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This study analyzes the role of the hemoglobin, albumin, lymphocyte, and platelet score (HALP), a pre-catheterization blood parameter, in predicting the occurrence of thrombophlebitis. We recruited 268 in-hospital patients who visited the Department of Oncology of our hospital and underwent peripherally inserted central catheter between January 2021 and January 2024. The cutoff value of the HALP score was defined using receiver's operating characteristic curve, and the differences were analyzed with log-rank test. The significance of HALP in predicting thrombophlebitis was evaluated using a multivariate Cox proportional hazards model. A total of 240 patients were enrolled and divided into a high-HALP (≥31.4) group (n = 125) and a low-HALP (<31.4) group (n = 115). The relationship between the composition of HALP and clinical pathological parameters was analyzed. HALP was significantly correlated with gender (X2 = 4.74), limb restriction (X2 = 3.69), performance status score (X2 = 11.9), D-dimer (X2 = 7.88), and platelet count (X2 = 5.22). Multivariate regression analysis found male (hazard ratio [HR] 0.29 (0.12-0.69)), more puncture times (HR 0.01 (0.001-0.15)), lower HALP (HR 1.93 (0.82-4.52)), and sterile couplant (HR 20.6 (4.7-91.2)) were independent factors affecting the occurrence of thrombophlebitis. Receiver's operating characteristic curve analysis showed the area under the curve of the HALP score was 0.718 (95% confidence interval 0.638-0.798), which was significantly larger than the other 3 parameters. Hence, we believe the predictive efficiency of HALP is higher than other parameters. The pre-catheterization HALP score can be used as a simple, accessible, and reliable tool for predicting thrombophlebitis in patients to undergo peripherally inserted central catheter., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy of the digestive system. Hypoxia is a crucial player in tumor ferroptosis resistance. However, the molecular mechanism of hypoxia-mediated ferroptosis resistance in ESCC remains unclear. Here, USP2 expression was decreased in ESCC cell lines subjected to hypoxia treatment and was lowly expressed in clinical ESCC specimens. Ubiquitin-specific protease 2 (USP2) depletion facilitated cell growth, which was blocked in USP2-overexpressing cells. Moreover, USP2 silencing enhanced the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells. Furthermore, knockout of USP2 in ESCC models discloses the essential role of USP2 in promoting ESCC tumorigenesis and inhibiting ferroptosis. In contrast, overexpression of USP2 contributes to antitumor effect and ferroptosis events in vivo. Specifically, USP2 stably bound to and suppressed the degradation of nuclear receptor coactivator 4 (NCOA4) by eliminating the Lys48-linked chain, which in turn triggered ferritinophagy and ferroptosis in ESCC cells. Our findings suggest that USP2 plays a crucial role in iron metabolism and ferroptosis and that the USP2/NCOA4 axis is a promising therapeutic target for the management of ESCC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The immune environment in tumors is the key factor affecting the survival and immunotherapeutic response of patients. This research aimed to explore the underlying association between focal adhesion tyrosine kinase (FAK/PTK2) and cancer immunotherapy in 33 human cancers. Gene expression data and clinical features of 33 cancers were retrieved from the Cancer Genome Atlas Database. The immunotherapy cohorts included GSE67501, GSE78220, and IMVIGOR210, which were derived from the comprehensive gene expression database or from previous studies. Clinical parameters including patient age, gender, survival rate, and tumor stage were analyzed to evaluate the prognostic value of FAK/PTK2. FAK/PTK2 activity was detected by single-sample gene set enrichment analysis and used to compare the difference between FAK/PTK2 transcriptome and protein expression levels. To better understand the role of FAK/PTK2 in cancer immunotherapy, we analyzed its correlations with tumor microenvironment and with immune processes/elements (e.g., immune cell infiltration, immunosuppressants, and stimulants) and major histocompatible complexes. Potential pathways associated with FAK/PTK2 signaling in cancers were also explored. Correlations between FAK/PTK2 and 2 immunotherapeutic biomarkers (tumor mutation load and microsatellite instability) were studied. Finally, the 3 independent immunotherapy cohorts were used to study the relationship between FAK/PTK2 and immunotherapeutic response. Although FAK/PTK2 is not closely associated with age (13/33), gender (5/33), or tumor stage (5/33) in any of the studied human cancers, it has potential prognostic value for predicting patient survival. Consistency between FAK/PTK2 activity and expression exists in some cancers (3/33). Generally, FAK/PTK2 is robustly correlated with immune cell infiltration, immune modulators, and immunotherapeutic markers. Moreover, high FAK/PTK2 expression is significantly related to immune-relevant pathways. However, FAK/PTK2 is not significantly correlated with the immunotherapeutic response. Research on the immunotherapeutic value of FAK/PTK2 in 33 human cancers provides evidence regarding the function of FAK/PTK2 and its role in clinical treatment. However, given the use of a bioinformatics approach, our results are preliminary and require further validation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Ethnopharmacological Relevance: Epimedium brevicornu Maxim. is a traditional medicinal Chinese herb that is enriched with flavonoids, which have remarkably high medicinal value. Icariin (ICA) is a marker compound isolated from the total flavonoids of Epimedium brevicornu Maxim. It has been shown to improve Neurodegenerative disease, therefore, ICA is probably a potential drug for treating AD., Materials and Methods: The 6-8-week-old SPF-class male ICR mice were randomly divided into 8 groups for modeling, and then the mice were administered orally with ICA for 21 days. The behavioral experiments were conducted to evaluate if learning and memory behavior were absent in mice, confirming that infusion of Amyloid β-protein (Aβ) 1-42 caused significant memory impairment. The morphological changes and damage of neurons in the mice's brains were observed by HE and Nissl staining. The spinous protrusions (dendritic spines) on neuronal dendrites were investigated by Golgi-Cox staining. The molecular mechanism of ICA was examined by Western Blot. The protein docking of ICA and Donepezil with BDNF were analyzed to determine their interaction., Results: The behavioral experimental results showed that in Aβ 1-42 -induced AD mice, the learning and memory abilities were improved after using ICA. At the same time, the low, medium, and high doses of ICA could reduce the content of Aβ 1-42 in the hippocampus of AD mice, repair neuronal damage, enhance synaptic plasticity, as well as increase the expression of BDNF, TrκB, CREB, Akt, GAP43, PSD95, and SYN proteins in the hippocampus of mice. However, the effect with high doses of ICA is more pronounced. The high-dose administration of ICA has the best therapeutic effect on AD mice. After administering the inhibitor k252a, the therapeutic effect of ICA was reversed. The macromolecular docking results of ICA and BDNF protein demonstrated a strong interaction of -7.8 kcal/mol, which indicates that ICA plays a therapeutic role in AD mice by regulating the BDNF-TrκB signaling pathway., Conclusions: The results confirm that ICA can repair neuronal damage, enhance synaptic plasticity, as well as ultimately improve learning and memory impairment through the regulation of the BDNF-TrκB signaling pathway., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Depression has increasingly become a disease that seriously harms people's mental health around the world. Icariin is the main active component of Epimedii Herba and effective on protecting the central nervous system. The purpose of this study was to explore the mechanism of icariin against depression based on network pharmacology and molecular docking. The potential targets related to icariin and depression were obtained by accessing network databases. The Metascape database was used for the enrichment analysis of GO function and KEGG pathways. A common target-pathway network was constructed using Cytoscape 3.9.0 software. Schrödinger Maestro 12.8 was adopted to evaluate the binding ability of icariin to core targets. Mice were induced by the chronic unpredictable mild stress (CUMS) model, and the prediction results of this study were verified by in vivo experiments. A total of 109 and 3294 targets were identified in icariin and depression, respectively. The common target-pathway network was constructed, and 7 core target genes were obtained. The molecular docking results of the 7 core target genes with icariin showed good affinity. In a CUMS-induced depression model, we found that icariin could effectively improve depression-like behavior of mice, increase the expression of monoamine neurotransmitters 5-hydroxytryptamine, dopamine, and norepinephrine, decrease the secretion of inflammatory factors tumor necrosis factor-α, interleukin-6, and interleukin-1β, and upregulate the relative expression levels of BDNF, p-TrkB/TrkB, p-Akt/Akt, p-CREB/CREB, MAPK3, MAPK1, Bcl-2, EGFR, and mTOR. The results suggest that icariin has certain antidepressant effects, and may be mediated by the BDNF-TrkB signaling pathway. It provides new ideas for the treatment of depression in the future., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The hemoglobin, albumin, lymphocyte and platelet (HALP) score and the Gustave Roussy immune score (GRIm⁃Score) are prognostic markers in several types of malignant tumors. The prognostic values of HALP score and GRIm⁃Score in concurrent chemoradiotherapy for unresectable esophageal cancer remain unknown., Methods: We enrolled 150 esophageal squamous cell carcinoma (ESCC) patients who underwent concurrent chemoradiotherapy in our institution between 2013 and 2018. The cutoff values for HALP, and GRIm⁃Score were defined by using receiver's operating characteristic curves. Survival was analyzed with the Kaplan- Meier method, with differences analyzed with the log-rank test. Multivariate Cox proportional-hazards models were used to evaluate the prognostic significance of HALP and GRIm for ESCC., Results: HALP was significantly associated with the Zubrod ECOG WHO performance status, tumor location, and the clinical tumor, node, metastasis stage. Modified GRIm (mGRIm) was only significantly associated with metastasis / recurrence before radiotherapy (χ 2  = 6.25). Univariate Cox regression analysis showed that higher mGRIm (HR 1.9 95%CI 1.3-2.9) and lower HALP (HR 2.4 95%CI 1.6-3.7) were all associated with worse OS. Multivariate COX analysis found that higher mGRIm score (HR 1.7 95%CI 1.1-2.6), and lower HALP score (HR 2 95%CI 1.3-3.2) were both independent risk factors of overall survival. The nomogram c-index in inside validation was 0.66., Conclusion: Both HALP and mGRIm are independent prognostic factors for patients with unresectable ESCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

To clarify the effect of catheter indwelling depth on the occurrence of thrombophlebitis, a total of 339 hospitalized patients were randomly enrolled and divided by the catheter indwelling depth into 2 groups. Then the effect of indwelling depth on thrombophlebitis was analyzed, and the independent influence factors on the occurrence of thrombophlebitis were clarified. There were 49 cases of thrombophlebitis, including 8 tumor-bearing patients and 41 patients with lung infection. Thirteen of the 135 patients with indwelling depth of 1 cm, and 36 of the 204 patients with indwelling depth of 1.9 cm suffered thrombophlebitis. The relationship between incidence rate of thrombophlebitis and clinicopathological parameters was analyzed. It was found the incidence of thrombophlebitis was significantly correlated with males (X2 = 5.77), lung infection (X2 = 7.79), and indwelling depth of 1.9 cm (X2 = 4.223). Multifactor analysis of variance showed the significant independent risk factors of thrombophlebitis were male [hazard ratio (HR) 3.12 (1.39-6.98)], and lung infection (HR 0.22 [0.06-0.69]), and the indwelling depth of 1.9 cm affected the occurrence of thrombophlebitis (HR 0.79 [0.42 -3.09]) but was not an independent risk factor. In our treatment center, while appropriate fixation was ensured, the catheter indwelling depth shall be as short as possible, so as to reduce the occurrence of thrombophlebitis. For patients with lung infection, nursing at the intubation site shall be strengthened, so as to decrease thrombophlebitis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Treatment of head and neck squamous cell carcinoma (HNSCC) is a substantial clinical challenge due to the high local recurrence rate and chemotherapeutic resistance. This project seeks to identify new potential biomarkers of prognosis prediction and precision medicine to improve this condition. A synthetic data matrix for RNA transcriptome datasets and relevant clinical information on HNSCC and normal tissues was downloaded from the Genotypic Tissue Expression Project and The Cancer Genome Atlas (TCGA). The necrosis-associated long-chain noncoding RNAs (lncRNAs) were identified by Pearson correlation analysis. Then 8-necrotic-lncRNA models in the training, testing and entire sets were established through univariate Cox (uni-Cox) regression and Lasso-Cox regression. Finally, the prognostic ability of the 8-necrotic-lncRNA model was evaluated via survival analysis, nomogram, Cox regression, clinicopathological correlation analysis, and receiver operating characteristic (ROC) curve. Gene enrichment analysis, principal component analysis, immune analysis and prediction of risk group semi-maximum inhibitory concentration (IC50) were also conducted. Correlations between characteristic risk score and immune cell infiltration, immune checkpoint molecules, somatic gene mutations, and anti-cancer drug sensitivity were analyzed. Eight necrosis-associated lncRNAs (AC099850.3, AC243829.2, AL139095.4, SAP30L-AS1, C5orf66-AS1, LIN02084, LIN00996, MIR4435-2HG) were developed to improve the prognosis prediction of HNSCC patients. The risk score distribution, survival status, survival time, and relevant expression standards of these lncRNAs were compared between low- and high-risk groups in the training, testing and entire sets. Kaplan-Meier analysis showed the low-risk patients had significantly better prognosis. The ROC curves revealed the model had an acceptable predictive value in the TCGA training and testing sets. Cox regression and stratified survival analysis indicated that the 8 necrosis-associated lncRNAs were risk factors independent of various clinical parameters. We recombined the patients into 2 clusters through Consensus ClusterPlus R package according to the expressions of necrotic lncRNAs. Significant differences were found in immune cell infiltration, immune checkpoint molecules, and IC50 between clusters, suggesting these characteristics can be used to evaluate the clinical efficacy of chemotherapy and immunotherapy. This risk model may serve as a prognostic signature and provide clues for individualized immunotherapy for HNSCC patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The prognostic evaluation of GRIm score has been confirmed in many tumor species. The purpose of this study is to clarify the value of GRIm score in the prognostic evaluation of patients with resectable proximal gastric cancer. A single center retrospective study was conducted in 174 patients with proximal gastric cancer who underwent radical total gastrectomy. An in-depth analysis was carried out to explore the prognostic differences between high and low GRIm, and the influencing factors of disease-free survival rates and overall survival rates were analyzed by Cox regression model and Kaplan-Meier method. A total of 174 patients were divided into two groups: 135 patients were marked in L-mGRIm and 39 patients in H-mGRIm groups respectively. The median OS of the H-mGRIm and L-mGRIm groups were 23.2 and 38.6 months, respectively. The median DFS of the H-mGRIm and L-mGRIm groups was 16.9 and 31.7 months, respectively. Both DFS and OS were significantly different between groups (P = .000, P = .000). In multivariate analysis, ZPS (2 vs 0-1: HR 1.99 95% CI 1.05-3.76 P = .035), LDH (≥193 vs <193:HR 0.6; 95% CI 0.38-0.95 P = .028), mGRIm score (2-3 vs 0-1: HR 2.4; 95% CI 1.09-5.23 P = .029) was independent risk factors of OS. The age (>65 vs ≤65 years HR 0.63; 95% CI 0.4-0.95 P = .003), LDH (>193 U/L vs ≤193 U/L: HR 0.55; 95% CI 0.37-0.82 P = .004) and mGRIm score (2-3 vs 0-1: HR 4.74; 95% CI 2.24-9.9 P = .000) as an independent risk factor for DFS. mGRIm score is a novel, simple and effective index for prognosis evaluation of resectable cardiac cancer and can be used as a part of the risk stratification process., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aging is highly associated with tumor formation and progression. However, little research has explored the association of aging-related lncRNAs (ARLs) with the prognosis and tumor immune microenvironment (TIME) of head and neck squamous cell carcinoma (HNSCC). RNA sequences and clinicopathological data of HNSCC patients and normal subjects were downloaded from The Cancer Genome Atlas. In the training group, we used Pearson correlation, univariate Cox regression, least absolute shrinkage/selection operator regression analyses, and multivariate Cox regression to build a prognostic model. In the test group, we evaluated the model. Multivariate Cox regression was done to screen out independent prognostic factors, with which we constructed a nomogram. Afterward, we demonstrated the predictive value of the risk scores based on the model and the nomogram using time-dependent receiver operating characteristics. Gene set enrichment analysis, immune correlation analysis, and half-maximal inhibitory concentration were also performed to reveal the different landscapes of TIME between risk groups and to predict immuno- and chemo-therapeutic responses. The most important LINC00861 in the model was examined in HNE1, CNE1, and CNE2 nasopharyngeal carcinoma cell lines and transfected into the cell lines CNE1 and CNE2 using the LINC00861-pcDNA3.1 construct plasmid. In addition, CCK-8, Edu, and SA-β-gal staining assays were conducted to test the biofunction of LINC00861 in the CNE1 and CNE2 cells. The signature based on nine ARLs has a good predictive value in survival time, immune infiltration, immune checkpoint expression, and sensitivity to multiple drugs. LINC00861 expression in CNE2 was significantly lower than in the HNE1 and CNE1 cells, and LINC00861 overexpression significantly inhibited the proliferation and increased the senescence of nasopharyngeal carcinoma cell lines. This work built and verified a new prognostic model for HNSCC based on ARLs and mapped the immune landscape in HNSCC. LINC00861 is a protective factor for the development of HNSCC., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2023 Gao et al.)

Purpose: Cervical cancer (CC) is one of the most common gynecologic neoplasms. Hypoxia is an essential trigger for activating immunosuppressive activity and initiating malignant tumors. However, the determination of the role of immunity and hypoxia on the clinical outcome of CC patients remains unclear., Methods: The CC independent cohort were collected from TCGA database. Consensus cluster analysis was employed to determine a molecular subtype based on immune and hypoxia gene sets. Cox relevant analyses were utilized to set up a risk classifier for prognosis assessment. The underlying pathways of classifier genes were detected by GSEA. Moreover, we conducted CIBERSORT algorithm to mirror the immune status of CC samples., Results: We observed two cluster related to immune and hypoxia status and found the significant difference in outcome of patients between the two clusters. A total of 251 candidate genes were extracted from the two clusters and enrolled into Cox relevant analyses. Then, seven hub genes (CCL20, CXCL2, ITGA5, PLOD2, PTGS2, TGFBI, and VEGFA) were selected to create an immune and hypoxia-based risk classifier (IHBRC). The IHBRC can precisely distinguish patient risk and estimate clinical outcomes. In addition, IHBRC was closely bound up with tumor associated pathways such as hypoxia, P53 signaling and TGF β signaling. IHBRC was also tightly associated with numerous types of immunocytes., Conclusion: This academic research revealed that IHBRC can be served as predictor for prognosis assessment and cancer treatment estimation in CC., Competing Interests: All the authors declare that they have no conflict of interest., (Copyright © 2022 Yujing Shi et al.)

Background: Radiation-induced bystander effect (RIBE) can promote tumor metastasis contributing to the failure of radiotherapy for esophageal squamous cell carcinoma (ESCC). Aberrant expression of DJ-1 has been identified in ESCC; however, the relationship between DJ-1 and RIBE in ESCC remains unknown., Methods: We detected DJ-1 in the serum and cell supernatants by enzyme-linked immunosorbent assay (ELISA) and evaluated tumor metastasis by phenotypic experiments in vivo and in vitro. RNA-seq, mass spectrometry, western blot (WB), immunoprecipitation (IP), and dual-luciferase reporter assays were performed to explore the underlying mechanisms., Results: DJ-1 was highly expressed in the serum of patients with ESCC receiving radiotherapy and was significantly overexpressed in the medium of ESCC cells receiving irradiation. DJ-1 promoted tumor metastasis via the TGF-β1 pathway. Mechanistic studies revealed that DJ-1 bound to HSC70 to promote Smad3 phosphorylation and nuclear aggregation in a protein-interaction manner, which activated the transcription of Thrombospondin-1 (TSP1). Subsequently, the activation of TGF-β1 by TSP1 re-promoted Smad3 phosphorylation and nuclear aggregation, constituting a positive feedback loop to strengthen the metastasis of ESCC cells, which was effectively blocked by LY2109761 and LSKL. Moreover, higher levels of serum DJ-1 in patients with ESCC were related to a poorer prognosis of radiotherapy., Conclusions: Irradiation can induce ESCC cells secreting DJ-1. Secreted DJ-1 enters bystander cells to initiate activation of the TGF-β1 pathway via the DJ-1/HSC70/Smad3 signaling axis. The TSP1/TGF-β1/Smad3 positive feedback pathway constitutes the core pathway that promotes ESCC metastasis. DJ-1 is a useful biomarker for predicting the efficacy of radiotherapy and a potential therapeutic target for reversing RIBE in ESCC. Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells., (© 2022. The Author(s).)

This study was aimed to evaluate the clinical values of single markers and combination in the diagnosis, short-term efficacy and recurrence risk assessment of esophageal squamous cell carcinoma (ESCC)., Methods: Totally 50 patients with I-IVa stage ESCC, 50 healthy controls and 11 patients with recurrent esophageal cancer after comprehensive treatment were enrolled. Serum biomarkers were collected and evaluated. Serum concentrations of carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) and neuron specific enolase (NSE) were measured by enzyme-linked immunosorbent assay before and after treatment., Results: The diagnostic efficacy ROC curve area of CEA, CYFRA21-1 and NSE in esophageal cancer was 0.70, 0.71 and 0.64(all P <0.05), respectively, the sensitivity was 80%, 88.89% and 60% respectively, and the specificity was 53%, 58.5% and 58% respectively. The sensitivity and specificity of the combined detection were 68% and 78% respectively. The area under ROC curve was 0.75. CEA, CYFRA21-1 and NSE were significantly higher than the healthy control group and thus can be used as diagnostic markers of esophageal cancer (all P <0.05). After standard treatment, the clinical CR and PR rate of patients with positive CYFRA21-1 or NSE before treatment was significantly lower than that of patients with negative CYFRA21-1 or NSE (X 2 = 4.52,P =0.03). A significant negative correlation was found between N stage and clinical efficacy (HR 2.48, 95%CI 1.07-5.73). After comprehensive treatment, the serum CYFRA21-1 and NSE levels in recurrent patients also increased significantly(all P<0.05), indicating these two markers play obvious roles in recurrence monitoring., Conclusion: CYFRA21-1 and NSE may help to predict the response of ESCC to CRT, and play important roles in the diagnosis and recurrence monitoring of esophageal cancer. These markers have a diagnostic value of esophageal cancer when combined with CEA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ju, Ge, Di, Zhang, Liang and Shi.)

Esophageal cancer has high incidence and mortality rates and a low five-year survival rate of <15% owing to its strong capabilities of invasion, relapse and metastasis. The classic view holds that metastasis and diffusion is an advanced event during cancer progression, but recent studies show that distant diffusion of primary cancer cells may actually be an early event. Detection of circulating tumor cells (CTCs) in the circulation may indicate tumor spread, so CTCs are considered to be the key factor of metastatic cascade. In recent years, despite research progress on CTCs, there is a lack of systematic and important evidence to confirm the diagnostic, monitoring and prognostic values of CTCs in esophageal squamous cell carcinoma (ESCC). In this review, we clarify the relationship between CTC values and ESCC and provide more reliable evidence to improve the management and treatment of ESCC., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Shi et al.)

Introduction: Radiotherapy (RT) is the main treatment for unoperated esophageal cancer (EC) patients. It is controversial whether adding chemotherapy (CT) to RT is beneficial for elderly EC patients. The purpose of our study was to compare the efficacy of chemoradiotherapy (CRT) with RT alone for non-surgical elderly esophageal cancer patients., Methods: A total of 7,101 eligible EC patients older than 65 years diagnosed between 2000 and 2018 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. All the samples were divided into the radiotherapy group and the chemoradiotherapy group. After being matched by propensity score matching (PSM) at a 1:1 ratio, 3,020 patients were included in our analysis. The Kaplan-Meier method and log-rank test were applied to compare overall survival (OS) and cancer-specific survival (CSS)., Results: After PSM, the clinical characteristics of patients between the RT and CRT groups were comparable. For EC patients older than 65 years, the 3-year OS and CSS in the CRT group were 21.8% and 27.4%, and the 5-year OS and CSS in the CRT group were 12.7% and 19.8%, respectively. The 3-year OS and CSS in the RT group were 6.4% and 10.4%, and the 5-year OS and CSS in the RT group were 3.5% and 7.2%, respectively. Next, these patients were divided into five subgroups based on the age stratification (ages 65-69; 70-74; 75-79; 80-84; ≥85). In each subgroup analysis, the 3- and 5-year OS and CSS showed significant benefits in the CRT group rather than in the RT group (all p < 0.05). We were unable to assess toxicities between the two groups due to a lack of correlated information., Conclusions: CRT could improve OS and CSS for non-surgical EC patients older than 65 years. Adding chemotherapy to radiation showed a significant prognostic advantage for elderly esophageal cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xia, Gao, Ge, Liu, Di, Sun and Yang.)

Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for nonsurgical esophageal cancer (EC). However, esophageal cancer patients receiving CCRT alone are still unsatisfactory in terms of local control and overall survival (OS) benefit. Clinicians generally add consolidation chemotherapy (CCT) after CCRT. It remains controversial whether CCT following CCRT is beneficial for esophageal cancer. We, therefore, undertook a meta-analysis to assess the need for CCT in inoperable esophageal cancer., Materials and Methods: We combed PubMed, Embase, Cochrane Library, Web of Science, and CNKI for relevant published articles up to July 2020 that compared CCRT plus CCT to CCRT alone for patients with nonsurgical EC. Our primary endpoint was OS and progression-free survival (PFS), and the secondary endpoint was treatment toxicity. We analyzed the hazard ratio (HR) to estimate the time-to-event data and the odds ratio (OR) to compare the treatment-related effect. To assess heterogeneity, we performed the I 2 test and examined publication bias using funnel plots analysis., Results: The 11 retrospective studies involved 2008 patients. Of these 2008 patients, 1018 received CCRT plus CCT, and 990 received CCRT. Compared to CCRT alone, CCT after CCRT did not improve disease control rate (DCR) (OR 1.66; 95% CI 0.53-5.15, p=0.384) and objective response rate (ORR) (OR 1.44; 95% CI 0.62-3.35, p=0.393). However, OS (HR 0.72; 95% CI 0.59-0.86, p < 0.001) and PFS (HR 0.61; 95% CI 0.44-0.84, p=0.003) did increase. Our results show that CCT plus CCRT had a clear survival advantage over CCRT alone. The risk of treatment toxicity did not increase for EC patients who received CCT., Conclusion: CCT after CCRT significantly increases OS and PFS in patients with nonsurgical EC and could provide them remarkable survival benefits. The results provide an evidence-based framework for the use of CCT after CCRT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xia, Liu, Qin, Di, Zhang, Sun and Ge.)

Radioresistance reduces the success of therapy for patients with ESCC. Enhancing our understanding of the cardinal principles of radioresistance may improve the response of patients to irradiation. MicroRNAs perform a key role in posttranscriptional regulation, which is linked with the response of tumors to irradiation. Here, we successfully constructed a radioresistant cell line model, ECA109R, from parental esophageal cancer cell line ECA109. We used RNA-Seq analysis and qRT-PCR to compare the miRNA expression profiles of the ECA109 and ECA109R cell lines. The results revealed that miR-450a-5p was downregulated in the radioresistant cells. Functional analysis indicated that miR-450a-5p increases cellular radiosensitivity and suppresses autophagy in ESCC cells. We utilized a luciferase reporter assay to identify the target gene, DUSP10, as an indispensable regulator of the p38 and SAPK/JNK signaling pathways. Upregulation or downregulation of DUSP10 expression could reverse the effects of miR-450a-5p overexpression or inhibition. Tumor xenograft experiments verified that miR-450a-5p overexpression could increase sensitivity to radiation therapy in vivo. In general, our findings indicate that miR-450a-5p is a latent radiosensitizer and may represent a potential novel therapeutic target for radioresistance in ESCC., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript. We declare that the original research has not been published previously, and not under consideration for publication elsewhere, in whole or in part., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The optimal therapeutic strategy in locally advanced esophageal squamous cell carcinoma (ESCC) primarily treated by surgery remains unknown. This study was designed to evaluate the impact of postoperative chemoradiotherapy and postoperative sequential chemoradiotherapy on survival in this population., Methods: The study included a total of 228 consecutive patients who underwent radical esophagectomy and were confirmed to have stage pT3-4 or pN+ ESCC from September 2011 to September 2017 at our institution. All patients received postoperative radiotherapy with or without concurrent or sequential chemotherapy after esophagectomy. Univariate and multivariate analyses were used to compare the survival of patients with postoperative radiotherapy, postoperative concurrent chemoradiotherapy, and postoperative sequential chemoradiotherapy., Results: After a median follow-up of 52 months, the 3- and 5-year overall survival (OS) rates were 70.2% [95% confidence interval (CI), 63.7-76.7%] and 62.2% (95% CI, 54.6-69.8%), respectively. The disease-free survival (DFS) rates at 3 and 5 years were 65.2% (95% CI, 58.7-71.7%) and 55.2% (95% CI, 47.6-62.8%), respectively. The 3- and 5-year locoregional recurrence-free survival (LRFS) rates were 65.1% (95% CI, 58.4-71.8%) and 55.5% (95% CI, 47.7-63.3%). Of the 228 patients, 38 (16.7%) had distant metastases. Subgroup analysis showed that being male and having a higher T stage were independent poor prognostic factors for OS and DFS in patients with pN+ or stage III + IVA ESCC. The results also showed that in patients with stage III + IVA ESCC, the DFS of the patients in the concurrent chemotherapy (CCT) group was improved compared with that in the no CCT group [hazard ratio (HR), 0.551; 95% CI, 0.323-0.938; P=0.028]. Multivariate analysis showed that sequential chemoradiotherapy was associated with poor LRFS (HR, 2.312; 95% CI, 1.078-4.959; P=0.031), especially in stage T3-4 patients, and it was also related to the poor DFS (HR, 1.781; 95% CI, 1.086-2.921; P=0.022) in patients with stage T3-4 ESCC., Conclusions: In patients with locally advanced ESCC, those who underwent sequential chemoradiotherapy had a worse LRFS. Postoperative concurrent chemoradiotherapy was the most effective adjuvant therapy for resected stage III-IVA ESCC. In addition, being male, having a higher T stage, and being node-positive were independent poor prognostic factors for OS and DFS.

Background and Aim: The high-mobility group box 1 (HMGB1) protein plays an important role in a lot of biological behaviors, including DNA damage repair, gene transcription, cell replication, and cell death, and its expression is higher in many solid tumors tissues than in their adjacent normal tissues, and it is always involved in tumor proliferation, metastasis, therapeutic tolerance, and poor prognosis. However, HMGB1 in proliferation and radioresistance of esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, the effect of HMGB1 on proliferation, cell death, DNA damage repair and radioresistance, and its underlying mechanism was investigated in human ESCC., Methods: The immunohistochemistry scores of tumor and adjacent normal tissues in ESCC tissue microarray were analyzed. Stable HMGB1 knockdown cell lines were constructed using Kyse150 and Kyse450 cells. Cell viability, radioresistance, apoptosis, autophagy, and DNA damage were determined using CCK-8, 5-ethynyl-2'-deoxyuridine, clonogenic survival assay, immunofluorescence, flow cytometry, and western blot assays., Results: Differential analyses showed that the expression of HMGB1 in esophageal cancer tissue was significantly higher than that in adjacent normal tissues. The downregulation of HMGB1 could effectively inhibit proliferation, increase radiosensitivity, impair DNA damage repair abilities, reduce autophagy, and increase apoptosis rates in ESCC cells after irradiation., Conclusions: HMGB1 is expected to be a potential target for ESCC therapy and radiosensitization., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Endocrine therapy and radiotherapy are the main treatments for luminal A breast cancer. However, drug and radiotherapy resistance could occur during long-term treatment, leading to local recurrence and distant metastasis. Some studies have found that drug resistance might be related to human epidermal growth factor receptor-3 (HER3) overexpression. However, whether HER3 plays a role in radiotherapy resistance is unknown. The purpose of this study is to elucidate the effect of HER3 in radiotherapy and to assess whether HER3 could be a potential target for radiosensitivity. We used retroviruses to construct stable low expression of HER3 in MCF-7 and ZR75-1cells. The CCK-8 assay was used to observe proliferation. Colony-forming assay was used to detect radiosensitivity. Flow cytometry was used to observe the cell cycle and apoptosis. Immunofluorescence assay was used to detect the number of γH2AX foci in the nucleus with or without ionizing radiation (IR). Western blot analysis was used to verify the change of relative proteins. Nude mice were used to observe tumor growth in vivo. In our study, silencing HER3 reduced cell proliferation and clone formation ability after IR, so silencing HER3 increased the sensitivity of luminal A breast cancer cells to radiotherapy. In terms of radiosensitivity mechanisms, it is suggested that the silencing of HER3 enhanced IR-induced DNA damage, reduced DNA repair, and increased apoptosis and G 2 /M arrest. In addition, silencing HER3 combined with IR clearly inhibited the transplanted tumor growth in vivo. Therefore, we concluded that HER3 played a role in radiotherapy resistance. Silencing HER3 increased the radiosensitivity of luminal A breast cancer cells and HER3 could be a potential target for radiosensitivity., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The optimal timing of esophagectomy after neoadjuvant chemoradiation treatment (nCRT) remains unclear. Here, a meta-analysis was conducted to determine whether prolonged interval between nCRT and surgery can affect the outcomes in esophageal cancer., Materials and Methods: The databases PubMed, Embase, Web of Science, and Cochrane were systematically searched for studies reporting the outcomes in esophageal cancer according to the length of interval between nCRT and surgery. The primary outcome was rate of pathologic complete response (pCR), and the secondary outcomes included R0 resection rate, incidence of anastomotic leak, postoperative mortality, and two or five-year overall survival (OS). The intervals were classified into dichotomous (≤7-8 weeks and >7-8 weeks) for the pooled analysis, and a combined relative risk (RR) was calculated., Results: A total of 13 studies involving 15,086 patients were analyzed. The overall results indicated that an interval longer than 7-8 weeks between the end of nCRT and the surgery was significantly associated with an improved pCR rate (RR, 1.13; 95% confidence interval [CI], 1.05-1.21; P = 0.001). However, it was related to a higher 30-day surgical mortality (RR, 1.51; 95% CI, 1.19-1.92; P = 0.0006). The subgroup analyses only detected a significant association of the extended interval with pCR and the surgical mortality rate in adenocarcinoma patients. Moreover, an increased time interval resulted in a lower 2-year (RR, 0.94; 95% CI, 0.90-0.98; P = 0.002) and 5-year OS (RR, 0.88; 95% CI, 0.82-0.95; P = 0.0009). No association with R0 resection rate or anastomotic complication resulting from delayed resection was detected., Conclusions: Although increasing the time interval from nCRT to esophagectomy was associated with significantly higher pathologic complete response rates in esophageal cancer, delaying the surgery might be disadvantageous for the long-term survival., (Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Murine double minute 2 (MDM2) negatively regulates the activity of the p53 protein and plays a vital role in cell cycle arrest, apoptosis, and senescence mediated by p53. Nutlin-3, an antagonist of MDM2, is frequently used in anti-cancer studies. In many human tumors, nutlin-3 stabilizes p53 status and enhances p53 expression in cells with wild-type p53. However, the effect of nutlin-3 combined with radiotherapy on esophageal squamous cancer (ESCC) has not been reported. In this study, we examined whether nutlin-3 increases the radiosensitivity of ESCC in vitro and in vivo.We chose two cell lines, ECA-109 (wild-type p53) and TE-13 (p53 mutated), for the following experiments. Cell proliferation and clonogenic survival experiments showed that nutlin-3 inhibits the cell growth and colony formation of ECA-109 cells in a dose-dependent manner. Flow cytometry analysis showed that the apoptosis rate of ECA-109 cells co-treated with nutlin-3 and irradiation(IR) was significantly increased compared with cells treated with irradiation or nutlin-3 alone. Western blotting detected the expression of apoptosis-associated proteins in ECA-109 cells in response to nutlin-3 and irradiation. These effects were not evident in TE-13 cells. Xenograft mouse models indicated that nutlin-3 suppresses tumor growth and promotes radiosensitivity in the ESCC cell line ECA-109 in vivo. We have demonstrated that co-treatment of nutlin-3 with irradiation can significantly inhibit the growth and improve the radiosensitivity of ESCC cells with wild-type p53. The study suggests that nutlin-3 may be a potent therapeutic agent in conjunction with radiotherapy in ESCC.

Introduction: Radiotherapy is by means of ionizing radiation to kill tumor cells, inhibit and control the growth, metastasis and diffusion of tumor cells. During the last few decades, application of radiotherapy combined with chemotherapy and surgery are clinical mainstream treatments. However, little is known what radio-sensitization agents have been patented in China and what the potential drug candidates for patents are in China. Areas covered: This reviews covers research and patent literature of the last 10 years dealing with the discovery and development of novel radio-sensitization patents in China. Expert opinion: The 94 radio-sensitization patents granted from 2006 to 2015 mainly focus on six types of products. They are: traditional Chinese medicines (TCM), synthetic compounds, combinations of synthetic compounds and TCM, biological products, medical apparatus and others. In the course of tumor treatment, radiotherapy occupies an irreplaceable position. Previously believed that due to the prevalence of hypoxic cells in solid tumors, most of the tumor exist a certain degree of radiation resistance. To find effective ways to improve the sensitivity of tumor cells to radiation therapy has become a focus in scientific research and clinical treatment. So radiation sensitivity has been proposed and widely studied.

Objectives: To investigate the biological function of eEF2K in esophageal squamous cell carcinoma (ESCC)., Materials and Methods: Tissue microarrays containing 100 pairs of ESCC tumor and adjacent normal tissues were completed. Overexpression and knockdown of eEF2K were constructed in ECA-109 and TE-13 ESCC cells. DNA damage, cell viability, migration and invasion, radioresistance, apoptosis and autophagy were determined by immunofluorescence, CCK-8, transwell assay, colony formation assay, flow cytometry and western blot, respectively. Tumor growth and radioresistance were also evaluated using xenograft models created in nude mice., Results: eEF2K expression was higher in ESCC tissues compared with matched non-tumor tissues (P<0.05). Proliferation was increased in eEF2K overexpressing cells compared with controls (P<0.05), while silencing eEF2K reduced cell proliferation (P<0.05). Furthermore, lower levels of eEF2K expression correlated with slower migration and invasion rates (P<0.05), while higher levels of eEF2K expression with faster migration and invasion rates (P<0.05). eEF2K overexpression resulted in radioresistance and radiation-induced autophagy, and reduced radiation-induced apoptosis compared with controls, but silencing eEF2K promoted radiosensitivity and apoptosis, and reduced autophagy. In addition, eEF2K overexpression promoted the tumor growth in vivo (P<0.01). Combined treatment of NH125 (a pharmacological inhibitor of eEF2K) and radiation was more effective at delaying xenograft tumor growth than NH125 and radiation alone (P<0.05)., Conclusion: eEF2K induced progression and radioresistance in ESCC, which may be a novel therapeutic target for ESCC to increase radiosensitivity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: This meta-analysis was designed to fully assess the curative effects of radiotherapy-based therapies for human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC)., Methods: English articles were retrieved through searching Cochrane library, PubMed, and Embase databases updated to February 2017. Studies were selected based on the inclusion and exclusion criteria. The curative effects of radiotherapy-based therapies forHER2+ BC patients were assessed using hazard rates (HRs) or odds ratios (ORs), as well as their 95% confidence intervals (CIs). In addition, Egger test was used to assess publication bias, followed by sensitivity analysis. All statistic methods were conducted using R 3.12 software., Results: A total of 9 eligible studies were included into this meta-analysis, which involved 2236 HER2+ BC patients. Egger test showed that the eligible studies had no publication bias (t = 2.198, P = .05918). Sensitivity analysis demonstrated that the results were stable. HER2+ BC patients in radiotherapy group had lower locoregional recurrences than those in other groups. Moreover, meta-analysis showed that no significant difference was found between HER2+ BC patients in radiotherapy group and other groups on the 1-year overall survival (P = 0.5263, I = 65.4%), 3-year overall survival (P = 0.4591, I = 0), and 5-year overall survival (P = 0.06277, I = 0)., Conclusion: Radiotherapy-based therapies might have certain advantages in treating HER2+ BC patients.