Survival In Esophageal Squamous Cell Carcinoma Research Articles

NEK2 contributes to radioresistance in esophageal squamous cell carcinoma by inducing protective autophagy via regulating TRIM21

BackgroundRadiotherapy (RT) has been identified as a vital treatment for esophageal squamous cell carcinoma (ESCC), while the development of radioresistance remains a major obstacle in ESCC management. The aim of this study was to investigate the effect of NIMA-related kinase 2 (NEK2) on radioresistance in ESCC cells and to reveal potential molecular mechanisms.MethodsHuman esophageal epithelial cells (HEEC) and human ESCC cell lines were obtained from the Research Center of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China). Cell Counting Kit-8 (CCK-8) and flow cytometry assays were applied to assess the proliferation ability, cell cycle, apoptosis rates, and ROS production of ESCC cells. The colony-forming assay was used to estimate the effect of NEK2 on radiosensitivity. Autophagy was investigated by western blotting analysis, GFP-mRFP-LC3 fluorescence assay, and transmission electron microscopy (TEM).ResultsIn the present study, our results showed that NEK2 was associated with radioresistance, cell cycle arrest, apoptosis, ROS production, and survival of ESCC. NEK2 knockdown could significantly inhibit growth while enhancing radiosensitivity and ROS production in ESCC cells. Interestingly, NEK2 knockdown inhibited ESCC cell autophagy and reduced autophagic flux, ultimately reversing NEK2-induced radioresistance. Mechanistically, NEK2 bound to and regulated the stability of tripartite motif-containing protein 21 (TRIM21). The accumulation of NEK2-induced light chain 3 beta 2 (LC3B II) can be reversed by the knockdown of TRIM21.ConclusionThese results demonstrated that NEK2 activated autophagy through TRIM21, which may provide a promising therapeutic strategy for elucidating NEK2-mediated radioresistance in ESCC.

Network pharmacology and molecular docking reveal the mechanisms of curcumin activity against esophageal squamous cell carcinoma.

Background: Curcumin (CUR), an effective traditional Chinese medicinal extract, displays good anti-cancer activity against various cancers. Nevertheless, the impacts and fundamental mechanisms of CUR to treat esophageal squamous cell carcinoma (ESCC) yet to be comprehensively clarified. This study examined the suppressive impacts of CUR on ESCC. Methods: For a comprehensive understanding of the effect of CUR in ESCC. The CUR targets and ESCC-related genes were identified respectively, and the intersection targets between CUR and ESCC were acquired. Then, we examined the intersection targets and discovered genes that were expressed differently in ESCC. Using DAVID, enrichment analyses were conducted on the targets of CUR-ESCC. The STRING database and Cytoscape v.3.9.1 were utilized to build networks for protein-protein interaction (PPI) and drug-target-pathway. Furthermore, the interactions between CUR and its core targets were confirmed by molecular docking studies. To confirm the effects of CUR on ESCC cells, in vitro experiments were finally conducted. Results: Overall, 47 potential CUR targets for ESCC treatment were identified. The KEGG pathway enrichment analysis identified 61 signaling pathways, primarily associated with the FoxO signaling, the cell cycle, cellular senescence, the IL-17 signaling pathway which play important roles in ESCC progression. In the PPI network and the docking results identified CHEK1 and CDK6 as the core targets that positively associated with ESCC survival. CUR arrested ESCC cells at the G2/M and S phases, as shown by flow cytometry. Colony formation and CCK8 assays showed that CUR can inhibit the proliferative ability of ESCC cells. The Transwell invasion results validated that CUR can significantly inhibit the invasion rates of ESCC cells. Conclusion: Collectively, these findings indicate that CUR exhibits pharmacological effects on multiple targets and pathways in ESCC.

Predictive role of ctDNA in esophageal squamous cell carcinoma receiving definitive chemoradiotherapy combined with toripalimab

The combination of toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) demonstrated encouraging efficacy against locally advanced esophageal squamous cell carcinoma (ESCC) in the EC-CRT-001 phase II trial (NCT04005170). The primary endpoint of this trial was the clinical complete response rate (cCR), and the secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response, and quality of life. The exploratory analyses of EC-CRT-001 include exploring the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) in predicting the response and survival. In total, 118 blood and 35 tissue samples from 42 enrolled patients were included in the analyses. We found that ctDNA-negative patients achieved a higher cCR compared to those with detectable ctDNA during CRT (83%, 19/23 vs. 39%, 7/18; p = 0.008) or post-CRT (78%, 21/27 vs. 30%, 3/10; p = 0.017). Patients with detectable ctDNA during CRT had shorter PFS (p = 0.014). Similarly, patients with post-CRT detectable ctDNA had a significantly shorter PFS (p = 0.012) and worse OS (p = 0.004). Moreover, patients with high bTMB levels during CRT had prolonged OS (p = 0.027). In conclusion, ctDNA and bTMB have the potential to predict treatment efficacy and survival in ESCC treated with CRT and immunotherapy.

HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis

Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance.Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

Racial Disparity in Esophageal Squamous Cell Carcinoma Treatment and Survival in the United States.

Esophageal squamous cell carcinoma (ESCC) has a higher incidence and prevalence than esophageal adenocarcinoma among Black individuals in the United States. Black individuals have lower ESCC survival. These racial disparities have not been thoroughly investigated. We examined the disparity in treatment and survival stratified by ESCC stage at diagnosis. The Surveillance, Epidemiology, and End Results database was queried to identify patients with ESCC between 2000 and 2019. The identified cohort was divided into subgroups by race. Patient and cancer characteristics, treatment received, and survival rates were compared across the racial subgroups. A total of 23,768 patients with ESCC were identified. Compared with White individuals, Black individuals were younger and had more distant disease during diagnosis (distant disease: 26.7% vs 23.8%, P < 0.001). Black individuals had lower age-standardized 5-year survival for localized (survival % [95% confidence interval]: 19.3% [16-22.8] vs 27.6% [25.1-30.2]), regional (14.3% [12-16.7] vs 21.1% [19.6-22.7]), and distant (2.9% [1.9-4.1] vs 6.5% [5.5-7.5]) disease. Black individuals were less likely to receive chemotherapy (54.7% vs 57.5%, P = 0.001), radiation (58.5% vs 60.4%, P = 0.03), and surgery (11.4% vs 16.3%, P < 0.0001). Black individuals with ESCC have a lower survival rate than White individuals. This could be related to presenting at a later stage but also disparities in which treatments they receive even among individuals with the same stage of disease. To what extent these disparities in receipt of treatment is due to structural racism, social determinants of health, implicit bias, or patient preferences deserves further study.

Different Radiation Dose of Neoadjuvant Chemoradiation for Resectable Thoracic Esophageal Squamous Carcinoma: A Randomized Phase II Clinical Trial

Radiation dose used in the neoadjuvant chemoradiotherapy (nCRT) for patients with locally advanced esophageal squamous cell carcinoma (ESCC) varies in clinical practice, no prospective studies have been conducted on this issue. The hypothesis of this study is that higher radiation dose in nCRT was associated with improved progression free survival in resectable ESCC. A phase II prospective randomized controlled trial was conducted from February 22, 2018 to February 22, 2021 in Zhejiang Cancer Hospital (NCT03381651). Patient with locally resectable advanced thoracic ESCC (cT2-T4aNxM0, T1-3N+M0) were randomized 1:1 to receive nCRT with different radiation doses of 50.4 Gy/28F and 41.4 Gy/23F, weekly TC regimen (paclitaxel 50 mg/m2, d1, carboplatin AUC = 2, d1) was administered as concurrent chemotherapy. The primary endpoint was 2-year progression free survival (PFS), and the secondary endpoints included complete pathological response (pCR) rate, overall survival (OS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The last follow-up date was February 22, 2022 and data analysis was performed from May 1, 2022, to October 31, 2022. A total of 147 patients were enrolled in the prospective study, including 72 patients in 50.4 Gy/28F group and 75 patients in 41.4 Gy/23F group. Among all the patients, 101 patients finally underwent surgical resection, 23/46(50%) achieved pCR in the high-dose group, while 18/55(32.7%) achieved pCR in the low-dose group (P = 0.10). In intention-to-treat population analysis, 2-year PFS in the high-dose and low-dose groups were 53.5% (95% CI: 42.9-66.7%) and 45.5% (95% CI: 35.4%-58.5%), respectively, and hazard ratio (HR) was 0.72 (95% CI: 0.46-1.12, P = 0.14). Median PFS were 44.4 months (95% CI: 16-NA) versus 20.8 months (95% CI: 15-NA) in high and low dose groups. 2-year OS in the high and low-dose groups were 61.8% (95% CI: 51.2 -74.5%) and 60.5% (95% CI: 50.3 -72.8%), respectively, with a HR = 0.78(95% CI: 0.48-1.27, P = 0.32). Median OS were not arrived in both groups up to the last follow-up. In addition, 2-year LRFS were 87.9% (95% CI: 78.4-98.5%) and 74.8% (95% CI: 63.3-88.3%) in high and low-dose groups, while 2-year DMFS were 70.6% (95% CI: 58.3-85.5%) and 73.6% (95% CI: 61.7-87.8%), respectively. No significant statistical difference was observed between the two groups in terms of side effects during nCRT and postoperative complications. Our results showed that neoadjuvant high-dose radiotherapy failed to improve overall survival in ESCC. However, it was found that pCR and local tumor control rates tended to be increased at 50.4 Gy/28F, compared to 41.4 Gy/23F, although the trend was not statistically significant. There was no significant difference in treatment side effects between the two groups. Longer-term follow-up is required to verify our findings.

Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma.

Analysis of intratumoral microbiota in patients with esophageal cancer identifies a microbiota signature that is associated with chemoimmunotherapy response and reveals that Streptococcus induces a favorable response by stimulating CD8+ T-cell infiltration. See related commentary by Sfanos, p. 2985.

Exosomal PIK3CB promotes PD-L1 expression and malignant transformation in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC), which accounts for 90% of esophageal carcinomas, seriously endangers human health. Worse still, the 5-year overall survival of ESCC is approximately 20%. Elucidation of the potential mechanism and exploration of promising drugs for ESCC are urgently needed. In this study, a high level of exosomal PIK3CB protein was found in the plasma of ESCC patients, which might indicate a poor prognosis. Moreover, a significant Pearson's correlation was observed at the protein level between exosomal PIK3CB and exosomal PD-L1. Further study revealed that cancer cell-intrinsic and exosome-derived PIK3CB promoted the transcriptional activity of the PD-L1 promoter in ESCC cells. Moreover, treatment with exosomes with lower levels of exosomal PIK3CB decreased the protein level of the mesenchymal marker β-catenin while increasing that of the epithelial marker claudin-1, indicating the potential regulation of epithelial-mesenchymal transition. Consequently, the migratory ability and cancer stemness of ESCC cells and the growth of tumors formed by ESCC cells were decreased with the downregulation of exosomal PIK3CB. Therefore, exosomal PIK3CB plays an oncogenic role by promoting PD-L1 expression and malignant transformation in ESCC. This study may provide new insight into the inherent biological aggressiveness and the poor response to currently available therapies of ESCC. Exosomal PIK3CB may be a promising target for the diagnosis and therapy of ESCC in the future.

Identification of the pyroptosis-related gene signature and risk score model for esophageal squamous cell carcinoma.

Advanced esophageal squamous cell carcinoma (ESCC) still has a dismal prognostic outcome. However, the current approaches are unable to evaluate patient survival. Pyroptosis represents a novel programmed cell death type which widely investigated in various disorders and can influence tumor growth, migration, and invasion. Furthermore, few existing studies have used pyroptosis-related genes (PRGs) to construct a model for predicting ESCC survival. Therefore, the present study utilized bioinformatics approaches for analyzing ESCC patient data obtained from the TCGA database to construct the prognostic risk model and applied it to the GSE53625 dataset for validation. There were 12 differentially expressed PRGs in healthy and ESCC tissue samples, among which eight were selected through univariate and LASSO cox regression for constructing the prognostic risk model. According to K-M and ROC curve analyses, our eight-gene model might be useful in predicting ESCC prognostic outcomes. Based on the cell validation analysis, C2, CD14, RTP4, FCER3A, and SLC7A7 were expressed higher in KYSE410 and KYSE510 than in normal cells (HET-1A). Hence, ESCC patient prognostic outcomes can be assessed by our PRGs-based risk model. Further, these PRGs may also serve as therapeutic targets.

Prognostic significance of epidermal growth factor receptor and programmed cell death-ligand 1 co-expression in esophageal squamous cell carcinoma.

Our study aimed to observe the correlation between epidermal growth factor receptor (EGFR) and programmed cell death-ligand 1 (PD-L1) expression and evaluate prognostic potential of their co-expression in esophageal squamous cell carcinoma (ESCC) patients. EGFR and PD-L1 expression were evaluated by immunohistochemical analysis. We revealed that there was a positive correlation between EGFR and PD-L1 expression in ESCC (P = 0.004). According to the positive relationship between EGFR and PD-L1, all patients were divided into four groups: EGFR (+)/PD-L1 (+), EGFR (+)/PD-L1 (-), EGFR (-)/PD-L1 (+), and EGFR (-)/PD-L1 (-). In 57 ESCC patients without surgery, we found that EGFR and PD-L1 co-expression were statistically correlated with a lower objective response rate (ORR) (p = 0.029), overall survival (OS) (p = 0.018) and progression-free survival (PFS) (p = 0.045) than those with one or none positive protein. Furthermore, PD-L1 expression has a significant positive correlation with infiltration level of 19 immune cells, EGFR expression was significantly correlated with infiltration level of 12 immune cells. The infiltration level of CD8 T cell and B cell were negatively correlated with EGFR expression. On the contrary with EGFR, the infiltration level of CD8 T cell, and B cell were positively correlated with PD-L1 expression. In conclusion, EGFR and PD-L1 co-expression could predict poor ORR and survival in ESCC without surgery, indicating a subset of patients who may benefit from a combination of targeted therapy against EGFR and PD-L1, which may expand the population benefiting from immunotherapy and reduce the occurrence of hyper progressive diseases.

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

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. 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. Patients who received IC/CRT experienced improved overall survival (OS) (38.5 vs. 28.8months) and progression-free survival (PFS) (41.0 vs. 22.0months) 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. 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.

Molecular subtyping of esophageal squamous cell carcinoma by large-scale transcriptional profiling: Characterization, therapeutic targets, and prognostic value

The tumor heterogeneity of the transcriptional profiles is independent of genetic variation. Several studies have successfully identified esophageal squamous cell carcinoma (ESCC) subtypes based on the somatic mutation profile and copy number variations on the genome. However, transcriptome-based classification is limited. In this study, we classified 141 patients with ESCC into three subtypes (Subtype 1, Subtype 2, and Subtype 3) via tumor sample gene expression profiling. Differential gene expression (DGE) analysis of paired tumor and normal samples for each subtype revealed significant difference among subtypes. Moreover, the degree of change in the expression levels of most genes gradually increased from Subtype 1 to Subtype 3. Gene set enrichment analysis (GSEA) identified the representative pathways in each subtype: Subtype 1, abnormal Wnt signaling pathway activation; Subtype 2, inhibition of glycogen metabolism; and Subtype 3, downregulation of neutrophil degranulation process. Weighted gene co-expression network analysis (WGCNA) was used to elucidate the finer regulation of biological pathways and discover hub genes. Subsequently, nine hub genes (CORO1A, CD180, SASH3, CD52, CD300A, CD14, DUSP1, KIF14, and MCM2) were validated to be associated with survival in ESCC based on the RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database. The clustering analysis of ESCC granted better understanding of the molecular characteristics of ESCC and led to the discover of new potential therapeutic targets that may contribute to the clinical treatment of ESCC.

A novel immune-related radioresistant lncRNAs signature based model for risk stratification and prognosis prediction in esophageal squamous cell carcinoma.

Background and purpose: Radioresistance remains a major reason of radiotherapeutic failure in esophageal squamous cell carcinoma (ESCC). Our study is to screen the immune-related long non-coding RNA (ir-lncRNAs) of radiation-resistant ESCC (rr-ESCC) via Gene Expression Omnibus (GEO) database and to construct a prognostic risk model. Methods: Microarray data (GSE45670) related to radioresistance of ESCC was downloaded from GEO. Based on pathologic responses after chemoradiotherapy, patients were divided into a non-responder (17 samples) and responder group (11 samples), and the difference in expression profiles of ir-lncRNAs were compared therein. Ir-lncRNA pairs were constructed for the differentially expressed lncRNAs as prognostic variables, and the microarray dataset (GSE53625) was downloaded from GEO to verify the effect of ir-lncRNA pairs on the long-term survival of ESCC. After modelling, patients are divided into high- and low-risk groups according to prognostic risk scores, and the outcomes were compared within groups based on the COX proportional hazards model. The different expression of ir-lncRNAs were validated using ECA 109 and ECA 109R cell lines via RT-qPCR. Results: 26 ir-lncRNA genes were screened in the GSE45670 dataset with differential expression, and 180 ir-lncRNA pairs were constructed. After matching with ir-lncRNA pairs constructed by GSE53625, six ir-lncRNA pairs had a significant impact on the prognosis of ESCC from univariate analysis model, of which three ir-lncRNA pairs were significantly associated with prognosis in multivariate COX analysis. These three lncRNA pairs were used as prognostic indicators to construct a prognostic risk model, and the predicted risk scores were calculated. With a median value of 2.371, the patients were divided into two groups. The overall survival (OS) in the high-risk group was significantly worse than that in the low-risk group (p < 0.001). The 1-, 2-, and 3-year prediction performance of this risk-model was 0.666, 0.702, and 0.686, respectively. In the validation setting, three ir-lncRNAs were significantly up-regulated, while two ir-lncRNAs were obviouly down-regulated in the responder group. Conclusion: Ir-lncRNAs may be involved in the biological regulation of radioresistance in patients with ESCC; and the prognostic risk-model, established by three ir-lncRNAs pairs has important clinical value in predicting the prognosis of patients with rr-ESCC.

Targeting stearoyl-coa desaturase enhances radiation induced ferroptosis and immunogenic cell death in esophageal squamous cell carcinoma

ABSTRACT Overcoming resistance to radiation is a major challenge in cancer treatment. Stearoyl-coa desaturase (SCD1) is the enzyme responsible for oleic acid (OA) and palmitoleic acid (POA) formation. Here, we provided evidence that targeting SCD1 was capable of inducing ferroptosis and immunogenic cell death (ICD), thereby improving the radiation sensitivity of esophageal squamous cell carcinoma (ESCC). ESCC cell lines with high SCD1 expression were treated with MF-438 (SCD1 inhibitor) to determine cell viability. Colony formation assay was performed to evaluate the radiation sensitization of SCD1 inhibitor. Tumor cell ferroptosis and ICD was analyzed in MF-438, radiation therapy (RT) and the combination treatment group. The potential molecular mechanisms underlying MF-438 as a novel radiation sensitizer in ESCC were explored. We concluded by assessing SCD1 as a prognostic factor in ESCC. MF-438 exhibited antitumor activity in ESCC cells. Our outcomes revealed significant improvement of radiation sensitivity by MF-438. Moreover, the combination treatment enhanced tumor cell ferroptosis and ICD. Further analyses revealed SCD1 conferred radiation resistance via alleviating ferroptosis in tumor cells; targeting SCD1 inhibited the biosynthesis of OA and POA, and improved radiation induced ferroptosis in ESCC cells. Clinical analysis indicated high expression of SCD1 was associated with unfavorable survival in patients of ESCC. In summary, our results demonstrated that MF-438 acted as a ferroptosis inducer. Targeting SCD1 conferred the immunogenicity of ferroptotic cancer cells and increased the effectiveness of RT in ESCC. SCD1 could be considered as a useful prognostic indicator of survival in ESCC.

TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway.

The dynamics of mitochondrial biogenesis regulation is critical in maintaining cellular homeostasis for immune regulation and tumor prevention. Here, we report that mitochondrial biogenesis disruption through TFAM reduction significantly impairs mitochondrial function, induces autophagy, and promotes esophageal squamous cell carcinoma (ESCC) growth. We found that TFAM protein reduction promotes mitochondrial DNA (mtDNA) release into the cytosol, induces cytosolic mtDNA stress, subsequently activates the cGAS-STING signaling pathway, thereby stimulating autophagy and ESCC growth. STING depletion or mtDNA degradation by DNase I abrogates mtDNA stress response, attenuates autophagy, and decreases the growth of TFAM depleted cells. In addition, autophagy inhibitor also ameliorates mitochondrial dysfunction-induced activation of the cGAS-STING signaling pathway and ESCC growth. In conclusion, our results indicate that mtDNA stress induced by mitochondria biogenesis perturbation activates the cGAS-STING pathway and autophagy to promote ESCC growth, revealing an underappreciated therapeutic strategy for ESCC.

Overexpression of GNA13 correlates with poor prognosis in esophageal squamous cell carcinoma after esophagectomy.

This study aimed to explore the expression and clinical implication of guanine nucleotide-binding protein alpha 13 (GNA13) in esophageal squamous cell carcinoma (ESCC). We first employed western blot analysis to test the GNA13 protein expression level in ESCC tissues. Subsequently, we used immunohistochemistry assays to detect the GNA13 in ESCC specimens from 173 patients who underwent esophagectomy. Survival analysis was performed to define the impact of GNA13 expressions on the prognosis of the ESCC patients based on the clinical and follow-up data. The GNA13 protein was shown to be considerably higher in ESCC tissues than in normal esophageal tissues. The level of expression was closely related to the tumor, node, TNM stage, and tumor size. More importantly, ESCC patients with high GNA13 expression carried an increased risk of tumor recurrence compared to those with low GNA13 expression. In addition, a high GNA13 expression level could independently predict worse overall survival and disease-free survival in ESCC. GNA13 could be a novel prognostic biomarker for ESCC patients after esophagectomy.

Association of Dietary Phytosterols Intake and Survival of Esophageal Squamous Cell Carcinoma: A Prospective Cohort Study

Background The association of dietary phytosterols intake with survival of esophageal squamous cell carcinoma (ESCC) remains unclear. This study was to examine the effect of dietary phytosterols intake on ESCC survival in a Chinese rural population. Methods A total of 942 incident ESCC patients diagnosed between 2011 and 2013 in Yanting area were followed up until March 1st, 2020. Dietary intake five years before ESCC diagnosis was collected using a food frequency questionnaire. The outcome of interest was all-cause mortality. Cox proportional hazards regression model was used to estimate hazard ratio (HR) and 95% confidence intervals (CI). Results When comparing the highest with lowest intake quartiles, intake of five specific and total phytosterols was not significantly associated with risk of death after adjustment for covariates, the adjusted HR (95% CI) for β-sitosterol, campesterol, stigmasterol, β-sitostanol, campestanol and total phytosterols was 0.90 (95% CI: 0.70-1.16), 0.92 (95% CI: 0.71-1.19), 0.86 (95% CI: 0.66-1.12), 0.93 (95% CI: 0.73-1.20), 0.94 (95% CI: 0.72-1.21), 0.89 (95% CI: 0.69-1.15), respectively. Conclusion This study does not find any association between pre-diagnostic phytosterols intake and risk of all-cause mortality among ESCC patients. Further research is required to determine the effect of post-diagnostic phytosterols intake on ESCC survival.

A study of neoadjuvant sintilimab combined with chemotherapy TP for locally advanced esophageal squamous cell carcinoma (ESCC).

e16038 Background: Although preoperative chemoradiotherapy is the standard of care for patients with locally advanced esophageal cancer, ESCC still has a dismal prognosis. Sintilimab, a humanized IgG4 monoclonal antibody with high affinity and specificity for PD-1, has shown promising efficacy with overall survival in ESCC in a phase II study (ORIENT-02, NCT03116152)1. KEEP-G 03 given the encouraging MPR and favorable tolerability of preoperative sintilimab in combination with triplet chemotherapy in resectable ESCC (KEEP-G 03, NCT03946969)2. This trial evaluates the feasibility and safety of preoperative sintilimab in combination with chemotherapy of TP in ESCC. Methods: This is a single-arm, single center research, phase 2 trial to assessment the efficacy and safety of asintilimab and chemotherapy of TP(Q3W 2-4 cycle) as neoadjuvant treatment of locally advanced ESCC. The key eligibility criteria was locally advanced ESCC, ECOG PS 0 or 1, and at least one measurable lesion per RESIST v1.1. aSintilimab: 200mg for 60kg, 3mg/kg for body weight &lt; 60kg; TP: pacilitaxel 175mg/m2 plus cisplatin 75mg/m2. Primary Objectives: pCR, MPR. Secondary Objectives: R0 rate, RFS, OS, Safety (CTCAE 5.0). Exploratory Objectives: The alteration of molecular biomarkers to neoadjuvant treatment including PD-L1, TMB, DDR, etc. Results: From 1/2020 to 12/2021, 20 eligible patients were recruited in the Jiangxi Tumor Hospital, NanChang, China. Conclusions: Given the encouraging MPR and favorable tolerability, the combination of sintilimab and chemotherapy of TP could be a potentially feasible and safe neoadjuvant option for locally advanced ESCC. The trial will be continued to evaluate the feasibility of this regimen.[Table: see text][Table: see text][Table: see text]

APEC: Efficacy and toxicity of anlotinib plus PD-1 inhibitors as later-line therapy in advanced/metastatic esophageal squamous cell carcinoma (ESCC): A retrospective real-world study.

e16014 Background: Anlotinib has been approved in ESCC treatment because of its good tolerance and efficacy. Antiangiogenic target therapy plus immunotherapy has been initially recognized, whereas the data on the third &amp; above line is still unknown. We aimed to retrospectively analyze the effect of anlotinib plus PD-1 inhibitor as later-line therapy on the survival of ESCC in the real world. (APEC, NCT 04984096). Methods: Retrospective data analysis was performed on ESCC patients (pts) treated with anlotinib plus PD-1 inhibitors as later-line therapy between Sep 2019 and Nov 2021 at Shanghai Chest Hospital, China. Demography, previous treatment, performance status, pathological classification, comorbidities, and distant metastatic organ status were collected. Progression free survival (PFS) was the primary end point of this study. The secondary end points were objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Tumor response was assessed per RECIST version 1.1 by the investigators. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Results: There were 21 pts in the cohort. The average age was 61.5 (range 48-77) years old, and 95.2% patients were male. 7 cases (33.3%) had comorbidities. 2 cases (9.5%) had other tumor history. In addition, 19 pts (90.5%) had received radiotherapy, 21 pts (100.0%) had received chemotherapy and 19 pts (90.5%) had received immunotherapy. Among all pts, 1 patient achieved complete response (CR), 6 pts partial response (PR), 10 pts stable disease (SD), illustrating an ORR of 33.3 % and a DCR of 81.0%. Median PFS reached 8.1 months (95%CI 3.8-12.4) while median OS was not reached. All grades of TRAEs occurred in 95.2% pts and 90.5% were grade 1-2. Of note, grade 3-4 hematological toxicity (lymphocytopenia) was reported in only 2 patient (9.5%). All AEs were resolved after symptomatic treatment. Conclusions: Our data suggest that treatment with anlotinib plus PD-1 inhibitors as later-line therapy can result in curative effect of ESCC, which can achieve promising ORR, DCR and PFS with mild toxicity. To our knowledge, this is the first analysis to demonstrate the benefits of anlotinib plus PD-1 inhibitors as later-line therapy in ESCC. The data suggests that anlotinib plus PD-1 inhibitor is a new treatment in ESCC pts, and further validation in a larger cohort is needed. Clinical trial information: 04984096.

Prognostic score model based on six m6A-related autophagy genes for predicting survival in esophageal squamous cell carcinoma.

BackgroundPrognostic signatures based on autophagy genes have been proposed for esophageal squamous cell carcinoma (ESCC). Autophagy genes are closely associated with m6A genes. Our purpose is to identify m6A‐related autophagy genes in ESCC and develop a survival prediction model.MethodsDifferential expression analyses for m6A genes and autophagy genes were performed based on TCGA and HADd databases followed by constructing a co‐expression network. Uni‐variable Cox regression analysis was performed for m6A‐related autophagy genes. Using the optimal combination of feature genes by LASSO Cox regression model, a prognostic score (PS) model was developed and subsequently validated in an independent dataset.ResultsThe differential expression of 13 m6A genes and 107 autophagy genes was observed between ESCC and normal samples. The co‐expression network contained 13 m6A genes and 96 autophagy genes. Of the 12 m6A‐related autophagy genes that were significantly related to survival, DAPK2, DIRAS3, EIF2AK3, ITPR1, MAP1LC3C, and TP53 were used to construct a PS model, which split the training set into two risk groups with significant different survival ratios (p = 0.015, 1‐year, 3‐year, and 5‐year AUC = 0.873, 0.840, and 0.829). Consistent results of GSE53625 dataset confirmed predictive ability of the model (p = 0.024, 1‐year, 3‐year, and 5‐year AUC = 0.793, 0.751, and 0.744). The six‐gene PS score was an independent prognostic factor from clinical factors (HR, 2.362; 95% CI, 1.390–7.064; p‐value = 0.012).ConclusionOur study recommends 6 m6A‐related autophagy genes as promising prognostic biomarkers and develops a PS model to predict survival in ESCC.