Prognostic of Poor Outcome for Locally Advanced Squamous Cell Carcinoma in Lung: A Nomogram and Recursive Partitioning Risk Stratification Analysis

OBJECTIVES: This study aimed to: (1) assess the prognostic significance of serum tumor markers in locally advanced squamous cell carcinoma in lung (LA-SCCL); (2) generate a nomogram to predict the overall survival (OS) and (3) identify a prognostic stratification to assist the therapeutic decision-making. METHODS: LA-SCCL patients receiving definitive radiotherapy and baseline tumor marker measurement were eligible for this retrospective study. Cox proportional hazards regression was used to determine independent factors associated with various survival indexes and a nomogram was created to estimate the 5-year OS probability for individual patient. The identified prognostic factors were recruited into a recursive partitioning analysis (RPA) for OS to stratify patients with distinct outcome. RESULTS: A total of 224 patients were eligible for analysis. Increased cytokeratin-19 fragment (CYFRA 21-1) was independently associated with inferior OS, progression free survival (PFS) and a borderline decreased local-regional progression free survival (LRPFS). Elevated carcino-embryonic antigen (CEA) served as an unfavorable determinant for OS and increased neuron-specific enolase (NSE) was predictive of poor distant metastasis free survival (DMFS). A nomogram integrating KPS, TNM stage, CEA and CYFRA 21-1 was created, resulting in a c-index of 0.62. RPA identified 4 prognostic classifications, with median OS of 27.6, 19.9, 17.3 and 10.9?months for low, intermediate, high and very-high risk groups, respectively. CONCLUSIONS: Baseline tumor marker panel including CYFRA 21-1, CEA and NSE can be prognostic of outcome for LA-SCCL receiving definitive radiotherapy. The RPA identified four prognostic subgroups, which could assist personalized therapy and clinical trial design in LA-SCCL.     

MicroRNA expression and clinical outcome of small cell lung cancer

The role of microRNAs in small-cell lung carcinoma (SCLC) is largely unknown. miR-34a is known as a p53 regulated tumor suppressor microRNA in many cancer types. However, its therapeutic implication has never been studied in SCLC, a cancer type with frequent dysfunction of p53. We investigated the expression of a panel of 7 microRNAs (miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a) in 31 SCLC tumors, 14 SCLC cell lines, and 26 NSCLC cell lines. We observed significantly lower miR-21, miR-29b, and miR-34a expression in SCLC cell lines than in NSCLC cell lines. The expression of the 7 microRNAs was unrelated to SCLC patients' clinical characteristics and was neither prognostic in term of overall survival or progression-free survival nor predictive of treatment response. Overexpression or downregulation of miR-34a did not influence SCLC cell viability. The expression of these 7 microRNAs also did not predict in vitro sensitivity to cisplatin or etoposide in SCLC cell lines. Overexpression or downregulation of miR-34a did not influence sensitivity to cisplatin or etoposide in SCLC cell lines. In contrast to downregulation of the miR-34a target genes cMET and Axl by overexpression of miR-34a in NSCLC cell lines, the intrinsic expression of cMET and Axl was low in SCLC cell lines and was not influenced by overexpression of miR-34a. Our results suggest that the expression of the 7 selected microRNAs are not prognostic in SCLC patients, and miR-34a is unrelated to the malignant behavior of SCLC cells and is unlikely to be a therapeutic target.     

The Prognostic Significance of Pretreatment Serum CEA Levels in Gastric Cancer: A Meta-Analysis Including 14651 Patients

Background

Carcinoembryonic antigen (CEA) is commonly used as a serum tumor marker in clinical practice; however, its prognostic value for gastric cancer patients remains uncertain. This meta-analysis was performed to assess the prognostic value of CEA and investigate CEA as a tumor marker.

Methods

PubMed, EMBASE and other databases were searched for potentially eligible studies. Forty-one studies reporting the prognostic effect of pretreatment serum CEA expression in gastric cancer patients were selected. Data on 14651 eligible patients were retrieved for the meta-analysis. Based on the data extracted from the available literature, the hazard ratio (HR) and 95% confidence interval (CI) for an adverse prognosis were estimated for gastric cancer patients with elevated pretreatment serum levels of CEA (CEA+) relative to patients with normal pretreatment CEA levels (CEA-).

Results

The CEA+ patients had a significantly poorer prognosis than the CEA- patients in terms of overall survival (OS: HR 1.716, 95% CI 1.594 - 1.848, P< 0.001), disease-specific survival (DSS: HR 1.940, 95% CI 1.563 - 2.408, P< 0.001), and disease-free survival (DFS: HR 2.275, 95% CI 1.836 - 2.818, P< 0.001). Publication bias and an influence of different cut-off values were not observed (all P> 0.05). In the pooled analyses of multivariate-adjusted HRs, the results suggested that pretreatment serum CEA may be an independent prognostic factor in gastric cancer (OS: HR 1.681, 95% CI 1.425 - 1.982; DSS: HR 1.900, 95% CI 1.441 - 2.505; DFS: HR 2.579, 95% CI 1.935 - 3.436).

Conclusion/Significance

The meta-analysis based on the available literature supported the association of elevated pretreatment serum CEA levels with a poor prognosis for gastric cancer and a nearly doubled risk of mortality in gastric cancer patients. CEA may be an independent prognostic factor for gastric cancer patients and may aid in determining appropriate treatment which may preferentially benefit the CEA+ patients.