Advanced Glycation End Products' Receptor DNA Methylation Associated with Immune Infiltration and Prognosis of Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Background: Advanced glycation end products' receptor (AGER) is a multiligand receptor that interacts with a wide range of ligands. Previous studies have shown that abnormal AGER expression is closely related to immune infiltration and tumorigenesis. However, the AGER DNA methylation relationship between prognosis and infiltrating immune cells in LUAD and LUSC is still unclear. Methods: AGER expression in pan-cancer was obtained by using the UALCAN databases. Kaplan-Meier plotter showed the correlation of AGER mRNA expression levels and clinicopathological parameters. The protein expression levels for AGER were derived from Human Protein Atlas Database Analysis. The copy number, somatic mutation, and DNA methylation of AGER were presented with UCSC Xena database. TIMER platform and TISIDB website were used to show the correlation between AGER expression and tumor immune cell infiltration level. Results: The expression level of AGER was significantly reduced in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Low expression of AGER was significantly correlated with histology, stage, lymph node metastasis, and tumor protein 53 (TP53) mutation and could be used as a potential indicator of poor prognosis of LUAD and LUSC. Moreover, AGER expression was positively correlated with the infiltrating immune cells. Further analysis showed that copy number variation (CNV), mutation, and DNA methylation were involved in AGER downregulation. In addition, we also found that hypermethylated AGER was significantly correlated with tumor-infiltrating lymphocytes. Conclusion: AGER may be a candidate for the prognostic biomarker of LUAD and LUSC related to tumor immune microenvironment.

Clinical outcomes and toxicities of locally advanced esophageal squamous cell carcinoma patients treated with early thoracic radiation therapy after induction chemotherapy.

OBJECTIVE: The purpose of this study was to compare the clinical outcomes and toxicities between induction chemotherapy (IC) + chemo-radiotherapy (CRT) and CRT alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC), to explore the appropriate thoracic radiotherapy (TRT) timing after IC and to identify prognostic factors. METHODS: 450 ESCC patients were included from September 2011 to December 2020, 238 of whom received IC/CRT. Propensity score matching was performed to balance potential confounders between the two groups. Multivariate Cox regression analysis was used to identify the independent prognostic factors. RESULTS: Patients who received IC/CRT experienced improved overall survival (OS) (38.5 vs. 28.8 months) and progression-free survival (PFS) (41.0 vs. 22.0 months) before matching, with similar results after matching. In the IC/CRT group, early TRT had more favorable survival than late TRT both matching before and after. In subgroup analysis, early TRT combination concurrent chemotherapy had better OS and PFS than late TRT combination concurrent chemotherapy. In addition, early TRT had better survival benefits regardless of the N stage. Notably, the IC/CRT group and early TRT group had manageable toxicities reaction compared with CRT alone group and the late TRT group. The nomogram was developed to predict the OS and PFS based on multivariate analysis results. The C-index was 0.743 and 0.722, respectively. CONCLUSION: IC/CRT and early TRT could yield satisfactory clinical outcomes and controllable toxicities in locally advanced ESCC. The IC plus early concurrent CRT might be a promising treatment strategy for improving further survival in ESCC.

CANT1 serves as a potential prognostic factor for lung adenocarcinoma and promotes cell proliferation and invasion in vitro.

BACKGROUND: Calcium-activated nucleotidase 1 (CANT1), functions as a calcium-dependent nucleotidase with a preference for UDP. However, the potential clinical value of CANT1 in lung adenocarcinoma (LA) has not been fully clarified. Thus, we sought to identify its potential biological function and mechanism through bioinformatics analysis and in vitro experiments in LA. METHODS: In the present study, we comprehensively investigated the prognostic role of CANT1 in LA patients through bioinformatics analysis and in vitro experiments. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were utilized to analyze the expression of CANT1 in LA patients and their clinical-prognostic value. The immunohistochemistry staining was obtained from the Human Protein Atlas (HPA). A Cox regression model was used to evaluate prognostic factors. Gene ontology (GO) and Gene set enrichment analysis (GSEA) was performed to explore the potential regulatory mechanism of CANT1 in the development of LA. Moreover, we also examined the relationship between CANT1 expression and DNA methylation. Finally, we did in vitro experiments to evaluate the biological behavior and role of CANT1 in LA cells (LACs). RESULTS: Our study showed that the CANT1 expression was significantly elevated in the LA tissues compared with the normal lung tissues. Increased CANT1 expression was significantly associated with the TN stage. A univariate Cox analysis indicated that high CANT1 expression levels were correlated with poor overall survival (OS) in LA. Besides, CANT1 expression was independently associated with OS in multivariate analysis. GO and GSEA analysis showed the enrichment of mitotic nuclear division, DNA methylation, and DNA damage. Then we found that the high expression of CANT1 is positively correlated with hypomethylation. The methylation level was associated with prognosis in LA patients. Finally, in vitro experiments indicated that knockdown of CANT1 resulted in decreased cell proliferation, invasion, and G1 phase cell-cycle arrest in LACs. CONCLUSION: The present study suggested that CANT1 may serve as a potential prognosis biomarker in patients with LA. High CANT1 expression and promoter demethylation was associated with worse outcome. Finally, in vitro experiments verified the biological functions and behaviors of CANT1 in LA.

Prognostic value of SEC61G in lung adenocarcinoma: a comprehensive study based on bioinformatics and in vitro validation.

BACKGROUND: Studies have shown that the Sec61 gamma subunit (SEC61G) is overexpressed in several tumors and could serve as a potential prognostic marker. However, the correlation between SEC61G and lung adenocarcinoma (LUAD) remains unclear. In the current study, we aimed to demonstrate the prognostic value and potential biological function of the SEC61G gene in LUAD. METHODS: Public datasets were used for SEC61G expression analyses. The prognostic value of SEC61G in LUAD was investigated using the Kaplan-Meier survival and Cox analyses. The correlation between the methylation level of SEC61G and its mRNA expression was evaluated via cBioPortal. Additionally, MethSurv was used to determine the prognostic value of the SEC61G methylation levels in LUAD. Functional enrichment analysis was conducted to explore the potential mechanism of SEC61G. Also, single sample GSEA (ssGSEA) and TIMER online tool were applied to identify the correlation between SEC61G and immune filtration. Furthermore, cell functional experiments were conducted to verify the biological behavior of SEC61G in lung adenocarcinoma cells (LAC). RESULTS: SEC61G was upregulated in pan-cancers, including LUAD. High SEC61G expression was significantly correlated with worse prognosis in LUAD patients. Multivariate analysis demonstrated that high SEC61G expression was an independent prognostic factor in the TCGA cohort. (HR = 1.760 95% CI: 1.297-2.388, p < 0.001). The methylation level of SEC61G negatively correlated with the SEC61G expression (R = - 0.290, p < 0.001), and patients with low SEC61G methylation had worse overall survival. (p = 0.0014). Proliferation-associated terms such as cell cycle and cell division were significantly enriched in GO and KEGG analysis. Vitro experiments demonstrated that knockdown of SEC61G resulted in decreased cell proliferation, invasion and facilitated apoptosis in LAC. GSEA analysis found that SEC61G expression was associated with the E2F targets. Moreover, SEC61G expression was negatively correlated with the immune cell infiltration including CD4+ T cell, CD8+ T cell, B cell, macrophage, neutrophil, and dendritic cell. CONCLUSION: Our study indicated that overexpression of SEC61G was significantly associated with poor prognosis of LUAD patients and the malignant phenotypes of LUAD cells, suggesting that it could be a novel prognostic biomarker and potential therapeutic target of LUAD.

Systemic Immune-Inflammatory Index, Tumor-Infiltrating Lymphocytes, and Clinical Outcomes in Esophageal Squamous Cell Carcinoma Receiving Concurrent Chemoradiotherapy.

Background: Systemic inflammation may be involved in the entire cancer process as a promoter and is associated with antitumor immunity. The systemic immune-inflammation index (SII) has been shown to be a promising prognostic factor. However, the relationship between SII and tumor-infiltrating lymphocytes (TIL) have not been established in esophageal cancer (EC) patients receiving concurrent chemoradiotherapy (CCRT). Methods: Retrospective analysis of 160 patients with EC was performed, peripheral blood cell counts were collected, and TIL concentration was assessed in H&E-stained sections. Correlations of SII and clinical outcomes with TIL were analyzed. Cox proportional hazard model and Kaplan-Meier method were used to perform survival outcomes. Results: Compared with high SII, low SII had longer overall survival (OS) (P = 0.036, hazard ratio (HR) = 0.59) and progression-free survival (PFS) (P = 0.041, HR = 0.60). Low TIL showed worse OS (P < 0.001, HR = 2.42) and PFS (P < 0.001, HR = 3.05). In addition, research have shown that the distribution of SII, platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio were negatively associated with the TIL state, while lymphocyte-to-monocyte ratio presented a positive correlation. Combination analysis observed that SIIlow + TILhigh had the best prognosis of all combinations, with a median OS and PFS of 36 and 22 months, respectively. The worst prognosis was identified as SIIhigh + TILlow, with a median OS and PFS of only 8 and 4 months. Conclusion: SII and TIL as independent predictors of clinical outcomes in EC receiving CCRT. Furthermore, the predictive power of the two combinations is much higher than a single variable.

Higher radiation dose on immune cells is associated with radiation-induced lymphopenia and worse prognosis in patients with locally advanced esophageal squamous cell carcinoma.

Background: To explore the effective dose to immune cells (EDIC) for better prognosis while avoiding radiation-induced lymphopenia (RIL) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Materials and methods: Overall, 381 patients with locally advanced ESCC receiving definitive radiotherapy with or without chemotherapy (dRT ± CT) between 2014 and 2020 were included in this study. The EDIC model was calculated by radiation fraction number and mean doses to the heart, lung, and integral body. The correlation between EDIC and clinical outcomes was analyzed using Cox proportional hazards regression, and risk factors for RIL were determined by logistic regression analysis. Results: The median EDIC was 4.38 Gy. Multivariate analysis revealed that low-EDIC significantly improved the OS of patients when compared with high-EDIC (HR = 1.614, P = 0.003) and PFS (HR = 1.401, P = 0.022). Moreover, high-EDIC was associated with a higher incidence of grade 4 RIL (OR = 2.053, P = 0.007) than low-EDIC. In addition, we identified body mass index (BMI), tumor thickness, and nodal stage as independent prognostic factors of OS and PFS, while BMI (OR = 0.576, P = 0.046) and weight loss (OR = 2.214, P = 0.005) as independent risk factors of grade 4 RIL. In subgroup analyses, the good group had better clinical outcomes than the remaining two groups (P< 0.001). Conclusion: This study demonstrated that EDIC significantly correlates with poor clinical outcomes and severe RIL. Optimizing treatment plans to decrease the radiation doses to immune cells is critical for improving the outcomes.

Prognostic significance of platelet-to-albumin ratio in patients with esophageal squamous cell carcinoma receiving definitive radiotherapy.

Accumulating evidence indicates that inflammation and nutrition status are associated with clinical outcomes in patients with various malignancies. This study aimed to evaluate the prognostic significance of the pretreatment platelet to albumin ratio (PAR) in esophageal squamous cell carcinoma (ESCC) patients undergoing definitive radiotherapy. A total of 470 patients who underwent definitive radiotherapy with or without chemotherapy were enrolled. The optimal cut-off values of PAR and other indicators were determined by the X-tile. The Kaplan-Meier method, multivariate analyses Cox regression were conducted to identify the association between those indicators and the survival outcomes. The median follow-up time was 23.5 months. The optimal cut-off value of PAR was 5.7 × 109 and patients were stratified as the low PAR group and the high PAR group. In the univariate analysis, a low overall survival rate was significantly associated with T stage (P = 0.005), TNM stage (P < 0.001), Adjuvant chemotherapy (P = 0.007), neutrophil to lymphocyte ratio (NLR) (P = 0.006), platelet to lymphocyte ratio (P < 0.001), systemic immune-inflammation index (P < 0.001), prognostic nutritional index (P < 0.001) and platelet to albumin ratio (PAR) (P < 0.001). Patients with high PAR were associated with poorer OS and PFS than patients with low PAR. On multivariate analysis, TNM stage (P = 0.001), adjuvant chemotherapy (P < 0.001), and PAR (P = 0.033) were independent prognostic factors in ESCC treated with definitive radiotherapy. PAR is a novel, convenient, and inexpensive prognostic indicator for patients with ESCC undergoing definitive radiotherapy. Future validation from prospective larger-scale studies is warranted.

Using inflammatory indexes and clinical parameters to predict radiation esophagitis in patients with small-cell lung cancer undergoing chemoradiotherapy.

Objective: Radiation esophagitis (RE) is a common adverse effect in small cell lung cancer (SCLC) patients undergoing thoracic radiotherapy. We aim to develop a novel nomogram to predict the acute severe RE (grade≥2) receiving chemoradiation in SCLC patients. Materials and methods: the risk factors were analyzed by logistic regression, and a nomogram was constructed based on multivariate analysis results. The clinical value of the model was evaluated using the area under the receiver operating curve (ROC) curve (AUC), calibration curves, and decision curve analysis (DCA). The correlations of inflammation indexes were assessed using Spearman correlation analysis. Results: Eighty-four of 187 patients (44.9%) developed grade ≥2 RE. Univariate analysis indicated that concurrent chemoradiotherapy (CCRT, p < 0.001), chemotherapy cycle (p = 0.097), system inflammation response index (SIRI, p = 0.048), prognostic-nutrition index (PNI, p = 0.073), platelets-lymphocyte radio (PLR, p = 0.026), platelets-albumin ratio (PAR, p = 0.029) were potential predictors of RE. In multivariate analysis, CCRT [p < 0.001; OR, 3.380; 95% CI, 1.767-6.465], SIRI (p = 0.047; OR, 0.436; 95% CI, 0.192-0.989), and PAR (p = 0.036; OR, 2.907; 95% CI, 1.071-7.891) were independent predictors of grade ≥2 RE. The AUC of nomogram was 0.702 (95% CI, 0.626-0.778), which was greater than each independent predictor (CCRT: 0.645; SIRI: 0.558; PAR: 0.559). Calibration curves showed high coherence between the predicted and actual observation RE, and DCA displayed satisfactory clinical utility. Conclusion: In this study, CCRT, SIRI, and PAR were independent predictors for RE (grade ≥2) in patients with SCLC receiving chemoradiotherapy. We developed and validated a predictive model through these factors. The developed nomogram with superior prediction ability can be used as a quantitative model to predict RE.

The novel pretreatment immune prognostic index discriminates survival outcomes in locally advanced non-operative esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy: a 6-year retrospective study.

OBJECTIVE: We aimed to construct risk stratification to help set individualized treatment strategies and intensities for different subgroups of patients. METHODS: The Esophagus Immune Prognostic Index (EIPI) scores were constructed according to the levels of derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) before treatment, and the patients were divided into low-, medium-, and high-risk groups. Finally, restricted cubic splines (RCS) were used to explore the relationship between dNLR, LDH, and survival outcomes. RESULTS: The median follow-up period of overall survival (OS) and progression-free survival (PFS) were 25.2 and 17.6 months, respectively. Multivariate Cox regression analysis showed dNLR were the independent prognostic factors that were associated with OS and PFS. The 3-year OS and PFS rates in the low-, medium-, and high-risk groups were 44.4% and 38.2%, 26.1% and 23.6%, and 10.5% and 5.3%, respectively. Patients who received chemotherapy had better OS and PFS than those who did not receive chemotherapy in low-risk and medium/high-risk groups (all p < 0.05). Besides, the results also revealed significant differences for patients with clinical T, N, and TNM stage groups of the OS and PFS in different risk groups. Finally, RCS analysis indicated a nonlinear relationship between the dNLR, LDH, and survival for esophageal squamous cell carcinoma (ESCC) patients. The death hazard ratios of dNLR and LDH sharply increased at 1.97 and 191, respectively. CONCLUSIONS: In summary, the EIPI, a novel inflammatory-based and immune-related prognostic score, is an independent prognostic indicator in locally advanced ESCC patients undergoing definitive chemoradiotherapy (dCRT).

A New Nomogram and Risk Stratification of Brain Metastasis by Clinical and Inflammatory Parameters in Stage III Small Cell Lung Cancer Without Prophylactic Cranial Irradiation.

Background: This study was conducted to determine risk factors for developing brain metastasis (BM) and to predict brain metastasis free survival (BMFS) and overall survival (OS) by combining several clinical parameters and inflammatory indexes. Materials and Methods: A nomogram and risk stratification were developed based on multivariate analysis results. The prognostic index (PI) predicting the high risk of BM was calculated by multiplying the weighted factor (ß coefficient) with each variable. Results: Thirty-two of one hundred patients (32.0%) developed BM. Multivariate cox regression analysis revealed that concurrent chemoradiotherapy (CCRT; hazard ratio (HR), 3.356; p = 0.020), monocyte-lymphocyte ratio (MLR; HR, 4.511; p = 0.002), neutrophil-lymphocyte ratio (NLR; HR, 4.023; p = 0.033), and prognostic-nutrition index (PNI; HR, 2.902; p = 0.018) were independent prognostic factors of BMFS. The nomogram has good accuracy in predicting BMFS, and the C-index was 0.73. The ROC curve showed that these risk factors have good discriminant ability. Similarly, tumor location (HR, 1.675; p = 0.035) and MLR (HR, 2.076; p = 0.013) were independent prognostic factors of OS. In the subgroup analysis of OS, the good group had a better prognosis than the other groups. Risk stratification by PI: the high-risk group had worse BMFS than the low-risk group, which also has certain practical significance for clinical practice in OS. Conclusion: We developed a nomogram and corresponding risk stratification in stage III SCLC patients who developed BM. This model and risk stratification can help clinicians improve patient treatment management and better deliver personalized therapy.

A Novel Model Combining Tumor Length, Tumor Thickness, TNM_Stage, Nutritional Index, and Inflammatory Index Might Be Superior to the 8th TNM Staging Criteria in Predicting the Prognosis of Esophageal Squamous Cell Carcinoma Patients Treated With Definitive Chemoradiotherapy.

Background: We aimed to determine whether the tumor length and tumor thickness should be used as prognostic factors for esophageal squamous cell carcinoma (ESCC) patients treated with definitive chemoradiotherapy (dCRT). Methods: A retrospective analysis consists of 902 non-operative ESCC patients received dCRT. The nomogram was used to predict the survival. Besides, Restricted Cubic Splines (RCS) was used to examine the relationship between prognostic factors and survival outcomes. Finally, the prognostic index (PI) scores were constructed according to the tumor length and tumor thickness, and the patients were divided into the low-, medium-, and high-risk groups. Results: The median follow-up of overall survival (OS) and progression-free survival (PFS) were 23.0 months and 17.5 months. Multivariate Cox regression analysis showed that tumor length and tumor thickness were independent prognostic factors associated with survival. Our novel nomograms for OS and PFS were superior to the TNM classification (p < 0.001). Besides, RCS analysis demonstrated that the death hazard of tumor length and tumor thickness sharply increased at 7.7 cm and 1.6 cm (p < 0.001). Finally, there were significant differences for ESCC patients with clinical TNM stage group of the OS and PFS in different risk groups. The higher risk group was significantly associated with shorter OS and PFS in ESCC patients (both p < 0.001 for all). Conclusion: The study results suggest that the novel models integrating tumor length and tumor thickness may provide a simple and widely available method for evaluating the prognosis of non-operative ESCC patients. The tumor length and tumor thickness should be considered as prognostic factors for ESCC.

A Nutrition-Related Factor-Based Risk Stratification for Exploring the Clinical Benefits in the Treatment of Patients With Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Definitive Chemoradiotherapy: A Retrospective Cohort Study.

Objective: No study has reported the risk stratification of BMI and PNI in patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing definitive chemoradiotherapy (dCRT). This study aimed to construct a risk stratification to guide the treatment of ESCC following dCRT. Methods: A total of 1,068 patients with locally advanced ESCC who received dCRT were retrospectively analyzed. The impacts of clinicopathological factors on overall survival (OS) and progression-free survival (PFS) were analyzed. Besides, the novel prognostic indices of pre-therapeutic nutritional index (PTNI) and prognostic index (PI) were developed. Results: The median follow-up period of OS and PFS were 22.9 and 17.4 months, respectively. The high body mass index (BMI) group had better 5-year OS and PFS (36.4 and 34.0%) than the low BMI group (18.8 and 17.2%). The high prognostic nutritional index (PNI) group also had better 5-year OS and PFS (33.4 and 30.9%) than the low PNI group (17.5 and 17.2%). Multivariate Cox regression analysis showed that BMI and PNI were independent prognostic factors for OS and PFS. Based on nutritional indices, patients were categorized into the low-risk (PTNI = 1), medium-risk (PTNI = 2), and high-risk (PTNI = 3) groups with 5-year OS rates of 38.5, 18.9, 17.5%, respectively (p < 0.001) and 5-year PFS rates of 35.8, 17.6, 16.8%, respectively (p < 0.001). Besides, we also constructed a prognostic index (PI) for OS and PFS which was calculated based on statistically significant factors for predicting OS and PFS. The results revealed that the high-risk group had worse OS and PFS than the low-risk group (p < 0.001). Finally, RCS analysis demonstrated a non-linear relationship between the PNI, BMI, and survival for patients with ESCC. The death hazard of PNI and BMI sharply decreased to 41.8 and 19.7. Conclusion: The decreased pre-therapeutic BMI and PNI levels were associated with a worse survival outcome. BMI and PNI are readily available and can be used to stratify risk factors for locally advanced ESCC patients undergoing dCRT. The novel risk stratification may help to evaluate patients' pre-therapeutic status and guide dCRT for locally advanced ESCC patients.

GREB1L overexpression correlates with prognosis and immune cell infiltration in lung adenocarcinoma.

GREB1L is a protein-coding gene that is an important paralog of GREB1. However, its effects in lung adenocarcinoma (LUAD) have not been determined. Thus, we evaluated the prognostic value of GREB1L in LUAD using bioinformatics approaches. In particular, we evaluated the relationship between GREB1L and LUAD using a wide range of databases and analysis tools, including TCGA, GEO, HPA, TIMER, cBioPortal, and MethSurv. Compared with its expression in normal lung tissues, GREB1L expression was significantly increased in LUAD tissues. A univariate Cox analysis showed that high GREB1L expression levels were correlated with a poor OS in LUAD. Additionally, GREB1L expression was independently associated with OS through a multivariate Cox analysis. GSEA analysis revealed enrichment in cell cycle, immune regulation, and methylation. Moreover, high GREB1L expression was associated with poor survival. We also found that the methylation and genetic alteration level was associated with prognosis in patients with LUAD. Finally, an analysis of immune infiltration showed that GREB1L is correlated with immune cell infiltration, PD-1, and PD-L1. In summary, these results indicate that GREB1L is a potential molecular marker for poor prognosis in LUAD and provide additional insight for the development of therapies and prognostic markers.

GALNT2/14 overexpression correlate with prognosis and methylation: potential therapeutic targets for lung adenocarcinoma.

OBJECTIVE: GALNT2/14 are members of the glycosyltransferase protein family, which initiate mucin-type O-glycosylation of peptides in the Golgi apparatus. However, the correlation between GALNT2/14 and disease prognosis and methylation in lung adenocarcinoma (LUAD) remains unclear. Thus, we sought to identify their potential values in LUAD. METHODS: GALNT2/14 expressions were analyzed using publicly-available datasets. The association between GALNT2/14 and disease prognosis was evaluated. In addition, gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to explore the potential biological functions of GALNT2/14. The correlation between the copy number variations and methylation level of GALNT2/14 and their mRNA expressions was analyzed via cBioPortal. Finally, we explored the prognostic value of the GALNT2/14 methylation levels by MethSurv in LUAD. RESULTS: GALNT2/14 were highly expressed in LUAD tumor tissue than normal tissue (P < 0.001). Multivariate analysis showed that high GALNT2/14 expressions were both an independent prognostic factor. GSEA found that GALNT2/14 expressions were associated with the methylation, gene silencing, and cell division, whereas immune analysis showed that GALNT2/14 expressions positively correlated with the expression level of PD-L1. Finally, the methylation levels of GALNT2/14 negatively correlated with the GALNT2/14 expressions (R = -0.26 and -0.36, P < 0.001, respectively), and patients with GALNT2/14 hypomethylation had worse overall survival than patients with high methylation (P < 0.05). CONCLUSIONS: This study demonstrated that the overexpression of GALNT2/14 in LUAD can serve as biomarkers for poor prognosis. The biological functions of GALNT2/14 are potentially related to methylation, gene silencing, tumorigenesis, and cell division. These findings help elucidate the role of GALNT2/14 in tumorigenesis and provide additional insight for therapy and prognosis of LUAD.

FAM72 serves as a biomarker of poor prognosis in human lung adenocarcinoma.

FAM72A-D promote the self-renewal of neural progenitor cells. There is accumulating evidence that FAM72 promotes tumorigenicity. However, its effects in lung adenocarcinoma (LUAD) have not been determined. Thus, we evaluated the prognostic value of FAM72A-D in LUAD using bioinformatics approaches. In particular, we evaluated the relationship between FAM72 and LUAD using a wide range of databases and analysis tools, including TCGA, GEO, GEPIA, Metascape, cBioPortal, and MethSurv. Compared with its expression in normal lung tissues, FAM72 expression was significantly increased in LUAD tissues. A univariate Cox analysis showed that high FAM72 expression levels were correlated with a poor OS in LUAD. Additionally, FAM72 expression was independently associated with OS through a multivariate Cox analysis. GO and GSEA revealed enrichment in mitotic nuclear division and cell cycle. Moreover, high FAM72 expression was associated with poor survival. An analysis of immune infiltration showed that FAM72 is correlated with immune cell infiltration. Finally, we found that the methylation level was associated with prognosis in patients with LUAD. In summary, these results indicate that FAM72 is a potential molecular marker for poor prognosis in LUAD and provide additional insight for the development of therapies and prognostic markers.

CKS2 Overexpression Correlates with Prognosis and Immune Cell Infiltration in Lung Adenocarcinoma: A Comprehensive Study based on Bioinformatics and Experiments.

Objective: Cyclin-dependent kinase regulatory subunit 2 (CKS2) plays a vital role in regulation of the cell cycle and cancer progression. However, the role of CKS2 in lung adenocarcinoma (LUAD) remains unkonwn. Here, we examined the prognostic value and biological functions of CKS2 in LUAD by using omics data of 1,235 LUAD samples from TCGA, GEO, and our own cohort as well as data of in vitro experiments. Methods: Kaplan-Meier was conducted to evaluate the prognostic value of CKS2 expression. The association between CKS2 expression level and tumor immune infiltration was explored using the single-sample Gene Set Enrichment Analysis (ssGSEA) and TIMER database. Functional enrichment analyses were performed to annotate the biological functions of CKS2 in LUAD. Furthermore, a series of in vitro experiments and immunohistochemistry were performed for validation. Results: CKS2 overexpression was correlated with the advanced stage, TP53 status, PD-L1 expression, and DNA hypomethylation. Moreover, patients with LUAD and high CKS2 expression exhibited poor overall survival. Functional enrichment analysis indicated that CKS2 was involved in cell division, cell cycle, DNA replication. Experiments in vitro indicated that CKS2 knockdown decreased the invasion and proliferation of LUAD cells and facilitated their apoptosis. ssGSEA and TIMER analysis revealed a negative correlation between CKS2 expression and the immune cell infiltration. Conclusions: In summary, High CKS2 expression was associated with poor prognosis and low levels of infiltrating immune cells in LUAD as well as with malignant phenotypes. Therefore, CKS2 may be a promising prognostic biomarker and therapeutic target in LUAD.

Benefit of chemotherapy based on platinum with definitive radiotherapy in older patients with locally advanced esophageal squamous cell carcinoma.

OBJECTIVE: There is still no definitely therapeutic evidence of a beneficial effect of chemotherapy with radiotherapy for older patients with esophageal squamous cell carcinoma (ESCC). We aim to determine the influence of chemoradiotherapy (CRT) and radiotherapy (RT) alone in patients aged 65 years or older with locally advanced ESCC. METHODS: We retrospectively analyzed 581 ESCC patients who underwent CRT and RT alone. Univariate and multivariate Cox regression analysis was used to analyze the impact of clinical factors on long-term overall survival (OS) and progression-free survival (PFS). Finally, we compared the toxicity rates of these patients. RESULTS: The median OS and PFS of the overall population were 23.2 months (2.0-162.6 months) and 18.6 months (1.1-159.6 months). Multivariate Cox regression analysis showed that chemotherapy (p < 0.05), tumor thickness (p < 0.01), and N stage (p < 0.05) were independent prognostic factors associated with both OS and PFS. In the chemotherapy subgroup, patients who received 2-8 cycles of chemotherapy had better OS than those who received 1 cycle (p = 0.015). The results also revealed that the CRT group has better OS and PFS than RT alone group for patients aged 65-74 years (both p < 0.01). However, for patients aged 75 years or older, there was no statistically significant difference between CRT and RT alone (both p > 0.05). Besides, higher staged ESCC has the inferior OS and PFS than lower staged ESCC for patients received RT alone and aged 65-74 years (both p < 0.05). Finally, there were significantly more severe hematologic toxicities in the CRT group than in those treated with RT alone in this study (p < 0.001). CONCLUSIONS: The present study suggested that CRT for locally advanced ESCC in patients aged 65 years or older had a significant benefit over RT alone in terms of OS and PFS. However, for patients aged 75 years or older, there was no statistically significant difference between CRT and RT alone. CRT should be performed with special attention in patients aged 75 years or older.

Predicting Severe Radiation Esophagitis in Patients With Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Definitive Chemoradiotherapy: Construction and Validation of a Model Based in the Clinical and Dosimetric Parameters as Well as Inflammatory Indexes.

OBJECTIVE: Radiation esophagitis (RE) is common in patients treated with radiotherapy (RT) for locally advanced esophageal squamous cell carcinoma (ESCC). We aim to construct a nomogram predicting the severe RE (grade ≥2) in patients with ESCC receiving definitive chemoradiotherapy (dCRT). MATERIALS AND METHODS: Logistic regression was performed to evaluate the risk factors in predicting RE. Nomogram was built based on the multivariate analysis result. The model was validated using the area under the receiver operating curve (ROC) curve (AUC), calibration curves, and decision curve analyses (DCA). Spearman correlation analysis was used to evaluate the correlation between inflammation indexes. RESULTS: A total of 547 patients with stage II-IVA ESCC treated with dCRT from the retrospective study were included. Two hundred and thirty-two of 547 patients (42.4%) developed grade ≥2 RE. Univariate analysis indicated that gender (p = 0.090), RT dose (p < 0.001), targeted therapy (p = 0.047), tumor thickness (p = 0.013), lymphocyte-monocyte ratio (LMR, p = 0.016), neutrophil-lymphocyte ratio (NLR, p < 0.001), and platelet-lymphocyte ratio (PLR, p < 0.001) were the significant factors for a higher incidence of RE. In multivariate analysis, RT dose [p < 0.001; odds ratio (OR), 4.680; 95% confidence interval (CI), 2.841-6.709], NLR (p < 0.001; OR, 0.384; 95% CI, 0.239-0.619), and PLR (p < 0.001; OR, 3.539; 95% CI: 2.226-5.626) were independently associated grade ≥2 RE and were involved in the nomogram. ROC curves showed the AUC of the nomogram was 0.714 (95% CI, 0.670-0.757), which was greater than each factor alone (RT dose: 0.615; NLR: 0.596; PLR: 0.590). Calibration curves showed good consistency between the actual observation and the predicted RE. DCA showed satisfactory positive net benefits of the nomogram among most threshold probabilities. CONCLUSIONS: The study demonstrated that RT dose, NLR, and PLR were independent risk factors for grade ≥2 RE in patients with locally advanced ESCC receiving dCRT. A predictive model including all these factors was built and performed better than it based on each separately. Further validation in large patient populations is still warranted.