Predictive potential of preoperative Naples prognostic score-based nomogram model for the prognosis in surgical resected thoracic esophageal squamous cell carcinoma patients: A retrospective cohort study.

The present study aimed to establish an effective prognostic nomogram model based on the Naples prognostic score (NPS) for resectable thoracic esophageal squamous cell carcinoma (ESCC). A total of 277 patients with ESCC, who underwent standard curative esophagectomy and designated as study cohort, were retrospectively analyzed. The patients were divided into different groups, including NPS 0, NPS 1, NPS 2, and NPS 3 or 4 groups, for further analysis, and the results were validated in an external cohort of 122 ESCC patients, who underwent surgery at another cancer center. In our multivariate analysis of the study cohort showed that the tumor-node-metastasis (TNM) stage, systemic inflammation score, and NPS were the independent prognostic factors for the overall survival (OS) and progression-free survival (PFS) durations. In addition, the differential grade was also an independent prognostic factor for the OS in the patients with ESCC after surgery (all P < .05). The area under the curve of receiver operator characteristics for the PFS and OS prediction with systemic inflammation score and NPS were 0.735 (95% confidence interval [CI] 0.676-0.795, P < .001) and 0.835 (95% CI 0.786-0.884, P < .001), and 0.734 (95% CI 0.675-0.793, P < .001) and 0.851 (95% CI 0.805-0.896, P < .001), respectively. The above independent predictors for OS or PFS were all selected in the nomogram model. The concordance indices (C-indices) of the nomogram models for predicting OS and PFS were 0.718 (95% CI 0.681-0.755) and 0.669 (95% CI 0.633-0.705), respectively, which were higher than that of the 7th edition of American Joint Committee on Cancer TNM staging system [C-index 0.598 (95% CI 0.558-0.638) for OS and 0.586 (95% CI 0.546-0.626) for PFS]. The calibration curves for predicting the 5-year OS or PFS showed a good agreement between the prediction by nomogram and actual observation. In the external validation cohort, the nomogram discrimination for OS was better than that of the 7th edition of TNM staging systems [C-index: 0.697 (95% CI 0.639-0.755) vs 0.644 (95% CI 0.589-0.699)]. The calibration curves showed good consistency in predicting the 5-year survival between the actual observation and nomogram predictions. The decision curve also showed a higher potential of the clinical application of predicting the 5-years OS of the proposed nomogram model as compared to that of the 7th edition of TNM staging systems. The preoperative NPS-based nomogram model had a certain potential role for predicting the prognosis of ESCC patients.

Genetic Evidence for a Causal Relationship Between Innate Leukocytes and the Risk of Digestive System Cancers in East Asians and Europeans.

Background: Peripheral traditional immune cell disorder plays an important role in cancer onset and development. The causal relationships between leukocytes prior to cancer and the risk of digestive system cancer remain unknown. This study assesses the causal correlations between leukocytes and digestive system cancer risk in East Asians and Europeans. Methods: Summary-level data on leukocyte-related genetic variation were extracted from Biobank Japan (107,964 participants) and a recent large-scale meta-analysis (563,946 participants). Summary-level data for the cancers were obtained from Biobank Japan (212,978 individuals) and the FinnGen consortium (178,802 participants). Univariable and multivariable Mendelian randomization (MR) analyses were performed on East Asians and Europeans separately. Results: Univariable MR analysis demonstrated the significant association between circulating eosinophil counts and risk of colorectal cancer (CRC) in East Asians (odds ratio (OR) = 0.80, 95% confidence interval (CI): 0.69 - 0.92, P = 0.002) and a suggestive relationship in the European population (OR = 0.86, 95% CI: 0.77 - 0.97, P = 0.013). An inverse suggestive association was observed between levels of basophils and the risk of gastric cancer (GC) in East Asians (OR = 0.83, 95% CI: 0.72 - 0.97, P = 0.019). The multivariable MR analysis showed the independent causal effect of eosinophil count on CRC risk in East Asians (OR = 0.72, 95% CI: 0.57 - 0.92, P = 0.009) and Europeans (OR = 0.80, 95% CI: 0.70 - 0.92, P = 0.002). Circulating basophils served as the negative causal factor in GC risk in East Asians (OR = 0.80, 95% CI: 0.67 - 0.94, P = 0.007). Conclusions: Our MR analyses revealed a genetic causal relationship between reduced blood eosinophils and an increased CRC risk in both Europeans and East Asians. Furthermore, our results suggested a causal association between decreased basophils and an elevated GC risk specifically in East Asians.

A bioinformatics analysis to evaluate the prognostic value of stemness-related genes in gastric cancer.

BACKGROUND: This study aimed to identify potential stemness-related targets in gastric cancer (GC) in order to support the development of new treatment strategies and improve patient survival. METHODS: Using the edgeR package, we identified stemness-related differentially expressed genes (DEGs) using GSE112631 and the stemness-related signaling pathways in the Gene Set Enrichment Analysis (GSEA) database. Lasso-penalized Cox regression analysis and multivariate Cox regression analysis tested by Akaike Information Criterion (AIC) were used to screen out survival genes in order to construct a prognostic model. We verified the accuracy of our prognostic model using a nomogram and receiver operating characteristic (ROC) curve analysis. Patients were divided into two groups based on the median risk score, and functional enrichment analysis was used to explore the differences between the two groups. RESULTS: Eight genes were selected to establish a prognostic model of The Cancer Genome Atlas (TCGA) and a validation model of the GSE84437 dataset from the Genome Expression Omnibus (GEO). In both models, we found that the low risk score group had better overall survival (OS) than the high-risk score group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between the two risk groups were totally different. CONCLUSIONS: We used eight stemness-related genes to build a prognostic model. The high-risk score group had a worse prognosis compared to the low-risk score group.

Nomogram-Integrated C-Reactive Protein/Albumin Ratio Predicts Efficacy And Prognosis In Patients With Thoracic Esophageal Squamous Cell Carcinoma Receiving Chemoradiotherapy.

OBJECTIVE: To investigate the therapeutic effect and survival outcome using nomogram by incorporating significant inflammatory markers in patients with thoracic esophageal squamous cell carcinoma (ESCC) who received chemoradiotherapy (CRT) or single radiotherapy (RT). METHOD: A total of 266 patients diagnosed with thoracic ESCC receiving standard curative RT only or concurrent CRT were retrospectively analysed. The patients were grouped for statistical analysis depending on the median values of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein/albumin (CRP/Alb) ratio. The therapeutic effect was analysed by univariate and multivariate logistic analyses. The survival prognosis was estimated by univariate and multivariate Cox analyses. At last, the nomogram was developed by incorporating the significant inflammatory markers and clinicopathological parameters, and the predictive value was verified by calibration curve, concordance index (C-index) and decision curve. RESULTS: The treatment responses were highly associated with clinical stage, tumor location, NLR, PLR and CRP/Alb ratio (all P<0.05) by univariate logistic analysis. However, in the multivariate logistic analysis, the results showed that only CRP/Alb ratio (P=0.000) and TNM stage (P=0.008) were independent risk parameters for tumour response. In addition, NLR, PLR, CRP/Alb ratio, age and TNM stage were significantly associated with OS by the univariate Cox analysis (all P<0.05). Furthermore, the multivariate Cox analysis showed that only CRP/Alb ratio (P=0.000), TNM stage (P=0.000) and age (P=0.001) were considered independent prognostic factors for OS. Finally, the calibration curves of nomogram were highly consistent with actual observation for the therapeutic effect and prognosis, and the decision curve analysis showed more potential of clinical benefit of the nomogram compared with TNM staging system. CONCLUSION: This research found that nomogram-integrated CRP/Alb ratio was promising as a predictive model for the therapeutic effect and survival outcome in patients with thoracic ESCC receiving CRT or single RT.

Pretreatment NRS-2002 scores combined with hematologic inflammation markers are independent prognostic factors in patients with resectable thoracic esophageal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to investigate the prognostic values of Nutritional Risk Screening 2002 (NRS-2002) and hematologic inflammation markers in patients with esophageal squamous cell carcinoma (ESCC) receiving curative esophagectomy. MATERIALS AND METHODS: A total of 277 patients with ESCC treated with standard curative esophagectomy were retrospectively analyzed. These patients were grouped for further analysis according to the systemic inflammation score (SIS), the combination of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (CNP) score and NRS-2002 score. The Kaplan-Meier method and log-rank test were adopted to calculate and compare the progression-free survival (PFS) and overall survival (OS) rates with these parameters. The Cox proportional hazards model was used to carry out univariate and multivariate analyses. Receiver operating characteristic (ROC) curves were applied to verify the accuracy of SIS, CNP and NRS-2002 for survival prediction. RESULTS: In univariate analysis, the following factors were significantly associated with poor PFS and OS: sex, T stage, N stage, TNM stage, SIS, CNP and NRS-2002 (all P<0.05). Furthermore, multivariate Cox regression analysis showed that CNP (hazard ratio [HR]=1.602; 95% confidence interval [CI] 1.341-1.913; P=0.000), NRS-2002 (HR=2.062; 95% CI 1.523-2.792; P=0.000) and TNM stage (HR=1.194; 95% CI 1.058-1.565; P=0.048) were independent prognostic factors for PFS. Correspondingly, CNP (HR=1.707; 95% CI 1.405-2.074; P=0.000), NRS-2002 (HR=2.716; 95% CI 1.972-3.740; P=0.000) and TNM stage (HR=1.363; 95% CI 1.086-1.691; P=0.036) were also independent prognostic factors for OS. Finally, the results of ROC curves indicated that CNP and NRS-2002 were superior to SIS as a predictive factor for PFS or OS in patients with ESCC receiving surgery. CONCLUSION: This study demonstrated that CNP combined with NRS-2002 is promising as a predictive marker for predicting clinical outcomes in patients with ESCC receiving surgery.

Influential factors on radiotherapy efficacy and prognosis in patients with secondary lymph node metastasis after esophagectomy of thoracic esophageal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to clarify whether pretreatment tumor burden-related index, including the gross tumor volume (GTV) of metastatic lymph nodes (VLN) and maximum diameter of metastatic lymph nodes (DLN), and inflammatory markers, consisting of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), are useful for assessing the therapeutic effects and prognosis with secondary lymph node metastasis (LNM) receiving chemoradiotherapy (CRT) or radiotherapy (RT) alone after resection of esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A total of 119 patients with secondary LNM after resection of ESCC were recruited and received curative RT only or CRT. The enrolled patients were grouped according to the median values of NLR, PLR, VLN, and DLN. The relationship between the responsiveness to treatment and these markers was analyzed by logistic analysis. The Kaplan-Meier method and log-rank test were adopted to calculate and compare the overall survival (OS) rates with these markers. The Cox models were used to carry out multivariate analyses. RESULTS: Univariate logistic regression analysis showed that the responses to treatment were highly associated with treatment method (P=0.011), NLR (P=0.000), PLR (P=0.003), VLN (P=0.000), and DLN (P=0.000). Next, multivariate logistic regression analysis showed that therapeutic method (hazard ratio [HR]=1.225, P=0.032), NLR (HR=2.697, P=0.019), and VLN (HR=4.607, P=0.034) were independent risk factors for tumor response. Additionally, Kaplan-Meier survival analysis of this cohort revealed that NLR (χ2 =27.298, P=0.000), PLR (χ2=16.719, P=0.000), VLN (χ2=48.823, P=0.000), DLN (χ2=40.724, P=0.000), and treatment methods (χ2=18.454, P=0.018) were significantly associated with OS. Furthermore, multivariate analysis was performed, and the results showed that therapeutic method (HR=1.223, P=0.048), NLR (HR=2.000, P=0.018), VLN (HR=2.379, P=0.020), and DLN (HR=2.901, P=0.002) were considered independent prognostic factors for OS. CONCLUSION: This study found that NLR and VLN were promising as predictive markers for therapeutic effects, and NLR combined with VLN and with DLN might be useful biomarkers in predicting outcomes in patients with secondary LNM receiving CRT or single RT after esophagectomy.

The p75 neurotrophin receptor regulates cranial irradiation-induced hippocampus-dependent cognitive dysfunction.

Cognitive deficits, characterized by progressive problems with hippocampus-dependent learning, memory and spatial processing, are the most serious complication of cranial irradiation. However, the underlying mechanisms remain obscure. The p75 neurotrophin receptor (p75NTR) is involved in a diverse arrays of cellular responses, including neurite outgrowth, neurogenesis, and negative regulation of spine density, which are associated with various neurological disorders. In this study, male Sprague-Dawley (SD) rats received 10 Gy cranial irradiation. Then, we evaluated the expression of p75NTR in the hippocampus after cranial irradiation and explored its potential role in radiation-induced synaptic dysfunction and memory deficits. We found that the expression of p75NTR was significantly increased in the irradiated rat hippocampus. Knockdown of p75NTR by intrahippocampal infusion of AAV8-shp75 ameliorated dendritic spine abnormalities, and restored synapse-related protein levels, thus preventing memory deficits, likely through normalization the phosphor-AKT activity. Moreover, viral-mediated overexpression of p75NTR in the normal hippocampus reproduced learning and memory deficits. Overall, this study demonstrates that p75NTR is an important mediator of irradiation-induced cognitive deficits by regulating dendritic development and synapse structure.

Ionizing irradiation inhibits keloid fibroblast cell proliferation and induces premature cellular senescence.

Keloids are one of the common refractory conditions in dermatology and aesthetic plastic surgery. The most effective treatment is superficial radiotherapy followed by surgical removal. The rate of recurrence is strongly associated with the total dose of ionizing irradiation, and the underlying mechanism remains unclear. In this study, we used primary keloid fibroblasts (KFb) isolated from patient samples to investigate the effects of X-ray radiation on cell proliferation, cell toxicity and cell cycle, as detected by CCK-8 assay kit and flow cytometer. In addition, we examined senescence-associated ß-galactosidase activity and the associated gene expression using real-time polymerase chain reaction and western blot in KFb exposed to X-ray radiation. X-ray radiation inhibited cell proliferation and induced cell senescence in KFb in a dose-dependent manner. Inhibition of cell proliferation and induction of cellular senescence were mediated by interruption of the cell cycle with an extended G0/G1 phase. Furthermore, the expressions of senescence-associated genes p21, p16 and p27 were upregulated both at mRNA and protein levels in KFb exposed to X-ray radiation. Taken together, our data indicate that X-ray radiation may prevent the recurrence of keloids by controlling fibroblast proliferation, arresting the cell cycle and inducing premature cellular senescence.

Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway.

Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating the effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague-Dawley rats received a single dose of 20Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF-pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF-pCREB signaling in non-irradiation group. These results suggest that forced running exercise offers a potentially effective treatment for radiation-induced cognitive deficits.

Effects of expression level of DNA repair-related genes involved in the NHEJ pathway on radiation-induced cognitive impairment.

Cranial radiation therapy can induce cognitive decline. Impairments of hippocampal neurogenesis are thought to be a paramountly important mechanism underlying radiation-induced cognitive dysfunction. In the mature nervous system, DNA double-strand breaks (DSBs) are mainly repaired by non-homologous end-joining (NHEJ) pathways. It has been demonstrated that NHEJ deficiencies are associated with impaired neurogenesis. In our study, rats were randomly divided into five groups to be irradiated by single doses of 0 (control), 0 (anesthesia control), 2, 10, and 20 Gy, respectively. The cognitive function of the irradiated rats was measured by open field, Morris water maze and passive avoidance tests. Real-time PCR was also used to detect the expression level of DNA DSB repair-related genes involved in the NHEJ pathway, such as XRCC4, XRCC5and XRCC6, in the hippocampus. The influence of different radiation doses on cognitive function in rats was investigated. From the results of the behavior tests, we found that rats receiving 20 Gy irradiation revealed poorer learning and memory, while no significant loss of learning and memory existed in rats receiving irradiation from 0-10 Gy. The real-time PCR and Western blot results showed no significant difference in the expression level of DNA repair-related genes between the 10 and 20 Gy groups, which may help to explain the behavioral results, i.e. DNA damage caused by 0-10 Gy exposure was appropriately repaired, however, damage induced by 20 Gy exceeded the body's maximum DSB repair ability. Ionizing radiation-induced cognitive impairments depend on the radiation dose, and more directly on the body's own ability to repair DNA DSBs via the NHEJ pathway.