Overexpression SPRY2 Suppresses Esophageal Squamous Cell Carcinoma Progression Via Inactivation of ERK/AKT Signaling / La Sobreexpresión SPRY2 Suprime la Evolución del Carcinoma de Células Escamosas de Esófago Mediante la Inactivación de la Señalización ERK/AKT

SUMMARY: Esophageal cancer is one of the most aggressive gastrointestinal cancers. Invasion and metastasis are the main causes of poor prognosis of esophageal cancer. SPRY2 has been reported to exert promoting effects in human cancers, which controls signal pathways including PI3K/AKT and MAPKs. However, the expression of SPRY2 in esophageal squamous cell carcinoma (ESCC) and its underlying mechanism remain unclear. In the present study, we aimed to investigate the detailed role of SPRY2 in the regulation of cell proliferation, invasion and ERK/AKT signaling pathway in ESCC. It was identified that the expression level of SPRY2 in ESCC was remarkably decreased compared with normal tissues, and it was related to clinicopathologic features and prognosis ESCC patients. The upregulation of SPRY2 expression notably inhibited the proliferation, migration and invasion of Eca-109 cells. In addition, the activity of ERK /AKT signaling was also suppressed by the SPRY2 upregulation in Eca-109 cells. Our study suggests that overexpression of SPRY2 suppress cancer cell proliferation and invasion of by through suppression of the ERK/AKT signaling pathways in ESCC. Therefore, SPRY2 may be a promising prognostic marker and therapeutic target for ESCC.

El cáncer de esófago es uno de los cánceres gastrointestinales más agresivos. La invasión y la metástasis son las principales causas de mal pronóstico del cáncer de esófago. Se ha informado que SPRY2 ejerce efectos promotores en los cánceres humanos, que controla las vías de señales, incluidas PI3K/AKT y MAPK. Sin embargo, la expresión de SPRY2 en el carcinoma de células escamosas de esófago (ESCC) y su mecanismo subyacente aún no están claros. En el presente estudio, nuestro objetivo fue investigar el papel detallado de SPRY2 en la regulación de la proliferación celular, la invasión y la vía de señalización ERK/AKT en ESCC. Se identificó que el nivel de expresión de SPRY2 en ESCC estaba notablemente disminuido en comparación con los tejidos normales, y estaba relacionado con las características clínico-patológicas y el pronóstico de los pacientes con ESCC. La regulación positiva de la expresión de SPRY2 inhibió notablemente la proliferación, migración e invasión de células Eca-109. Además, la actividad de la señalización de ERK/AKT también fue suprimida por la regulación positiva de SPRY2 en las células Eca-109. Nuestro estudio sugiere que la sobreexpresión de SPRY2 suprime la proliferación y la invasión de células cancerosas mediante la supresión de las vías de señalización ERK/AKT en ESCC. Por lo tanto, SPRY2 puede ser un marcador de pronóstico prometedor y un objetivo terapéutico para la ESCC.

Effect of complement C1s on biological behavior of esophageal squamous cell carcinoma / 中国免疫学杂志

Objective:To explore the effect of complement component C1s on the proliferation,migration and adhesion of esophageal squamous cell carcinoma(ESCC)cells and on the growth of xenograft tumors in nude mice.Methods:The C1S mRNA ex-pression of ESCC tissues and adjacent normal tissues(ANTs)were analyzed using NCBI-GEO database.The C1s expression of ESCC cell lines was analyzed with RT-qPCR and Western blot.The knockdown or overexpression of C1s in ESCC cells lines was performed using C1s small interfering RNA(siRNA),C1s short hairpin RNA(shRNA)or C1s overexpression lentivirus,and the cell prolifera-tion was detected by CCK-8 assay,cell migration was detected by cell wound healing assay,cell adhesion was detected by cell-matrix adhesion assay,the expressions of matrix metalloproteinases MMP1 and MMP13 were detected by Western blot,and the effect of C1s on the growth of xenograft tumors in nude mice was detected by subcutaneous tumorigenesis assay in nude mice.The expression of CD34 in the xenograft tumors was detected by immunohistochemistry,and the formation of tumor microvessel was analyzed.Results:The expression of C1S mRNA in ESCC tissues was significantly higher than that in ANTs.Knockdown of C1s significantly suppressed proliferation,migration and cell-matrix adhesion of ESCC cells,as well as growth of xenograft tumors in nude mice,while overexpres-sion of C1s had the opposite effects.The expressions of MMP1 and MMP13 were decreased in ESCC cells TE-1 with C1s knockdown.Compared with control group,the microvessel of the xenograft tumors in the C1s overexpression group were more abundant.Conclu-sion:C1s is significantly upregulated in ESCC tissues,and promotes proliferation,migration,cell-matrix adhesion of ESCC cells,and the growth of xenograft tumors.C1s may play an important role in the occurrence and development of ESCC.

Meta-analysis of clinical value of adjuvant radiotherapy versus surgery alone in the treatment of stage pT 2-3N 0M 0 esophageal squamous cell carcinoma / 中华放射肿瘤学杂志

Objective:To compare the efficacy and safety of adjuvant radiotherapy versus surgery alone in patients with stage pT 2-3N 0M 0 esophageal squamous cell carcinoma after radical resection. Methods:The search was conducted through Web of Science, Emabse, PubMed, Cochrane Library, CNKI, Chongqing VIP, China Biomedical Literature Database, and Wanfang database, etc. The search time was ranged from the establishment of the database to December 2022. Searched studies were screened according to the inclusion and exclusion criteria. Review Manager 5.4 software was used for analysis.Results:Clinical data of 2 424 patients from 8 controlled clinical studies were finally included. Meta-analysis showed that postoperative adjuvant radiotherapy had higher 3-year and 5-year disease-free survival rates ( OR=2.33, 95%CI=1.71-3.17, P<0.001; OR=2.38, 95% CI=1.73-3.27, P<0.001) and 3-year and 5-year overall survival rates ( OR=1.89, 95% CI=1.37-2.60, P<0.01; OR=1.94,95% CI=1.50-2.49, P<0.001) than surgery alone. Meanwhile, the local recurrence rate ( OR=0.33, 95% CI=0.21-0.50, P<0.001) and distant metastasis rate ( OR=0.62, 95% CI=0.39-0.98, P=0.040) of postoperative adjuvant radiotherapy group were lower than those in the surgery alone group. The incidence of radiation esophagitis (1.4%-9.5%), radiation pneumonitis (2.1%) and anastomotic stenosis (5.3%) was reported. Conclusions:For patients with stage pT 2-3N 0M 0 squamous cell carcinoma after radical resection of esophageal cancer, adjuvant radiotherapy may improve 3-year and 5-year disease-free survival rates and 3-year and 5-year overall survival rates compared with surgery alone. In addition, adjuvant radiotherapy may reduce the local recurrence and distant metastasis rates. Therefore, postoperative adjuvant radiotherapy is an optional treatment for stage pT 2-3N 0M 0 esophageal squamous cell carcinoma.

Analysis of long-term efficacy of radiotherapy for elderly patients with esophageal squamous cell carcinoma / 中华放射肿瘤学杂志

Objective:To evaluate the long-term efficacy of radiotherapy for elderly patients with esophageal squamous cell carcinoma.Methods:Clinical data of 118 elderly patients aged ≥65 years with esophageal squamous cell carcinoma treated with radiotherapy alone or concurrent chemoradiotherapy in Cancer Hospital affiliated to Xinjiang Medical University from January 2013 to January 2016 were retrospectively analyzed. All patients were randomly divided into the radiotherapy alone ( n=57) and concurrent chemoradiotherapy groups ( n=61). The effective rate, survival rate, adverse reactions and causes of death were compared between two groups. Rate and constituent ratio were used to describe the categorical variables, and Pearson Chi-square test was used for univariate analysis. Results:The effective rate (68.4% vs. 86.9%, P=0.016) and incidence of adverse reactions (21.1% vs. 50.9%, P<0.001) between radiotherapy alone and concurrent chemoradiotherapy groups were significantly differed. The 1-year overall survival rate significantly differed between two groups (75.4% vs. 91.8%, P=0.016), while no significant differences were observed in the 3-year overall survival rate (36.8% vs. 42.7%, P=0.088) and 5-year overall survival rate (10.7% vs. 18.0%, P=0.746). The main cause of death in two groups was recurrence combined with distant metastasis. Conclusion:Compared with the radiotherapy alone, concurrent chemoradiotherapy can significantly improve the effective rate and survival rate for elderly patients with esophageal squamous cell carcinoma, whereas it may increase the incidence of adverse reactions.

Clinical analysis of minimally invasive McKeown esophagectomy for esophageal squamous cell carcinoma in Peking Union Medical College Hospital / 中华胸心血管外科杂志

Objective:To summarize and analyze the clinical outcome of minimally invasive McKeown esophagectomy for esophageal squamous cell carcinoma.Methods:We retrospectively analyzed the clinical data of patients with esophageal squamous cell carcinoma who received minimally invasive McKeown esophagectomy in Peking Union Medical College Hospital from January 2017 to December 2022. Improved anesthesia methods, monitoring of recurrent laryngeal nerve, minimally invasive gastrostomy, and jejunostomy techniques were introduced in surgical procedure. We evaluated perioperative data and long-term follow-up survival in these patients.Results:A total of 226 esophageal squamous cell carcinoma patients who met the inclusion and exclusion criteria were enrolled, of which 48.2% received neoadjuvant therapy. The mean operation time was( 327 ± 68) min, with a total of 40.5(33, 50) lymph nodes and 27(19, 33) thoracic lymph nodes harvested. The postoperative hospital stay was 9(7, 12) days, and the postoperative complication rate was 36.3%. In terms of learning curve, after 50 patients intraoperative blood loss, postoperative hospital stay, and recurrent laryngeal nerve injury rate were significantly decreased. The number of total lymph nodes, thoracic lymph nodes, and the 106tbl harvested was significantly increased. The median follow-up time was 23.5(14, 47) months, with a loss of follow-up rate of 3.5%. The overall 2-year and 5-year survival rates were 82.6% and 71.8%, respectively.Conclusion:Improved minimally invasive McKeown esophagectomy for esophageal squamous cell carcinoma are safe and acceptable. Learning curve can be shortened, with increased lymph node harvested and decreased postoperative complications, which improving the short-term and long-term outcomes of patients.

Short-term efficacy of minimally invasive esophagectomy combined with three-field versus two-field lymphadenectomy for 257 patients / 中国胸心血管外科临床杂志

@#Objective To explore the safety of minimally invasive esophagectomy (MIE) with three-field lymphadenectomy (3-FL) for esophageal squamous cell carcinoma (ESCC) by comparing the short-term outcomes between the 3-FL and the two-field lymphadenectomy (2-FL) in MIE. Methods The clinical data of patients with ESCC who underwent minimally invasive McKeown esophagectomy in our hospital from July 2015 to March 2022 were collected retrospectively. Patients were divided into a 3-FL group and a 2-FL group according to lymph node dissection method. And the clinical outcomes and postoperative complications were compared between the two groups. Results A total of 257 patients with ESCC were included in this study. There were 211 males and 46 females with an average age of 62.2±8.1 years. There were 109 patients in the 3-FL group and 148 patients in the 2-FL group. The operation time of the 3-FL group was about 20 minutes longer than that of the 2-FL group (P<0.001). There was no statistical difference between the two groups in the intraoperatve blood loss (P=0.376). More lymph nodes (P<0.001) and also more positive lymph nodes (P=0.003) were obtained in the 3-FL group than in the 2-FL group, and there was a statistical difference in the pathological N stage between the two groups (P<0.001). But there was no statistical difference in the incidence of anastomotic leak (P=0.667), chyle leak (P=0.421), recurrent laryngeal nerve injury (P=0.081), pulmonary complications (P=0.601), pneumonia (P=0.061), cardiac complications (P=0.383), overall complications (P=0.147) or Clavien-Dindo grading (P=0.152) between the two groups. Conclusion MIE 3-FL can improve the efficiency of lymph node dissection and the accuracy of tumor lymph node staging, but it does not increase the postoperative complications, which is worthy of clinical application.

Construction and verification of nomogram prediction model for survival prognosis of patients with esophageal squamous cell carcinoma / 中国胸心血管外科临床杂志

@#Objective To investigate the prognostic value of preoperative serum albumin-to-globulin ratio (AGR) and neutrophil-lymphocyte ratio (NLR) in the overall survival (OS) of patients with esophageal squamous cell carcinoma (ESCC), and to establish an individualized nomogram model and evaluate its efficacy, in order to provide a possible evaluation basis for the clinical treatment and postoperative follow-up of ESCC patients. Methods AGR, NLR, clinicopathological and follow-up data of ESCC patients diagnosed via pathology in the Department of Thoracic Surgery, The First Affiliated Hospital of Xinjiang Medical University from 2010 to 2017 were collected. The correlation between NLR/AGR and clinicopathological data were analyzed. Kaplan-Meier analysis and log-rank test were used for survival analysis. The optimal cut-off values of AGR and NLR were determined by X-tile software, and the patients were accordingly divided into a high-level group and a low-level group. At the same time, univariate and multivariate Cox regression analyses were used to identify independent risk factors affecting OS in the ESCC patients, and a nomogram prediction model was constructed and internally verified. The diagnostic efficacy of the model was evaluated by receiver operating characteristic (ROC) curve and calibration curve, and the clinical application value was evaluated by decision curve analysis. Results A total of 150 patients were included in this study, including 105 males and 45 females with a mean age of 62.3±9.3 years, and the follow-up time was 1-5 years. The 5-year OS rate of patients in the high-level AGR group was significantly higher than that in the low-level group (χ2=6.339, P=0.012), and the median OS of the two groups was 25 months and 12.5 months, respectively. The 5-year OS rate of patients in the high-level NLR group was significantly lower than that in the low-level NLR group (χ2=5.603, P=0.018), and the median OS of the two groups was 18 months and 39 months, respectively. Multivariate Cox analysis showed that AGR, NLR, T stage, lymph node metastasis, N stage, and differentiation were independent risk factors for the OS of ESCC patients. The C-index of the nomogram model was 0.689 [95%CI (0.640, 0.740)] after internal validation. The area under the ROC curve of predicting 1-, 3-, and 5-year OS rate was 0.773, 0.724 and 0.725, respectively. At the same time, the calibration curve and the decision curve suggest that the model had certain efficacy in predicting survival and prognosis. Conclusion Preoperative AGR and NLR are independent risk factors for ESCC patients. High level of AGR and low level of NLR may be associated with longer OS in the patients; the nomogram model based on AGR, NLR and clinicopathological features may be used as a method to predict the survival and prognosis of ESCC patients, which is expected to provide a reference for the development of personalized treatment for patients.

Expression and clinical significance of phosphorylated FGFR1Y654 in esophageal squamous cell carcinoma / 陆军军医大学学报

Objective To explore the relationship between p-FGFR1Y654 expression and clinical pathological characteristics of esophageal squamous cell carcinoma patients and its prognostic value.Methods Tumor tissue samples from 103 cases of esophageal squamous cell carcinoma and 58 normal esophageal tissues were surgically collected in the General Hospital of Western Theater between January 2017 and July 2020.The expression of p-FGFR1Y654 in the tissues was detected using immunohistochemical assay,and its correlation with relevant clinicopathological parameters and prognosis was analyzed.Results The expression of p-FGFR1Y654 in esophageal squamous cell carcinoma tissues was significantly higher than that in normal tissue(P＜0.01).Its expression level was closely related to overall survival(OS,P＜0.05),but not related to age,gender,tumor stage or tumor size.Multivariate COX regression analysis showed that N-stage was identified as an independent prognostic factor for recurrence free survival(RFS)in esophageal squamous cell carcinoma patients.Survival analysis indicated that patients with low expression of p-FGFR1Y654 had significantly higher RFS and OS than those with high expression(P=0.032,95％CI:1.08～4.65;P=0.004,95％CI:2.14-11.51).Conclusion p-FGFR1Y654 is highly expressed in esophageal squamous cell carcinoma tissue,and is associated with poor prognosis in these patients.p-FGFR1Y654 may be a potential therapeutic target for esophageal squamous cell carcinoma.

Research progress of liquid biopsy technology in esophageal squamous cell carcinoma / 国际肿瘤学杂志

In recent years, with the continuous development of biotechnology, liquid biopsy techno-logy has gradually become a research hotspot in the field of tumor research. As a non-invasive diagnostic method, liquid biopsy has great advantages compared with traditional methods. The liquid biopsy technology is precise, convenient, non-invasive and safe, and has an increasingly important clinical significance in the early diagnosis, treatment and prognosis assessment of esophageal squamous cell carcinoma.

A real-world clinical study of immunocheckpoint inhibitor maintenance therapy after radical radiotherapy and chemotherapy in stage Ⅲ-ⅣA esophageal squamous cell carcinoma / 国际肿瘤学杂志

Objective:To investigate the efficacy of immune checkpoint inhibitor maintenance therapy after radical radiotherapy and chemotherapy for stage Ⅲ-ⅣA esophageal squamous cell carcinoma (ESCC) in the real world.Methods:The clinical data of 65 patients with stage Ⅲ-ⅣA ESCC treated by radical radiotherapy and chemotherapy from January 1, 2018 to December 31, 2022 in Hefei Cancer Hospital, Chinese Academy of Sciences were retrospectively analyzed. According to whether to undergo immune checkpoint inhibitor maintenance therapy after radical radiotherapy and chemotherapy, the patients were divided into a control group ( n=29) and an immune maintenance therapy group ( n=36) . The objective response rate (ORR) , progression-free survival (PFS) , and overall survival (OS) between the two groups were compared. Kaplan-Meier method was used to draw the survival curve accompanied with log-rank test. Cox regression model was used to conduct both univariate and multivariate analyses. Results:The ORR was 34.5% (10/29) in the control group and 61.1% (22/36) in the immune maintenance therapy group, with a statistically significant difference ( χ2=4.56, P=0.032) . The median PFS of control group and immune maintenance therapy group were 7.2 and 17.9 months, respectively, with a statistically significant difference ( χ2=7.86, P=0.005) . The median OS was 14.1 and 27.8 months, respectively, with a statistically significant difference ( χ2=5.40, P=0.020) . Univariate analysis showed that, objective response ( HR=0.09, 95% CI: 0.03-0.28, P<0.001) and immune maintenance therapy ( HR=0.38, 95% CI: 0.17-0.88, P=0.024) were the influential factors of OS in ESCC patients treaded by radical chemoradiotherapy in stage Ⅲ-ⅣA. Multivariate analysis showed that, objective response ( HR=0.09, 95% CI: 0.03-0.29, P<0.001) and immune maintenance therapy ( HR=0.40, 95% CI: 0.17-0.92, P=0.032) were the independent influencing factors for OS in ESCC patients treaded by radical chemoracial therapy in stage Ⅲ-ⅣA. The incidence of adverse reactions was 22.22% (8/36) in the immune maintenance therapy group and 10.34% (3/29) in the control group, with no statistically significant difference ( χ2=1.61, P=0.204) . All the adverse reactions were grade 1-2, and the symptoms were relieved after symptomatic treatment. Conclusion:Maintenance therapy with immune checkpoint inhibitors after radical chemoradiotherapy of stage Ⅲ-ⅣA ESCC can significantly improve the prognosis of patients with good safety.

Adjuvant strategies for patients with T1b invasion after endoscopic submucosal dissection for esophageal squamous cell carcinoma / 上海交通大学学报（医学版）

Objective·To compare the prognostic effects of radical resection of esophageal cancer,concurrent chemoradiotherapy and simple follow-up observation on the prognosis of patients with T1b invasion of superficial esophageal squamous cell carcinoma after endoscopic submucosal dissection(ESD).Methods·From May 2016 to May 2021,the clinical data of 67 patients with esophageal squamous cell carcinoma who were pathologically confirmed as pT1b after ESD and treated in Shanghai Chest Hospital were retrospectively analyzed.According to the additional treatment after ESD,the patients were divided into additional surgery group(S group),chemoradio-therapy group(CRT group)and observation group(O group).χ2 test was used to compare the clinical baseline data and pathological information of the three groups of patients.The Kaplan-Meier survival curve and log-rank test were used to compare the disease free survival(DFS)and recurrence free survival(RFS)of the three groups of patients,and the Cox proportional hazards regression model was used on DFS and RFS by univariate and multivariate analysis.Results·Among all 67 patients,there were 23 cases in the S group,19 cases in the CRT group,and 25 cases in the O group.There was no significant difference in age(P=0.080),gender(P=0.078),tumor length(P=0.485),tumor location(P=0.655),lesion circumferential ratio(P= 0.310),histological grading(P=0.084),depth of tumor invasion(P=0.066)and lymphovascular invasion(P=0.279)among the three groups.During(42.6±16.7)months of follow-up,tumor recurrence was observed in 10 cases(14.9%),including 6 patients(60%)with local recurrence,2 patients(20%)with regional lymph recurrence and 2 patients(20%)with distant metastasis.The median recurrence time of group S,group CRT,and group O was 40.1,36.6,and 22.1 months,and the 3-year DFSs were 100%,89.5%,and 74.5%(P-trend=0.040).Multivariate Cox analysis showed that additional esophagectomy was the key to improving independent protective factors of RFS(HR=0.097,95%CI 0.010?0.956,P=0.046).Conclusion·For patients with superficial esophageal squamous cell carcinoma confirmed as pT1b after ESD,additional surgery can significantly reduce the possibility of long-term recurrence.

Application value of CT texture analysis for evaluating Ki-67 expression in patient with esophageal squamous cell carcinoma / 实用放射学杂志

Objective To explore the application value of CT texture analysis for evaluating Ki-67 expression in patient with esophageal squamous cell carcinoma.Methods Sixty-one cases of pathologically confirmed esophageal squamous cell carcinoma patients were selected to obtain the Ki-67 protein expression status of the patients'pathological tissues,and the patients were divided into a high-expression group and a low-expression group.All patients underwent plain and enhanced chest CT within two weeks before surgery.Lesions delineation and texture feature extraction of esophageal cancer were obtained via Omni-Kinetics software.The texture parameters included Min Intensity,Max Intensity,Median Intensity,Mean Intensity,Deviation,Skewness,Kurtosis,Entropy,Energy,Correlation,Haralick,short run high grey level emphasis(SRHGLE),short run low grey level emphasis(SRLGLE),long run high grey level emphasis(LRHGLE),long run low grey level emphasis(LRLGLE),Grey Level Nonuniformity,Run Length Nonuniformity.The differences of texture features among different Ki-67 expression groups were compared,and the receiver operating characteristic(ROC)curve was used to analyze the predictive value of Ki-67 expression in patient with esophageal cancer.Results In plain CT images,the SRHGLE and Grey Level Nonuniformity of the high expression group were significantly higher than those of the low expression group(P=0.010,0.002,respectively).In enhanced CT images,the Mean Intensity,Entropy and Grey Level Nonuniformity of the high expression group were significantly higher than those of the low expression group(P=0.026,0.037,0.001,respectively),and SRHGLE and LRHGLE of the high expression group were significantly lower than those of the low expression group(P=0.016,0.010,respectively).The area under the curve(AUC)of texture features in plain CT were 0.676-0.740,and the AUC of combined diagnosis reached 0.770[95%confidence interval(CI):0.645,0.868],and sensitivity and specificity was 0.921,0.565,respectively.In enhanced CT,the AUC of texture features were 0.629-0.750,the AUC of combined diagnosis increased to 0.903(95%CI:0.799,0.964),and sensitivity and specificity was 0.816,0.826,respectively.Conclusion CT texture analysis can early and non-invasively predict Ki-67 expression in patient with esophageal squamous cell carcinoma,it can be used as an imaging marker to evaluate the proliferative activity of esophageal cancer cells,and may provide diagnosis and treatment information for clinical decision-making of esophageal squamous cell carcinoma.

The predictive value of 18F-FDG PET/CT metabolic heterogeneity parameters combined with clinical features for the prognosis of esophageal squamous cell carcinoma before definitive radiochemotherapy / 实用医学杂志

Objective This study aimed to explore the prognostic value of 18F-FDG PET/CT Metabolic and Heterogeneity Parameters Combined with Clinical Features Before Definitive Chemoradiotherapy(D-CRT)in predicting the prognosis of esophageal squamous cell carcinoma(ESCC)Patients.Methods A retrospective analysis was conducted on clinical data from 106 patients with ESCC who received D-CRT at the first affiliated Hospital of University of Science and Technology of China between January 2017 and December 2021.All patients underwent 18F-FDG PET/CT examination before the treatment.The primary tumor′s metabolic and heterogeneity parameters were obtained through data processing.All patients were followed up for overall survival.The Kaplan-Meier method and Cox proportional hazards models were used to analyze the association between clinical features,tumor metabo-lism and heterogeneity parameters and patient prognosis.Results The 1-and 1.5-year overall survival rates of all patients were 77.4%and 51.9%.The median survival time was 20 months.Univariate analysis showed that N stage,M stage,metabolic tumor volume,total lesion glycolysis,heterogeneity index-2(HI-2),and coefficient of variation with a threshold of 40%maximum standard uptake value(CV40%)were correlated with the prognosis of ESCC(all P<0.05).Multivariate analysis showed that N stage and CV40%were independent predictors of prognosis in patients with ESCC(P = 0.039 and P<0.001,respectively).Conclusion N stage and tumor metabolic heterogeneity parameter CV40%,which offering a degree of predictive value,are closely related to the prognosis of patients with ESCC treated with D-CRT.

Effect of Survivin Down-Regulation by Egr1-Survivin shRNA Combined with Radiotherapy on Radiosensitivity of Esophageal Squamous Carcinoma / Efecto de la Regulación Negativa de Survivina por shRNA de Egr1-Survivina Combinado con Radioterapia sobre la Radiosensibilidad del Carcinoma Escamoso de Esófago

SUMMARY: This study is to investigate the effect of survivin down-regulation by Egr1-survivin shRNA combined with radiotherapy on the apoptosis and radiosensitivity of esophageal squamous cell carcinoma ECA109 and KYSE150 cells. ECA109 and KYSE150 cells were transfected with Egr1-survivin shRNA, and then treated with radiotherapy. After 24 h, the mRNA and protein levels of Egr1-survivin were detected by qPCR and Western-Blot. Cell cycle and apoptosis were detected by flow cytometry. Western blot also detected levels of cleavaged Caspase 3 and Caspase 9. YM155 was used as a positive control to inhibit survivin expression. The levels of survivin mRNA and protein in ECA109 and KYSE150 cells treated with Egr1-survivin shRNA combined with radiotherapy were significantly lower than those of the blank control group, the empty vector control group, and, the YM155 + radiotherapy group (P<0.05). Meanwhile, after survivin down-regulation, the ratio of G2 to S phase of ECA109 and KYSE150 cells increased significantly, leading to significant G2 and S phase arrest. Additionally, apoptosis of ECA109 and KYSE150 cells increased significantly (P <0.01). Further, protein levels of cleavaged Caspase 3 and Caspase 9 significantly increased in Egr1-survivin shRNA combined with radiotherapy group. Egr1-survivin shRNA combined with radiotherapy can down-regulate survivin expression, which further increases the apoptosis, and enhances the radiosensitivity of ECA109 and KYSE150 cells.

Este estudio tuvo como objetivo investigar el efecto de la regulación negativa de survivina por el shRNA de Egr1-survivina combinado con radioterapia sobre la apoptosis y la radiosensibilidad del carcinoma de células escamosas de esófago Células ECA109 y KYSE150. Las células ECA109 y KYSE150 se transfectaron con shRNA de survivina Egr1 y luego se trataron con radioterapia. Después de 24 h, los niveles de ARNm y proteína de Egr1-survivina se detectaron mediante qPCR y Western-Blot. El ciclo celular y la apoptosis se detectaron mediante citometría de flujo. La transferencia Western también detectó niveles de Caspasa 3 y Caspasa 9 escindidas. Se usó YM155 como control positivo para inhibir la expresión de survivina. Los niveles de ARNm y proteína de survivina en células ECA109 y KYSE150 tratadas con shRNA de survivina Egr1 combinado con radioterapia fueron significativamente más bajos que los del grupo control en blanco, el grupo control de vector vacío y el grupo de radioterapia YM155 + (P <0,05). Mientras tanto, después de la regulación negativa de survivina, la proporción entre las fases G2 y S de las células ECA109 y KYSE150 aumentó significativamente, lo que llevó a una detención significativa de las fases G2 y S. Además, la apoptosis de las células ECA109 y KYSE150 aumentó significativamente (P <0,01). Además, los niveles de proteína de Caspasa 3 y Caspasa 9 escindidas aumentaron significativamente en el shRNA de Egr1- survivina combinado con el grupo de radioterapia. El shRNA de survivina de Egr1 combinado con radioterapia puede regular negativamente la expresión de survivina, lo que aumenta aún más la apoptosis y mejora la radiosensibilidad de las células ECA109 y KYSE150.

Cost-utility analysis of sintilimab combined with chemotherapy in first-line treatment of advanced，recurrent or metastatic esophageal squamous cell carcinoma / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of sintilimab combined with chemotherapy than single-use chemotherapy in the first-line treatment of advanced， recurrent or metastatic esophageal squamous cell carcinoma （ESCC） from the perspective of health system of our country， and provide reference for rational use of drug in clinic. METHODS Based on ORIENT-15 study data， TreeAge Pro 2011 software was used to establish a three-state Markov model of non-progressive survival （PFS）， disease progression and death for cost-utility analysis. The model period was 3 weeks， the research time limit was 10 years， and the discount rate was 5%. The main outputs of the model were total cost， quality-adjusted life year （QALY） and incremental cost-effectiveness ratio （ICER）. The 1-3 times of China’s GDP per capita in 2021 was taken as the threshold of willing- ness to pay （WTP）. The uncertainty of the parameters was analyzed by single factor sensitivity analysis and probability sensitivity analysis， and the cost-effectiveness of the two schemes was discussed under three situations： different discount rates， comparison with other similar treatment schemes and charitable drug donation schemes. RESULTS The results of basic analysis showed that compared with chemotherapy plan alone， the ICER of sintilimab combined with chemotherapy was 64 208.75 yuan/QALY， which was less than WTP threshold. The results of single factor sensitivity analysis show that PFS state utility value， cycle cost of sintilimab and discount rate had relatively great influence on the results. Probability sensitivity analysis showed that when WTP≥120 000 yuan， the economic probability of sintilimab combined with chemotherapy plan was 100%. The results of situational analysis showed that sintilimab combined chemotherapy was more cost- effective than single-use chemotherapy. CONCLUSIONS Sintilimab combined with chemotherapy is more cost-effective than single-use chemotherapy in the first-line treatment of advanced， recurrent or metastatic ESCC.

Cost-utility analysis of tislelizumab monotherapy for second-line treatment of advanced or metastatic esophageal squamous cell carcinoma / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of tislelizumab monotherapy in the second-line treatment of advanced or metastatic esophageal squamous cell carcinoma （ESCC），so as to provide reference for rational use of drug in clinic. METHODS A three-state partitioned survival model was constructed from the perspective of China’s health system， based on the data of RATIONALE-302 study，with simulation time limit of 10 years， cycle period of 1 month. The incremental cost-effectiveness ratio （ICER） was calculated with quality-adjusted life year （QALY） as utility index. The cost-effectiveness of tislelizumab monotherapy was compared with that of chemotherapy for second-line treatment of advanced or metastatic ESCC by cost-utility analysis. The stability of basic analysis results was validated through sensitivity analysis and scenario analysis. RESULTS The results of basic analysis showed that compared with chemotherapy group， incremental cost per capita of tislelizumab group was 35 025.32 yuan，and incremental utility per capita was 2.71 QALYs； ICER was 12 892.31 yuan/QALY， which was far lower than the willingness-to-pay （WTP） threshold of 3 times of China’s per capita gross domestic product （GDP） 242 928 yuan in 2021. The results of univariate sensitivity analysis showed that parameters such as the cost of apatinib， the utility value of disease progression status and the cost of adverse reactions in the chemotherapy group had a great impact on the ICER value， but these parameters could not cause the reversal of the basic analysis results. Probabilistic sensitivity analysis showed that WTP threshold was higher than 80 000 yuan/QALY，the probability of tislelizumab monotherapy possessed cost-effectiveness was 100%. Results of scenario analysis showed that in which model simulation time lasted for 5 or 20 years，ICER of tislelizumab was 8 331.00 yuan/QALY and 12 981.00 yuan/QALY， which were less than 3 times of China’s per capita GDP in 2021 as WTP threshold. CONCLUSIONS When three times of China’s GDP per capita in 2021 is taken as the WTP threshold， the second-line treatment of tirelizumab monotherapy for advanced or metastatic ESCC is more cost-effective than chemotherapy.

Analysis of risk factors for depth of invasion and angiolymphatic invasion for circumferential superficial esophageal squamous cell carcinoma and precancerous lesion / 中华肿瘤杂志

Objective: To analyze clinicopathological features of circumferential superficial esophageal squamous cell carcinoma and precancerous lesions and investigate the risk factors for deep submucosal invasion and angiolymphatic invasion retrospectively. Methods: A total of 116 cases of esophageal squamous epithelial high-grade intraepithelial neoplasia or squamous cell carcinoma diagnosed by gastroscopy, biopsy pathology and endoscopic resection pathology during November 2013 to October 2021 were collected, and their clinicopathological features were analyzed. The independent risk factors of deep submucosal invasion and angiolymphatic invasion were analyzed by logistic regression model. Results: The multivariate logistic regression analysis showed that drinking history (OR=3.090, 95% CI: 1.165-8.200; P<0.05), The AB type of intrapapillary capillary loop (IPCL) (OR=11.215, 95% CI: 3.955-31.797; P<0.05) were the independent risk factors for the depth of invasion. The smoking history (OR=5.824, 95% CI: 1.704-19.899; P<0.05), the presence of avascular area (AVA) (OR=3.393, 95% CI: 1.285-12.072; P<0.05) were the independent factors for the angiolymphatic invasion. Conclusions: The risk of deep submucosal infiltration is greater for circumferential superficial esophageal squamous cell carcinoma patients with drinking history and IPCL type B2-B3 observed by magnifying endoscopy, while the risk of angiolymphatic invasion should be vigilant for circumferential superficial esophageal squamous cell carcinoma patients with smoking history and the presence of AVA observed by magnifying endoscopy. Ultrasound endoscopy combined with narrowband imagingand magnification endoscopy can improve the accuracy of preoperative assessment of the depth of infiltration of superficial squamous cell carcinoma and precancerous lesions and angiolymphaticinvasion in the whole perimeter of the esophagus, and help endoscopists to reasonably grasp the indications for endoscopic treatment.

Study on the prognostic influencing factors of esophageal squamous cell carcinoma and the predictive value of inflammatory reaction indexes on its postoperative recurrence / 中华肿瘤杂志

Objective: To explore the influence factors of poor prognosis of esophageal squamous cell carcinoma (ESCC) and the predictive value of inflammatory reaction indexes including neutrophils and lymphocytes ratio (NLR), platelet and lymphocyte ratio (PLR), monocyte and lymphocyte ratio (MLR) provision and differentiation degree, infiltration depth, lymph node metastasis number on the postoperative recurrence of ESCC. Methods: A total of 130 patients with ESCC who underwent radical resection from February 2017 to February 2019 in Nanyang Central Hospital were selected and divided into good prognosis group (66 cases) and poor prognosis group (64 cases) according to the prognostic effect. The clinical data and follow-up data were collected. Multivariate logistic regression analysis was used to determine the independent influencing factors of poor prognosis. Spearman correlation analysis was used to determine the correlation between preoperative NLR, PLR and MLR with the degree of differentiation, depth of invasion and number of lymph node metastases. Receiver operating characteristic (ROC) curve analysis was used to evaluate the efficacy of NLR, PLR and MLR in predicting poor prognosis of ESCC. Results: Univariate analysis showed that the degree of differentiation, the degree of invasion and the number of lymph node metastasis were related to the prognoses of patients with ESCC (P<0.05). Multivariate logistic regression analysis showed that the degree of differentiation, depth of invasion and number of lymph node metastases were independent influencing factors for poor prognosis of patients with ESCC, moderate differentiation (OR=2.603, 95% CI: 1.009-6.715) or low differentiation (OR=9.909, 95% CI: 3.097-31.706), infiltrating into fibrous membrane (OR=14.331, 95% CI: 1.333-154.104) or surrounding tissue (OR=23.368, 95% CI: 1.466-372.578), the number of lymph node metastases ≥ 3 (OR=9.225, 95% CI: 1.693-50.263) indicated poor prognosis. Spearman correlation analysis showed that NLR was negatively correlated with the degree of differentiation and the number of lymph node metastases (r=-0.281, P=0.001; r=-0.257, P=0.003), PLR was negatively correlated with the degree of differentiation, depth of invasion and number of lymph node metastasis (r=-0.250, P=0.004; r=0.197, P=0.025; r=-0.194, P=0.027), MLR was positively correlated with the degree of differentiation and the number of lymph node metastasis (r=0.248, P=0.004; r=0.196, P=0.025). ROC curve analysis showed that the areas under the curve of NLR, PLR and MLR in predicting poor prognosis of ESCC were 0.971, 0.925 and 0.834, respectively. The best cut-off value of NLR was 2.87. The sensitivity and specificity of NLR in predicting poor prognosis of ESCC were 90.6% and 87.9%, respectively. The optimal cut-off value of PLR was 141.75. The sensitivity and specificity for predicting poor prognosis of ESCC were 92.2% and 87.9%, respectively. The best cut-off value of MLR was 0.40. The sensitivity and specificity of MLR in predicting poor prognosis of esophageal squamous cell carcinoma were 54.7% and 100.0%, respectively. Conclusions: The degree of differentiation, the degree of invasion and the number of lymph node metastases are closely related to the poor prognosis of patients with esophageal squamous cell carcinoma. NLR, PLR and MLR can provide important information for predicting the poor prognosis of esophageal squamous cell carcinoma.

GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma / 医学前沿

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

PAFR/Stat3 axis maintains the symbiotic ecosystem between tumor and stroma to facilitate tumor malignancy

Stroma surrounding the tumor cells plays crucial roles for tumor progression. However, little is known about the factors that maintain the symbiosis between stroma and tumor cells. In this study, we found that the transcriptional regulator-signal transducer and activator of transcription 3 (Stat3) was frequently activated in cancer-associated fibroblasts (CAFs), which was a potent facilitator of tumor malignancy, and formed forward feedback loop with platelet-activating factor receptor (PAFR) both in CAFs and tumor cells. Importantly, PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells. Two central Stat3-related cytokine signaling molecules-interleukin 6 (IL-6) and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs. Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model. Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.