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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.
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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 20â¯% 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.
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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.
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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.
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Neoplasias Esofágicas , Esófago , ARN Ribosómico 16S , Humanos , Neoplasias Esofágicas/microbiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Incidencia , ARN Ribosómico 16S/genética , Esófago/microbiología , Esófago/patología , Microbiota , Bacterias/aislamiento & purificación , Bacterias/clasificación , Bacterias/genética , Mucosa Esofágica/microbiología , Mucosa Esofágica/patología , BiopsiaRESUMEN
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.
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Neoplasias Esofágicas , Genotipo , Virus del Papiloma Humano , Infecciones por Papillomavirus , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Esofágicas/virología , Neoplasias Esofágicas/epidemiología , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/aislamiento & purificación , Virus del Papiloma Humano/genética , Virus del Papiloma Humano/aislamiento & purificación , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Prevalencia , Factores de Riesgo , Tanzanía/epidemiologíaRESUMEN
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.
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Proteínas de Ciclo Celular , Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Pronóstico , Proteínas de Ciclo Celular/genética , Ratones , Animales , Masculino , Femenino , Microambiente Tumoral/genética , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Proliferación Celular/genética , Línea Celular Tumoral , Proteínas NuclearesRESUMEN
BACKGROUND: The current understanding of the prognostic significance of B cells and their role in the tumor microenvironment (TME) in esophageal carcinoma (ESCA) is limited. METHODS: We conducted a screening for B-cell-related genes through the analysis of single-cell transcriptome data. Subsequently, we developed a B-cell-related gene signature (BRGrisk) using LASSO regression analysis. Patients from The Cancer Genome Atlas cohort were divided into a training cohort and a test cohort. Patients were categorized into high- and low-risk groups based on their median BRGrisk scores. The overall survival was assessed using the Kaplan-Meier method, and a nomogram based on BRGrisk was constructed. Immune infiltration profiles between the risk groups were also compared. RESULTS: The BRGrisk prognostic model indicated significantly worse outcomes for patients with high BRGrisk scores (p < 0.001). The BRGrisk-based nomogram exhibited good prognostic performance. Analysis of immune infiltration revealed that patients in the high-BRGrisk group had notably higher levels of immune cell infiltration and were more likely to be in an immunoresponsive state. Enrichment analysis showed a strong correlation between the prognostic gene signature and cancer-related pathways. IC50 results indicated that patients in the low-BRGrisk group were more responsive to common drugs compared to those in the high-BRGrisk group. CONCLUSIONS: This study presents a novel BRGrisk that can be used to stratify the prognosis of ESCA patients and may offer guidance for personalized treatment strategies aimed at improving prognosis.
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Neoplasias Esofágicas , Transcriptoma , Microambiente Tumoral , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Pronóstico , Microambiente Tumoral/inmunología , Masculino , Femenino , Nomogramas , Linfocitos B/inmunología , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , AncianoRESUMEN
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.
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BACKGROUND: Definitive chemoradiotherapy is recommended as the primary treatment for cervical esophageal carcinoma (CEC). However, local control rates remain unsatisfactory for some patients. Therefore, in this study, we introduced a new treatment paradigm for individuals with CEC, customizing the choice between subsequent local treatments based on their response to induction chemotherapy and immunotherapy. PATIENTS AND METHODS: Induction treatment comprised two to four cycles of chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitors. Patients achieving complete response (CR) or near CR after induction treatment underwent definitive chemoradiotherapy (dCRT), while those not achieving CR or near CR underwent surgical resection. RESULTS: Among the 40 eligible patients, 14 (35.0%) achieved a CR or near CR after induction treatment. Of the ten patients achieving a CR or near CR, one developed an esophageal fistula after dCRT (10.0%). Among the eight non-CR or non-near CR patients receiving chemoradiotherapy, six developed esophageal fistula (75.0%). Among the 26 patients who did not achieve CR or near CR after induction treatment, the 1-year cancer specific survival (CSS) rates were 93.3% [95% confidence interval (CI) 0.815-1%] for the 18 patients in the surgery group, and 71.4% (95% CI 0.447-1%) for the 8 patients in the chemoradiotherapy group (p = 0.027). The overall laryngeal preservation rate was 85.0% (34/40), with a functional laryngeal preservation rate of 77.5% (31/40). CONCLUSION: The approach consisting of combined immunotherapy and chemotherapy successfully identified patients who were responding well to induction treatment and who were sensitive to radiotherapy, for chemoradiotherapy; thus, improving laryngeal preservation rates. In addition, it also identified patients with poor responses to induction treatment and radiotherapy, for timely surgery; hence, reducing radiotherapy complications and enhancing survival.
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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.
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Proteína Axina , Neoplasias Esofágicas , Glucólisis , Ratones Desnudos , Humanos , Proteína Axina/metabolismo , Proteína Axina/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Glucólisis/fisiología , Animales , Línea Celular Tumoral , Ratones , Ratones Endogámicos BALB C , Hipoxia de la Célula/fisiologíaRESUMEN
Background: Radiotherapy combined with fluorouracil (5FU) and cisplatin for locally advanced esophageal cancer is associated with a 20-25% pathologic complete response (pCR) rate. Cetuximab increases the efficacy of radiotherapy in patients with head and neck carcinomas. The aim of this phase I/II trial was to determine the optimal doses and the pCR rate with chemoradiotherapy (C-RT) plus cetuximab. Methods: A 45-Gy radiotherapy regimen was delivered over 5 weeks. The phase I study determined the dose-limiting toxicity and the maximum tolerated dose of 5FU-cisplatin plus cetuximab. The phase II trial aimed to exhibit a pCR rate > 20 % (25 % expected), requiring 33 patients (6 from phase I part plus 27 in phase II part). pCR was defined as ypT0Nx. Results: The phase I study established the following recommended doses: weekly cetuximab (400 mg/m2 one week before, and 250 mg/m2 during radiotherapy); 5FU (500 mg/m2/day, d1-d4) plus cisplatin (40 mg/m2, d1) during week 1 and 5. In the phase II part, 32 patients received C-RT before surgery, 31 patients underwent surgery, and resection was achieved in 27 patients. A pCR was achieved in five patients (18.5 %) out of 27. After a median follow-up of 19 months, the median progression-free survival was 13.7 months, and the median overall survival was not reached. Conclusions: Adding cetuximab to preoperative C-RT was toxic and did not achieve a pCR > 20 % as required. The recommended doses, determined during the phase I part, could explain these disappointing results due to a reduction in chemotherapy dose-intensity. Trial registration: This trial was registered with EudraCT number 2006-004770-27.
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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.
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INTRODUCTION: Despite the widespread use of minimally invasive techniques, open left thoracoabdominal esophagectomy (LTE) can offer excellent visualization and adaptability. The current study aimed to present and evaluate the outcomes related to an open LTE in esophageal malignancy treatment. METHODS: A retrospective cohort analysis of data collected from two institutions was performed, including patients with distal esophageal or junctional tumors who underwent open LTE between November 2018 and December 2023. RESULTS: Twenty-two patients were included (16 males; mean age 62.8 years). Postoperative complications occurred in eight patients (36%), with pulmonary complications being the most prevalent (seven patients; 32%). One patient experienced a clinical anastomotic leak. No reoperations or escalation to a higher level of care were required. In-hospital and 30-day mortality were zero. Tumor cells were found at the surgical margins in six patients (27%). The mean lymph node yield was 27. During the follow-up period, there were nine deaths and 11 cases of disease recurrence. Isolated locoregional recurrence was seen in five patients (23%). The one-year and two-year overall survival rates were 79% and 47%, respectively. CONCLUSION: In selected cases, open LTE remains a valid and safe operation with acceptable morbidity and oncological efficacy.
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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.
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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.
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OBJECTIVES: This study aimed to explore the value of D-dimer levels in predicting the treatment efficacy and prognosis of advanced esophageal squamous cell carcinoma (ESCC) treated with programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. METHODS: The study retrospectively analyzed 233 ESCC patients who received PD-1/PD-L1 inhibitors. The optimal cut-off values for platelets, fibrinogen, and D-dimer were calculated based on maximally selected rank statistics for patients' overall survival. Univariate and multivariate analyses of progression-free survival and overall survival were conducted by Cox proportional hazards regression model. Subgroup analyses of D-dimer levels in different fibrinogen levels were performed by log-rank test. RESULTS: The multivariate Cox regression analyses demonstrated that ESCC patients with D-dimer levels > 236 ng/mL exhibited both poorer progression-free survival (P = 0.004) and overall survival (P < 0.0001) compared to those with low D-dimer levels. The subgroup analyses further indicated that in the group of low fibrinogen levels, the higher D-dimer levels of ESCC patients exhibited significantly shorter progression-free survival (P = 0.0021) and overall survival (P < 0.0001). CONCLUSIONS: The study revealed that the D-dimer levels possess predictive value for the treatment efficacy and prognosis of ESCC patients treated with PD-1/PD-L1 inhibitors.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Productos de Degradación de Fibrina-Fibrinógeno , Humanos , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Femenino , Masculino , Pronóstico , Persona de Mediana Edad , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/sangre , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/sangre , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Estudios Retrospectivos , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Adulto , Resultado del Tratamiento , Biomarcadores de Tumor/sangre , Anciano de 80 o más Años , Receptor de Muerte Celular Programada 1/antagonistas & inhibidoresRESUMEN
BACKGROUND: Proton-based, definitive chemoradiotherapy (P-CRT) for esophageal squamous cell carcinoma (ESCC) previously showed comparable survival outcomes with the surgery-based therapy, i.e., neoadjuvant chemotherapy followed by esophagectomy (NAC-S), in a single-institutional study. This study aimed to validate this message in a Japanese multicenter study. METHODS: Eleven Japanese esophageal cancer specialty hospitals have participated. A total of 518 cases with clinical Stage I-IVA ESCC between 2010 and 2019, including 168 P-CRT and 350 NAC-S patients, were enrolled and long-term outcomes were evaluated. Propensity-score weighting analyses with overlap weighting for confounding adjustment were used. RESULTS: The 3-year overall survival (OS) of the P-CRT group was equivalent to the NAC-S group (74.8% vs. 72.7%, hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.61-1.25). Although, the 3-year P-CRT group progression-free survival (PFS) was inferior to the NAC-S group (51.4% vs. 59.6%, HR 1.39, 95% CI 1.04-1.85), the progression P-CRT group cases showed better survival than the NAC-S group (HR 0.58, 95% CI 0.38-0.88), largely because of salvage surgery or endoscopic submucosal dissection for local progression. The survival advantage of P-CRT over NAC-S was more pronounced in the cT1-2 (HR 0.61, 95% CI 0.29-1.26) and cStage I-II (HR 0.50, 95% CI 0.24-1.07) subgroups, although this trend was not evident in other populations, such as cT3-4 and cStage III-IVA. CONCLUSIONS: Proton-based CRT for ESCC showed equivalent OS to surgery-based therapy. Especially for patients with cT1-2 and cStage I-II disease, proton-based CRT has the potential to serve as a first-line treatment.
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Quimioradioterapia , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Esofagectomía , Terapia de Protones , Humanos , Masculino , Femenino , Esofagectomía/métodos , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/mortalidad , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Persona de Mediana Edad , Japón/epidemiología , Estudios Retrospectivos , Anciano , Quimioradioterapia/métodos , Terapia de Protones/métodos , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/estadística & datos numéricos , Estadificación de Neoplasias , Resultado del Tratamiento , Puntaje de Propensión , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Cancer stem cells (CSCs) play a significant role in the recurrence and drug resistance of esophageal carcinoma (ESCA). Ferroptosis is a promising anticancer therapeutic strategy that effectively targets CSCs exhibiting high tumorigenicity and treatment resistance. However, there is a lack of research on the combined role of ferroptosis-related genes (FRGs) and stemness signature in the prognosis of ESCA. METHODS: The cellular compositions were characterized using single-cell RNA sequencing (scRNA-seq) data from 18 untreated ESCA samples. 50 ferroptosis-related stemness genes (FRSGs) were identified by integrating FRGs with stemness-related genes (SRGs), and then the cells were grouped by AUCell analysis. Next, functional enrichment, intercellular communication, and trajectory analyses were performed to characterize the different groups of cells. Subsequently, the stem-ferr-index was calculated using machine learning algorithms based on the expression profiles of the identified risk genes. Additionally, therapeutic drugs were predicted by analyzing the GDSC2 database. Finally, the expression and functional roles of the identified marker genes were validated through in vitro experiments. RESULTS: The analysis of scRNA-seq data demonstrates the diversity and cellular heterogeneity of ESCA. Then, we identified 50 FRSGs and classified cells into high or low ferroptosis score stemness cells accordingly. Functional enrichment analysis conducted on the differentially up-regulated genes between these groups revealed predominant enrichment in pathways associated with intercellular communication and cell differentiation. Subsequently, we identified 9 risk genes and developed a prognostic signature, termed stem_ferr_index, based on these identified risk genes. We found that the stem-ferr-index was correlated with the clinical characteristics of patients, and patients with high stem-ferr-index had poor prognosis. Furthermore, we identified four drugs (Navitoclax, Foretinib, Axitinib, and Talazoparib) with potential efficacy targeting patients with a high stem_ferr_index. Additionally, we delineated two marker genes (STMN1 and SLC2A1). Particularly noteworthy, SLC2A1 exhibited elevated expression levels in ESCA tissues and cells. We provided evidence suggesting that SLC2A1 could influence the migration, invasion, and stemness of ESCA cells, and it was associated with sensitivity to Foretinib. CONCLUSION: This study constructed a novel ferroptosis-related stemness signature, identified two marker genes for ESCA, and provided valuable insights for developing more effective therapeutic targets targeting ESCA CSCs in the future.
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Neoplasias Esofágicas , Ferroptosis , Células Madre Neoplásicas , Análisis de la Célula Individual , Ferroptosis/genética , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Pronóstico , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Análisis de la Célula Individual/métodos , Regulación Neoplásica de la Expresión Génica , Análisis de Secuencia de ARN/métodos , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Masculino , FemeninoRESUMEN
The ubiquitination-mediated protein degradation exerts a vital role in the progression of multiple tumors. NEDD4L, which belongs to the E3 ubiquitin ligase NEDD4 family, is related to tumor genesis, metastasis and drug resistance. However, the anti-tumor role of NEDD4L in esophageal carcinoma, and the potential specific recognition substrate remain unclear. Based on public esophageal carcinoma database and clinical sample data, it was discovered in this study that the expression of NEDD4L in esophageal carcinoma was apparently lower than that in atypical hyperplastic esophageal tissue and esophageal squamous epithelium. Besides, patients with high expression of NEDD4L in esophageal carcinoma tissue had longer progression-free survival than those with low expression. Experiments in vivo and in vitro also verified that NEDD4L suppressed the growth and metastasis of esophageal carcinoma. Based on co-immunoprecipitation and proteome analysis, the NEDD4L ubiquitination-degraded protein ITGB4 was obtained. In terms of the mechanism, the HECT domain of NEDD4L specifically bound to the Galx-ß domain of ITGB4, which modified the K915 site of ITGB4 in an ubiquitination manner, and promoted the ubiquitination degradation of ITGB4, thus suppressing the malignant phenotype of esophageal carcinoma.
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Progresión de la Enfermedad , Neoplasias Esofágicas , Integrina beta4 , Ubiquitina-Proteína Ligasas Nedd4 , Proteolisis , Ubiquitinación , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Humanos , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/genética , Animales , Línea Celular Tumoral , Integrina beta4/metabolismo , Integrina beta4/genética , Ratones Desnudos , Ratones , Proliferación Celular , Masculino , Regulación Neoplásica de la Expresión Génica , FemeninoRESUMEN
BACKGROUND: A recent phase I/II study determined the optimal dose of definitive carbon-ion radiotherapy (CIRT) for cT1bN0M0 esophageal cancer. This study aimed to further confirm the efficacy and feasibility of the recommended dose fractionation of CIRT with long-term follow-up results in a larger sample size. METHODS: This single center retrospective study evaluated patients with cT1bN0M0 esophageal squamous cell carcinoma treated with the recommended dose fractionation of 50.4 Gy relative biological effectiveness in 12 fractions, between 2012 and 2022. RESULTS: Thirty-eight patients underwent CIRT at our hospital. Although eight (21.1%) patients were older than 80 years, 15 (39.5%) had high surgical risk, and seven (18.4%) were at high risk for chemotherapy, all patients underwent CIRT as scheduled. Grade 3 esophagitis occurred in eight (21.1%) patients and grade 3 pneumonia in one (2.6%) patient in this study, but no grade 4 adverse events occurred. The only grade 3 late adverse event was pneumonia in one patient (2.6%). The 5-year overall survival rate, local control rate, and disease-free survival rates were 76.6% (95% CI, 90.9-62.4), 74.9% (95% CI, 90.7-59.0), and 66.4% (95% CI, 83.3-49.5), respectively. Additionally, post CIRT recurrence was as follows: seven (18.4%) patients had recurrence in another part of the esophagus, three (7.9%) in the primary site, three (7.9%) in lymph nodes outside the irradiated area, and one (2.6%) patient had liver metastasis. CONCLUSIONS: Our study demonstrates that CIRT using the recommended dose fractionation is feasible and effective for cT1bN0M0 esophageal squamous cell carcinoma.