Prognostic value of pre-therapeutic nutritional risk factors in elderly patients with locally advanced esophageal squamous cell carcinoma receiving definitive chemoradiotherapy or radiotherapy.

BACKGROUND: The nutritional status of cancer patients is a crucial factor in determining their prognosis. The objective of this study was to investigate and compare the prognostic value of pretreatment nutrition-related indicators in elderly esophageal squamous cell carcinoma (ESCC). Risk stratification was performed according to independent risk factors and a new nutritional prognostic index was constructed. METHODS: We retrospectively reviewed 460 older locally advanced ESCC patients receiving definitive chemoradiotherapy (dCRT) or radiotherapy (dRT). This study included five pre- therapeutic nutrition-related indicators. The optimal cut-off values for these indices were calculated from the Receiver Operating Curve (ROC). Univariate and multivariate COX analyses were employed to determine the association between each indicator and clinical outcomes. The predictive ability of each independently nutrition-related prognostic indicator was assessed using the time-dependent ROC (time-ROC) and C-index. RESULTS: Multivariate analyses indicated that the geriatric nutrition risk index (GNRI), body mass index (BMI), the controlling nutritional status (CONUT) score, and platelet-albumin ratio (PAR) could independently predict overall survival (OS) and progression-free survival (PFS) in elderly patients with ESCC (all p < 0.05), except for prognostic nutritional index (PNI). Based on four independently nutrition-related prognostic indicators, we developed pre-therapeutic nutritional prognostic score (PTNPS) and new nutritional prognostic index (NNPI). No-risk (PTNPS = 0-1 point), moderate-risk (PTNPS = 2 points), and high-risk (PTNPS = 3-4 points) groups had 5-year OS rates of 42.3%, 22.9%, and 8.8%, respectively (p < 0.001), and 5-year PFS rates of 44.4%, 26.5%, and 11.3%, respectively (p < 0.001). The Kaplan-Meier curves showed that the mortality of elderly ESCC patients in the high-risk group was higher than that in the low-risk group according to the NNPI. Analysis of time-AUC and C-index revealed that the NNPI (C-index: 0.663) had the greatest predictive power on the prognosis in older ESCC patients. CONCLUSIONS: In elderly ESCC patients, the GNRI, BMI, CONUT score, and PAR can be used as objective assessment measures for the risk of nutrition-related death. Compared to the other four indexes, the NNPI has the greatest prognostic value for prognosis, and elderly patients with a higher nutritional risk have a poor prognosis, which is helpful in guiding early clinical nutrition intervention.

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.

M7G-Related lncRNAs predict prognosis and regulate the immune microenvironment in lung squamous cell carcinoma.

BACKGROUND: N7-Methylguanosine (m7G) and long non-coding RNAs (lncRNAs) have been widely studied in cancer and have been found to be useful for assessing tumor progression. However, the role of m7G-related lncRNAs in lung squamous cell carcinoma (LUSC) remains unclear. Thus, it is crucial to identify m7G-associated lncRNAs with definitive prognostic value. This study aimed to investigate the prognostic value, correlation with tumor mutation burden, and impact on the tumor immune microenvironment of m7G-related lncRNAs in LUSC.  METHODS: LUSC transcriptome data and clinical data were downloaded from The Cancer Genome Atlas, and an m7G-related lncRNA-mRNA co-expression network was constructed using Pearson's correlation analysis. Cox regression analyses were used to determine a risk model for m7G-associated lncRNAs with prognostic value. The risk signature was verified using the Kaplan-Meier method, receiver operating characteristic curve analysis, and principal component analysis. A nomogram based on risk scores and clinical characteristics was then developed. Gene set enrichment analysis was used for functional annotation to analyze the risk signature. The association among the risk signature, tumor mutational burden, and tumor-infiltrating immune cells was then analyzed. RT-qPCR was used to investigate the expression of 6 m7G-related lncRNAs in LUSC cells. The cytological function of SRP14-AS1 was verified by wound-healing assay and transwell assay. RESULTS: A total of 293 m7G-related lncRNAs were identifed, 27 candidate m7G-related lncRNAs were signifcantly associated with overall survival (OS). Six of these lncRNAs (CYP4F26P, LINC02178, MIR22HG, SRP14-AS1, TMEM99, PTCSC2) were selected for establishment of the risk model. The OS of patients in the low-risk group was higher than that of patients in the high-risk group (p < 0.001). Multivariate cox regression analysis indicated that the model could be an independent prognostic factor for LUSC (HR = 1.859; 95% CI 1.452-2.380, p < 0.001). The ROC curve analysis revealed that the AUCs for OS in the 3-, and 5-year were 0.682, 0.657, respectively. GSEA analysis revealed that the risk model was closely related to immune-related pathways. Compared with normal lung epithelial cells, four m7G-related lncRNAs were higher expressed in cancer cells and two were lower expressed, among which knockdown of SRP14-AS1 promoted the proliferation and migration of LUSC cells. CONCLUSION: A risk model based on six m7G-related lncRNAs with prognostic value may be a promising prognostic tool in LUSC and guide individualized patient treatment.

Disulfidptosis-related prognostic signature correlates with immunotherapy response in colorectal cancer.

Disulfidptosis (DSP), a form of cell death caused by disulphide stress, plays an important role in tumour progression. However, the mechanisms by which DSP regulates the tumour microenvironment remain unclear. Thus, we analysed the transcriptome profiles and clinical data, which were obtained from the TCGA database, of 540 patients with colorectal cancer. Compared with the patients with low DSP expression, those with high DSP expression exhibited significantly better survival outcomes; lower stromal and ESTIMATE scores; significantly higher numbers of CD4+ T cells, M2 macrophages, dendritic cells, and neutrophils; higher expression of immune checkpoint-related genes; and lower Tregs and HLA-DQB2 levels. A prognostic signature established based on DSP-related genes demonstrated an increase in risk score with a higher clinical stage. Risk scores negatively correlated with dendritic cells, eosinophils, and CD4+ T cells and significantly positively correlated with Treg cells. Patients with higher risk scores experienced significantly worse survival outcomes and immunotherapy non-response. Our nomogram model, combining clinicopathological features and risk scores, exhibited robust prognostic and predictive power. In conclusion, DSP-related genes actively participated in regulating the tumour microenvironment. Thus, they can serve as biomarkers to provide targeted treatment for colorectal cancer.

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.

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.

Gut Microbiota Characteristics Are Associated With Severity of Acute Radiation-Induced Esophagitis.

Background: Acute radiation-induced esophagitis (ARIE) is one of the most debilitating complications in patients who receive thoracic radiotherapy, especially those with esophageal cancer (EC). There is little known about the impact of the characteristics of gut microbiota on the initiation and severity of ARIE. Materials and Methods: Gut microbiota samples of EC patients undergoing radiotherapy (n = 7) or concurrent chemoradiotherapy (n = 42) were collected at the start, middle, and end of the radiotherapy regimen. Assessment of patient-reported ARIE was also performed. Based on 16S rRNA gene sequencing, changes of the gut microbial community during the treatment regimen and correlations of the gut microbiota characteristics with the severity of ARIE were investigated. Results: There were significant associations of several properties of the gut microbiota with the severity of ARIE. The relative abundance of several genera in the phylum Proteobacteria increased significantly as mucositis severity increased. The predominant genera had characteristic changes during the treatment regimen, such as an increase of opportunistic pathogenic bacteria including Streptococcus. Patients with severe ARIE had significantly lower alpha diversity and a higher abundance of Fusobacterium before radiotherapy, but patients with mild ARIE were enriched in Klebsiella, Roseburia, Veillonella, Prevotella_9, Megasphaera, and Ruminococcus_2. A model combining these genera had the best performance in prediction of severe ARIE (area under the curve: 0.907). Conclusion: The characteristics of gut microbiota before radiotherapy were associated with subsequent ARIE severity. Microbiota-based strategies have potential use for the early prediction of subsequent ARIE and for the selection of interventions that may prevent severe ARIE.

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.