Exploring the effects of simulated microgravity on esophageal cancer cells: insights into morphological, growth behavior, adhesion, and genetic damage.

The exploration of microgravity has garnered substantial scholarly attention due to its potential to offer unique insights into the behavior of biological systems. This study presents a preliminary investigation into the effects of simulated microgravity on esophageal cancer cells, examining various aspects such as morphology, growth behavior, adhesion, inhibition rate, and DNA damage. To achieve this, a novel microgravity simulator named "Gravity Challenge" was utilized for its effectiveness in minimizing external influences that could compromise microgravity conditions. The international cell line SK-GT-4 was utilized as the focal point of this investigation. Results revealed noticeable alterations in the growth behavior of cancer cells following exposure to simulated microgravity for 24 h, characterized by a loss of adhesion properties compared to control cells. Concurrently, cell viability exhibited a decline, as evidenced by cytotoxicity testing. Furthermore, the comet assay test demonstrated that cells subjected to microgravity simulation experienced a higher incidence of DNA damage compared to their control counterparts. In conclusion, this comprehensive examination of the impact of simulated microgravity on esophageal cancer cells extends beyond morphological changes, delving into genetic implications through observed DNA damage. The diminished vitality of cells under microgravity conditions underscores the multifaceted effects on cellular behavior in response to environmental variations. These findings represent a significant step towards understanding the dynamics of cancer cells, laying the groundwork for future research aimed at identifying potential therapeutic strategies for this disease.

Identification of genome-wide copy number variation-driven subtypes for the treatment and prognostic prediction of esophageal carcinoma.

Background: Esophageal carcinoma (ESCA) is a frequently detected gastrointestinal cancer. Copy number variants (CNVs) have a dramatic impact on the screening, diagnosis and prognostic prediction of cancers. However, the mechanism of action of CNVs on ESCA occurrence and progression remains unclear. Methods: ESCA samples from The Cancer Genome Atlas (TCGA) were typed by consensus clustering using CNV-associated genes. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to section gene modules closely related to the two clusters, and sub-networks were constructed as hub genes. In addition, seven prognosis-correlated genes were further screened and retained by multivariate Cox regression analysis to develop a prognostic assessment model. The ssGSEA algorithm assessed energy metabolism levels in patients from different clusters and risk groups. Finally, quantitative real-time PCR (qRT-PCR) and live-dead cell staining verified the expression of genes associated with CNV risk scores. Results: ESCA was classified into two subtypes based on CNV values. Compared with cluster 1, cluster 2 had significantly higher level of immune score and tumor-associated immune cell infiltration as well as a noticeably better overall survival. The three modules most associated with the two clusters were identified by WGCNA, and a prognostic model with a strong prediction performance was constructed with their genes. Glycolysis, lactate metabolism, fatty acid synthesis, glutathione, methionine, and tryptophan metabolic pathway enrichment scores were remarkably higher in patients in cluster 1 and the high-risk group than in cluster 2 and the low-risk group. Knockdown PIK3C2A promoted ESCA cells apoptosis and inhibited cell vibiality. Conclusion: The current research maybe provides new understanding for the pathogenesis of ESCA based on CNV, providing an effective guidance for its clinical diagnosis and prognostic evaluation.

Involved-field high-dose chemoradiotherapy with respiratory motion management for esophageal squamous cell carcinoma.

BACKGROUND: We investigated the clinical outcomes of involved-field high-dose (≥66 Gy) chemoradiotherapy (CRT) combined with respiratory motion management for esophageal squamous cell carcinoma (ESCC). METHODS: Patients who underwent definitive CRT for histologically confirmed ESCC in our department between 2012 and 2018 were retrospectively analyzed. Respiratory motion management strategies included breath-holding (63%) and mask immobilization (29%) based on individual measurements of respiratory tumor motion using radiographic fluoroscopy with endoscopically placed clip markers as landmarks. We evaluated patient characteristics, treatment efficacy, failure patterns, and toxicities. RESULTS: We enrolled 35 patients with a prescribed dose of 66-70 Gy in 33-35 fractions. The overall response rate within 6 months post-CRT was 94.3%; the median follow-up period for survivors was 43 months. The 2-year overall survival (OS), progression-free survival, and locoregional failure-free survival rates were 51.4%, 42.9%, and 42.9%, respectively. A significant difference in OS was observed between patients with and without esophageal fistulas after CRT (p = 0.002, log-rank test). Disease failure occurred in 16 patients (45.7%), including one (2.9%) with out-of-field regional nodal failure. Major grade 3 or higher toxicities included decreased white blood cell count (48.6%), neutrophil count (34.3%), and esophageal stenosis (31.4%). No grade 3 or higher cardiopulmonary toxicities were observed. Bronchial/tracheal tumor compression and a higher radiotherapy dose (70 Gy) were significantly correlated with esophageal fistulas. CONCLUSION: Involved-field high-dose CRT with respiratory motion management may be a feasible treatment option for ESCC. However, a comprehensive assessment of esophageal fistula risk is required to identify suitable candidates.

Clinical evaluation of oxaliplatin-loaded drug-eluting callispheres beads transarterial chemoembolization for unresectable or recurrent esophageal carcinoma.

BACKGROUND: A majority of esophageal carcinoma patients are diagnosed at an advanced stage and are no longer suitable for surgical resection. Drug-eluting beads transarterial chemoembolization (DEB-TACE) with oxaliplatin-loaded CalliSpheres beads (CB) have been used for advanced hepatocellular carcinoma and lung cancer, but they have not been reported for the treatment of unresectable or recurrent esophageal carcinoma. METHODS: DEB-TACE was performed on 22 patients with unresectable or recurrent esophageal carcinoma between March 2019 and May 2022. The clinical outcomes, complications, and efficacy were retrospectively recorded and analyzed. RESULTS: A total of 39 sessions of DEB-TACE were performed in 22 patients, with a technical success rate of 92.3% and clinical success rate of 65.0%. No severe complications such as procedure-related death, esophageal rupture or paraplegia were observed. Complete response, partial response, and stable disease were observed in 14.3% (2/14), 42.9% (6/14), and 21.4% (3/14) of patients 6 months after DEB-TACE, respectively. The objective response rates were 62.5%, 42.9% and 57.1% respectively at 1-, 3-, and 6-month after DEB-TACE. Subsequent interventional treatments were administered to 12 patients, including DEB-TACE for hepatic metastasis in 3 (13.6%), esophageal stenting in 5 (22.7%), and airway stent placement in 5 (22.7%). Two patients were lost to follow up. A total of 9 patients died due to tumor progression (n = 5), pneumatic infection (n = 1), and tumor-related massive esophageal hemorrhage (n = 3). The median overall survivals were 13.9 months and 26.5 months from the first session of DEB-TACE and the diagnosis of esophageal carcinoma, respectively. CONCLUSIONS: DEB-TACE with oxaliplatin-loaded CB is suggested as a safe and effective treatment of unresectable or recurrent esophageal carcinoma, and more studies are required to confirm its efficacy and safety.

Mediastinal drainage combined with upper mediastinal re-tunneling vs. mediastinal drainage alone in McKeown esophagectomy of esophageal cancer: a retrospective study.

Background: Although mediastinal drainage may lower the risk of anastomotic leakage, the incident rate of anastomotic leakage is still high. The current study aimed to compare the effects of mediastinal drainage combined with upper mediastinal re-tunneling with mediastinal drainage only on anastomotic leakage after McKeown esophagectomy for esophageal cancer. Methods: From October 2018 to March 2021, 52 patients diagnosed as esophageal carcinoma were included in the study. 21 patients received mediastinal drainage combined with upper mediastinal re-tunneling (re-tunneling group) and 31 received mediastinal drainage only (standard group) after McKeown esophagectomy. The incidence rate of anastomotic leakage, mediastinal infection, chylothorax, thoracic infection, the peak value of leukocyte count and the mortality related to anastomotic leakage were compared between the two groups. Results: One (4.8%) patient in the re-tunneling group developed anastomotic leakage, and no patient experienced mediastinal infection or thoracic infection. Four (12.9%) patients in the standard group developed anastomotic leakage, and all these patients experienced mediastinal infection and thoracic infection (p < 0.05). The drainage volumes of patients in the re-tunneling group and the standard group were (170 ± 60) ml and (155 ± 45) ml, respectively, with no significant difference between the two groups (p > 0.05). The peak values of leukocyte count and temperature in the re-tunneling group were (14.28 ± 1.12) × 109/L and (38.6 ± 1.1) °C, both lower than that of the standard group[ (16.48 ± 1.15) × 109/L and (38.9 ± 1.2) °C, respectively]. But the difference was not statistically significant (p > 0.05). No anastomotic leakage related death occurred in both groups. Conclusion: Mediastinal drainage combined with upper mediastinal re-tunneling after McKeown esophagectomy for esophageal cancer may decrease the risk of anastomotic leakage, mediastinal and thoracic infection, reduce the inflammatory response of patients, but did not increase the mortality related to anastomotic leakage. Trial registration: The study was retrospectively registered.

Evaluation of patient satisfaction with an enhanced recovery protocol for esophageal resections: a concurrent quantitative and qualitative analysis.

Patient satisfaction during hospitalization for esophagectomy has been little studied. The aim of this study was to evaluate patients' satisfaction with a newly introduced enhanced recovery protocol (ERP) for esophagectomy. At hospital discharge, patients were invited to complete a questionnaire. This pseudonymized questionnaire contained 5-point Likert scales regarding items on multidisciplinary care (n = 7), information/communication (n = 7), length of stay (n = 1), and specific adaptations of care in the ERP (n = 11). One open question asked for patient experiences and suggestions for improving the ERP. Between May 2017 and December 2021, 521 patients were included in the ERP after esophagectomy. Of them, 327 patients (63%) completed the questionnaire. Response rates were evenly distributed between genders and slightly higher in younger patients (<60 years; 68%) as compared to elderly patients (>70 years; 60%). Quantitative analysis revealed high satisfaction rates for multidisciplinary care (86.8%), information/communication (84.9%), and ERP adaptations (82.2%), and length of stay was considered optimal in 80%. There were no significant differences in satisfaction observed between gender nor age groups. For the qualitative analysis, there were 108 open answers, resulting in 268 statements. Sentiments expressed in these statements were evaluated as negative, positive, or unspecified. Negative sentiments were attributable to alimentation, organizational factors, and communication. Positive sentiments were attributed to interpersonal relations, multidisciplinary care, and ERP. Overall, patients are very satisfied with the ERP for esophagectomy during hospitalization. By incorporating qualitative data, the results of this quantitative analysis are expanded and elucidated, showing areas where improvements to our ERP are possible to increase patient satisfaction.

Prediction of Survival in Patients With Esophageal Cancer After Immunotherapy Based on Small-Size Follow-Up Data.

Esophageal cancer (EC) poses a significant health concern, particularly among the elderly, warranting effective treatment strategies. While immunotherapy holds promise in activating the immune response against tumors, its specific impact and associated reactions in EC patients remain uncertain. Precise prognosis prediction becomes crucial for guiding appropriate interventions. This study, based on data from the First Affiliated Hospital of Xiamen University (January 2017 to May 2021), focuses on 113 EC patients undergoing immunotherapy. The primary objectives are to elucidate the effectiveness of immunotherapy in EC treatment and to introduce a stacking ensemble learning method for predicting the survival of EC patients who have undergone immunotherapy, in the context of small sample sizes, addressing the imperative of supporting clinical decision-making for healthcare professionals. Our method incorporates five sub-learners and one meta-learner. Leveraging optimal features from the training dataset, this approach achieved compelling accuracy (89.13%) and AUC (88.83%) in predicting three-year survival status, surpassing conventional techniques. The model proves efficient in guiding clinical decisions, especially in scenarios with small-size follow-up data.

Non-invasive assessment of programmed cell death ligand-1 expression using 18F-FDG PET-CT imaging in esophageal squamous cell carcinoma.

Programmed cell death ligand-1 (PD-L1) is an ideal checkpoint for immunohistochemical detection. The method of obtaining PD-L1 expression through biopsy can impact the accurate assessment of PD-L1 expression due to the spatial and temporal heterogeneity of tumors. Because of the limited sample size, biopsies often give only a localized picture of the tumor. In this retrospective study, a total of 2,386 metabolic tumor volume (MTV) features were extracted from 18F-FDG PET-CT images. A radiomics model was developed to holistically and non-invasively assess PD-L1 expression in patients with esophageal squamous cell carcinoma by identifying seven independent factors through feature screening. The radiomics model shows effective discrimination, with an area under the receiver operating characteristic curve of 0.888 [95% confidence interval (CI): 0.831-0.945] and 0.889 (95% CI: 0.706-1.000) for the training and validation cohorts, respectively. The results of the decision curve analysis demonstrated that utilizing the radiation model to forecast PD-L1 expression levels yielded more net benefits at threshold probabilities below 0.669. The clinical impact curves demonstrate that when the threshold probability is less than 0.501, the loss-to-benefit ratio is less than one in all cases.

Perforated Esophageal Cancer.

Esophageal perforation in the setting of malignancy is a surgical emergency for which there is little direct evidence in the literature to guide treatment. Instead, treatment is based on a combination of our understanding of managing benign esophageal perforations and a contemporary understanding of the treatment and prognosis of esophageal cancer. Due to the numerous challenges of managing perforated esophageal cancer, incorporating clinicians with expertise in esophageal cancer, advanced endoscopy, and esophageal surgery into shared decision-making discussions with patients and their families is essential.

Changes in the gut microbiota of esophageal carcinoma patients based on 16S rRNA gene sequencing: a systematic review and meta-analysis.

Background: This study conducts a systematic review through meta-analysis, comparing the composition and diversity of the gut microbiome in patients with esophageal cancer and healthy individuals, and explores the relationship between risk factors and related factors of esophageal cancer. Methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we comprehensively searched the databases of PubMed, Web of Science, Embase, Cochrane Library. In addition, we applied the R programming language version 4.0.3 and Stata 15.1 software for data analysis. We also implemented the Newcastle-Ottawa Scale (NOS), funnel plot analysis, Egger's test, and Begg's test to assess the risk of bias. Results: In this study, a total of 328 studies were identified through the literature search. Among them, 117 duplicate studies were removed, and 202 studies were excluded based on inclusion and exclusion criteria. Finally, 9 studies were included in the analysis, involving a total of 216 patients with esophageal carcinoma and 352 healthy controls. Four studies provided Chao1 index for quantitative consolidation (ES = 637.41, 95% CI: 549.16 to 725.66, p = 0.000, I2 = 98.2%). Two studies [27, 29] reported ACE index (ES = 438.89, 95% CI: 362.42 to 515.35, p = 0.000, I2 = 97%). Seven studies [26,27,29,30,32] reported the Shannon index for quantitative consolidation (ES = 4.38, 95% CI: 3.95 to 4.81, p = 0.000, I2 = 99%). At the phylum level, the abundance of Bacteroidetes(ES = 37.8, 95% CI: 25.75 to 49.85, p = 0.000, I2 = 87.2%) and Proteobacteria(ES = 7.48, 95% CI: 5.02 to 8.85, p = 0.04, I2 = 2.4%) have statistical difference between ESCC and HC. There was no significant difference between ESCC and HC in the abundance of genera(p>0.05). Conclusions: This observational meta-analysis revealed that changes in the GM were correlated with esophageal carcinoma, and variations in some advantageous GM might involve regional differences. Additionally, the study aims to facilitate early diagnosis of esophageal cancer and improve screening and diagnostic efficiency.

Berbamine promotes ferroptosis of esophageal squamous cell carcinoma by facilitating USP51-mediated GPX4 ubiquitination and degradation.

Esophageal cancer ranks among the most prevalent malignant tumors globally. The prognosis for esophageal squamous cell carcinoma remains poor, with a 5-year survival rate below 20 % due to limited advances in therapy. Ferroptosis, a novel form of iron-dependent lipid peroxidation-driven regulated cell death (RCD), shows significant promise in cancer treatment. Berbamine (BBM), a natural bisbenzylisoquinoline alkaloid derived from Berberis amurensis, exhibits anti-tumor effects against various cancers, yet its impact on esophageal cancer remains to be elucidated. This study aimed to explore the role of BBM in inducing ferroptosis in the treatment of esophageal cancer, focusing on its molecular mechanisms. Gene set enrichment analysis(GSEA) analysis highlighted the potential of BBM as an anti-cancer agent through ferroptosis induction. We found that BBM inhibited growth and epithelial-mesenchymal transition (EMT) in esophageal cancer cell lines, promoting Fe accumulation, ROS, and malondialdehyde (MDA) production, thereby triggering cell death. These suppressive effects were successfully reversed by Ferrostatin-1 (Fer-1). Mechanistically, BBM decreased deubiquitination enzyme USP51 levels, leading to ubiquitin degradation and glutathione peroxidase 4(GPX4) instability, and it stimulated ferroptosis. The Overexpression of USP51 mitigated the downregulation of GPX4 induced by BBM.BBM significantly inhibited tumor xenograft growth in nude mice. This discovery positions BBM as a promising therapeutic candidate for the treatment of esophageal cancer.

Microbiome of esophageal endoscopic wash samples is associated with resident flora in the esophagus and incidence of cancer.

Change in mucosal microbiome is associated with various types of cancer in digestive tract. We hypothesized that microbial communities in the esophageal endoscopic wash fluids reflects resident flora in esophageal mucosa that is associated with esophageal carcinoma (EC) risk and/or directly correlates microbiome derived from EC tumor tissue. Studying microbial communities in esophageal endoscopic wash samples would be therefore useful to predict the incidence or risk of EC. We examined microbial communities of the endoscopic wash samples from 45 primary EC and 20 respective non-EC controls using 16S rRNA V3-V4 amplicon sequencing. The result was also compared with microbial communities in matched endoscopic biopsies from EC and non-cancerous esophageal mucosa. Compared with non-EC controls, 6 discriminative bacterial genera were detected in EC patients. Among them, relative abundance ratio of Prevotella and Shuttlewarthia, as well as decrease of genus Prevotella presented good prognostic performance to discriminate EC from controls (area under curve, 0.86, 0.82, respectively). Multivariate analysis showed occurrence of EC was an independent factor associated with decrease of this bacteria. Abundance of genus Prevotella in the esophageal endoscopic wash samples was significantly correlated with the abundance of this bacteria in the matched endoscopic biopsies from non-cancerous esophageal mucosa but not in the EC tissues. Our findings suggest that microbiome composition in the esophageal endoscopic wash samples reflects resident flora in the esophagus and significantly correlates with the incidence of EC.

Identifying and validating the roles of the cuproptosis-related gene DKC1 in cancer with a focus on esophageal carcinoma.

BACKGROUND: Esophageal cancer is a common malignancy of the digestive tract. Despite remarkable advancements in its treatment, the overall prognosis for patients remains poor. Cuproptosis is a form of programmed cell death that affects the malignant progression of tumors. This study aimed to examine the impact of the cuproptosis-associated gene DKC1 on the malignant progression of esophageal cancer. METHODS: Clinical and RNA sequencing data of patients with esophageal cancer were extracted from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis was used to identify the differentially expressed genes related to cuproptosis that are associated with prognosis. We then validated the difference in the expression of DKC1 between tumor and normal tissues via three-dimensional multiomics difference analysis. Subsequently, we investigated the association between DKC1 expression and the tumor microenvironment by employing the TIMER2.0 algorithm, which was further validated in 96 single-cell datasets obtained from the TISCH database. Additionally, the functional role of DKC1 in pancarcinoma was assessed through GSEA. Furthermore, a comprehensive pancancer survival map was constructed, and the expression of DKC1 was verified in various molecular subtypes. By utilizing the CellMiner, GDSC, and CTRP databases, we successfully established a connection between DKC1 and drug sensitivity. Finally, the involvement of DKC1 in the progression of esophageal cancer was investigated through in vivo and in vitro experiments. RESULTS: In this study, we identified a copper death-related gene, DKC1, in esophageal cancer. Furthermore, we observed varying levels of DKC1 expression across different tumor types. Additionally, we conducted an analysis to determine the correlation between DKC1 expression and clinical features, revealing its association with common cell cycle pathways and multiple metabolic pathways. Notably, high DKC1 expression was found to indicate poor prognosis in patients with various tumors and to influence drug sensitivity. Moreover, our investigation revealed significant associations between DKC1 expression and the expression of molecules involved in immune regulation and infiltration of lymphocyte subtypes. Ultimately, the increased expression of DKC1 in esophageal cancer tissues was verified using clinical tissue samples. Furthermore, DKC1-mediated promotion of esophageal cancer cell proliferation and migration was confirmed through both in vitro and in vivo experiments. Additionally, it is plausible that DKC1 may play a role in the regulation of cuproptosis. CONCLUSION: In this study, we conducted a systematic analysis of DKC1 and its regulatory factors and experimentally validated its excellent diagnostic and prognostic abilities in various cancers. Further research indicated that DKC1 may reshape the tumor microenvironment (TME), highlighting the potential of DKC1-based cancer treatment and its usefulness in predicting the response to chemotherapy.

Real-world retrospective study of anti-PD-1 antibody in combination with chemotherapy as a neoadjuvant treatment strategy for locally advanced resectable esophageal squamous cell carcinoma.

Background: Neoadjuvant therapy has become a mainstay of treatment for locally advanced resectable esophageal cancer. The objective of this research was to investigate the effectiveness and safety of neoadjuvant immunotherapy combined with chemotherapy in treating surgically removable esophageal squamous cell carcinoma (ESCC). Methods: From January 1, 2016 to April 1, 2023, we conducted a retrospective analysis of patients diagnosed with resectable esophageal cancer who underwent neoadjuvant immunotherapy combined with chemotherapy at The First Affiliated Hospital of Nanchang University. The primary endpoints of this study were pathologic complete response (pCR), major pathologic response (MPR) and disease-free survival (DFS). The secondary endpoints of this study were overall survival (OS), objective response rate (ORR) and safety. Results: A total of 122 patients with ESCC receiving neoadjuvant immune-chemotherapy (nICT) were included. Fifty-four patients achieved partial response (PR) and two patients achieved complete response (CR), with an ORR of 45.9%. Of the 106 patients who underwent surgery, a total of 28 patients achieved pCR (26.4%) and a total of 37 patients achieved MPR (34.9%). Grade 3 or higher adverse events occurred in 26 patients (21.3%). The most common postoperative complication was pneumonitis (25.5%). Conclusions: Neoadjuvant immunotherapy combined with chemotherapy demonstrates satisfactory efficacy in the treatment of locally advanced ESCC, with manageable treatment-related adverse events and postoperative complications.

Epidemiological distribution of high-risk human papillomavirus genotypes and associated factors among patients with esophageal carcinoma at Bugando medical center in Mwanza, Tanzania.

BACKGROUND: Esophageal carcinoma is a growing concern in regions that have a high incidence of human papillomavirus (HPV) infection such as East Africa. HPV, particularly the high-risk genotypes, is increasingly recognized as a risk factor for esophageal carcinoma. We set out to investigate the prevalence and associated factors of high-risk HPV in formalin-fixed paraffin-embedded (FFPE) tissue blocks with esophageal carcinoma at Bugando Medical Center, a tertiary referral hospital in Mwanza, Tanzania, East Africa. METHODS: A total of 118 esophageal carcinoma FFPE tissue blocks, collected from January 2021 to December 2022, were analyzed. Genomic DNA was extracted from these tissues, and multiplex polymerase chain reaction (PCR) was performed to detect HPV using degenerate primers for the L1 region and type-specific primers for detecting HPV16, HPV18, and other high-risk HPV genotypes. Data were collected using questionnaires and factors associated with high-risk HPV genotypes were analyzed using STATA version 15 software. RESULTS: Of the 118 patients' samples investigated, the mean age was 58.3 ± 13.4 years with a range of 29-88 years. The majority of the tissue blocks were from male patients 81/118 (68.7%), and most of them were from patients residing in Mwanza region 44/118 (37.3%). Esophageal Squamous Cell Carcinoma (ESCC) was the predominant histological type 107/118 (91.0%). Almost half of the tissue blocks 63/118 (53.3%) tested positive for high-risk HPV. Among these, HPV genotype 16 (HPV16) was the most common 41/63 (65.1%), followed by HPV genotype 18 (HPV18) 15/63 (23.8%), and the rest were other high-risk HPV genotypes detected by the degenerate primers 7/63 (11.1%). The factors associated with high-risk HPV genotypes were cigarette smoking (p-value < 0.001) and alcohol consumption (p-value < 0.001). CONCLUSION: A substantial number of esophageal carcinomas from Bugando Medical Center in Tanzania tested positive for HPV, with HPV genotype 16 being the most prevalent. This study also revealed a significant association between HPV status and cigarette smoking and alcohol consumption. These findings provide important insights into the role of high-risk HPV in esophageal carcinoma in this region.

Hypoxia exposure induces lactylation of Axin1 protein to promote glycolysis of esophageal carcinoma cells.

The hypoxic microenvironment in esophageal carcinoma is an important factor promoting the rapid progression of malignant tumor. This study was to investigate the lactylation of Axin1 on glycolysis in esophageal carcinoma cells under hypoxia exposure. Hypoxia treatment increases pan lysine lactylation (pan-kla) levels of both TE1 and EC109 cells. Meanwhile, ECAR, glucose consumption and lactate production were also upregulated in both TE1 and EC109 cells. The expression of embryonic stem cell transcription factors NANOG and SOX2 were enhanced in the hypoxia-treated cells. Axin1 overexpression partly reverses the induction effects of hypoxia treatment in TE1 and EC109 cells. Moreover, lactylation of Axin1 protein at K147 induced by hypoxia treatment promotes ubiquitination modification of Axin1 protein to promote glycolysis and cell stemness of TE1 and EC109 cells. Mutant Axin1 can inhibit ECAR, glucose uptake, lactate secretion, and cell stemness in TE1 and EC109 cells under normal or hypoxia conditions. Meanwhile, mutant Axin1 further enhanced the effects of 2-DG on inhibiting glycolysis and cell stemness. Overexpression of Axin1 also inhibited tumor growth in vivo, and was related to suppressing glycolysis. In conclusion, hypoxia treatment promoted the glycolysis and cell stemness of esophageal carcinoma cells, and increased the lactylation of Axin1 protein. Overexpression of Axin1 functioned as a glycolysis inhibitor, and suppressed the effects of hypoxia exposure in vitro and inhibited tumor growth in vivo. Mechanically, hypoxia induces the lactylation of Axin1 protein and promotes the ubiquitination of Axin1 to degrade the protein, thereby exercising its anti-glycolytic function.

Effectiveness and safety of combined nimotuzumab and S-1 chemotherapy with concurrent radiotherapy for locally advanced esophageal cancer in malnourished and elderly patients: A prospective phase II study.

Objective: Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable locally advanced esophageal cancer. However, this treatment is associated with substantial toxicity, and most malnourished or elderly patients are unable to complete this therapy. Therefore, there is a need for a more suitable radiotherapy combination regimen for this population. This study was aimed to evaluate the efficacy and safety of a combination regimen comprising chemotherapy with nimotuzumab and S-1 and concurrent radiotherapy for patients with fragile locally advanced esophageal cancer with a high Nutritional Risk Screening 2002 (NRS-2002) score. Methods: Eligible patients with unresectable esophageal carcinoma who had an NRS-2002 score of 2 or higher were enrolled. They were treated with S-1 and nimotuzumab with concurrent radiotherapy, followed by surgery or definitive radiotherapy. The primary endpoint was the locoregional control (LRC) rate. Results: A total of 55 patients who met the study criteria were enrolled. After completion of treatment, surgery was performed in 15 patients and radiotherapy was continued in 40 patients. The median follow-up period was 33.3 [95% confidence interval (95% CI), 31.4-35.1)] months. The LRC rate was 77.2% (95% CI, 66.6%-89.4%) at 1 year in the entire population. The overall survival (OS) rate and event-free survival (EFS) rate were 57.5% and 51.5% at 3 years, respectively. Surgery was associated with better LRC [hazard ratio (HR)=0.16; 95% CI, 0.04-0.70; P=0.015], OS (HR=0.19; 95% CI, 0.04-0.80; P=0.024), and EFS (HR=0.25; 95% CI, 0.08-0.75; P=0.013). Most adverse events were of grade 1 or 2, and no severe adverse events occurred. Conclusions: For malnourished or elderly patients with locally advanced esophageal cancer, radiotherapy combined with nimotuzumab and S-1 is effective and has a good safety profile.

SPP1 promotes tumor progression in esophageal carcinoma by activating focal adhesion pathway.

Background: Recurrence and metastasis are the major obstacles affecting the therapeutic efficacy and clinical outcomes for patients with esophageal carcinoma (ESCA). Secreted phosphoprotein 1 (SPP1) is considered as a hub gene in ESCA and is negatively associated with disease-free survival (DFS) in ESCA. However, the exact roles and underlying mechanisms remain elusive. This study aims to examine the roles of SPP1 on ESCA, and elucidate the potential mechanisms. Methods: Bioinformatics were used to analyze the expression of SPP1 in ESCA tissues, and its relations with clinicopathological characteristics and clinical prognosis in patients with ESCA based on The Cancer Genome Atlas (TCGA) dataset. Loss-of-function was conducted to examine the roles of SPP1 on malignant behaviors of ESCA cells by cell counting kit-8 (CCK8), plate clone, wound healing, and transwell assays. Gene set enrichment analysis (GSEA) was conducted to screen the pathways associated with SPP1 in ESCA. Then, the enriched pathway and the underlying mechanism were elucidated by western blotting, cell adhesion, and cell spreading assays. Lastly, Y15 [a specific inhibitor of focal adhesion kinase (FAK)] was used to examine its potential to inhibit tumor growth in ESCA cells. Results: SPP1 was upregulated in ESCA tissues compared to the adjacent nontumorous tissues, which was closely associated with clinical stage, lymph node metastasis, histological subtype, and p53 mutation. A high expression of SPP1 indicated a poor clinical prognosis in patients with ESCA. The knockdown of SPP1 inhibited cell proliferative, migratory, and invasive capacities in ESCA cells. GSEA indicated that the focal adhesion pathway was closely related with SPP1 in ESCA. Further studies confirmed that the knockdown of SPP1 suppressed cell adhesion ability and reduced the expression of p-FAK and p-Erk in ESCA cells. In addition, Y15 inhibited FAK autophosphorylation and dramatically inhibited cell proliferation, migration, and invasion in ESCA cells. Conclusions: SPP1 promotes tumor progression in ESCA by activating FAK/Erk pathway, and FAK is a potential therapeutic target to overcome tumor recurrence and metastasis of ESCA.

Outcomes from a single institution cohort of 248 patients with stage I-III esophageal cancer treated with radiotherapy: Comparison of younger and older populations.

Outcomes for patients receiving radiotherapy (RT) for non-metastatic esophageal cancer at a single institution were assessed, as well as the impact of factors including age and intensity modulated RT (IMRT) planning on patient outcomes. A retrospective cohort of patients treated with RT for stage I-III esophageal cancer between 2010 and 2018 was identified. Among 248 identified patients, 28 % identified as older (≥75 years of age). Other than histology, there were no other statistically significant differences in patient and tumour characteristics between the younger and older populations. Treatments varied between the two age groups, with significantly less older patients completing trimodality treatments (17 % vs 58 %). Median overall survival (M-OS) and progression-free survival (M-PFS) were 20 months and 12 months for all patients and 40 months and 26 months for trimodality patients, respectively. In the older patients, the M-OS improved from 13 months for all to 34 months for trimodality patients; and M-PFS from 10 months to 16 months. On multivariate analysis, the use of trimodality therapy showed improved OS (HR 0.26, p < 0.001). In the non-surgical older patient group, significantly better survival was seen in patients who had a heart V30Gy under 46 %. There was no significant difference in M-OS in patients planned with IMRT compared with 3D-conformal RT. Clinical outcomes in the treatment of esophageal cancer vary significantly by treatment approach, with the most favourable results in those receiving trimodality therapy. Among older patients deemed fit after assessment by the multidisciplinary team for trimodality treatments, the M-OS is comparable to the younger patient group.

Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives.

The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested for their anticancer activities against esophageal adenocarcinoma (EAC) cells. In addition, antifungal activity against a panel of Madurella mycetomatis strains, the most abundant causative agent of the neglected tropical disease eumycetoma, was evaluated. The new compounds revealed higher activities against EAC and fungal cells than the parent compound niclosamide. The ethanolamine salt 3a was the most active compound against EAC cells (IC50 = 0.8-1.0 µM), and its anticancer effects were mediated by the downregulation of anti-apoptotic proteins (BCL2 and MCL1) and by decreasing levels of ß-catenin and the phosphorylation of STAT3. The plausibility of binding to the latter factors was confirmed by molecular docking. The compounds 2a and 2b showed high in vitro antifungal activity against M. mycetomatis (IC50 = 0.2-0.3 µM) and were not toxic to Galleria mellonella larvae. Slight improvements in the survival rate of G. mellonella larvae infected with M. mycetomatis were observed. Thus, salicylanilides such as 2a and 3a can become new anticancer and antifungal drugs.