Exploration of lymph node recurrence patterns and delineation guidelines of radiation field in middle thoracic oesophageal carcinomas after radical surgery: a real-world study.

BACKGROUND: Oesophageal squamous cell carcinoma is one of the most commonly diagnosed carcinomas in China, and postoperative radiotherapy plays an important role in improving the prognosis of patients. Carcinomas in different locations of the oesophagus could have different patterns of lymph node metastasis after surgery. METHODS: In this multicentric retrospective study, we enrolled patients with middle thoracic oesophageal squamous cell carcinomas from 3 cancer centres, and none of the patients underwent radiotherapy before or after surgery. We analysed the lymph node recurrence rates in different stations to explore the postoperative lymphatic recurrence pattern. RESULTS: From January 1st, 2014, to December 31st, 2019, 132 patients met the criteria, and were included in this study. The lymphatic recurrence rate was 62.1%. Pathological stage (P = 0.032) and lymphadenectomy method (P = 0.006) were significant predictive factors of lymph node recurrence. The recurrence rates in the supraclavicular, upper and lower paratracheal stations of lymph nodes were 32.6%, 28.8% and 16.7%, respectively, showing a high incidence. The recurrence rate of the subcarinal node station was 9.8%, while 8.3% (upper, middle and lower) thoracic para-oesophageal nodes had recurrences. CONCLUSIONS: We recommend including the supraclavicular, upper and lower paratracheal stations of lymph nodes in the postoperative radiation field in middle thoracic oesophageal carcinomas. Subcarinal station is also potentially high-risk, while whether to include thoracic para-oesophageal or abdominal nodes needs careful consideration.

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

BACKGROUND: Radiotherapy (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. METHODS: Human 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). RESULTS: In 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. CONCLUSION: These results demonstrated that NEK2 activated autophagy through TRIM21, which may provide a promising therapeutic strategy for elucidating NEK2-mediated radioresistance in ESCC.

Immune checkpoint inhibitors combined with or without radio(chemo)therapy for locally advanced or recurrent/metastatic esophageal squamous cell carcinoma.

OBJECTIVE: This study was designed to investigate the efficacy and prognostic factors for immune checkpoint inhibitors (ICIs) combined with or without radio(chemo)therapy and to evaluate their toxicity in patients with locally advanced or recurrent/metastatic esophageal squamous cell carcinoma (LA/RM ESCC). METHODS: In this study, 198 patients with locally advanced or recurrent/metastatic (LA/RM) ESCC who received ICIs combined with or without radiotherapy/chemotherapy in the Department of Radiotherapy of the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS) and progression free survival (PFS). The factors affecting treatment response and the occurrences of treatment-related adverse events (trAEs) were analyzed. RESULTS: The median OS and PFS were 30.4 months (95% confidence interval [CI] 15.1-45.7 months) and 15.3 months (95% CI 12.8-17.8 months), respectively. Univariate and multivariate analysis showed that the number of ICI cycles, the intervention of radiotherapy and dysphagia were independent factors affecting OS (Hazard ratio [HR] = 0.39, 2.043 and 0.365, respectively; P = 0.018, 0.001 and 0.032, respectively). The intervention of radiotherapy was an independent factor for PFS (hazard ratio [HR] = 18.149, P = 0.013). The median OS and PFS for patients who had complete response and partial response (Objective response, ORR) were 50.8 months (95% CI 25.8-75.7 months) and 20.5 months (95% CI 14.1-27.0), respectively, which were significantly higher than those in the non-ORR group (OSnon-ORR:17.5 months, 95% CI 14.0-21.0; χ2 = 13.881, P < 0.001; PFSnon-ORR: 12.1 months, 95% CI 10.1-14.1, χ2 = 10.676, P = 0.001). The intervention of radiotherapy could improve treatment response (χ2 = 47.725, P = 0.000). In entire study population, 83 patients (41.9%) had ≥ grade 2 trAEs. CONCLUSIONS: ICIs combined with radiotherapy/chemotherapy are safe and effective in LA/RM ESCC patients. Intervention of radiotherapy, the number of immunotherapy cycles and occurrence of dysphagia affecting the overall survival of LR/RM ESCC patients. Intervention of radiotherapy was an independent prognosis factor for OS and PFS and associated with better treatment response.

NEK2 promotes esophageal squamous cell carcinoma cell proliferation, migration and invasion through the Wnt/ß-catenin signaling pathway.

OBJECTIVES: The NEK2 (never in mitosis gene A-related kinase 2), a serine/threonine kinase involved in chromosome instability and tumorigenesis. Hence, this study aimed to explore the molecular function of NEK2 in esophageal squamous cell carcinoma (ESCC). METHODS: By available transcriptome datasets (GSE53625 cohort, GSE38129 cohort, and GSE21293 cohort), we analyzed the differentially expressed genes in invading and non-invading ESCC. Subsequently, we evaluated the association between NEK2 expression level and clinical outcomes through Kaplan-Meier analysis method. The quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) analyses were performed to determine the expression levels of NEK2 mRNA and protein, respectively. We knocked down the NEK2 expression in ESCC cells (ECA109 and TE1), and evaluated the NEK2 biology function associated with ESCC cell proliferation, migration, invasion, and colony formation abilities. Finally, the downstream pathway of NEK2 was analyzed through Gene Set Enrichment Analysis (GSEA) and validated the regulatory mechanism of NEK2 on the potential pathway through WB. RESULTS: We found that NEK2 was highly expressed in ESCC cells compared with human esophageal epithelial cells (HEEC) (P < 0.0001), and high NEK2 expression was remarkably associated with poor survival (P = 0.019). Knockdown of NEK2 showed the significant inhibitory effect for tumorigenesis, and suppressed the ESCC cells proliferation, migration, invasion, and formation of colonies abilities. Additionally, GSEA revealed that Wnt/ß-catenin pathway was a downstream pathway of NEK2. WB results further validated the regulatory mechanism of NEK2 for Wnt/ß-catenin signaling. CONCLUSIONS: Our results indicated that NEK2 promotes ESCC cell proliferation, migration and invasion by activating the Wnt/ß-catenin pathway. NEK2 could be a promising target for ESCC.

A novel DNA damage repair gene-related prognostic model for evaluating the prognosis and tumor microenvironment infiltration of esophageal squamous cell carcinoma.

BACKGROUND: This study aimed to investigate the potential prognostic value of DNA damage repair genes (DDRGs) in esophageal squamous cell carcinoma (ESCC) and their relationship with immune-related characteristics. METHODS: We analyzed DDRGs of the Gene Expression Omnibus database (GSE53625). Subsequently, the GSE53625 cohort was used to construct a prognostic model based on least absolute shrinkage and selection operator regression, and Cox regression analysis was used to construct a nomogram. The immunological analysis algorithms explored the differences between the potential mechanism, tumor immune activity, and immunosuppressive genes in the high- and low-risk groups. Of the prognosis model-related DDRGs, we selected PPP2R2A for further investigation. Functional experiments were conducted to evaluate the effect on ESCC cells in vitro. RESULTS: A 5-DDRG (ERCC5, POLK, PPP2R2A, TNP1 and ZNF350) prediction signature was established for ESCC, stratifying patients into two risk groups. Multivariate Cox regression analysis showed that the 5-DDRG signature was an independent predictor of overall survival. Immune cells such as CD4 T cells and monocytes displayed lower infiltration levels in the high-risk group. Additionally, the immune, ESTIMATE, and stromal scores in the high-risk group were all considerably higher than those in the low-risk group. Functionally, knockdown of PPP2R2A significantly suppressed cell proliferation, migration and invasion in two ESCC cell lines (ECA109 and TE1). CONCLUSION: The clustered subtypes and prognostic model of DDRGs could effectively predict the prognosis and immune activity of ESCC patients.

YTHDF3 mediates HNF1α regulation of cervical cancer radio-resistance by promoting RAD51D translation in an m6A-dependent manner.

Radiotherapy, as an important primary treatment, has effectively improved the survival of patients with cervical cancer (CC). Some patients, however, do not benefit optimally from radiotherapy because of radio-resistance. Therefore, identifying radio-resistance biomarkers and unravelling the underlying mechanisms is of critical importance for these patients. In the present study, we found significant upregulation of hepatocyte nuclear factor 1-alpha (HNF1α) expression in radio-resistant cervical cancer tissues and cell lines. Depletion of HNF1α reduced and overexpression of HNF1α promoted the resistance of CC cells to irradiation in vitro and in vivo. HNF1α positively regulated DNA repair protein RAD51 homologue 4 (RAD51D) at the protein level but not at the mRNA level. Mechanistically, upregulation of HNF1α enhanced YTH domain-containing family protein 3 (YTHDF3) transcription, which in turn promoted RAD51D mRNA N6 -methyladenosine (m6A) modification. YTHDF3 mediates HNF1α regulation of cervical cancer radio-resistance by promoting RAD51D translation in an m6A-dependent manner. The HFN1α/YTHDF3/RAD51D regulatory axis was found to play a critical role in conferring radio-resistance of CC cells. In conclusion, dysregulation of the HFN1α/YTHDF3/RAD51D axis may promote the radio-resistance of CC cells. Blocking this pathway may provide therapeutic benefits against CC radio-resistance.

High-Dose Versus Standard-Dose Intensity-Modulated Radiotherapy With Concurrent Paclitaxel Plus Carboplatin for Patients With Thoracic Esophageal Squamous Cell Carcinoma: A Randomized, Multicenter, Open-Label, Phase 3 Superiority Trial.

PURPOSE: The standard dose (SD) of definitive concurrent chemoradiotherapy (dCRT) remains 50.4 Gy in patients with esophageal cancer; a higher dose, when applied with conventional radiation therapy techniques, increases toxicities without improving survival. We investigated whether a high dose of 59.4 Gy using intensity-modulated radiation therapy (IMRT) would improve survival without increasing toxicities. METHODS: Patients with inoperable thoracic esophageal squamous cell carcinoma (SCC) referred for dCRT were randomly assigned (1:1) to high-dose (HD) IMRT (59.4 Gy) or SD IMRT (50.4 Gy). Chemotherapy consisted of 6 cycles of concurrent weekly paclitaxel and carboplatin and a maximum of 2 cycles of consolidation chemotherapy. Nutritional intervention was implemented for patients with malnutrition on the basis of nutritional screening. The primary endpoint was median overall survival (mOS). Analyses were by modified intention to treat. RESULTS: Between April 30, 2016, and April 30, 2019, 167 patients were enrolled at 9 participating centers in China. Seventy-one patients in the HD and 73 patients in the SD groups were included in the analysis; 86.8% of the patients completed radiation therapy and 70.1% received 5 or 6 cycles of concurrent chemotherapy. The median follow-up was 36.0 months. The mOS was 28.1 and 26.0 months in the HD and SD arms, respectively (P = .54). A total of 7 treatment-related deaths were observed. Grade 3 or worse treatment-related toxicities were observed in 62% and 68.5% of the patients in the HD and SD arms, respectively (P = .675). CONCLUSIONS: For patients with inoperable thoracic esophageal SCC, a dose of 59.4 Gy did not improve survival compared with the SD of dCRT using IMRT.

Construction of a predictive model of abdominal lymph node metastasis in thoracic esophageal squamous cell carcinoma and preliminary analysis of its effect on target for postoperative radiotherapy.

Purpose: To investigate the influencing factors of abdominal lymph node metastasis in thoracic esophageal squamous cell carcinoma (TESCC), and to construct its predictive model, in order to analyze the targets for postoperative radiotherapy. Methods and materials: From January 2008 to December 2014, the clinicopathological data of 479 patients who underwent radical resection for esophageal cancer in the Fourth Hospital of Hebei Medical University were collected and retrospectively analyzed. The influencing factors of postoperative abdominal lymph node metastasis were analyzed, and a predictive model was constructed based on their independent influencing factors. Receiver operating characteristic (ROC) curve was utilized to analyze the predictive value of this model; in the meantime, the postoperative locoregional recurrence (LRR) of this group was analyzed. Results: The postoperative pathology of all patients showed that the lymph node metastasis rate (LNR) was 39.7%, of which the abdominal lymph node metastasis rate was 22.0%. Logistic regression analysis revealed that the patient's lesion location, pN stage, vascular invasion, LND and mediastinal lymph node metastasis were independent risk factors for the positive rate of abdominal lymph nodes after surgery (P = 0.000, 0.000, 0.033, 0.000, 0.000). The probability of abdominal lymph node metastasis was Y = ex/(1 + ex), and X = -5.502 + 1.569 × lesion location + 4.269 × pN stage + 1.890 × vascular invasion + 1.950 × LND-4.248 × mediastinal lymph node metastasis. The area under the ROC curve (AUC) of this model in predicting abdominal lymph node metastasis was 0.962 (95% CI, 0.946-0.977). This mathematical model had a high predictive value for the occurrence of abdominal lymph node metastasis (P = 0.000), and the sensitivity and specificity of prediction were 94.6% and 88.3% respectively. The overall survival rate was significantly higher (X2 = 29.178, P = 0.000), while abdominal lymph node recurrence rate was lower in patients with negative abdominal lymph nodes than in those with negative lymph nodes (1.4%&7.7%, X2 = 12.254, P = 0.000). Conclusion: The lesion location, pN stage, vascular invasion, LND and mediastinal lymph node metastasis are independent influencing factors of abdominal lymph node metastasis in patients with TESCC. The mathematical model constructed by these indicators can accurately predict abdominal lymph node metastasis, which can help clinicians to choose the targets for postoperative radiotherapy.

Irradiation-induced exosomal HMGB1 to confer radioresistance via the PI3K/AKT/FOXO3A signaling pathway in ESCC.

BACKGROUND: Radioresistance is a major cause of treatment failure in esophageal squamous cell carcinoma (ESCC) radiotherapy, and the underlying mechanisms of radioresistance are still unclear. Irradiation (IR) stimulates changes in tumor-derived exosome contents, which can be taken up by recipient cells, playing an important role in the proliferation, cell cycle and apoptosis of recipient cells. This study investigated the effect of IR-induced exosomal high mobility group box 1 (HMGB1) on radioresistance in ESCC cells. METHODS: Plasma exosomes were isolated from 21 ESCC patients and 24 healthy volunteers, and the expression of HMGB1 was examined. Then, the therapeutic effect of radiotherapy was analyzed according to the different expression levels of plasma exosomal HMGB1 in ESCC patients. The uptake of exosomes by recipient cells was verified by immunofluorescence staining, and the localization of exosomes and HMGB1 in cells before and after IR was evaluated. The effects of IR-induced exosomes on cell proliferation, invasion, apoptosis, cell cycle distribution and radioresistance after HMGB1 knockdown were verified. Moreover, western blotting was used to measure changes in the expression of cyclin B1, CDK1, Bax, Bcl2, phosphorylated histone H2AX and the PI3K/AKT/FOXO3A pathway in the HMGB1-knockdown exosome group and the negative control group. RESULTS: The expression of HMGB1 in ESCC plasma exosomes was significantly increased compared with that in healthy volunteers, and high expression of HMGB1 in plasma exosomes was associated with radioresistance (P = 0.016). IR-induced the release of exosomal HMGB1 and promoted proliferation and radioresistance in recipient cells, with a sensitization enhancement ratio (SER) of 0.906 and 0.919, respectively. In addition, IR-induced exosomal HMGB1 promotes G2/M phase arrest by regulating the proteins cyclin B1 and CDK1, cooperating with the proteins Bax and Bcl2 to reduce the apoptosis rate through the PI3K/AKT/FOXO3A signaling pathway, and participated in IR-induced DNA damage repair through γH2AX. CONCLUSION: These findings indicate that high expression of plasma exosomal HMGB1 is associated with an adverse radiotherapy response. IR-induced exosomal HMGB1 enhances the radioresistance of ESCC cells.

Progression-free survival as surrogate endpoint of overall survival in esophageal squamous cell carcinoma: a real-world data and literature-based analysis.

Background: The surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal squamous cell carcinoma (ESCC) remains unelucidated. This study aimed to determine the validity of PFS as a surrogate endpoint for OS in ESCC patients treated with definitive radiotherapy or definitive chemoradiotherapy (dRT/dCRT), as well as characterize the prognostic factors and survival of such patients. Methods: A total of 3662 patients from 10 cancer centers were enrolled. One-, 2-, and 3-year PFS (PFS12, PFS24, and PSF36, respectively) were used as time points for analysis. At each time point, ESCC-specific mortality and OS were characterized using competing risk and conditional survival models, while correlation between PFS and OS was evaluated by linear regression. Results: At PFS12, PFS24, and PFS36, a progressive decrease in 5-year ESCC-specific mortality (35.2%-13.4%) and increase in 5-year OS (46.6%-62.9%) were observed. Regardless, the OS of patients remained markedly lower than those of the age- and sex-matched Chinese general population. TNM stage remained a significant prognostic factor at PFS36. Strong correlation was found between 3-year PFS and 5-year OS, which was further externally validated. Conclusions: Three-year PFS may act as a potential surrogate endpoint for 5-year OS. TNM stage was considered a significant prognostic factor for OS, and may represent the optimal prognostic tool to guide clinical decision-making and post-treatment follow-up.

HMGB1 induces radioresistance through PI3K/AKT/ATM pathway in esophageal squamous cell carcinoma.

BACKGROUND: To explore the effect of HMGB1 on the radio-sensitivity of esophageal cancer cells through regulating the PI3K/Akt/ATM pathway. METHODS AND RESULTS: We observed the expression of HMGB1 and p-ATM in biopsies of esophageal cancer patients with immunohistochemical staining. Western blot and RT-qPCR were applied to detect the protein and RNA related to PI3K/Akt/ATM pathway, respectively. In addition, we inhibited the PI3K/Akt pathway with ly294002 and activated it with IGF1, then we explored the invasion, proliferation ability, and apoptosis of esophageal cancer cells in vitro by transwell, CCK8 assay, and flow cytometry respectively. In vivo, xenograft tumor model was established in nude mice to study the effect of HMGB1 on radioresistance via PI3K/AKT/ATM Signaling Pathway. The survival rate in patients with single positive/double negative expression of HMGB1 and p-ATM was significantly higher than in those with both positive expression of HMGB1 and p-ATM, the depletion of HMGB1 combined with ly294002 significantly inhibited cell proliferation and invasion ability, meanwhile, the addition of IGF1 reversed it. Meanwhile, depletion of HMGB1 and ly294002 promoted apoptosis and arrested the cancer cells in G0/G1 cell cycle with the decreased expression of Cyclin D1 and CDK4 and improved P16. We further validated these results in vivo, the application of HMGB1 silencing promoted apoptosis of xenograft tumors after radiation, especially combined with pathway inhibitor ly294002. CONCLUSIONS: Esophageal cancer patients with high expression of HMGB1 and p-ATM have a poor prognosis after chemo-radiotherapy. Down-regulation of HMGB1 may promote the radio-sensitivity of esophageal cancer cells through regulating PI3K/Akt/ATM pathway.

Novel nomograms predicting the survival of patients with nonsurgical thoracic esophageal squamous cell carcinoma treated with IMRT: A retrospective analysis.

The purpose of this study was to evaluate several preradiotherapy serum inflammatory indicators, including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation score (SIS), and compare which of these indicators had the highest value in predicting survival. Inflammatory markers were combined with traditional prognostic factors, and novel nomogram models were developed to predict overall survival (OS) and progression-free survival (PFS) for patients with esophageal squamous cell carcinoma. A total of 245 patients were enrolled. The Kaplan-Meier method and univariate and multivariate analyses were used to compare survival differences. A total of 239 patients met the eligibility criteria. The survival numbers at 1, 3, and 5 years were 176, 83, and 62, respectively. The OS and PFS rates estimated at 1, 3, and 5 years were 74.6%, 36.8%, and 26.5% and 58.4%, 31.3%, and 20.5%, respectively. The differences in patients' OS and PFS were significant when univariate analysis was applied based on inflammation-based measures. Multivariate analysis showed that tumor length, tumor stage, tumor/node/metastasis stage, chemotherapy, and SIS value were predictive variables for OS and PFS. The nomogram model established based on the multivariate models of the training data set had good predictive ability. The unadjusted C-index was 0.701 (95% CI, 0.662-0.740) and 0.695 (95% CI, 0.656-0.734) for OS and PFS, respectively. This study showed that the SIS-based nomogram could accurately predict the OS and PFS of patients with esophageal squamous cell carcinoma.

Patterns of failure and long-term outcome of postoperative radiotherapy on the survival of patients with pathological T3N0M0 esophageal cancer.

Purpose: The prognostic effect of postoperative radiotherapy (PORT) on pathological T3N0M0 (pT3N0M0) esophageal squamous cell carcinoma (ESCC) remains inconclusive. This study aimed to retrospectively investigate patterns of failure and whether PORT after R0 resection improves survival in patients with pT3N0M0 ESCC, compared with surgery alone. Patients and methods: The clinical data of 256 patients with pT3N0M0 ESCC from January 2007 to December 2010 were retrospectively reviewed. The included patients were classified into two groups: the surgery-plus-postoperative radiotherapy group (S + R) and the surgery-alone group (S). Propensity score matching (PSM) was used to create comparable groups that were balanced across several covariates (n = 71 in each group). Statistical analyses were performed using the Kaplan-Meier method and Chi-squared test. Results: In the study cohort, the 5- and 10-year overall survival (OS) rates in the S + R group were 53.4% and 38.4%, and those in the S group were 50.3%, 40.9% (p = 0.810), respectively. The 5- and 10-year disease-free survival (DFS) rates in the S + R group were 47.9% and 32.9%, and those in the S group were 43.2%, 24.0% (p = 0.056), respectively. The results were coincident in the matched samples (p = 0.883, 0.081) after PSM. Subgroup analysis showed that patients with upper thoracic lesions in the S + R group had significantly higher OS than patients in the S group (p = 0.013), in addition, patients with upper and middle thoracic lesions in the S + R group had significantly higher DFS than patients in the S group (p = 0.018, 0.049). The results were also confirmed in the matched samples after PSM. The locoregional recurrence between the two groups were significantly different before and after PSM (p = 0.009, 0.002). The locoregional control rate (LCR) in the S + R group was significantly higher than that in the S group before and after PSM (p = 0.015, 0.008). Conclusion: Postoperative radiotherapy may be associated with a survival benefit for patients with pT3N0M0 upper thoracic ESCC. A multicenter, randomized phase III clinical trial is required to confirm the results of this study.

HMGB1 overexpression promotes a malignant phenotype and radioresistance in ESCC.

Esophageal cancer is a common malignant disease that is generally treated with radiotherapy. High mobility group box 1 (HMGB1) plays an essential role in tumor cell proliferation, migration, and cell cycle progression. Here, we aimed to clarify the effects of HMGB1 on radioresistance in esophageal squamous cell carcinoma (ESCC) cell lines and patient survival. We performed immunohistochemistry for HMGB1 in biopsy samples of 39 stage I-III ESCC patients grouped by HMGB1 expression status. Then, 1-, 3-, 5-, and 10-year overall survival outcomes were calculated by Kaplan-Meier survival analysis. The cellular localization of HMGB1 was examined before and after irradiation by Immunofluorescence staining. Stable cell lines (KYSE30 and KYSE510) with differential HMGB1 expression were constructed using lentiviruses. Furthermore, we examined phosphorylated histone H2AX (γ-H2AX) expression in both HMGB1 overexpression and negative control groups by western blotting. HMGB1-negative expression was associated with superior ESCC patient 10-year survival (P=0.016). HMGB1 overexpression promoted cell migration, proliferation, and radioresistance and mitigated cell cycle arrest at the G0/G1 phase induced by irradiation. This demonstrates that HMGB1-positive expression is correlated with unfavorable clinical outcomes, and HMGB1 overexpression may promote the malignant phenotype of ESCC cells and induce radioresistance by regulating cell cycle distribution in ESCC.

The role of postoperative radiation therapy in stage I-III male breast cancer: A population-based study from the surveillance, epidemiology, and End Results database.

BACKGROUND: This study aimed to investigate the role of postoperative radiation therapy in a large population-based cohort of patients with stage I-III male breast cancer (MaBC). METHODS: Patients with stage I-III breast cancer treated with surgery were selected from the Surveillance, Epidemiology, and End Results cancer database from 2010 to 2015. Multivariate logistic regression identified the predictors of radiation therapy administration. Multivariate Cox regression model was used to evaluate the predictors of survival. RESULTS: We identified 1321 patients. Age, stage, positive regional nodes, surgical procedure, and HER2 status were strong predictors of radiation therapy administration. There was no difference between patients who received radiation therapy and those who did not (P = 0.46); however, after propensity score matching, it was associated with improved OS (P = 0.04). In the multivariate analysis of the unmatched cohort, the factors associated with better OS were administration of radiation therapy and chemotherapy. In the subset analysis of the unmatched cohort, postoperative radiation therapy was associated with improved OS in men undergoing breast-conserving surgery (BCS), with four or more node-positive or larger primary tumours (T3/T4). Furthermore, we found no benefit of radiation therapy, regardless of the type of axillary surgery in mastectomy (MS). In older MaBC patients with T1-2N1 who underwent MS, radiation therapy showed no significant effects, regardless of chemotherapy. CONCLUSION: Postoperative radiation therapy could improve the survival of MaBC patients undergoing BCS, with four or more node-positive or larger primary tumours. Moreover, it should be carefully considered in patients undergoing MS and older T1-2N1 patients.

Practice Patterns of Treatment Strategy of Limited-Stage Small-Cell Lung Cancer: Survey of Chinese Oncologists.

Background: Thoracic radiotherapy (TRT) with concurrent chemotherapy is the standard treatment of limited-stage small-cell lung cancer (LS-SCLC). However, there is still a controversy surrounding the treatment strategy especially optimal dosing and fractionation schedule. Current practice patterns among Chinese oncologists are unknown. Materials and Methods: We surveyed 212 Chinese oncologists using a questionnaire including 50 questions designed by experienced oncologists. Questions covered demographic data, treatment recommendations, and self-assessed knowledge of guidelines or key clinical trials for SCLC. The chi-square test and Fisher's exact test were utilized to describe the result of the study. Results: The response rate was 97% (207/212). Of all the respondents, 69% preferred TRT QD, 29% preferred BID, and 2% chose HFRT. For those who prefer TRT QD, 72% preferred a total dose of 60 Gy, followed by 15% opting for 66 Gy, 12% for <60 Gy, and 1% for 70 Gy. Of those who prefer BID, 79% preferred a total dose of 45 Gy, with 4% choosing 30 Gy, 8% choosing 50 Gy, 7% choosing 54 Gy, and 2% choosing >54 Gy. Regarding PCI, 82% of participants believed that PCI should be performed when treatment is completed and 13% believed that PCI should begin immediately after concurrent chemoradiotherapy. As for other therapies, 26% of participants choose concurrent anti-angiogenic therapy during SCLC treatment, and 49% recommended small-molecule TKI as the main anti-angiogenic therapy. Conclusion: Substantial variation exists in how Chinese oncologists approach TRT dosing and fractionation for LS-SCLC. Almost 70% of respondents reported administering TRT QD more often in daily work. The most common doses were 60 Gy QD and 45 Gy BID.

A Novel Score Combining Magnetic Resonance Spectroscopy Parameters and Systemic Immune-Inflammation Index Improves Prognosis Prediction in Non-Small Cell Lung Cancer Patients With Brain Metastases After Stereotactic Radiotherapy.

Objective: The aim of this study was to evaluate the prognostic significance of the combination of the magnetic resonance spectroscopy (MRS) parameters and systemic immune-inflammation index (SII) in patients with brain metastases (BMs) from non-small cell lung cancer (NSCLC) treated with stereotactic radiotherapy. Methods: A total of 118 NSCLC patients with BM who were treated with stereotactic radiotherapy were retrospectively enrolled in this study. All patients underwent MRS and blood samples test for SII analysis before the initiation of stereotactic radiotherapy. The correlation between the parameters of MRS and SII level was assessed using Spearman's correlation coefficient. The cutoff values for the parameters of MRS, SII, and clinical laboratory variables were defined by the receiver operating characteristic (ROC) curve analysis to quantify these predictive values. The prognostic factors of overall survival (OS) and progression-free survival (PFS) curves were assessed using the Kaplan-Meier and Cox proportional hazards models. Results: The median follow-up time was 25 months (range, 12-49 months). The optimal cutoff point for the choline/creatine (Cho/Cr) ratio and SII were 1.50 and 480, respectively. The Cho/Cr ratio was negatively correlated with SII (rs = 0.164, p = 0.075), but there was a trend. The C-SII score was established by combining the Cho/Cr ratio and SII. Patients with both an elevated Cho/Cr ratio (>1.50) and an elevated SII (>480) were given a C-SII score of 2, and patients with one or neither were given a C-SII score of 1 or 0, respectively. The Kaplan-Meier analysis showed that a C-SII score of 2 was significantly linked with poor OS and PFS (p < 0.001 and p < 0.001, respectively). In the Cox proportional hazards model, the C-SII score independently predicted OS [hazard ratio (HR), 1.749; 95% CI, 1.176-2.601; p = 0.006] and PFS (HR, 2.472; 95% CI, 1.624-3.763; p < 0.001). Conclusion: The C-SII score was more accurate for predicting the clinical outcomes of NSCLC patients with BM who underwent stereotactic radiotherapy. The C-SII score, which was superior to either score alone, could be used to identify BM in NSCLC patients with poor outcomes.

Postoperative lymphatic recurrence distribution and delineation of the radiation field in lower thoracic squamous cell esophageal carcinomas: a real-world study.

BACKGROUND: To study lymphatic recurrence distribution after radical surgery in the real world and guide clinical tumor volume delineation for regional lymph nodes during postoperative radiotherapy for lower thoracic squamous cell esophageal carcinomas. METHODS: We enrolled patients who underwent radical esophagectomy, without radiation before or after surgery, at 3 cancer hospitals. Patients were classified into groups according to tumor locations. We included patients with tumors in the lower thoracic segment and analyzed the postoperative lymph node recurrence mode. A cutoff value of 10% was used to differentiate high-risk lymph node drainage areas from others. RESULTS: We enrolled 1905 patients in the whole study series, including 652 thoracic esophageal carcinomas that met our inclusion criteria; there were 241 cases of lower thoracic esophageal carcinomas. 1st, 2nd, 4th, 7th, 8th groups of lymph nodes, according to the 8th edition of the AJCC classification, displayed as high-risk recurrence areas, representing 17.8%, 23.9%, 11.7%, 10.9% and 12.2% of lymph node recurrence. Stage III-IV tumors located in the lower segment of the thoracic esophagus showed a tendency to recur in the left gastric nodes (7.9%) and celiac nodes (10.6%). CONCLUSIONS: According to our results, we recommended including the 4th, 7th and 8th groups of lymph nodes in the radiation field, and for patients with stage III-IV disease, the 17th and 20th groups of nodes should be irradiated during postoperative treatment. Whether including 1st/2nd groups in preventive irradiation needed more proofs.

Effects of Enteral Nutrition on Patients With Oesophageal Carcinoma Treated With Concurrent Chemoradiotherapy: A Prospective, Multicentre, Randomised, Controlled Study.

Background: The oesophageal carcinoma patients show high incidence of malnutrition, which negatively affects their therapy outcome. Moreover, benefits of enteral nutrition remain to be studied in details in these patients. Therefore, we set to assess the effects of enteral nutrition on the nutritional status, treatment toxicities and survival in the oesophageal carcinoma patients treated with concurrent chemoradiotherapy (CCRT). Materials and Methods: Eligible patients were randomly assigned to either the experimental or control group. The patients in the experimental group were treated with a whole-course enteral nutrition management, while the control group were provided a unsystematic nutrition without setting intake goals for energy and protein. The primary endpoint was a change in body weight, while the secondary endpoints included nutrition-related haematological indicators, toxicities, completion rate of treatment and survival. Results: A total of 222 patients were randomised to either the experimental (n=148) or control (n=74) group. Patients in the experimental group showed significantly less decrease in body weight, serum albumin and haemoglobin levels, a lower incidence rates of grade ≥3 myelosuppression and infection, and a higher completion rate of CCRT than those in the control group. While analyses of the 2 and 3 year overall survival (OS) and progression-free survival (PFS) did not reveal differences between these groups, we observed a significantly higher OS at 1 year (83.6% vs. 70.0%). In the subgroup analysis, patients with patient-generated subjective global assessment (PG-SGA)=C were likely to have better OS and PFS with enteral nutrition. Conclusions: In EC patients treated with CCRT, enteral nutrition conferred positive effects on the nutritional status, treatment toxicities and prognosis, which mandate its inclusion in clinical practice. Clinical Trial Registration: This prospective trial has been registered with www.clinicaltrials.gov as NCT02399306.

Combining the systemic inflammation response index and prognostic nutritional index to predict the prognosis of locally advanced elderly esophageal squamous cell carcinoma patients undergoing definitive radiotherapy.

Background: The systemic inflammation response index (SIRI) and prognostic nutritional index (PNI) have been shown to be correlated with the prognosis of various solid tumors. This study sought to investigate the prognostic value of the SIRI and the PNI individually and in combination in locally advanced elderly esophageal squamous cell carcinoma (ESCC) patients treated with radical radiotherapy. Methods: The data of 192 ESCC patients aged ≥65 years, who had been treated with definitive radiotherapy between 2013 and 2016, were retrospectively analyzed. The optimal cutoff values of SIRI and PNI were determined by receiver operating characteristic curves. Kaplan-Meier curves and Cox proportional hazards models were used to analyze the effect of the SIRI and PNI on overall survival (OS) and progression-free survival (PFS). The areas under the curve were measured to evaluate the predictive ability of the SIRI, PNI, and SIRI combined with PNI for OS. Results: The optimal cutoff values of the pretreatment SIRI and PNI were 1.03 and 49.60, respectively. The univariate and multivariate analyses demonstrated that T stage (P=0.021), TNM stage (P=0.022), synchronous chemotherapy (P=0.032), the SIRI (P=0.001), and the PNI (P=0.045) were independent prognostic factors for OS and N stage (P=0.004), synchronous chemotherapy (P=0.016) and the SIRI (P=0.004) were independent prognostic factors for PFS. The AUC of the combined SIRI and PNI (0.706; 0.612-0.801) was higher than those of the SIRI (0.648; 0.540-0.756) and the PNI (0.621; 0.523-0.720). Patients in the low-SIRI and high-PNI groups, especially those in clinical stage II or who received synchronous chemotherapy (P<0.001, P=0.002), had better OS and PFS than those in the other groups (P<0.001). Conclusions: The SIRI and PNI are simple and reliable biomarkers for predicting long-term survival in elderly patients with locally advanced ESCC after radical radiotherapy. A high SIRI and a low PNI indicated poor prognosis, and the combination of the SIRI and PNI improved the accuracy of prognosis prediction and could be used to guide individualized treatment of patients.