Univariate Cox Survival Analysis Research Articles

A novel microRNA-based signature predicts prognosis among nasopharyngeal cancer patients

Nasopharyngeal cancer is one of the most common malignant tumors in the head and neck. Identification of promising miRNA biomarkers might benefit a lot to the detection of nasopharyngeal carcinoma. A three-miRNA signature (has-miR-142-3p, has-miR-29c, and has-miR-30e) was obviously associated with the overall survival of nasopharyngeal carcinoma patients. The model has better clinical independence and has better clinical prediction effect when combined with clinical characteristics. Our results revealed that a three-miRNA signature was a potential novel prognostic biomarker for nasopharyngeal carcinoma.

A Five-Gene Signature Based on Stromal/Immune Scores in the Tumor Microenvironment and Its Clinical Implications for Liver Cancer.

Increasing evidence highlights the clinical significance of stromal cells and immune cells in the liver cancer microenvironment. However, reliable prognostic models have not been well established. This study aimed to develop a gene signature for liver cancer based on stromal and immune scores. Using the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, stromal and immune scores were estimated based on the transcriptome profile of The Cancer Genome Atlas (TCGA) liver cancer cohort. Stromal-/immune-related differentially expressed genes were identified, followed by functional enrichment analysis. The Cox regression model was used to select prognostic genes and construct a gene signature. Its predictive potential was evaluated by receiver operating characteristic (ROC). The correlation between the risk score and immune cell infiltration was analyzed using Tumor Immune Estimation Resource (TIMER). Three hundred sixty-four upregulated and 10 downregulated stromal-/immune-related genes were identified, were mainly enriched in immune-related processes and pathways. Through univariate and multivariate cox survival analysis, a five-gene risk score was constructed, composed of FABP3, HTRA3, OLFML2B, PDZD4 and SLAMF6. Patients with high score indicated a poorer prognosis than those with low risk score. The areas under the ROC curves of overall survival (OS), progression-free interval, 3-, 5-year, OS status were 0.68, 0.57, 0.72, 0.74 and 0.728, indicating its well performance on predicting patients' prognoses. Furthermore, the risk score and the five genes were significantly correlated with immune cell infiltration in the tumor microenvironment. In this study, we proposed a prognostic five-gene signature based on stromal/immune scores in the liver cancer microenvironment.

Δ133p53/FLp53 Predicts Poor Clinical Outcome in Esophageal Squamous Cell Carcinoma.

Backgroundp53 isoform Δ133p53 is directly transactivated by p53 and antagonizes p53 activities in cancer progression. However, its correlation with prognosis and cancer recurrence in esophageal squamous cell carcinoma (ESCC) is still unclear.Patients and MethodsExpression of Δ133p53 and Δ133p53/full-length p53 (FLp53) in tissues and serums of 180 ESCC patients was evaluated using qRT-PCR. Patients were divided into high- and low-expression groups according to the cutoff value determined by X-tile 3.6.1 software. Survival analysis was performed by the Kaplan–Meier method. Univariate and multivariate Cox survival analyses were applied to assess the hazard ratios (HRs).ResultsTissue Δ133p53 expression and Δ133p53/FLp53 ratio were significantly increased in ESCC tissue compared with adjacent normal tissue. Pre-operative Δ133p53 expression and Δ133p53/FLp53 ratio in tissue or serum samples were positively associated with TNM stage and post-operative recurrence. Kaplan–Meier curve and multivariate cox regression analyses revealed that the tissue and serum Δ133p53/FLp53 ratios (cutoff value: 2.9160) were independent prognostic factors for overall survival (OS) and progression-free survival (PFS) in ESCC patients and showed no statistical difference in receiver-operating characteristic curve (ROC) analysis, while serum Δ133p53 showed no significant prognostic value. More importantly, the serum Δ133p53/FLp53 ratio in ESCC patients was significantly decreased within 72 h post tumor resection and patients with a consistently high serum Δ133p53/FLp53 ratio (≥2.9160) had higher recurrence rates than those with consistently low ratio values. In addition, dynamic detection in each follow-up timepoint showed that serum Δ133p53/FLp53 ratios were higher than 2.9160 upon recurrence, and they even increased prior to radiologic progression.ConclusionThe serum Δ133p53/FLp53 ratio can be a novel predictor for survival outcome and may serve as a real-time parameter for monitoring recurrence in ESCC patients after surgery.

ApoB/ApoA-1 Ratio as a Novel Prognostic Predictor in Patients With Primary Small Cell Carcinoma of the Esophagus.

Background and Aim: Primary small cell carcinoma of the esophagus (SCCE) is a rarely aggressive disease characterized by rapid progression, widespread metastasis, and poor prognosis. This study was aimed to evaluate the prognostic significance of serum lipids for overall survival (OS) in SCCE patients.Methods: We retrospectively analyzed SCCE patients in a training cohort (61 patients) and validated them in a validation cohort (27 patients). These cases were collected from Sun Yat-sen University Cancer Center from 2006 to 2017. Univariate and multivariate Cox survival analyses were performed to determine serum lipids as prognostic factors associated with the patient's OS. Time-dependent receiver operating characteristics (ROC) were used to compare predictive power of independent prognostic factors. The predictive accuracy and discriminative ability of the prognostic factors were measured by the concordance index (C-index) and decision curve, and were compared with the TNM stage system.Results: On multivariate analysis of the training cohort, independent factors for survival were gender, BAR (ApoB/ApoA-1) and TNM stage. The area under the curve (AUC) of BAR+TNM stage in the training cohort was higher than that of TNM stage for OS, and similar result was observed in the validation cohort. The c-index of BAR+TNM stage for predicting the OS was 0.655 (95% CI = 0.571–0.740), which was higher than that of TNM stage [0.614 (95% CI = 0.530–0.698)] in the training cohort. In the validation cohort, the C-index of the BAR+TNM stage for predicting OS was also higher than that of the TNM stage [0.688 (95% CI: 0.570~0.806) vs. (0.512; 95% CI: 0.392~0.632)]. In addition, decision curve analysis also showed that the predictive accuracy of BAR+TNM stage for OS was higher than TNM stage both in the training and the validation cohorts.Conclusions: BAR represents a promising prognostic indicator that might complement TNM stage in the prognosis of SCCE, and that warrant further assessment in large SCCE patient cohort.

Association of angiogenesis and inflammation-related gene functional polymorphisms with early-stage breast cancer prognosis.

Genetic variations in inflammation- and angiogenesis-related genes may alter the coded protein level and impact the pathogenesis of breast cancer (BC). The present study investigated the association of functional single nucleotide polymorphisms (SNPs) in the VEGFA, IL-1β, IL-1α and IL-6 genes with the early-stage BC phenotype and survival. Genomic DNA and clinical data were collected for 202 adult Eastern European (Lithuanian) women with primary I–II stage BC. Genotyping of the SNPs was performed using TaqMan SNP genotyping assays. Nine VEGFA, IL-1β, IL-1α and IL-6 polymorphisms were analysed. The VEGFA and IL-6 haplotypes were inferred using Phase software. Patients were prospectively followed-up for recurrence, occurrence of metastasis and mortality until April 30, 2019. All studied genotypes were in Hardy-Weinberg equilibrium and had the same distribution as the 1,000 Genomes project Phase 3 dataset for European population. Significant associations of the studied SNPs with clinicopathologic variables were observed between IL-1α rs1800587 C allele and larger primary tumour size; IL-6 rs1800797 A allele, rs1800797 GA genotype, rs1800795 C allele, IL-6 (rs1800797-re1800795) AC diplotype and hormonal receptor-positive disease; IL-6 rs1800797 A allele and HER2 negative status. In univariate Cox survival analysis, IL-1α rs1800587 CC and IL-6 rs1800797 GG genotype carriers exhibited worse disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS). The IL-6 rs1800795 GG genotype was associated with worse OS. IL-6 (rs1800797, rs1800795) GG/GG diplotype carriers had shorter MFS and OS. Multivariate Cox survival analysis revealed that the IL-1α rs1800587 CC genotype was an independent negative prognostic factor for DFS, MFS and OS, and the IL6 GG/GG diplotype was an independent negative prognostic factor for MFS and OS. According to the present study, functional SNPs in the IL-1α and IL-6 genes may contribute to the identification of patients at higher risk of BC recurrence, development of metastases and worse OS among early-stage patients with BC.

A new immune signature for survival prediction and immune checkpoint molecules in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is the most frequent subtype of lung cancer. The prognostic signature could be reliable to stratify LUAD patients according to risk, which helps the management of the systematic treatments. In this study, a systematic and reliable immune signature was performed to estimate the prognostic stratification in LUAD.MethodsThe profiles of immune-related genes for patients with LUAD were used as one TCGA training set: n = 494, other validation set 1: n = 226 and validation set 2: n = 398. Univariate Cox survival analysis was used to identify the candidate immune-related genes from each cohort. Then, the immune signature was developed and validated in the training and validation sets.ResultsIn this study, functional analysis showed that immune-related genes involved in immune regulation and MAPK signaling pathway. A prognostic signature based on 10 immune-related genes was established in the training set and patients were divided into high-risk and low-risk groups. Our 10 immune-related gene signature was significantly related to worse survival, especially during early-stage tumors. Further stratification analyses revealed that this 10 immune-related gene signature was still an effective tool for predicting prognosis in smoking or nonsmoking patients, patients with KRAS mutation or KRAS wild-type, and patients with EGFR mutation or EGFR wild-type. Our signature was negatively correlated with B cell, CD4+ T cell, CD8+ T cell, neutrophil, dendritic cell (DC), and macrophage immune infiltration, and immune checkpoint molecules PD-1 and CTLA-4 (P < 0.05).ConclusionsThese findings suggested that our signature was a promising biomarker for prognosis prediction and can facilitate the management of immunotherapy in LUAD.

The identification and preliminary study of lncRNA TUG1 and its related genes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumour of the digestive system, which is a threat to public health. The purpose of this study was to investigate the featured genes and pathways of HCC from a bioinformatics database, and verify their correlation with diagnosis and prognosis of HCC. We downloaded the gene expression profile on HCC from the Gene Expression Omnibus (GEO), and software R was used to identify differentially expressed lncRNA (DEL). The target genes of the lncRNA were further predicted by using a cluster database and molecular interaction database. Subsequently, a combined interaction network of target genes was constructed using the Cytoscape platform with preliminary verification at the level of different databases, cell lines, and tissues. Finally, we explored the effectiveness of TUG1 and its target genes on the diagnosis and prognosis of HCC by univariate Cox analysis and survival analysis. A total of four DELs were identified and the most remarkably up-regulated lncRNA was TUG1, which included 12 high-confidence target genes. Moreover, we found that the expression changes of TUG1 and its target genes in different databases, cell lines, and liver cancer tissues were consistent with the prediction. The high expression of TUG1 and its target genes could significantly predict the shorter survival time of HCC patients, among which NCAPG, MCM6, PIGC, PEA15, and RACGAP1 have significant diagnostic value for HCC (AUC > 0.9). This study provides a starting point for the screening of therapeutically relevant targets in HCC. Further experiment should be conducted to verify our findings.

High hnRNP AB expression is associated with poor prognosis in patients with colorectal cancer.

Heterogeneous ribonucleoprotein AB (hnRNP AB) is a member of the heterogeneous nuclear ribonucleoprotein family, which serves important functions in gene expression and signal transduction. However, the expression and clinicopathological significance of hnRNP AB in colorectal cancer (CRC) remain to be elucidated. To investigate the expression and clinical significance of hnRNP AB in CRC, hnRNP AB expression levels were analysed in two independent cohorts of patients with CRC. The results of reverse transcription-quantitative PCR, immunohistochemistry and western blot analysis demonstrated that hnRNP AB was upregulated in CRC tissues compared with the corresponding adjacent normal tissues. Immunohistochemical analyses indicated that a high expression of hnRNP AB was significantly associated with preoperative carcinoembryonic antigen (CEA; P<0.001) and carbohydrate antigen 19-9 (P=0.014) levels, tumour size (P=0.022) and infiltration (P=0.026), lymph node metastasis (P<0.001) and Tumour-Node-Metastasis stage (P<0.001). Univariate and multivariate Cox survival analyses revealed that hnRNP AB expression and preoperative CEA levels were significant independent factors affecting overall survival in patients with CRC (P<0.05). According to the Kaplan-Meier model, patients with CRC with high hnRNP AB expression exhibited significantly poorer prognosis compared with those with low hnRNP AB expression (P<0.001). In conclusion, the results of the present study demonstrated that hnRNP AB expression may serve an important role in the progression of CRC and that hnRNP AB may be considered a predictor of prognosis for patients with CRC.

Thyroid Lobectomy for T1b-T2 Papillary Thyroid Cancer with High-Risk Features

Thyroid lobectomy (TL) has been proposed as definitive surgical treatment for papillary thyroid cancers (PTC) up to 4 cm. This study evaluates the use and appropriateness of TL for T1b and T2 PTC. The National Cancer Database was interrogated for adult patients having TL for T1b-T2 PTC between 2004 and 2014. Patients who should have undergone total thyroidectomy (TT) instead of lobectomy based on high-risk tumor features were identified. The 2 groups were compared for clinical and demographic characteristics, and overall survival. Of 8,083 patients undergoing lobectomy, 1,552 patients had high-risk features and should have undergone TT. These included 194 with cN1, 571 with pN1, 307 with lymphovascular invasion (LVI), 645 with extra thyroidal extension (ETE), 567 with positive margins, 42 with poorly differentiated PTC, and 25 with M1 disease. At 10 years of follow-up, 92.4% of appropriate lobectomy (aTL) patients were alive compared with 88.5% of inappropriate lobectomy (iTL) patients (p < 0.001). On univariate and multivariable Cox survival analysis, age greater than 45 years, male sex, comorbidities, government or no insurance, low income, and tumor size >2 cm were associated with poorer survival (all p < 0.05). Thyroid lobectomy patients with high-risk features had significantly higher mortality on unadjusted (hazard ratio [HR] 1.98, 95% CI 1.52 to 2.59, p < 0.001) and adjusted survival analysis (HR 1.97, 95% CI 1.51 to 2.58, p < 0.001). Total thyroidectomy with radioiodine treatment had improved overall survival in comparison to iTL (HR 0.65, 95% CI 0.51 to 0.83, p < 0.001). A substantial number of patients (19.2%) with tumor size >1 cm and high-risk features undergo thyroid lobectomy for PTC. Exclusion of high-risk features is important when adopting lobectomy as the definitive surgical therapy for T1b and T2 PTC because they have a potential adverse effect on long-term survival.

A Novel Nomogram Integrated with Inflammation-Based Factors to Predict the Prognosis of Gastric Cancer Patients

Background: Gastric cancer (GC) is the fifth most common cancer worldwide, approximately 950,000 individuals are diagnosed with gastric cancer worldwide, causing 800,000 mortalities every year. Our study aimed to establish an effective nomogram to predict the prognosis of GC patients, which based on inflammation biomarkers. Methods: We retrospectively analysed GC patients from the Sun Yat-sen University Cancer Center between 2009 and 2017. The nomogram was developed with a primary cohort (n=1067), and 537 patients was included in the validation cohort. Univariate and multivariate Cox survival analyses were used to identify the prognostic factors. We tested the accuracy of the nomogram by discrimination and calibration tests and then performed a decision curve analysis that compared the nomogram with the AJCC TNM stage. Furthermore, according to the total points assigned by the nomogram, GC patients were stratified into three risk groups. Findings: The univariate survival analyses included 19 biomarkers. The multivariate analysis showed that tumour stage (P<0.001), metastasis stage (P<0.001), and C-reactive protein (CRP) (P<0.001), albumin (ALB) (P = 0.013), carcinoembryonic antigen (CEA) (P = 0.001) and carbohydrate antigen-199 (CA199) (P =0.001) levels as well as lymphocyte (LYM) (P = 0.002) count were independent risk factors for the prognosis of GC patients. The nomogram was based on the above factors. In the primary cohort, the nomogram had a concordance index (C-index) of 0.825 (95% CI 0.796-0.854), which was higher than the C-index of the AJCC TNM stage (0.769, 95% CI 0.741-0.797) and that the other biomarkers (CEA and CA199). The calibration plot suggested good agreement between the actual and nomogram-predicted overall survival (OS) probabilities, and the decision curve analyses showed that the nomogram model had a higher overall net benefit in predicting OS than the AJCC TNM stage. Moreover, we divided the patients were into the following three distinct risk groups for OS based on the nomogram points: a low-risk group, middle-risk group and high-risk group. The differences in OS rates were significant among the subgroups (P<0.001). Interpretation: A novel nomogram integrated with inflammatory prognostic factors was proposed, which is highly predictive of OS in GC patients. Funding Statement: This study was supported by Natural Science Foundation of Guangdong Province, China (grant no. 2018A030310260) and Medical Scientific Research Foundation of Guangdong Province, China (grant no. 2018102516469945). Declaration of Interests: The authors have declared that they have no conflict of interest. Ethics Approval Statement: Written informed consent for the use of plasma and serum samples was obtained from all HCC patients. This study was approved by the Institute Research Ethics Committee of the Sun Yat-Sen University Cancer Center, Guangzhou, China.

Prediabetes is a risk factor for cardiovascular disease following renal transplantation

Prediabetes and post-transplant diabetes mellitus affect about 20-30% of renal transplant patients. The latter is a risk factor for cardiovascular disease. However, no clear evidence linking prediabetes and cardiovascular disease is available. To study this we analyzed the impact of prediabetes on cardiovascular disease in 603 renal transplant patients followed with repeated oral glucose tests for up to five years and a long term survival evaluation. Prediabetes and post-transplant diabetes mellitus were defined at 12 months after transplantation to avoid their high reversibility rate before this period. 73 cardiovascular events were observed. The incidence of events was significantly higher in patients with either prediabetes, (17%; 0.023 person/year) or post-transplant diabetes mellitus (20%; 0.028 person/year) than in normal individuals, (7%; 0.0095 person/year). The incidence of events was comparable between prediabetes and post-transplant diabetes mellitus. Prediabetes at 12 months was a risk factor for cardiovascular events in univariate and multivariate Cox survival analyses (hazard ratio 2.24, 95% confidence interval 1.11-4.52). Prediabetes at three months and hemoglobin A1c at 12 months were not significantly associated with cardiovascular disease. Thus, prediabetes is a risk factor for cardiovascular disease in renal transplantation, a population at high risk for cardiovascular events. Since prediabetes is potentially a reversible condition, there is an opportunity to prevent cardiovascular disease in this population.

Increased lymph node yield indicates improved survival in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

PurposeIt is recommended for colorectal cancer to harvest at least 12 lymph nodes (LNs) during surgery to avoid understaging of the disease. However, it is still controversial whether it is necessary to harvest from locally advanced rectal cancer (LARC) patients who underwent neoadjuvant chemoradiotherapy (neo‐CRT). The impact of lymph node yield (LNY) on prognosis in LARC patients was analyzed.Materials/MethodsIn total, 495 LARC patients who underwent neo‐CRT in 2006‐2015 were analyzed. After examining clinicopathological distribution differences between the LNY subgroups (with the threshold of 12), univariate and multivariate Cox survival analyses were performed. Survival plots were obtained from Kaplan‐Meier analyses. Similar subgroup analyses were performed according to the tumor regression grade (TRG) and metastatic status of post‐operational LNs.ResultsOf the 495 patients, 287 (57.98%) had an LNY of less than 12. Nearly no significant clinicopathological difference was found between the LNY subgroups, including the TRG scores. Multivariate survival analysis demonstrated that at least 12 LNs examined was an independent prognostic feature of good overall survival (OS), disease‐free survival (DFS), and distant metastasis free survival (DMFS), but not local recurrence free survival (LRFS). However, in the subgroup analyses, no association was found between LNY and prognosis in patients with good TRG scores (0‐1) or negative LNs.ConclusionsFor LARC patients treated with neo‐CRT, an LNY of at least 12 indicated an improved survival. Decreased LNY was not related to better tumor regression. It suggests that a sufficiently high LNY is still required, especially in those with a potentially poor tumor response.

Incorporation of the SUVmax Measured From FDG PET and Neutrophil-to-lymphocyte Ratio Improves Prediction of Clinical Outcomes in Patients With Locally Advanced Non–small-cell Lung Cancer

IntroductionThe aim of the present study was to investigate the value of incorporation 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) maximum standardized uptake value (SUVmax) and neutrophil-to-lymphocyte ratio (NLR) for improving prediction of clinical outcomes of patients with locally advanced non–small-cell lung cancer (LA NSCLC). Materials and MethodsWe retrospectively enrolled 138 patients with unresectable LA NSCLC at our institution from July 2010 to August 2017. Spearman correlation analyses were used to estimate the correlations between SUVmax and NLR level. The univariate and multivariate Cox survival analyses were used to evaluate the prognostic indicators, including the incorporation of SUVmax and NLR. We defined the SUVmax and NLR grade (SNG = 0, 1, or 2) score as the number of risk factors among (1) SUVmax > 11.95 and (2) NLR > 3.82. The SNG score prognostic value was evaluated for overall survival (OS) and progression-free survival (PFS). ResultsUnivariate analysis showed that tumor stage, SUVmax, SUVmean, NLR, and SNG score were significantly associated with OS and PFS in patients with LA NSCLC. Kaplan-Meier analysis and log-rank test demonstrated significant differences in both OS and PFS among patients in SNG score (OS, P < .001; PFS, P < .001). Spearman correlation analyses showed that SUVmax had a correlation with the NLR (r = 0.237; P = .005). In subgroup analyses for patients with tumor pathologic stage IIIA/IIIB, we found that the SNG score was significantly associated with OS and PFS in each subgroup (P < .001, P < .001 for OS and P = .027, P < .001 for PFS, respectively). Multivariate analysis showed that the SNG score was a significantly independent prognostic factor for OS (hazard ratio, 1.612; 95% confidence interval, 1.157-2.246; P = .005) and PFS (hazard ratio, 2.241; 95% confidence interval, 1.486-3.379; P < .001). ConclusionIncorporation of the SUVmax and NLR improves prediction of clinical outcomes in patients with LA NSCLC.

Prediabetes and Cardiovascular Disease After Renal Transplantation

Background: Prediabetes and post-transplant diabetes mellitus (PTDM) affect about 20-30% of renal transplant patients. PTDM is a risk factor for cardiovascular disease. However, no clear evidence linking prediabetes and cardiovascular disease is available. Methods: We analyzed the impact of prediabetes on cardiovascular disease in 603 renal transplant patients followed with repeated OGTTs up to 5 years and a long term survival evaluation. Findings: Prediabetes and PTDM were defined at 12 months after transplantation to avoid their high reversibility rate before this period. 73 cardiovascular events were observed. The incidence of events was higher in patients with prediabetes, 28 (17%) or PTDM 20 (20%) than in normal subjects, 25 (7%), p = 0·001 and < 0·0001, respectively. The incidence of events was comparable between prediabetes and PTDM (p = 0·27). Prediabetes at 12 months was a risk factor for cardiovascular events in univariate and multivariate COX survival analyses (HR:2·24 95% CI 1·11-4·52). Prediabetes at 3 months and HbA1c at 12 months were not significant. Interpretation: Prediabetes was a risk factor for cardiovascular disease in renal transplantation, a population at high risk for cardiovascular events. Prediabetes is a potentially reversible condition, which offers the opportunity to prevent cardiovascular disease in this population. Funding Statement: Instituto de Salud Carlos III: The authors would like to acknowledge (a) the IMBRAIN project (FP7-RE6-POT-2012-CT2012- 31637-IMBRAIN) funded under the 7th Frameworks Programme (capacities), (b) the Instituto de Salud Carlos III (Fondo de Investigacioen Sanitaria: FIS) and Fondos FEDER for the following grants: PI 07/0732, the REDINREN RD/0021/0008 and PI10/02428 and (c) the funding of the Spanish Research Network for Kidney Diseases (REDINREN RD12/0021/0008). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the Ethics Committee of each hospital and followed the Declaration of Helsinki.

A novel four‑snoRNA signature for predicting the survival of patients with uveal melanoma.

Uveal melanoma (UM), the predominant histological subtype of intraocular malignant tumors in adults, often results in high rates of mortality; effective prognostic signatures used to predict the survival of patients with UM are limited. Small nucleolar RNAs (snoRNAs) are emerging as important regulators in the processes of carcinogenesis and tumor progression, but knowledge of their application as prognostic markers in UM is limited. In the present study, the expression profiles of snoRNAs in UM were determined; a total of 60 snoRNAs were notably associated with the overall survival of patients with UM via univariate Cox survival analysis. Subsequently, a prognostic signature based on four snoRNAs was proposed, which retained their prognostic significance determined by a multivariate Cox survival analysis. The formula is as follows: ACA17 * (‑1.602) + ACA45 * 0.803 + HBII‑276 * 0.603 + SNORD12 * 1.348. Furthermore, the results of insilico analysis indicated that perturbation of the phototransduction, GABAergic synapse and amphetamine addiction pathways may be the potential molecular mechanisms underlying the poor prognosis of patients with UM. Collectively, the present study proposed a potential prognostic signature for patients with UM and the prospective mechanisms at the genome‑wide level were determined.

PDZ Binding Kinase (PBK) - a Novel Gene Driving Genomic Evolution in Multiple Myeloma

As in all cancers, genomic instability leads to ongoing acquisition of new genetic changes in multiple myeloma (MM). This adaptability underlies the development of drug resistance and progression in MM. This genomic instability is driven by cellular processes, mainly related with DNA repair and perturbed by functional changes in limited number of genes. Since kinases play a critical role in the regulation of biological processes, including DNA damage/repair signaling and are relatively easy to screen for inhibitors, we investigated for novel genes involved in the acquisition of new genomic changes in MM. Using a large genomic database which had both the gene expression and CGH array-based copy number information (gse26863, n=246), we first identified a total of 890 expressed kinases in MM and correlated their expression with genomic instability defined as a change in ≥3 and/or 5 consecutive amplification and/or deletion events. We identified 198 kinases whose elevated expression correlated with increased genomic instability (based on FDR ≤ 0.05). Amongst these kinases, using univariate Cox survival analysis, elevated expression of 15 kinases correlated with poor overall as well as event free survival (P ≤0.05) in two MM datasets (IFM70, n=170; gse24080; n=559). We further confirmed the correlation of these 15 genes in both EFS and OS in additional two MM datasets (MMRF CoMMpass Study, IFM-DFCI 2009) as well as in additional solid tumor datasets from TCGA from patients with lung and pancreatic adenocarcinoma (P values ranging from 0.01 to <0.000002). A pathway analysis identified phosphorylation and regulation of proteasome pathway, mitotic spindle assembly/checkpoint, chromosomal segregation and cell cycle checkpoints as among major pathways regulated by these genes.To investigate the relevance of these genes with genomic instability, we performed a functional siRNA screen to evaluate impact of their suppression on homologous recombination (HR). PDZ Binding Kinase (PBK) was one of the top genes whose knockdown caused the maximal inhibition of HR activity in initial screen. To investigate it further in detail, we suppressed PBK in MM cells using shRNA and confirmed that its suppression significantly reduces HR activity. PBK-knockdown also reduced gH2AX levels (marker of DNA breaks) measured by Western blotting and decreased number of micronuclei (a marker of ongoing genomic rearrangements and instability) as assessed by flow cytometry . A small molecule inhibitor of PBK also confirmed a similar reduction in gH2AX levels as well as micronuclei, indicating inhibition of spontaneous DNA breaks and genomic instability. Using mass spectrometry and co-immunoprecipitation, we identified that PBK interacts with FEN1, a nuclease with roles in base excision repair and HR pathways. We confirmed that PBK induces phosphorylation of FEN1 and that inhibition of PBK, suppressed the phosphorylation of FEN1, RAD51 expression and gH2AX levels and it reversed FEN1-induced HR activity. These results confirm that phosphorylation of FEN1 nuclease by PBK contributes to its ability to impact DNA breaks, HR and genome stability in MM. PBK inhibition also significantly sensitized MM cells to melphalan and inhibited cell viability in a panel of MM cell lines (IC50 in MM cell lines ~20-30 nM vs ~100 nM in normal PBMCs) at the same time also reversed melphalan-induced genomic instability, as assessed by micronucleus assay. These data identify PBK as an important target affecting genomic instability, and its inhibitor as a potential drug, to inhibit genomic evolution and MM cell growth. DisclosuresMunshi:OncoPep: Other: Board of director.

Prognostic significance of combined preoperative platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio in patients undergoing surgery with stage IB non-small-cell lung cancer.

BackgroundResearch indicates that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with cancer. The aim of this study was to investigate the prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index, and the combination of preoperative LMR and PLR (LMR-PLR) in predicting the survival of patients with stage IB non-small-cell lung cancer (NSCLC).Materials and methodsWe retrospectively analyzed clinical data of 577 patients with stage IB NSCLC who underwent pneumonectomy from January 1999 to December 2009. Univariate and multivariate Cox survival analyses were used to evaluate the prognostic indicators, including LMR-PLR. The cutoff values for LMR and PLR were defined by the receiver operating characteristic (ROC) curve analysis. According to the ROC curve, the recommended cutoff values of LMR and PLR were 3.16 and 81.07, respectively. We divided the patients into three groups according to their LMR and PLR status and defined them with different scores. Patients with both high LMR (>3.16) and low PLR (≤81.07) were given a score of 2, whereas those with one or neither were scored 1 or 0, respectively. Survival curves were plotted using the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazards analyses were used to identify the factors associated with overall survival (OS).ResultsThe median follow-up time was 93.77 months. The allocation of the LMR-PLR score was as follows: LMR-PLR = 0, 193 (33.4%) patients; LMR-PLR = 1, 308 (53.4%) patients; and LMR-PLR = 2, 76 (13.2%) patients. After multivariate analysis, our results showed that LMR-PLR was an independent prognostic indicator for OS (P=0.001). The 10-year OS rates were 70.0%, 60.4%, and 49.5% for LMR-PLR =2, LMR-PLR =1, and LMR-PLR =0, respectively (P<0.001).ConclusionThis study demonstrated that preoperative LMR and PLR are simple, readily available, and low-cost biomarkers. Preoperative LMR-PLR score can be used as a valuable prognostic marker for long-term survival in stage IB NSCLC patients who underwent surgery.

A novel prognostic signature of seven genes for the prediction in patients with thymoma

PurposeA thymoma is a tumor arising from the epithelium of the thymus, mostly occurring in the anterior mediastinum. The incidence of this disease is low and research progress in this field is slow. Consequently, there is an urgent need to investigate the correlation between molecular regulation and the prediction of survival and prognosis in patients with thymoma.MethodsWe collected thymoma datasets from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) of TCGA datasets were then determined using R software. A gene signature was obtained by screening prognostic DEGs from the TCGA datasets using univariate and multivariate Cox survival analysis. The summation of the weighted expression levels was calculated as a risk score, which could then be used to predict the survival rate and prognosis of patients with thymoma. The validity of this model was verified by the analysis of receiver operating characteristic (ROC) curves and area under the curve (AUC).ResultsIn total, 297 DEGs were identified from the integrated results of TCGA datasets. A seven-gene signature, along with a regression model of prognostic risk, was obtained by Cox survival analysis. The expression levels of the seven genes were then weighted and summed to calculate the risk score for each sample. Patients were effectively divided into high- and low-risk groups using the median risk score (P < 0.05). ROC analysis showed that this Cox regression model was effective in predicting the prognosis of patients with thymus tumors (AUC = 0.983, P < 0.05).ConclusionFor the first time, we identified an effective seven-gene signature in patients with thymic tumors. In the future, the risk and prognosis of patients can be preliminarily assessed using this model, although further testing is required to improve rigor.

Identification of a six-gene signature with prognostic value for patients with endometrial carcinoma.

Uterine corpus endometrial carcinoma (UCEC) is frequently diagnosed among women worldwide. However, there are different prognostic outcomes because of heterogeneity. Thus, the aim of the current study was to identify a gene signature that can predict the prognosis of patients with UCEC. UCEC gene expression profiles were first downloaded from the The Cancer Genome Atlas (TCGA) database. After data processing and forward screening, 11 390 key genes were selected. The UCEC samples were randomly divided into training and testing sets. In total, 996 genes with prognostic value were then examined by univariate Cox survival analysis with a P‐value <0.01 in the training set. Next, using robust likelihood‐based survival modeling, we developed a six‐gene signature (CTSW, PCSK4, LRRC8D, TNFRSF18, IHH, and CDKN2A) with a prognostic function in UCEC. A prognostic risk score system was developed by multivariate Cox proportional hazard regression based on this six‐gene signature. According to the Kaplan‐Meier curve, patients in the high‐risk group had significantly poorer overall survival (OS) outcomes than those in the low‐risk group (log‐rank test P‐value <0.0001). This signature was further validated in the testing dataset and the entire TCGA dataset. In conclusion, we conducted an integrated study to develop a six‐gene signature for the prognostic prediction of patients with UCEC. Our findings may provide novel biomarkers for prognosis and have significant implications in the understanding of therapeutic targets for UCEC.

Outcomes of conventional phacoemulsification versus femtosecond laser–assisted cataract surgery in eyes with Fuchs endothelial corneal dystrophy

To compare the outcomes in eyes with Fuchs endothelial corneal dystrophy after standard phacoemulsification with those of femtosecond laser-assisted cataract surgery. Bascom Palmer Eye Institute, Miami, Florida, USA. Retrospective case series. Charts from patients diagnosed with Fuchs endothelial corneal dystrophy who had phacoemulsification cataract surgery at Bascom Palmer Eye Institute between January 1, 2014, and January 1, 2017, were reviewed. The Institutional Review Board, University of Miami Human Subjects Research Office, approved the study protocol. Complicated surgeries and cases with concurrent keratoplasty, previous keratoplasty or glaucoma surgery, or a follow-up shorter than 3months were excluded. The corrected distance visual acuity (CDVA), central corneal thickness (CCT), and corneal edema at each visit were analyzed. Clinically significant corneal decompensation was defined by corneal edema with CDVA worse than 20/50 lasting more than 3months, any case resulting in keratoplasty, or both. The study comprised 207 eyes of 207 patients (64femtosecond laser-assisted cataract surgery, 143 conventional phacoemulsification). Demographics, baseline guttata and cataract grades, and follow-up time (mean 30months) were similar between groups (P>.05). The proportion of cases progressing to clinically significant decompensation (13%) was similar between groups (P>.05). Univariate Cox survival analysis also found no difference (hazard ratio, 1.0; 95% confidence interval, 0.4-2.7; P=.96). Compared with conventional phacoemulsification, femtosecond laser-assisted cataract surgery did not lower the rate of corneal decompensation in eyes with mild to moderate Fuchs endothelial corneal dystrophy.