Multivariate Cox Survival Analysis Research Articles

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.

Clinical Efficacy of Allo-HSCT on FLT3-ITD Positive AML Patients

To study the clinical efficacy of allo-HSCT on FLT3-ITD positive AML patients. The clinical data and curative efficacy of 56 FLT3-ITD+ AML patients treated with allo-HSCT in our hospital from January 2012 to December 2018 were analyzed and evaluated. Neutrophil implantation was successful for all the patients; The median time of granulocyte hematopoietic reconstruction and megakaryocyte hematopoietic reconstruction was 13 (10-20) d and 15 (9-23) d respectively. The median follow-up time for patients 34.3 (5.6-101.4) months, 41 patients were alive and 15 patients dead at the end of follow-up. The 3 years-OS and -DFS rate was 71.2% and 65.6%, respectively. Univariate analysis showed that the OS rate of patients without aGVDH (81.2±9.4)% was significantly higher than that of patients with aGVDH (55.4±9.1) % (χ2=5.309，P＜0.05). The OS rate of patients achieved CR after one chemotherapy course before allo-HSCT was (80.2±9.2)%, which was significantly higher than that of patients achieved CR after more chemotherapy courses (χ2=4.275，P＜0.05). Cox multivariate survival analysis showed that CR after more chemotherapy courses and aGVDH after transplantation were risk factors for OS rate. Allo-HSCT can improve the prognosis of FLT3-ITD+ AML patients. The patients achieved CR after one chemotherapy course before allo-HSCT and patients without aGVDH after allo-HSCT have a better prognosis.

Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study

Background and aimsThere is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. Methods and resultsRetrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6–14.7 for age ≥85 vs 18–44 y); HR = 4.7; 2.9–7.7 for estimated glomerular filtration rate levels <15 vs ≥ 90 mL/min/1.73 m2; HR = 2.3; 1.5–3.6 for C-reactive protein levels ≥10 vs ≤ 3 mg/L). No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. The associations between these variables and mortality were substantially homogenous across all sub-groups analyses. ConclusionsImpaired renal function, elevated C-reactive protein and advanced age were major predictors of in-hospital death in a large cohort of unselected patients with COVID-19, admitted to 30 different clinical centres all over Italy.

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival

Background Several studies show that subventricular zone (SVZ) contact of glioblastoma at diagnosis is a negative prognosticator of survival. In this report, we study glioblastoma patient survival, molecular biological and MRI-based volumetric findings according to SVZ contact. Patients and methods We conducted a retrospective study of adult patients diagnosed with supratentorial glioblastoma and uniformly treated with temozolomide-based chemoradiotherapy after surgery. The patient cohort was dichotomized according to tumor contact with the SVZ at diagnosis as determined on preoperative MR imaging. Tumor volume was measured using semi-automated segmentation technique. MGMT-gene promoter methylation and IDH mutation status were determined on stored tumor tissue. Kaplan-Meier survival curves were constructed. Cox regression analysis was used to adjust for known confounding factors of glioblastoma patient survival. Results A total of 214 patients were included in the study of whom 68% belonged to the SVZpos group. Median tumor volume was significantly larger in the SVZpos group (33,8 mL vs 15,6 mL; p < .001). MGMT-unmethylated glioblastoma was more frequent in the SVZpos group (61.4% vs 44.9%; p = .028). The overall survival and progression-free survival were 12.2 months and 5.9 months for the SVZpos patient group but 16.9 months and 10.3 months for the SVZneg group (log-rank p = .016 and .007 respectively). In multivariate Cox survival analysis, SVZ contact proved a negative prognostic parameter, independent from age, KPS, extent of resection, MGMT-methylation and IDH mutation status. Conclusions This study confirms SVZ contact at diagnosis as an independent negative prognostic factor for glioblastoma patient survival. SVZpos glioblastoma had larger tumor size and a larger proportion of unmethylated tumors than SVZneg glioblastoma. Further research is needed to establish whether the observed differences are solely explained by a different molecular profile of SVZpos glioblastoma or by interaction of glioblastoma with the unique SVZ microenvironment.

Prognostic Performance of Different Lymph Node Staging Systems in Patients With Small Bowel Neuroendocrine Tumors.

Background: The prognostic significance of the lymph node (LN) classification for small bowel neuroendocrine tumors (SBNETs) remains unknown. The aim of the present study was to evaluate and compare the prognostic assessment of different LN staging systems.Methods: Patients with SBNETs were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The X-tile program was used to determine the cutoff value of the resected lymph nodes (RLNs), negative lymph nodes (NLNs), lymph node ratio (LNR), and the log odds of positive lymph nodes (LODDS). Survival analyses were performed using Kaplan–Meier curves with log-rank test. Logistic regression analysis was used to evaluate the differences between different periods. Univariate and multivariate Cox proportional hazards models were used to assess the prognostic value of different LN staging systems on cause-specific survival (CSS). The relative discriminative abilities of the different LN staging systems were assessed using the Akaike information criterion (AIC) and the Harrell consistency index (HCI).Result: A total of 3,680 patients were diagnosed with SBNETs between 1988 and 2014 from the SEER database. A significant difference over time (1988–1999 vs. 2000–2014) was seen in age (P <0.001), tumor differentiation (P <0.001), T stage (P <0.001), and RLN (P <0.001) subgroups. Multivariate Cox survival analysis identified that LN status stratified by the number of RLNs, NLNs, LNR, and LODDS all predicted CSS in patients with SBNETs (all P <0.05), whereas the number of positive lymph nodes (PLNs) failed (P = 0.452). When assessed using categorical variables, LODDS staging systems showed the best prognostic performance (HCI: 0.766, AIC: 7,575.154) in the whole population. Further analysis based on different RLNs after eliminating the missing data showed that when the RLNs are <12, the LODDS (HCI: 0.769, AIC: 1,088.731) maintained the best prognostic performance as well when the RLNs are ≥12 (HCI: 0.835, AIC: 825.692). Among patients with LNR scores of 0 or 1, there was a residual heterogeneity of outcomes that were better stratified and characterized by the LODDS.Conclusion: LODDS was a better predicator of survival when LN status was stratified as a categorical variable and should be considered when assessing the prognosis of patients with SBNETs to allow a more reliable means to stratify patient survival.

Population-based analysis of small cell carcinoma of the esophagus using the SEER database.

BackgroundSmall cell cancer (SmCC) of the esophagus is a rare malignancy with an aggressive behavior associated with poor survival. The present study aims to determine the clinicopathological characteristics, therapeutic and prognosis.MethodsPatients with SmCC of the esophagus, diagnosed from 1975 to 2016, were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The clinicopathological characteristics were described and the prognostic factors were further determined using Cox regression analysis.ResultsThe median overall survival (mOS) of all 515 patients with SmCC of the esophagus was 7.0 months, and the 1-, 2-, and 5-year survival rates were 31.5%, 14.7%, 6.00%, respectively. Patients with chemoradiotherapy (mOS: 12.0 months) had better prognosis than those receiving surgery alone (mOS: 12.0 vs. 4.0 months). The patients receiving surgery combined with chemoradiotherapy had longest survival time (mOS: 19.0 months), followed by patients receiving surgery combined with chemotherapy (14.0 months). The multivariate Cox survival analysis demonstrated that older age, distant metastases were independent prognostic factors. The use of surgery, chemotherapy, radiotherapy were independent favorable prognostic factors (P<0.05 for all).ConclusionsSmCC of the esophagus is uncommon, older age and distant metastases were independently associated with poor survival. Chemotherapy could provide significant clinical benefit for those patients, especially chemoradiotherapy and surgery combined with chemotherapy.

Limb-bud and heart as a novel biomarker for gastric intestinal type adenocarcinoma.

The present study compared the expression levels of limb-bud and heart (LBH) between gastric intestinal-type adenocarcinoma (GITA) and healthy gastric tissues; with the aim of investigating the possible effect of LBH on the prognosis of patients with GITA and to analyze the associated signaling pathways in GITA. Three Oncomine gastric datasets were utilized for the preliminary prediction of the expression levels of LBH mRNA in GITA and healthy gastric tissues. Gene expression and corresponding clinical data of 163 patients with GITA were downloaded from The Cancer Genome Atlas. Wilcoxon signed rank-sum test was used to distinguish the clinical value of LBH expression in the various clinicopathological features. Subsequently, Kaplan-Meier univariate and Cox multivariate survival analyses were performed to determine the prognostic significance of LBH expression in patients with GITA. Function enrichment analysis was conducted for the co-expression gene of LBH, defined as correlation coefficient r>0.06 and P<0.05 using Pearson's χ2 test. Bioinformatics data demonstrated that compared with that in the normal gastric mucosa, LBH mRNA expression was dramatically higher in GITA tissues (P<0.05). There were significant relationships between the differential expression levels of LBH and clinicopathological parameters in GITA patients (all p<0.05), including pathological stage T (T3-4 vs. T1-2), lymph node metastasis (no vs. yes), distant metastasis (no vs. yes), histological grade (grade 3 vs. grades 1–2) and tumor stage (stages 3–4 vs. stages 1–2). Additionally, the overall survival and disease-free survival (DFS) of patients in the high expression group were poorer compared with those in the low expression group (P<0.05). Cox multivariate survival analysis indicated that increased LBH expression was an independent predictor of poor DFS prognosis in patients with GITA (P=0.045). In summary, LBH is highly expressed in GITA, which can be used as an independent predictor of poor prognosis in patients with GITA. LBH co-expressed genes are closely associated with GITA tumor migration and metastasis.

Death domain-associated protein (DAXX) expression is associated with poor survival in metastatic high-grade serous carcinoma

The objective of this study was to analyze the expression and clinical role of mitosis regulators α-thalassemia/mental retardation syndrome X-linked (ATRX) and death-domain-associated protein (DAXX) in metastatic high-grade serous carcinoma (HGSC). ATRX and DAXX protein expression by immunohistochemistry was analyzed in 400 HGSC effusions. DAXX expression was additionally studied in 15 cancer cell lines, including 4 ovarian carcinoma lines, and in 81 of the 400 HGSC effusions using Western blotting. ATRX and DAXX were expressed in HGSC cells in 386/400 (96%) and 348/400 (87%) effusions, respectively. Western blotting showed DAXX expression in all 15 cell lines and in 70/81 (86%) HGSC effusions. DAXX expression by immunohistochemistry was higher in pleural compared to peritoneal effusions (p = 0.006) and in post-chemotherapy compared to pre-chemotherapy effusions (p = 0.004), and its expression was significantly associated with poor overall survival in univariate of the entire cohort (p = 0.014), as well as analysis limited to chemo-naïve effusions tapped at diagnosis (p = 0.038). The former association retained its prognostic role in Cox multivariate survival analysis (p = 0.011). ATRX expression was unrelated to clinicopathologic parameters or survival. In conclusion, DAXX is associated with disease progression and could be a prognostic marker in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

Expression of the cancer stem cell marker SSEA1 is associated with poor survival in metastatic high-grade serous carcinoma

The objective of the present study was to perform a quantitative analysis of cancer stem cell (CSC) marker expression in ovarian carcinoma effusions. The clinical role of SSEA1 in metastatic high-grade serous carcinoma (HGSC) was additionally analyzed. CD133, Nanog, SOX2, Oct3/4, SSEA1, and SSEA4 protein expressions were quantitatively analyzed using flow cytometry (FCM) in 24 effusions. SSEA1 expression by immunohistochemistry was analyzed in 384 HGSC effusions. Highly variable expression of CSC markers by FCM was observed, ranging from 0 to 78% of Ber-EP4-positive cells in the case of CD133, with the largest number of negative specimens seen for SSEA4. SSEA1 expression by immunohistochemistry was found in HGSC cells in 336/384 (89%) effusions, most commonly focally (< 5% of cells). SSEA1 was overexpressed in post-chemotherapy disease recurrence specimens compared with chemo-naïve HGSC effusions tapped at diagnosis (p = 0.029). In univariate survival analysis, higher SSEA1 expression was significantly associated with poor overall survival (p = 0.047) and progression-free survival (p = 0.018), though it failed to retain its prognostic role in Cox multivariate survival analysis in which it was analyzed with clinical parameters (p = 0.059 and p = 0.111 for overall and progression-free survival, respectively). In conclusion, CSC markers are variably expressed in ovarian carcinoma effusions. SSEA1 expression is associated with disease progression and poor survival in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

A novel biosignature to assess residual risk in ductal carcinoma in situ (DCIS) patients after standard treatment.

548 Background: There is an unmet need to identify women diagnosed with DCIS with elevated risk after standard treatment for whom enhanced treatment strategies should be considered. A response type (RSt) signature has been assessed in women treated with breast conserving surgery (BCS) with or without radiotherapy (RT), or with mastectomy. Methods: Women diagnosed with pure DCIS and treated with BCS or, BCS with whole breast RT were consecutively collected in Sweden, 1986-2004 and the USA, 1999-2008. A third cohort treated with mastectomy was collected in Sweden from 1986-2004. Patients with FFPE tissue were included unless they had prior or simultaneous invasive breast cancer (IBC). The RSt and DCISionRT biosignatures were calculated using biomarkers (p16/INK4A, Ki-67, COX-2, PgR, HER2, FOXA1, SIAH2), scored by board certified pathologists. Pathology and clinical data were collected from medical records. Only women at elevated risk by DCISionRT (DS &gt; 3) and negative margins were included in analysis. Total breast event risk included either ipsilateral DCIS or IBC. Multivariate Cox proportional hazards and survival analysis were used to assess cumulative incidence risk differences, hazard ratios, and 10-year risks adjusted for year of diagnosis. Results: Women with a poor RSt were all HER2 positive and remained at particularly elevated risk after BCS and RT (23% 10-yr risk, p &lt; 0.0001, Table), with a risk profile similar to women treated with BCS without RT (RSt not evaluated). The distribution of age and size were not statistically different for good versus poor RSt, but poor RSt were more commonly Grade 3. In a small cohort of women treated with mastectomy, those women with a poor RSt were still at elevated risk after surgery, comparered to women with a good RSt (HR = 5.4, p = 0.014). The 10-year risk profile for women with a good RSt treated with BCS plus RT or mastectomy, was low (table). Conclusions: A novel biosignature identified women with a good and poor RSt, where the good RSt identified women with an apparent substantial benefit from RT, as well as women with a poor RSt who remained at particularly elevated risk after RT, and for whom enhanced treatment strategies should be considered. Additional validation studies are ongoing. [Table: see text]

Combination of four clinical indicators predicts the severe/critical symptom of patients infected COVID-19.

Despite the death rate of COVID-19 is less than 3%, the fatality rate of severe/critical cases is high, according to World Health Organization (WHO). Thus, screening the severe/critical cases before symptom occurs effectively saves medical resources. In this study, all 336 cases of patients infected COVID-19 in Shanghai to March 12th, were retrospectively enrolled, and divided in to training and test datasets. In addition, 220 clinical and laboratory observations/records were also collected. Clinical indicators were associated with severe/critical symptoms were identified and a model for severe/critical symptom prediction was developed. Totally, 36 clinical indicators significantly associated with severe/critical symptom were identified. The clinical indicators are mainly thyroxine, immune related cells and products. Support Vector Machine (SVM) and optimized combination of age, GSH, CD3 ratio and total protein has a good performance in discriminating the mild and severe/critical cases. The area under receiving operating curve (AUROC) reached 0.9996 and 0.9757 in the training and testing dataset, respectively. When the using cut-off value as 0.0667, the recall rate was 93.33 % and 100 % in the training and testing datasets, separately. Cox multivariate regression and survival analyses revealed that the model significantly discriminated the severe/critical cases and used the information of the selected clinical indicators. The model was robust and effective in predicting the severe/critical COVID cases.

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.

The prognostic value of lymph node ratio in Medullary thyroid carcinoma: A multi-center study

IntroductionThe lymph node ratio (LNR), which represents the proportion of metastatic lymph nodes resected, has been found to be a prognostic variable in several cancers, but data for Medullary thyroid carcinoma (MTC) are sparse. The aim of this study was to determine the value of the LNR in predicting outcome in patients with MTC. Materials and methodsA retrospective multicenter study design of 107 patients with MTC who underwent total thyroidectomy with neck dissection between 1984 and 2016. The association of LNR with patient and tumor characteristics and prognostic factors was evaluated. ResultsStudy population consisted of 53.3% female, mean age at diagnosis was 50.3 ± 18.4 years; 16.8% had inherited MTC. LNR was positively correlated with tumor size (p = 0.018) and inversely correlated with age at diagnosis (p = 0.024). A higher LNR was associated with extrathyroidal extension (p < 0.001), multifocality (p = 0.001), bilateral tumor (p = 0.002), distant metastases (p < 0.001), and tumor recurrence (OR = 14.7, p < 0.001). LNR was also correlated to postoperative calcitonin levels (p < 0.001) and carcinoembryonic antigen (p = 0.011). LNR >0.1 was associated with shorter disease-specific survival in patients at risk: tumor larger than 20 mm at diagnosis (p = 0.013), sporadic MTC (p = 0.01), and age above 40 years at diagnosis (p = 0.004). Cox multivariate survival analysis revealed LNR as the only significant independent factor for disease free survival (p = 0.005). ConclusionsThis study showed that LNR correlates well with patient and tumor characteristics and prognostic variables. We suggest that LNR should be considered an important parameter for predicting outcome in MTC.

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.

The role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 in esophageal squamous cell carcinoma.

6-phosphofructo-kinase-2/fructose diphosphatase-2 isoenzyme 3 (PFKFB3) is closely related to the growth of many types of cancer cells. Glycolysis not only provides Adenosine triphosphate for the growth of tumor cells, but also protects them from acid products, which is beneficial to the invasion and metastasis of tumors. However, PFKFB3 expression in esophageal squamous cell carcinoma (ESCC) has been scarcely reported. In this study, the role of PFKFB3 was studied in 120 ESCC samples using immunohistochemistry technique (IHC), western blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR). Both PFKFB3 protein and gene expression in ESCC tissues were significantly higher than in adjacent non-tumor tissues (P < .05). Single factor analysis showed that both PFKFB3 protein and gene expression are related to infiltration depth, stage, tumor metastasis, and the degree of tumor differentiation in ESCC. Multifactor Cox survival analysis revealed that PFKFB3 protein expression, tumor location, tumor metastasis, tumor differentiation degree, and tumor stage were independent factors affecting the overall survival of postoperative patients. Multivariate Cox survival analysis showed that PFKFB3 mRNA has a good performance for predicting 3-year survival of patients with ESCC 0.89 (0.79–0.99), with a sensitivity of 0.85 and specificity of 0.77. Encouragingly, the sensitivity and specificity of PFKFB3 in the diagnosis of early ESCC (stage I and stage II) can reach 87.8% and 91.5%. In conclusion, high PFKFB3 protein and gene expression may be associated with the occurrence, development, and prognosis of ESCC. PFKFB3 could be used to help develop new therapeutic and diagnostic strategies for ESCC patients.

The Clinical and Molecular Characteristics of Sex-Determining Region Y-Box 2 and its Prognostic Value in Breast Cancer: A Systematic Meta-Analysis

Objective: Transcription factor SOX2 (sex-determining region Y-box 2) has a crucial role in the maintenance of the stem cell state. However, current evidence regarding the role of SOX2 in breast cancer is conflicting. We conducted this meta-analysis to clarify the association of SOX2 expression with clinical and molecular features and its prognostic effect on breast cancer. Methods: All relevant articles were searched using electronic databases. The pooled odds ratios (ORs) or hazard ratios (HRs: multivariate Cox survival analysis) with their 95% confidence intervals (CIs) were calculated. Results: A final total of 18 studies containing 3,080 patients with breast cancer were included. SOX2 protein expression was not related to age, menopausal status, lymph node metastasis, lymphovascular invasion, molecular estrogen receptor status, progesterone receptor status, triple-negative status, and the overall survival in breast cancer, but was closely associated with advanced tumor grade (grade 3 vs. grade 1–2: OR = 2.74, 95% CI = 1.85–4.06, p < 0.001), clinical stage (stage 3–4 vs. stage 0–2: OR = 2.46, 95% CI = 1.37–4.40, p = 0.002), pT stage (T stage 2–4 vs. T stage 1: OR = 1.52, 95% CI = 1.07–2.17, p = 0.019), molecular human epidermal growth factor receptor 2 (HER2) status (positive vs. negative: OR = 1.61, 95% CI = 1.21–2.14, p = 0.001), epidermal growth factor receptor (EGFR) status (positive vs. negative: OR = 2.21, 95% CI = 1.13–4.33, p = 0.021), and worse disease-free survival (DFS) (HR = 2.66, 95% CI = 1.20–5.91, p = 0.016) of breast cancer. Conclusions: SOX2 expression is correlated with breast cancer progression, HER2 status, and EGFR status, and may be an independent prognostic marker for predicting poor DFS.

Identification of prognostic long noncoding RNAs associated with spontaneous regression of neuroblastoma.

BackgroundThe association between long noncoding RNAs (lncRNAs) and spontaneous regression of neuroblastoma (NB) has rarely been investigated and remains unknown.ObjectiveTo identify prognostic lncRNAs involved in the spontaneous regression of NB.MethodsDifferential expression analyses were performed between those samples with an outcome of death in stage 4 NB group and those samples with an outcome of survival in stage 4S NB group in two independent public datasets, respectively. Univariate Cox proportional hazard regression survival analysis was performed in each of the entire cohort to identify those lncRNAs significantly associated with overall survival (OS). Those lncRNAs independently associated with OS were then identified by multivariate Cox survival analysis and used to construct an lncRNA risk score.ResultsA total of 20 differentially expressed and survival‐related lncRNAs were identified sharing between the two independent cohorts. The expression of each of these 20 lncRNAs was significantly correlated with the expression of NTRK1, which is a well‐known factor involved in NB spontaneous regression. Four lncRNAs (LNC00839, FIRRE, LOC283177, and LOC101928100) were identified to be significantly associated with survival independent with each other and a four‐lncRNA signature risk score was constructed. Patients with high lncRNA signature risk score had a significantly poorer OS and event‐free survival than those with low lncRNA signature risk score. The four‐lncRNA signature has a good performance in predicting survival independent with MYCN amplification (nonamplified vs amplified), age status (<18 months vs ≥18 months), risk status (low risk vs high risk), and International Neuroblastoma Staging System (INSS) stage (INSS 1/2/3/4S vs INSS 4).ConclusionsWe identified 20 survival‐related lncRNAs that might be associated with the spontaneous regression of NB and developed a four‐lncRNA signature risk score. The four‐lncRNA signature is an independent prognostic factor for survival of NB patients.

Clinical and Survival Impact of Sex-Determining Region Y-Box 2 in Colorectal Cancer: An Integrated Analysis of the Immunohistochemical Study and Bioinformatics Analysis.

Transcription factor sex-determining region Y-box 2 (SOX2) involves in the maintenance of cancer stem cells. However, the role of SOX2 in colorectal cancer (CRC) remains unclear. This study was conducted to investigate the effect of SOX2 on CRC. Studies were searched using electronic databases. The combined odds ratios (ORs) or hazard ratios (HRs: multivariate Cox survival analysis) with their 95% confidence intervals (CIs) were calculated. The Cancer Genome Atlas (TCGA) and GEO datasets were further applied to validate the survival effect. The functional analysis of SOX2 was investigated. In this work, 13 studies including 2337 patients were identified, and validation data were enrolled from TCGA and GEO datasets. SOX2 expression was not significantly related to age, gender, microsatellite instability (MSI) status, clinical stage, histological grade, tumor size, pT-stage, lymph node metastasis, distal metastasis, and cancer-specific survival (CSS) but was correlated with worse overall survival (OS: n = 536 patients) (P < 0.05). Furthermore, TCGA data demonstrated similar results, with no significant correlation between SOX2 and pathological characteristics. Further validation data (OS: n = 1408 and disease-free survival (DFS): n = 1367) showed that SOX2 expression was correlated with worse OS (HR = 1.35, 95% CI: 1.11–1.65, P=0.004) and DFS (HR = 1.30, 95% CI: 1.04–1.62, P=0.02). The functional analyses showed that SOX2 involved in cell-cell junction, focal adhesion, extracellular matrix- (ECM-) receptor interaction, and MAP kinase activity. Our findings suggest that SOX2 expression may be correlated with the worse prognosis of CRC.

Long-term predictive value of acute kidney injury classification in diffuse proliferative lupus nephritis with acute kidney injury

BackgroundThe long-term predictive ability of acute kidney injury (AKI) classification based on “Kidney Disease: Improving Global Outcomes”(KDIGO) AKI diagnosis criteria has not been clinically validated in diffuse proliferative lupus nephritis (DPLN) patients with AKI. Our objective was to assess the long-term predictive value of KDIGO AKI classification in DPLN patients with AKI.MethodsRetrospective cohort study was conducted by reviewing medical records of biopsy-proven DPLN patients with AKI from the First Affiliated Hospital of Wenzhou Medical University between Jan 1, 2000 and Dec 31, 2014. Multivariate Cox regression and survival analysis were performed.ResultsOne hundred sixty-seven DPLN patients were enrolled,82(49%) patients were normal renal function (No AKI), 40(24%) patients entered AKI-1 stage (AKI-1), 26(16%) patients entered AKI-2 stage (AKI-2) and 19(16%) patients entered AKI-3 stage (AKI-3). The mean follow-up of all patients was 5.1 ± 3.8 years. The patient survival without ESRD of all patients was 86% at 5 years and 79% at 10 years. The patient survival rate without ESRD at 10 yr was 94.5% for No AKI patients, 81.8% for AKI-1 patients, 44.9% for AKI-2 patients and 14.6% for AKI-3 patients. The area under the ROC curve for KDIGO AKI classification to predict the primary end point was 0.83 (95% CI: 0.73–0.93) (P < 0.001). In Cox regression analysis, AKI stage was independently associated with primary endpoint, with an adjusted hazard ratio (HR) of 3.8(95% CI 2.1–6.7, P < 0.001).ConclusionSeverity of AKI based on KDIGO AKI category was associated with progression to ESRD in DPLN patients. Analytical data also confirmed the good discriminative power of the KDIGO AKI classification system for predicting long-term prognosis of DPLN patients with AKI.