Ribosomal protein L22 like 1: a promising biomarker for lung adenocarcinoma.

No studies have reported the effect of ribosomal protein L22 like 1 (RPL22L1) in lung adenocarcinoma (LUAD). Therefore, we aimed to systematically investigate the role of RPL22L1 in LUAD. The expression of RPL22L1 was analyzed using TCGA, GEO, TIMER, UALCAN databases, and validated by immunohistochemistry (IHC). Gene methylation analysis was performed using the UALCAN, GSCA and MethSurv databases. The immune infiltrates were investigated using the Single Sample Gene Set Enrichment Analysis (ssGSEA), TIMER database, and TISCH database. The results demonstrated that RPL22L1 was up-regulated in LUAD, and verified by IHC. Kaplan-Meier analysis suggested that patients with high RPL22L1 expression had poor prognosis. Multivariate analysis confirmed that RPL22L1 was an independent prognostic factor. Furthermore, RPL22L1 overexpression was associated with hypomethylation, and two CpGs of RPL22L1 were significantly associated with prognosis. Up-regulated RPL22L1 was enriched in MYC targets, E2F targets, G2M checkpoint, mTORC1 signaling, cell cycle, and so on. Moreover, RPL22L1 expression was negatively correlated with immune cell infiltration, and patients with high RPL22L1 expression had lower immune, stromal, and estimate scores. Single-cell analysis suggested that RPL22L1 might have a potential function in the tumor microenvironment (TME) of LUAD. In conclusion, RPL22L1 may be a promising biomarker for LUAD.

Hypoxia-induced factor-1α promotes radioresistance of esophageal cancer cells by transcriptionally activating LINC01116 and suppressing miR-3612 under hypoxia.

Esophageal cancer (EC) is a challenging tumor to treat with radiotherapy, often exhibiting resistance to this treatment modality. To explore the factors influencing radioresistance, we focused on the role of hypoxia-induced factor-1α (HIF-1α), and its interaction with the long noncoding RNA long intergenic nonprotein coding RNA 1116 (LINC01116). We analyzed the LINC01116 expression in EC and EC cell lines/human normal esophageal epithelial cell line (Het-1A). LINC01116 was silenced/overexpressed in EC109/KYSE30 cells under hypoxia, followed by radioresistance assessment. We measured HIF-1α levels in hypoxic EC cells and further validated the binding of HIF-1α with LINC01116, analyzing their interaction in EC cells. We then performed experiments in EC109 cells by transfection them with sh-HIF-1α/oe-LINC01116 to verify the effects. Additonally, we analyzed the localization of LINC01116 and its binding with miR-3612, followed by a combined experiment performed to validate the results. Our findings indicated that LINC01116 was highly expressed in EC and further elevated in hypoxic EC cells. LINC01116 was expressed at a high level in EC, which was further elevated in EC cells under hypoxic conditions. Knockdown of LINC01116 triggered EC cell apoptosis, thus suppressing radioresistance. Further investigation revealed that HIF-1α transcriptionally activated LINC01116 expression under hypoxia, and silencing HIF-1α lowered EC cell radioresistance by downregulating LINC01116. Under hypoxic conditions, LINC01116 could function as a sponge for miR-3612 and inhibit its expression. This interaction between LINC01116 and miR-3612 played a crucial role in mediating radioresistance in EC cells. Briefly, under hypoxic conditions, HIF-1α facilitates radioresistance of EC cells by transcriptionally activating LINC01116 expression and downregulating miR-3612.

Novel nomogram for predicting survival in advanced non-small cell lung cancer receiving anti-PD-1 plus chemotherapy with or without antiangiogenic therapy.

Background: This study aimed to develop and validate a novel nomogram to predict survival in advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD-1) inhibitor plus chemotherapy with or without antiangiogenic therapy. Methods: A total of 271 patients with advanced NSCLC who received anti-PD-1 plus chemotherapy with or without antiangiogenic therapy were enrolled in our center and randomized into the training cohort (n = 133) and the internal validation cohort (n = 138). Forty-five patients from another center were included as an independent external validation cohort. The nomogram was created based on the multivariate Cox regression analysis to predict overall survival (OS) and progression-free survival (PFS). The performance of the nomogram was assessed using the concordance index (C-index), the time-dependent area under the receiver operating (ROC) curves (AUCs), calibration curves, and decision curve analysis (DCA). Results: Four factors significantly associated with OS were utilized to create a nomogram to predict OS: Eastern Cooperative Oncology Group performance status (ECOG PS), programmed cell death-ligand 1 (PD-L1) expression, chemotherapy cycle, and pretreatment lactate dehydrogenase-albumin ratio (LAR). Six variables significantly associated with PFS were incorporated into the development of a nomogram for predicting PFS: ECOG PS, histology, PD-L1 expression, chemotherapy cycle, pretreatment platelet to lymphocyte (PLR), and pretreatment LAR. The C-indexes of the nomogram for predicting OS and PFS were 0.750 and 0.747, respectively. The AUCs for predicting the 6-month, 12-month, and 18-month OS and PFS were 0.847, 0.791, and 0.776 and 0.810, 0.787, and 0.861, respectively. The calibration curves demonstrated a good agreement between predictions and actual observations. The DCA curves indicated that the nomograms had good net benefits. Furthermore, the nomogram model was well-validated in the internal and external cohorts. Conclusion: The novel nomogram for predicting the prognosis of advanced NSCLC receiving anti-PD-1 plus chemotherapy with or without antiangiogenic therapy may help guide clinical treatment decisions.

LAPS score for individualized treatment of advanced EGFR-mutated non-small cell lung cancer receiving EGFR-TKIs with or without bevacizumab.

BACKGROUND: To establish a risk stratification score to facilitate individualized treatment for patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). METHODS: We enrolled 160 advanced EGFR-mutated NSCLC who received first-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) with or without bevacizumab. Kaplan-Meier curves were used for survival analysis. Univariate and multivariate analyses were used to identify independent prognostic factors associated with progression-free survival (PFS) and overall survival (OS). RESULTS: There were 107 patients in EGFR-TKI monotherapy (T group) and 53 patients in EGFR-TKI with bevacizumab (A + T group). The median PFS in the A + T group was significantly longer than that in the T group (p = 0.002). No difference in the median OS between the A + T and T groups (p = 0.721). The multivariate analyses showed that Eastern Cooperative Oncology Group performance status (ECOG PS) and the pre-treatment lactate dehydrogenase-albumin ratio (LAR) were independent prognostic factors for PFS and OS. The LAR-ECOG PS (LAPS) score was constructed by combining the pre-treatment LAR and ECOG PS. We defined ECOG PS 2 and high pre-treatment LAR as a score of 1. Then, patients with a total LAPS score of 0 were categorized as low-risk and those with 1-2 scores were classified as high-risk. For patients in low-risk group, there was no significant difference in PFS, OS, objective response rate (ORR), and disease control rate (DCR) among those who received EGFR-TKI with or without bevacizumab. However, patients in high-risk group had a significant benefit in PFS and DCR when treated with EGFR-TKI plus bevacizumab compared to those who received EGFR-TKI alone. CONCLUSIONS: Novel LAPS score may help to facilitate individualized treatment of advanced EGFR-mutated NSCLC receiving EGFR-TKI with or without bevacizumab.

The identification of genes associated T-cell exhaustion and construction of prognostic signature to predict immunotherapy response in lung adenocarcinoma.

T-cell exhaustion (Tex) is considered to be a reason for immunotherapy resistance and poor prognosis in lung adenocarcinoma. Therefore, we used weighted correlation network analysis to identify Tex-related genes in the cancer genome atlas (TCGA). Unsupervised clustering approach based on Tex-related genes divided patients into cluster 1 and cluster 2. Then, we utilized random forest and the least absolute shrinkage and selection operator to identify nine key genes to construct a riskscore. Patients were classified as low or high-risk groups. The multivariate cox analysis showed the riskscore was an independent prognostic factor in TCGA and GSE72094 cohorts. Moreover, patients in cluster 2 with high riskscore had the worst prognosis. The immune response prediction analysis showed the low-risk group had higher immune, stromal, estimate scores, higher immunophenscore (IPS), and lower tumor immune dysfunction and exclusion score which suggested a better response to immune checkpoint inhibitors (ICIs) therapy in the low-risk group. In the meantime, we included two independent immunotherapy cohorts that also confirmed a better response to ICIs treatment in the low-risk group. Besides, we discovered differences in chemotherapy and targeted drug sensitivity between two groups. Finally, a nomogram was built to facilitate clinical decision making.

First-generation EGFR-TKI plus bevacizumab and chemotherapy for advanced EGFR-mutated non-squamous non-small-cell lung cancer: a retrospective study.

BACKGROUND: This study aimed to compare the efficacy and safety of different treatment modalities for previously untreated advanced EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC). METHODS: This retrospective study included 196 advanced EGFR-mutated non-squamous NSCLC. 107 received EGFR-tyrosine kinase inhibitor (EGFR-TKI) monotherapy (T), 53 received EGFR-TKI + bevacizumab (T + A), and 36 received EGFR-TKI + bevacizumab + chemotherapy (T + A + C). The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: The median PFS was 27 months in the T + A + C group, 17 months in the T + A group, and 10 months in the T group. The multivariate analysis showed lower disease progression in the T + A + C group (HR, 0.377; 95% CI, 0.224-0.634; p < .001). Subgroup analysis showed that the T + A + C group did significantly improve PFS in patients with metastatic organs ≥2, brain metastases, liver metastases, and EGFR 19del compared to T + A group. No significant improvement in OS in the T + A + C group versus the T + A group, but a significant benefit in the subgroup of patients with metastatic organs ≥2. We also performed a subgroup analysis of the T + A + C group versus the T group, which similarly showed that the T + A + C group had better PFS than the T group in most subgroups, and the T + A + C group significantly improved OS in patients with metastatic organ ≥2 and liver metastases compared with the T group. The ORR was significantly higher in the T + A + C group than A + T and T groups (83.3% vs 71.7% vs 60.7%, p = .033). In safety, the T + A + C group had a higher incidence of AEs, but the majority was grade 1-2. The most frequent AEs of grade ≥ 3 were leukopenia (8.3%) and increased aminotransferase (8.3%) in the T + A + C group. CONCLUSIONS: First-generation EGFR-TKI plus bevacizumab plus chemotherapy was a promising strategy for advanced EGFR-mutated non-squamous NSCLC.

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.

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.

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.

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 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.

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).

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.

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.

Factors associated with immunotherapy respond and survival in advanced non-small cell lung cancer patients.

OBJECTIVES: This study aimed to explore factors associated with immunotherapy respond and survival in advanced non-small cell lung cancer (aNSCLC) patients treated with immune checkpoint inhibitors (ICIs). METHODS: A total of 101 patients with aNSCLC receiving ICIs were included. The association between clinical factors and multiple endpoints including objective response rate (ORR), disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) were investigated by multivariate analyses. RESULTS: Multivariate logistic analyses revealed that clinical stage, lactate dehydrogena (LDH), and any grade immune-related adverse events (irAEs) were independent predictors of ORR, while LDH and ICIs treatment type were independent predictors of DCR. In Multivariate Cox analysis, Eastern Cooperative Oncology Group performance status (ECOG PS), LDH, albumin (Alb), platelet to lymphocyte ratio (PLR), and any grade irAEs were independent factors for OS. Similarly, clinical stage, LDH, Alb, and any grade irAEs were independent factors for PFS. Pre-treatment prognostic score was established based on clinical stage, ECOG PS, LDH, Alb and PLR to classify patients into three groups: the good group (0-1 score), the intermediate group (2 scores) and the poor group (3-4 scores). The immunotherapy response was significantly different in various prognostic groups. Subset analyses showed pre-treatment prognostic score ≥ 3 tended to have a strong negative impact on survival among patients with programmed cell death-ligand 1 (PD-L1) expression ≥ 50%. CONCLUSIONS: Pre-treatment prognostic score based on clinical stage, ECOG PS, LDH, Alb and PLR may help to identify aNSCLC patients who may benefit from ICIs.

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.

Change in Maximal Esophageal Wall Thickness Provides Prediction of Survival and Recurrence in Patients with Esophageal Squamous Cell Carcinoma After Neoadjuvant Chemoradiotherapy and Surgery.

PURPOSE: This study aimed to evaluate the relationship of the percentage decrease of maximal esophageal wall thickness with pathological complete response (pCR) and recurrence in esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A total of 146 ESCC patients treated with neoadjuvant chemoradiotherapy (NCRT) and surgery were included. The prognostic factors for overall survival (OS) and disease-free survival (DFS) were analyzed. The recurrence site, time, and frequency were included in the analysis. The percentage decrease of maximal esophageal wall thickness after NCRT was determined with the formula: [(pre-post)/pre] × 100. RESULTS: Overall, only 42 patients achieved pCR. Multivariable logistic analyses showed that the percentage decrease of maximal esophageal wall thickness (HR: 2.504; 95% CI: 1.112-5.638, P=0.027) was independently correlated with pCR. In multivariable Cox analyses, a ≤40% percentage decrease of maximal esophageal wall thickness was an independent adverse factor for both OS (HR: 1.907, 95% CI: 1.149-3.165; P=0.012) and DFS (HR: 2.054, 95% CI: 1.288-3.277; P=0.003). Compared with patients with a ≤40% percentage decrease, those with a >40% percentage decrease had better 5-year OS (29.0% vs 60.1%, P<0.05) and DFS (27.8% vs 54.4%, P<0.05). Perineural invasion (PNI) was also an unfavorable factor for OS (HR: 2.138, 95% CI: 0.094-4.178; P=0.026). Lymph vessel invasion (HR: 2.874, 95% CI: 1.574-5.248; P=0.001) and PNI (HR: 2.050; 95% CI: 1.044-4.023; P=0.037) were independent prognosticators for DFS. The rates of local and distant recurrence were also significantly difference between those with a percentage decrease of ≤40% and of >40% (P<0.05). CONCLUSION: The percentage decrease of maximal esophageal wall thickness is associated with pCR and recurrence in ESCC patients who undergo NCRT and surgery and can thus be used to independently predict prognosis.