Construction and validation of classification models for predicting the response to concurrent chemo-radiotherapy of patients with esophageal squamous cell carcinoma based on multi-omics data.

BACKGROUND: Concurrent chemo-radiotherapy (CCRT) is the preferred non-surgical treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Unfortunately, some patients respond poorly, which leads to inappropriate or excessive treatment and affects patient survival. To accurately predict the response of ESCC patients to CCRT, we developed classification models based on the clinical, serum proteomic and radiomic data. METHODS: A total of 138 ESCC patients receiving CCRT were enrolled in this study and randomly split into a training cohort (n = 92) and a test cohort (n = 46). All patients were classified into either complete response (CR) or incomplete response (non-CR) groups according to RECIST1.1. Radiomic features were extracted by 3Dslicer. Serum proteomic data was obtained by Olink proximity extension assay. The logistic regression model with elastic-net penalty and the R-package "rms" v6.2-0 were applied to construct classification and nomogram models, respectively. The area under the receiver operating characteristic curves (AUC) was used to evaluate the predictive performance of the models. RESULTS: Seven classification models based on multi-omics data were constructed, of which Model-COR, which integrates five clinical, five serum proteomic, and seven radiomic features, achieved the best predictive performance on the test cohort (AUC = 0.8357, 95 % CI: 0.7158-0.9556). Meanwhile, patients predicted to be CR by Model-COR showed significantly longer overall survival than those predicted to be non-CR in both cohorts (Log-rank P = 0.0014 and 0.027, respectively). Furthermore, two nomogram models based on multi-omics data also performed well in predicting response to CCRT (AUC = 0.8398 and 0.8483, respectively). CONCLUSION: We developed and validated a multi-omics based classification model and two nomogram models for predicting the response of ESCC patients to CCRT, which achieved the best prediction performance by integrating clinical, serum Olink proteomic, and radiomic data. These models could be useful for personalized treatment decisions and more precise clinical radiotherapy and chemotherapy for ESCC patients.

Cisplatin-induced pyroptosis is mediated via the CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME axis in esophageal cancer.

Esophageal cancer is the seventh most common cancer globally. Chemotherapy resistance remains a significant challenge in the treatment of esophageal cancer patients. Cisplatin can damage tumor cells by inducing pyroptosis. However, the underlying molecular mechanisms remain unclear. In this work, we aim to investigate pyroptosis-dependent molecular mechanisms underlying cisplatin sensitivity and find potential biomarkers to predict response to cisplatin-based chemotherapy for esophageal cancer patients. Pyroptosis-associated proteins were screened via proteomics for esophageal cancer (n = 124) and bioinformatics analysis. We observed that high calpain-1 (CAPN1) and calpain-2 (CAPN2) expression were associated with favorable clinical outcomes and prolonged survival in esophageal cancer patients. We employed immunohistochemistry to evaluate the expression of CAPN1 and CAPN2 in pretreatment tumor biopsies from 108 patients with esophageal cancer who received concurrent chemoradiotherapy (CCRT). These results suggested that esophageal cancer patients with high expression of both CAPN1 and CAPN2 are likely to experience a complete response to CCRT and have significantly better survival. Western blotting, LDH release, calpain activity and cell viability assays indicated that cisplatin could activate calpain activity, while calpain inhibition or knockout suppressed cisplatin-induced pyroptosis. Mechanistically, we uncovered a novel mechanism whereby cisplatin induced pyroptosis via activation of a CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME signaling axis in esophageal cancer cells. Collectively, this study is the first to explore the effects of calpain on cisplatin-induced pyroptosis in esophageal cancer cells. Further, our findings also imply that the combination of CAPN1 and CAPN2 could be considered as a promising biomarker of cisplatin sensitivity and prognosis in patients with esophageal cancer, providing a possibility to guide individualized treatment.

CypA: A Potential Target of Tumor Radiotherapy and/or Chemotherapy.

Cyclophilin A (CypA) is a ubiquitous and highly conserved protein. CypA, the intracellular target protein for the immunosuppressant cyclosporine A (CsA), plays important cellular roles through peptidyl-prolyl cis-trans isomerase (PPIase). Increasing evidence shows that CypA is up-regulated in a variety of human cancers. In addition to being involved in the occurrence and development of multiple tumors, overexpression of CypA has also been shown to be strongly associated with malignant transformation. Surgery, chemotherapy and radiotherapy are the three main treatments for cancer. Chemotherapy and radiotherapy are often used as direct or adjuvant treatments for cancer. However, various side effects and resistance to both chemotherapy and radiotherapy bring great challenges to these two forms of treatment. According to recent reports, CypA can improve the chemosensitivity and/or radiosensitivity of cancers, possibly by affecting the expression of drug-resistant related proteins, cell cycle arrest and activation of the mitogen-activated protein kinase (MAPK) signaling pathways. In this review, we focus on the role of CypA in cancer, its impact on cancer chemotherapeutic and radiotherapy sensitivity, and the mechanism of action. It is suggested that CypA may be a novel potential therapeutic target for cancer chemotherapy and/or radiotherapy.

Development and validation of a radiomics-based model to predict local progression-free survival after chemo-radiotherapy in patients with esophageal squamous cell cancer.

PURPOSE: To develop a nomogram model for predicting local progress-free survival (LPFS) in esophageal squamous cell carcinoma (ESCC) patients treated with concurrent chemo-radiotherapy (CCRT). METHODS: We collected the clinical data of ESCC patients treated with CCRT in our hospital. Eligible patients were randomly divided into training cohort and validation cohort. The least absolute shrinkage and selection operator (LASSO) with COX regression was performed to select optimal radiomic features to calculate Rad-score for predicting LPFS in the training cohort. The univariate and multivariate analyses were performed to identify the predictive clinical factors for developing a nomogram model. The C-index was used to assess the performance of the predictive model and calibration curve was used to evaluate the accuracy. RESULTS: A total of 221 ESCC patients were included in our study, with 155 patients in training cohort and 66 patients in validation cohort. Seventeen radiomic features were selected by LASSO COX regression analysis to calculate Rad-score for predicting LPFS. The patients with a Rad-score ≥ 0.1411 had high risk of local recurrence, and those with a Rad-score < 0.1411 had low risk of local recurrence. Multivariate analysis showed that N stage, CR status and Rad-score were independent predictive factors for LPFS. A nomogram model was built based on the result of multivariate analysis. The C-index of the nomogram was 0.745 (95% CI 0.7700-0.790) in training cohort and 0.723(95% CI 0.654-0.791) in validation cohort. The 3-year LPFS rate predicted by the nomogram model was highly consistent with the actual 3-year LPFS rate both in the training cohort and the validation cohort. CONCLUSION: We developed and validated a prediction model based on radiomic features and clinical factors, which can be used to predict LPFS of patients after CCRT. This model is conducive to identifying the patients with ESCC benefited more from CCRT.

STAT3ß Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma.

Concurrent chemoradiotherapy (CCRT), especially platinum plus radiotherapy, is considered to be one of the most promising treatment modalities for patients with advanced esophageal cancer. STAT3ß regulates specific target genes and inhibits the process of tumorigenesis and development. It is also a good prognostic marker and a potential marker for response to adjuvant chemoradiotherapy (ACRT). We aimed to investigate the relationship between STAT3ß and CCRT. We examined the expression of STAT3α and STAT3ß in pretreatment tumor biopsies of 105 ESCC patients who received CCRT by immunohistochemistry. The data showed that ESCC patients who demonstrate both high STAT3α expression and high STAT3ß expression in the cytoplasm have a significantly better survival rate, and STAT3ß expression is an independent protective factor (HR = 0.424, p = 0.003). Meanwhile, ESCC patients with high STAT3ß expression demonstrated a complete response to CCRT in 65 patients who received platinum plus radiation therapy (p = 0.014). In ESCC cells, high STAT3ß expression significantly inhibits the ability of colony formation and cell proliferation, suggesting that STAT3ß enhances sensitivity to CCRT (platinum plus radiation therapy). Mechanistically, through RNA-seq analysis, we found that the TNF signaling pathway and necrotic cell death pathway were significantly upregulated in highly expressed STAT3ß cells after CCRT treatment. Overall, our study highlights that STAT3ß could potentially be used to predict the response to platinum plus radiation therapy, which may provide an important insight into the treatment of ESCC.

Prognostic Significance of Baseline Neutrophil Count and Lactate Dehydrogenase Level in Patients With Esophageal Squamous Cell Cancer Treated With Radiotherapy.

Background: This present study aimed to explore the prognostic value of pretreatment neutrophil and lactate dehydrogenase (LDH) and to develop a prognostic risk scoring model to predict prognosis in esophageal squamous cell cancer (ESCC) patients treated with definitive radiotherapy. Methods: Retrospectively collected data of patients who received definitive radiotherapy for ESCC at Shantou Central Hospital between January 2009 and December 2015 were included for the analysis. The association between the level of LDH and neutrophil and clinicopathological characteristics were analyzed. We performed univariate and multivariate analyses to identify the prognostic predictors for patients with ESCC. Based on the results, we also developed a prognostic risk scoring model and assessed its predictive ability in the subgroups. Results: A total of 567 patients who received definitive radiotherapy for ESCC were included in the present study. The optimal cutoff values were 4.5 × 109/L, 3.25, and 220 U/L for neutrophil, neutrophil-to-lymphocyte ratio (NLR), and LDH, respectively. A high level of LDH was significantly associated with advanced N stage (p = 0.031), and neutrophil count was significantly associated with gender (p = 0.001), T stage (p < 0.001), N stage (p = 0.019), clinical stage (p < 0.001), and NLR (p < 0.001). Multivariate survival analysis identified gender (p = 0.006), T stage (p < 0.001), N stage (p = 0.008), treatment modality (p < 0.001), LDH level (p = 0.012), and neutrophil count (p = 0.038) as independent prognostic factors for overall survival. Furthermore, a new prognostic risk scoring (PRS) model based on six prognostic factors was developed, in which the patients were divided into three groups with distinct prognosis (χ2 = 67.94, p < 0.0001). Conclusions: Elevated baseline LDH level and neutrophil count predicted poor prognosis for ESCC patients treated with definitive radiotherapy. A PRS model comprised of LDH, neutrophil count, and other prognostic factors would help identify the patients who would benefit the most from definitive radiotherapy.

Effect of modern high-dose versus standard-dose radiation in definitive concurrent chemo-radiotherapy on outcome of esophageal squamous cell cancer: a meta-analysis.

BACKGROUND AND OBJECTIVES: Radiation Therapy Oncology Group (RTOG) 94-05 has demonstrated that higher dose radiation didn't improve outcome of patients with esophageal cancer (EC). However, several retrospective studies showed that a higher dose radiation based on modern radiotherapy techniques could improve overall survival (OS) and local control rate (LCR) of patients with EC, especially esophageal squamous cell cancer (ESCC). As trials have provided updated and controversial data, we performed this updated meta-analysis to investigate whether high-dose (> = 60 Gy) radiotherapy in definitive concurrent chemo-radiotherapy (CCRT) could yield benefit compared to standard dose radiotherapy. METHODS: A systematic literature search was carried out in the database of MEDLINE, PubMed and Embase. All studies published between 1 January 1990 and 31 December 2018 on the association between radiation dose and curative efficiency in EC were included in this meta-analysis. The hazard ratio (HR) was used to evaluate the time-to-event data employing RevMan version 5.3. RESULTS: Eight articles with a total of 3736 patients were finally included. Results indicated that there was a significant benefit in favor of high dose radiotherapy (HD-RT) regarding OS (HR = 0.78, 95%CI: 0.72-0.84, p < 0.001; 2-year OS risk ratio (RR) = 1.25, 95%CI: 1.14-1.37, p < 0.001), progression-free survival (PFS) (P = 0.001, HR = 0.7, 95%CI: 0.57-0.87) and LRFS (P < 0.001, HR = 0.52, 95%CI: 0.36-0.74) . CONCLUSIONS: HD-RT (> = 60 Gy) based on modern radiotherapy techniques in definitive CCRT appears to improve OS, PFS amd LRFS compared to the SD-RT in patients with ESCC.

Impact of sex on the prognosis of patients with esophageal squamous cell cancer underwent definitive radiotherapy: a propensity score-matched analysis.

BACKGROUND: The impact of sex on prognosis of patients with esophageal squamous cell cancer (ESCC) who underwent definitive radiotherapy remained unclear. The present study aimed to determine the impact of sex on the prognosis of patients with ESCC underwent definitive radiotherapy. METHODS: Between January 2009 and December 2015, patients with ESCC underwent definitive radiotherapy in Shantou Central Hospital were included in this study. The Progression-free survival (PFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. The PFS and OS were compared between female and male patients. The Cox regression model was used to identify prognostic factors. Propensity score-matched analysis was performed to balance baseline characteristics between female and male patients. RESULTS: A total of 683 ESCC patients treated with definitive radiotherapy were included, with 497 male and 186 female patients. In the whole cohort, female patients had a significantly longer median PFS (14.0 months vs 10.6 months, P = 0.0001, HR = 0.688, 95% CI, 0.567-0.836) and OS (20.8 months vs 15.9 months, P = 0.0005, HR = 0.702, 95% CI, 0.575-0.857). In the matched cohort, female patients still had a significantly longer median PFS (13.5 months vs 11.6 months) and OS (19.6 months vs 16.1 months). Multivariate analysis showed that sex was an independent prognostic factor for PFS (HR = 0.746, 95% CI, 0.611-0.910, P = 0.004) and OS (HR = 0.755, 95% CI, 0.615-0.926, P = 0.007). CONCLUSIONS: This present study indicated that sex was an independent prognostic factor in Chinese patients with ESCC underwent definitive radiotherapy, with better survival outcome for women than men. Efforts should be made to investigate the underlying biological mechanism.

Analysis of definitive chemo-radiotherapy for esophageal cancer with supra-clavicular node metastasis based on CT in a single institutional retrospective study: a propensity score matching analysis.

BACKGROUND: The prognostic value of supra-clavicular lymph node (SCLN) metastases in esophageal cancer (EC) is still not clear. METHOD: From January 2009 to December 2015, a survival analysis was performed to retrospectively identify the prognostic value of SCLN metastasis on survival on 751 patients with EC treated with definitive chemo-radiotherapy (dCRT). RESULTS: The median follow-up duration for living patients was 56.6 months. The median overall survival (OS) for all patients was 16.6 months. Patients with SCLN metastasis had a much poorer prognosis for OS (χ2 = 17.342, P < 0.001), distant metastasis-free survival (DMFS) (χ2 = 24.793, P < 0.001) and progression-free survival (PFS) (χ2 = 25.802, P < 0.001) than those without SCLN metastasis. The same results were found after propensity score matching. Nonetheless, the prognosis of patients with cervical or upper thoracic EC metastasis in SCLN was better than those of patients with middle or lower thoracic EC metastasis in SCLN for OS (χ2 = 4.516, P = 0.038), DMFS (χ2 = 8.326, P = 0.004) and PFS (χ2 = 6.255, P = 0.012). Univariate analysis showed that gender, middle or lower thoracic EC with SCLN metastasis, tumor length, tumor diameter, concurrent chemo-radiotherapy (CCR) and number of lymph nodes were prognostic factors for PFS. Gender, age, middle or lower thoracic EC with SCLN metastasis, tumor diameter, tumor length, and number of lymph nodes were prognostic factors for DMFS. According to the multivariate analysis, only middle or lower thoracic EC with SCLN metastasis and number of lymph nodes were independent prognostic factors for DMFS and PFS. CONCLUSION: For patients with cervical or upper thoracic EC, metastasis in SCLN should be considered to be regional lymph nodes and treated with curative intent if the total number of lymph nodes is limited. However, for patients with middle or lower thoracic EC, metastasis should be considered to be a higher level N stage or M1 stage, and it is thus necessary to provide consolidation chemotherapy after dCRT.

Predictive biomarkers for response of esophageal cancer to chemo(radio)therapy: A systematic review and meta-analysis.

BACKGROUND: Esophageal cancer remains a major public health issue worldwide. In clinical practice, chemo(radio)therapy is an important approach to patients with esophageal cancer. Only the part of patients who respond to chemo(radio)therapy achieve better long-term outcome. In this case, predictive biomarkers for response of esophageal cancer patients treated with chemo(radio)therapy are of importance. Meta-analysis of P53 for predicting esophageal cancer response has been reported before and is not included in our study. We performed a systematic review and meta-analysis to summarize and evaluate the biomarkers for predicting response to chemo(radio)therapy. METHOD: PubMed, Web of Science and the Ovid databases were searched to identify eligible studies published in English before March 2017. The risk ratio (or relative risk, RR) was retrieved in articles regarding biomarkers for predicting response of esophageal cancer patients treated with neoadjuvant therapy or chemo(radio)therapy. Fixed and random effects models were used to undertake the meta-analysis as appropriate. RESULT: Forty-six articles reporting 56 biomarkers correlated with the response were finally included. Meta-analyses were carried out when there was more than one study related to the reported biomarker. Results indicated that low expression of (or IHC-negative) COX2, miR-200c, ERCC1 and TS was individually associated with prediction of response. The RR was 1.64 (n = 202, 95% CI 1.22-2.19, P < 0.001), 1.96 (n = 162, 95% CI 1.36-2.83, P < 0.001), 2.55 (n = 206, 95% CI 1.80-3.62, P < 0.001) and 1.69 (n = 144, 95% CI 1.10-2.61, P = 0.02), respectively. High expression of (or IHC-positive) CDC25B and p16 was individually related to prediction of response. The RR was 0.62 (n = 159, 95% CI 0.43-0.89, P = 0.01) and 0.62 (n = 142, 95% CI 0.43-0.91, P = 0.01), respectively. CONCLUSION: Low expression of (or IHC-negative) COX2, miR-200c, ERCC1 and TS, or high expression of (or IHC-positive) CDC25B and p16 are potential biomarkers for predicting the response of esophageal cancer patients treated with chemo(radio)therapy.

Effect of consolidation chemotherapy following definitive chemoradiotherapy in patients with esophageal squamous cell cancer.

Definitive chemoradiotherapy (dCRT) is a treatment option for patients with localized esophageal squamous cell carcinoma (ESCC). We investigated consolidation chemotherapy (CCT) in patients with ESCC who attained clinical complete response after dCRT. Between January 2009 and December 2012, medical records of ESCC patients treated with dCRT were retrospectively reviewed, and those who attained CCR were identified. Progression-free survival and overall survival rates were estimated by the Kaplan-Meier method. The Cox regression model was used to determine prognostic factors. Of the 522 patients treated with dCRT, 209 patients achieved CCR, with 67 receiving consolidation chemotherapy (the CCT group) and 142 receiving dCRT alone (the control group). CCT did not prolong progression-free survival (33.0 vs 18.0 months, P = 0.07, HR = 0.70, 95% CI, 0.48-1.04); however, CCT improved the median overall survival (53.4 vs 27.0 months, P = 0.04, HR = 0.67, 95% CI, 0.44-0.99) compared with dCRT alone. CCT remained a favorable prognostic factor for overall survival in a multivariate analysis (HR = 0.59, P = 0.02); however, a propensity score analysis failed to show an additional overall survival benefit with CCT. In the present analysis, CCT did not improve progression-free survival but may have extended overall survival in ESCC patients who achieved complete clinical response after dCRT.

[Expressions and correlation with radiotherapy's effect of five kinds of genes in nasopharyngeal carcinoma].

OBJECTIVE: To investigate the expressions of E-cadherin, CD44H, matrix metalloproteinase-3 (MMP-3), nm23H1 and vascular endothelial growth factor (VEGF) in nasopharyngeal carcinoma and its relationship to the effect of radiotherapy. Furthermore, to analyze the predict value of radiotherapy effect. METHODS: The expressions of E-cadherin, CD44H, MMP-3, nm23H1 and VEGF in 62 patients with nasopharyngeal carcinoma were determined by immunohistochemical SP method. There were 62 patients (17 to 70 years old) with nasopharyngeal carcinoma which were treated by radiotherapy from March 1995 to October 1995 and the period of follow-up had full 10 years. RESULTS: The expressions of CD44H (chi2 = 18.739, P = 0.028) and VEGF (chi2 = 18.523, P = 0.030) were closely related with short-term effect after radiotherapy in nasopharyngeal carcinoma. The short-term effect was descent along with enhancement of their expressions. In the group of low expressions in CD44H and nm23H1, 3-year overall survival rate were 65.5% and 45.5%, and 5-year overall survival rate were 47.3% and 22.7%. In the group of high expressions in CD44H and nm23H1, 3-year overall survival rate were 54.6% and 75.9%, and 5-year overall survival rate were 27.8% and 53.2%. There were respectively significant difference between two group of expressions in CD44H (chi2 = 7.31, P = 0.0069) and nm23H1 (chi2 = 15.64, P = 0.0001). CONCLUSIONS: These findings indicated that to detect the expressions of CD44H and VEGF gene may predict short-term effect of radiotherapy. Furthermore, to detect the expressions of CD44H and nm23H1 gene may predict long-term effect of radiotherapy in nasopharyngeal carcinoma.