Esophageal cancer (EC) is a gastrointestinal cancer with high morbidity and mortality, along with a low 5-year survival rate, which urgently requires the discovery of new drugs for prevention and treatment. Our previous studies have found a novel EGFR-targeted fusion protein-drug conjugate, Fv-LDP-D3-AE, which exhibits significant inhibitory activity against esophageal cancer. However, the effectiveness of monotherapy still faces major challenges in clinical translation for esophageal cancer treatment. Therefore, there is an urgent need to identify a candidate anti-tumor drug that can be combined with Fv-LDP-D3-AE to enhance therapeutic efficacy. In this study, we report a novel combination treatment regimen of paeonol with Fv-LDP-D3-AE, using human esophageal cancer cells KYSE70 and EC109 for in vitro studies and establishing a BALB/c nude mouse xenograft model for in vivo experiments to investigate the anti-tumor efficacy and potential mechanisms of the combination therapy in esophageal cancer. The results indicated that the combined treatment emerged a synergistic effect, which could effectively inhibit the proliferation, migration, and invasion of esophageal cancer cells, induce more obvious cell apoptosis and DNA damage, and suppress tumor growth in the xenograft mouse model with a tumor inhibition rate of 76%. This may be attributed to the combination therapy simultaneously inhibiting the EGFR/AKT/mTOR signaling pathway and downregulating the expression of nucleolin. Overall, these findings suggest that paeonol could synergize with Fv-LDP-D3-AE to enhance anti-esophageal cancer efficacy, which may be a promising therapeutic strategy for esophageal cancer.

Esophageal cancer is one of the most common digestive cancers in the world. Because of the limitation and resistence of the traditional chemotherapy drugs, it is important to explore new therapeutic targets and strategies for this refractory cancer. Recently, targeting deubiquitinases has emerged as a promising avenue for the development of anti-tumor drugs. However, the role and underlying mechanism of NSC632839, a broad-spectrum deubiquitinases inhibitor, in esophageal squamous cell carcinoma in vitro remain elusive.

Cell Counting Kit-8 assay, colony formation assay, EdU proliferation experiment and cell morphology observation were used to detect the effect of NSC632839 on cell growth. Flow cytometry was employed to detect cell apoptosis and cell cycle arrest. Immunoblot and immunofluorescence was used to evaluate the expression level of cell cycle-, apoptosis-, and autophagy-related proteins.

NSC632839 inhibited the proliferation of Kyse30 and Kyse450 cells. Mechanistically, NSC632839 induced the formation of multipolar spindles, and its concomitant spindle assembly checkpoint-dependent mitotic arrest, followed by CREB-Noxa-mediated apoptosis. Reversine, a classical MPS1 kinase inhibitor known for its ability to inhibit the spindle assembly checkpoint, could rescue NSC632839-induced cell cycle arrest and apoptosis. Additionally, NSC632839 could trigger pro-survival autophagy. Combination of autophagy inhibitor, CQ and BafA1, with NSC632839 could induce stronger cell proliferation inhibition and apoptosis than NSC632839 alone.

These findings provided a novel anti-cancer mechanism of NSC632839 and highlighted it as a potential anti-tumor agent for the treatment of esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) is a major contributor to cancer-related deaths, driven by its invasive and metastatic nature. Circular RNAs (circRNAs) are increasingly recognized as regulators of cancer progression, primarily through miRNA sponging and interactions with RNA-binding proteins. Their dysregulation has been linked to the development of in various cancers. The present study aimed to investigate the potential involvement of circSLC22A3 in the pathogenesis of ESCC.

CircSLC22A3 expression in ESCC tissues and cells was analyzed using transcriptome sequencing and RT-qPCR. Its circular structure was validated through Sanger sequencing, agarose gel electrophoresis, RNase R digestion, and random priming assays. Subcellular localization was determined by nucleoplasmic separation and fluorescence in situ hybridization (FISH). Clinical correlations were assessed via tissue microarrays. Functional roles of circSLC22A3 in ESCC progression were investigated through in vitro and in vivo assays. Downstream miR-19b-3p and target gene TRAK2 were screened by bioinformatics analysis and RT-qPCR, with binding confirmed via luciferase reporter assays. RNA pulldown combined with RNA immunoprecipitation (RIP) identified IGF2BP1 as a circSLC22A3-interacting protein. RNA-seq and RT-qPCR revealed ACSBG1 as a key downstream effector. IGF2BP1-mediated m6A modification of ACSBG1 was mapped by MeRIP-seq and RIP, with mRNA stability assessed via Actinomycin D assay. ACSBG1 expression and biological function in ESCC were confirmed by immunohistochemistry, RT-qPCR, and functional assays.

Significant downregulation of circSLC22A3 was observed in both ESCC tissues and cell lines. Overexpression of circSLC22A3 significantly reduced ESCC cells' migration and invasion capabilities. Mechanistic investigation revealed that circSLC22A3 played a pivotal role in the invasion and metastasis of esophageal cancer through distinct pathways. On one hand, circSLC22A3 functioned as a miR-19b-3p sponge to augment trafficking kinesin protein 2 (TRAK2) expression, while, on the other hand, circSLC22A3 formed a protein-RNA complex with IGF2BP1, resulting in the degradation of acyl-CoA synthetase bubblegum family member 1 (ACSBG1) mRNA through the recognition of m6A modification, thereby suppressing invasion and metastasis of ESCC.

The present study identified circSLC22A3 as a new tumor suppressor that inhibited ESCC progression through both the circSLC22A3/ miR-19b-3p/ TRAK2 and circSLC22A3/ IGF2BP1/ ACSBG1 axes.

Polyploid Giant Cancer Cells (PGCCs) play a critical role in tumor progression due to their distinctive biological behaviors. However, the mechanisms by which PGCCs regulate their composition and structure to adapt to dynamic environments during their formation remain poorly understood. In this study, we used multicolor labeling of major organelles in esophageal squamous cell carcinoma (ESCC) cells combined with high- and super-resolution time-lapse imaging to monitor induced PGCCs in three dimensions. In addition to abnormal PGCC division, we observed nuclear dynamics and transient cell-in-cell formations. PGCCs exhibited cell cycle abnormalities, including prolonged G1/S transitions, asynchronous micronuclei, and intranuclear mitosis. Notably, early progeny continued dividing despite cell cycle dysregulation, resulting in asymmetric offspring. Quantitative analysis of subcellular structures revealed asymmetric inheritance of organelles, particularly mitochondria and the Golgi apparatus, in recurrent cells. These adaptive mechanisms in PGCCs may also be relevant in the context of anticancer treatments, contributing to the heterogeneity of recurrent tumors arising from early PGCC progeny populations.

Esophageal cancer, a leading global cancer, lacks effective therapies. Inhibition of histone deacetylase 6 (HDAC6) is a promising antitumor strategy, yet its role in esophageal cancer remains underexplored. Through structural optimization of our previously developed 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors, we identified compound 38k, exhibiting remarkably enhanced HDAC6 inhibition (IC50 = 3.12 nM) and 352-fold selectivity over HDAC1. Molecular docking analysis, CETSA, and BLI confirmed its strong HDAC6 binding. Moreover, 38k displayed robust in vitro and in vivo antiesophageal cancer efficacy, along with an advantageous pharmacokinetic and safety profile. Notably, combining 38k with a PI3K inhibitor synergistically enhanced the efficacy (75.02% tumor growth inhibition vs 50.94% monotherapy), likely by counteracting HDAC6 inhibition-induced PI3K/AKT activation. These findings validate HDAC6 as a therapeutic target and highlight 38k as a promising candidate for esophageal cancer treatment, particularly in combination regimens.

Gastrointestinal (GI) cancers impose a significant disease burden, underscoring the critical importance of accurate prognosis prediction and treatment response evaluation. DNA methylation, one of the most extensively studied epigenetic modifications, has gained prominence due to its reliable measurement across various sample types. Numerous studies have reported that DNA methylation was linked to the diagnosis, prognosis and treatment response in malignancies, including GI cancers. While its diagnostic role in GI cancers has been comprehensively reviewed. Recent research has increasingly highlighted its potential in prognosis prediction and treatment response evaluation. However, no existing reviews have exclusively focused on these two aspects. In this review, we retrieved relevant studies and included 230 of them in our discussion, thereby providing an overview of the clinical applicability of aberrant DNA methylation in these two fields among patients with esophageal, gastric, colorectal, pancreatic cancers, and hepatocellular carcinomas. Additionally, we discuss the limitations of the current literature and propose directions for future research. Specifically, we emphasize the need for standardized DNA methylation methodologies and advocate for the integration of gene panels, rather than single genes, to address tumor heterogeneity more effectively.

Esophageal squamous cell carcinoma (ESCC) exhibits a long latency period and has a significant geographic disparity in incidence, which underscores the need for models predicting the long-term absolute risk adaptable to the regional disease burden.

A total of 31,883 participants in a large-scale population-based screening trial (Hua County, China) were enrolled to develop the model. Severe dysplasia and above cases identified at screening or follow-up were defined as the outcome. We calculated the absolute risk in three steps: (i) constructing a relative risk model using logistic regression, (ii) calculating the age-specific baseline hazard, and (iii) adjusting for the competing risk of all-cause death excluding ESCC. Flexible incidence rate parameters were integrated into the model to ensure its relevance across diverse regions worldwide.

A total of 295 severe dysplasia and above cases were detected. The relative risk model consisted of old age, male gender, an irregular meal pattern, a preference for hot or hard food, a BMI of less than 22 kg/m2, and ESCC family history. The AUC was 0.753 (95% confidence interval, 0.749-0.757). The averaged 5-and 10-year absolute risk were 0.53% and 1.30% among participants. Based on our model, we developed an online calculator and incorporated flexible incidence rate parameters, demonstrating ideal risk stratification tailored to regions with varying disease burdens (https://pkugenetics.shinyapps.io/escc_risk_prediction/).

We developed an absolute risk model to predict individualized long-term risk of ESCC, accounting for the local disease burden.

This model has the potential to mitigate the global burden of ESCC by enabling targeted screening and personalized prevention strategies.

Barrett's esophagus (BE) is a known premalignant precursor to esophageal adenocarcinoma (EAC). The prevalence rates continue to rise in the United States, but many patients who are at risk of EAC are not screened. Current practice guidelines include male gender as a predisposing factor for BE and EAC. The population-based clinical evidence regarding female gender remains limited.

To study comparative trends of gender disparities in patients with BE in the United States.

A nationwide retrospective study was conducted using the 2009-2019 National Inpatient Sample (NIS) database. Patients with a primary or secondary diagnosis code of BE were identified. The major outcome of interest was determining the gender disparities in patients with BE. Trend analysis for respective outcomes for females was also reported to ascertain any time-based shifts.

We identified 1204190 patients with BE for the study period. Among the included patients, 717439 (59.6%) were men and 486751 (40.4%) were women. The mean age was higher in women than in men (67.1 ± 0.4 vs 66.6 ± 0.3 years, P < 0.001). The rate of BE per 100000 total NIS hospitalizations for males increased from 144.6 in 2009 to 213.4 in 2019 (P < 0.001). The rate for females increased from 96.8 in 2009 to 148.7 in 2019 (P < 0.001). There was a higher frequency of obesity among women compared to men (17.4% vs 12.6%, P < 0.001). Obesity prevalence among females increased from 12.3% in 2009 to 21.9% in 2019 (P < 0.001). A lower prevalence of smoking was noted in women than in men (20.8% vs 35.7%, P < 0.001). However, trend analysis showed an increasing prevalence of smoking among women, from 12.9% in 2009 to 30.7% in 2019 (P < 0.001). Additionally, there was a lower prevalence of alcohol abuse, Helicobacter pylori (H. pylori), and diabetes mellitus among females than males (P < 0.001). Trend analysis showed an increasing prevalence of alcohol use disorder and a decreasing prevalence of H. pylori and diabetes mellitus among women (P < 0.001).

The prevalence of BE among women has steadily increased from 2009 to 2019. The existing knowledge concerning BE development has historically focused on men, but our findings show that the risk in women is not insignificant.

The genomic landscape of cancer cells is complex and heterogeneous, with aberrant DNA methylation being a common observation. Growing evidence indicates that oxidants produced from immune cells may interact with epigenetic processes, and this may represent a mechanism for the initiation of altered epigenetic patterns observed in both precancerous and cancerous cells. Around 20% of cancers are linked to chronic inflammatory conditions, yet the precise mechanisms connecting inflammation with cancer progression remain unclear. During chronic inflammation, immune cells release oxidants in response to stimuli, which, in high concentrations, can cause cytotoxic effects. Oxidants are known to damage DNA and proteins and disrupt normal signalling pathways, potentially initiating a sequence of events that drives carcinogenesis. While research on the impact of immune cell-derived oxidants on DNA methylation remains limited, this mechanism may represent a crucial link between chronic inflammation and cancer development. This review examines current evidence on inflammation-associated DNA methylation changes in cancers related to chronic inflammation.

Esophageal squamous-cell carcinoma (ESCC) is a highly aggressive cancer, predominantly affecting populations in Eastern Asia and parts of Africa. Its pathogenesis is influenced by both genetic and environmental factors. Despite recent therapeutic advances, survival rates remain dismal, underscoring an urgent need for novel therapeutic targets.

To investigate the role of hypoxia-inducible factor 1-alpha (HIF1A) in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A (LDHA), which is crucial for the glycolytic pathway in hypoxic tumor environments.

Utilizing transcriptomic data from multiple public databases, we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses. The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines.

Our findings reveal a significant upregulation of HIF1A in ESCC tissues, associated with poor prognosis. HIF1A directly regulates LDHA, enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness. Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis.

The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target, underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.

Quality metrics for Barrett's esophagus (BE) are anticipated to improve outcomes for patients through earlier detection of neoplasia. The European Society of Gastrointestinal Endoscopy has developed guidelines to homogenize endoscopic quality in BE. Our study aimed to assess the impact of recommended key performance measures (KPMs) and their sustainability.

A single-center, retrospective study (Phase 1) was conducted over 8 weeks. The KPMs assessed were: 1) pre-procedure metrics including indication, consent, safety checklist (target of 100%); and 2) Prague classification, Seattle protocol, or targeted biopsies, inspection time of 1 minute per cm, advanced imaging and surveillance recommendations (target of 90%). Following baseline analysis, multimodal educational interventions were implemented and repeated at 6-month intervals. Repeat analysis was performed at 6 months and 1 and 3 years (Phases 2, 3 and 4 respectively).

In Phase 1, 39 patients with BE underwent endoscopy. Phase 2 evaluated 40 patients with BE. Phase 3 analyzed 59 patients with BE, and Phase 4 identified 34 patients with BE. Pre-procedure metrics were met in 100% of patients across the 3-year period. Baseline analysis displayed suboptimal performance at 45% to 75% for all other KPMs. However, after regular multimodal educational interventions, quality standards significantly improved and were able to be maintained over all phases, achieving pre-set targets of >9 0% for all KPMs except one.

Sustaining improvements in quality metrics in Barrett's endoscopy is important. Our study suggests that regular, replicable education interventions have a positive effect and allow sustained long-term improvements in quality metrics.

The prognosis for esophageal cancer remains poor because it is often diagnosed late and patients often have unfavourable backgrounds. This is reflected in standardised 5-year net survival rates of no more than 20%, regardless of gender. Unlike gastric cancer (CDH1 gene mutation), there is currently no genetic predisposition to esophageal cancer that would justify prophylactic esophagectomy. Primary prevention by identifying and managing modifiable risk factors is therefore the best strategy for preventing esophageal cancer. The role of surgery in the prevention of esophageal cancer is discussed in this review. Although recommended, the value of antireflux surgery (fundoplication) for Barrett's esophagus with the sole aim of reducing the risk of esophageal adenocarcinoma remains controversial. With regard to bariatric surgery, national cohort studies report an equivalent or reduced incidence of esophageal adenocarcinoma in operated patients compared with non-operated obese patients. However, given the significant increase in the number of bariatric procedures, further studies with longer follow-up are needed. In addition, although surgical myotomy is a truly effective therapeutic option for the treatment of achalasia in the first-line setting, its impact on the risk of esophageal cancer remains uncertain and poorly studied.

Understanding of the factors influencing oesophageal cancer trends is crucial. Therefore, this cross-sectional cohort study sought to disentangle the age, period and cohort effects on the trends of oesophageal cancer in Kuwait.

The data on incident oesophageal carcinoma cases diagnosed between January 1, 1980, through December 31, 2019, and reference population were obtained. Age-period-cohort (APC) analysis was conducted using a loglinear Poisson regression model.

A total of 496 oesophageal carcinoma cases in 12.8 million person-years (i.e. squamous-cell carcinoma, 269, 54.23%), adenocarcinoma,147, 29.64% and unspecified cases, 80,16.13%) were diagnosed. The overall age-standardized incidence rate (per 105 person-years) of oesophageal carcinoma during the study period was 10.51 (95% CI: 6.62-14.41). The APC analysis results showed that the age and birth cohort effects were the significant determinants of declining, and subsequently steadying the oesophageal carcinoma incidence rates.

A substantial decline in oesophageal carcinoma incidence rates was recorded, which significantly varied in all three temporal dimensions. The observed birth cohort patterns suggest changing lifestyle and dietary patterns seem to be responsible for decreasing oesophageal carcinoma risk in Kuwait. Future studies may look for the component causes maintaining the endemicity of oesophageal carcinoma risk in this and similar countries in the region.

Brain metastases in esophageal adenocarcinoma (EAC) patients are associated with poor prognosis and remain understudied. We performed multi-omics analysis with whole-genome sequencing and single-cell spatial transcriptomics on the brain metastases and matched primary tumors. Our analysis identified ERBB2 as a recurrent oncogene in EAC brain metastases, with 9 out of 10 cases harboring amplifications. Single-cell whole-genome and multi-region sequencing revealed that ERBB2 alterations, occur early during disease progression and are associated with monoclonal seeding. Although the median survival in our cohort was 13 months, one patient on HER2 antibody-drug conjugate therapy remains a long-term survivor beyond 34 months. Interestingly, the sole patient without an ERBB2 alteration had JAK2 deletion, high T cell infiltration in the brain lesion, and survived 35 months after immune checkpoint therapy. Our findings have significant clinical implications for the treatment and management of EAC brain metastases.

Barrett's esophagus (BE) is described by the transformation of the normal squamous epithelium into metaplastic columnar epithelium, driven by chronic gastroesophageal reflux disease (GERD). BE is a recognized premalignant condition and the main precursor to esophageal adenocarcinoma (EAC). Understanding the molecular mechanisms underlying BE carcinogenesis is crucial for improving prevention, surveillance, and treatment strategies.

This narrative review examines the molecular abnormalities associated with the progression of BE to EAC.

This study highlights inflammatory, genetic, epigenetic, and chromosomal alterations, emphasizing key pathways and biomarkers. BE progression follows a multistep process involving dysplasia and genetic alterations such as TP53 and CDKN2A (p16) mutations, chromosomal instability, and dysregulation of pathways like PI3K/AKT/mTOR. Epigenetic alterations, including aberrant microRNA expression or DNA methylation, further contribute to this progression. These molecular changes are stage-specific, with some alterations occurring early in BE during the transition to high-grade dysplasia or EAC. Innovations in chemoprevention, such as combining proton pump inhibitors and aspirin, and the potential of antireflux surgery to halt disease progression are promising. Incorporating molecular biomarkers into surveillance strategies and advancing precision medicine may enable earlier detection and personalized treatments.

BE is the primary preneoplastic condition for EAC. A deeper understanding of its molecular transformation can enhance surveillance protocols, optimize the management of gastroesophageal reflux inflammation, and refine prevention and therapeutic strategies, ultimately contributing to a reduction in the global burden of EAC.

Zinc finger CCHC-type containing 4 (ZCCHC4) is a newly discovered N6-methyladenosine (m6A) RNA methyltransferase (MTase), which possesses an m6A MTase domain and an RNA-binding protein (RBP) Znf domain. Aberrantly expressed ZCCHC4 has been found to be correlated with poor prognosis and chemoresistance in various tumors, such as hepatocellular carcinoma, lung cancer and colorectal cancer. However, the expression and functional analysis of the role of ZCCHC4 in esophageal cancer (ESCA) is still elusive. The expression of ZCCHC4 in esophageal cancer tissues was evaluated by qPT-PCR and western blot. Serum esophageal tumor markers are detected by electrochemiluminescence immunoassay. Relationship between ZCCHC4 expression and pathway enrichment analysis were analyzed by R. The reactive oxygen species (ROS), cell proliferation, cell cycle and apoptosis of ZCCHC4 in esophageal squamous cell carcinoma (ESCC) cells tested by CCK8 assay and flow cytometry assay. Aberrant expression of ZCCHC4 is associated with cancer stages, lymph node metastasis (LNM), and tumor histology, and poorer Overall Survival (OS) in esophageal cancer. The mRNA level of ZCCHC4 in esophageal cancer patients correlates with serum carcinoembryonic antigen (CEA) levels, Squamous Cell Carcinoma (SCC) markers, and tissue polypeptide antigen (TPA) levels. Knockdown of ZCCHC4 induces DNA damage, leading to an elevation of reactive oxygen species (ROS), which in turn triggers S-phase arrest, enhances apoptosis, augments sensitivity to cisplatin treatment, and inhibits proliferation in esophageal cancer cells. Conversely, overexpression of ZCCHC4 promotes proliferation, inhibits apoptosis, and increases resistance to cisplatin in esophageal cancer cells. Furthermore, scavenging ROS reverses the effects of ZCCHC4 downregulation on both proliferation and apoptosis in esophageal cancer cells. Additionally, downregulation of ZCCHC4 inhibits the progression of esophageal cancer and reduces cisplatin resistance in vivo. In summary, downregulation of ZCCHC4 leads to increased sensitivity of ESCC cells to cisplatin, inhibits proliferation, and promotes apoptosis in esophageal cancer cells, potentially via the ROS/c-myc axis. The study suggests a potential adjunctive role for ZCCHC4 in the diagnosis and treatment of esophageal cancer and aids in further understanding the underlying mechanisms in ESCA progression.

Barrett esophagus (BE) is the strongest known risk factor for developing esophageal adenocarcinoma (EAC), the second-most lethal cancer in the United States. Esopredict is a novel validated methylation-based biomarker assay that provides precise quantification of neoplastic progression risk in BE patients. Inherit challenges, including tissue heterogeneity, sampling error, interobserver variability, and inconsistent adherence to surveillance biopsy guidelines, may affect the predictive value results of Esopredict obtained at different anatomic locations or different sampling time points.

To investigate the spatiotemporal performance of Esopredict across multiple spatiotemporal sampling points, we profiled 220 biopsies obtained from 58 BE patients, including 11 patients with overlapping spatial and temporal biopsies. We focused on spatial profiling (i.e., multiple biopsies obtained at several anatomic locations during a single endoscopy) and temporal profiling (i.e., biopsies obtained from multiple endoscopies performed at different time points). Each patient had an initial histologic diagnosis of nondysplastic Barrett esophagus, indefinite for dysplasia, or low-grade dysplasia. Final follow-up (endpoint) biopsies showed either high-grade dysplasia or EAC (progressors), or nondysplastic Barrett esophagus, indefinite for dysplasia, or low-grade dysplasia (nonprogressors). Biopsies were analyzed with Esopredict to compute a progression risk score, which quantified the likelihood of future progression to high-grade dysplasia or EAC within 5 years.

In 52 spatially profiled patients, Esopredict demonstrated a sensitivity of 81% (17/21 progressor patients), based on the highest-scoring biopsy from each patient; sensitivity increased to 100% (12/12) when end point biopsies occurred within 5 years of the index (initial) biopsy. In 28 temporally profiled patients, sensitivity was 100% (8/8 patients), based on the biopsy performed at the time point closest to the end point biopsy.

Esopredict showed high predictive performance in multiple spatiotemporal samples in BE patients. These data further support the use of Esopredict as a robust test to distinguish high-risk BE patients, who may benefit from endoscopic eradication therapy or increased surveillance frequency, from low-risk patients, who may be candidates for less frequent surveillance and noninterventional observation.

Esophageal squamous cell carcinoma (ESCC) is a prevalent tumor in the gastrointestinal tract, but our understanding of the molecular mechanisms underlying ESCC remains incomplete. Existing studies indicate that SUMO specific peptidase 1 (SENP1) plays a crucial role in the development and progression of various malignant tumors through diverse molecular mechanisms. However, the functional mechanism and clinical implications of SENP1 in the progression of ESCC remain unclear.

Bulk RNA-Sequencing (RNA-seq) was used to compare potential genes in the esophageal tissues of mice with ESCC to the control group. The up-regulated SENP1 was selected. The protein level of SENP1 in ESCC patient samples was analyzed by immunohistochemistry and western blot. The potential prognostic value of SENP1 on overall survival of ESCC patients was examined using tissue microarray analysis and the Kaplan-Meier method. The biological function was confirmed through in vitro and in vivo knockdown approaches of SENP1. The role of SENP1 in cell cycle progression and apoptosis of ESCC cells was analyzed by flow cytometry and western blot. The downstream signaling pathways regulated by SENP1 were investigated via using RNA-Seq. SENP1-associated proteins were identified through immunoprecipitation. Overexpression of Sirtuin 6 (SIRT6) wildtype and mutant was performed to investigate the regulatory role of SENP1 in ESCC progression in vitro.

Our study discovered that SENP1 was upregulated in ESCC tissues and served as a novel prognostic factor. Moreover, SENP1 enhanced cell proliferation and migration of ESCC cell lines in vitro, as well as promoted tumor growth in vivo. Thymidine kinase 1 (TK1), Geminin (GMNN), cyclin dependent kinase 1(CDK1), and cyclin A2 (CCNA2) were identified as downstream genes of SENP1. Mechanistically, SENP1 deSUMOylated SIRT6 and subsequently inhibited SIRT6-mediated histone 3 lysine 56 (H3K56) deacetylation on those downstream genes. SIRT6 SUMOylation mutant (4KR) rescued the growth inhibition upon SENP1 depletion.

SENP1 promotes the malignant progression of ESCC by inhibiting the deacetylase activity of SIRT6 pathway through deSUMOylation. Our findings suggest that SENP1 may serve as a valuable biomarker for prognosis and a target for therapeutic intervention in ESCC.

Cyclin G2 (CCNG2), a known inhibitor of cell cycle progression, has been identified as a suppressor for the canonical β-catenin pathway. This study explores the impact of CCNG2 on β-catenin activity and malignant characteristics of esophageal squamous cell carcinoma (ESCC) cells, and the mechanism behind CCNG2 dysregulation. In ESCC tissues and cells, CCNG2 was under-expressed and associated with poor clinical outcomes, whereas β-catenin showed an opposite trend. Inducing CCNG2 overexpression in ESCC cells led to a reduction in β-catenin levels, which in turn suppressed proliferation, cell cycle progression, migration, invasion, stemness, and tumorigenesis. Additionally, it enhanced the cytotoxicity and proliferation of T cells in co-culture systems. However, these beneficial effects were negated by the Wnt signaling agonist BML-284. Furthermore, PATZ1 was found as a transcription factor promoting CCNG2 transcription. However, the PATZ1 protein in ESCC cells was degraded by SMURF1. Silencing of SMURF1 restored CCNG2 expression and inhibited β-catenin, thereby suppressing the malignant phenotype of ESCC cells and reducing T cell exhaustion. Yet, these effects were blocked by further silencing of PATZ1. In summary, this research demonstrates that SMURF1 activates β-catenin signaling by suppressing the PATZ1/CCNG2 axis, thereby promoting the progression of ESCC.

Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is a crucial serine-threonine kinase involved in the process of cell mitosis. However, the precise relationship between NEK2 and esophageal squamous cell carcinoma (ESCC) remains inadequately understood. NEK2 expression in ESCC tissues was assessed through bioinformatics analysis, reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry, revealing a correlation with ESCC patient prognosis. Cultured ESCC cells and human normal esophageal epithelial cells (HEEC) were used to investigate the effects of NEK2 knockdown on the development and progression of ESCC by integrated confluence algorithm, colony formation, wound-healing, transwell, and ESCC xenograft tumor model, in vitro and in vivo. In ESCC tissues, NEK2 was found to be significantly upregulated, and its expression correlated with poor prognosis in ESCC patients. NEK2 may facilitate ESCC development by regulating cell proliferation, migration, and invasion. Additionally, results from in vivo experiments suggested that NEK2 knockdown can inhibit tumor growth. Moreover, forkhead box M1 (FOXM1) was identified as a potential downstream target of NEK2 in the regulation of ESCC, with its overexpression reversing the effects of NEK2 knockdown on ESCC. Mechanistic studies also indicated that NEK2 may promote the malignant progression of ESCC by inhibiting cellular senescence through the activation of the FOXM1/c-Myc/p27 signaling pathways, which may provide a novel perspective for the management of ESCC.

Prognostic assessment is of great significance for individualized treatment and care of cancer patients. Although the TNM staging system is widely used as the primary prognostic classifier for solid tumors in clinical practice, the complexity of tumor occurrence and development requires more personalized probability prediction models than an ordered staging system. By integrating clinical, pathological, and molecular factors into digital models through LASSO and Cox regression, a nomogram could provide more accurate personalized survival estimates, helping clinicians and patients develop more appropriate treatment and care plans. Esophageal adenocarcinoma (EAC) is a common pathological subtype of esophageal cancer with poor prognosis. Here, we screened and comprehensively reviewed the studies on EAC nomograms for prognostic prediction, focusing on performance evaluation and potential prognostic factors affecting survival. By analyzing the strengths and limitations of the existing nomograms, this study aims to provide assistance in constructing high-quality prognostic models for EAC patients.

Esophageal cancer, with its aggressive nature and high mortality, poses diverse epidemiological challenges worldwide. Over the past three decades, esophageal cancer has exhibited a substantial global burden, marked by a significant increase in absolute numbers, contrasting with a decline in age-standardized metrics. Prevalence nearly doubled, reaching 0.961 million in 2019, while the age-standardized rate (ASR) decreased to 11.6 per 100,000 cases. New incidence cases surged by 67.07%, yet the age-standardized incidence rate reduced to 6.5 per 100,000 cases. Deaths increased to 0.498 million, with a decline in age-standardized mortality to 6.1 per 100,000 cases. Disability-Adjusted Life Years (DALYs) rose to 11.67 million, but the ASR decreased to 139.8 per 100,000 cases. Gender-specific analysis revealed consistently higher rates in males, with increasing gaps over time. Correlations with SDI indicated a negative association, and frontier analysis underscored the impact of socio-economic progress on disease control. Projections suggest a continued rise in prevalence, incidence, deaths, and DALYs, with gender-specific variations. The research underscores the importance of continued efforts in public health and medical research to adapt to and manage the changing landscape of esophageal cancer globally.

This study investigates the role of small ubiquitin-like modifier (SUMO)-specific peptidase 5 (SENP5), a key regulator of SUMOylation, in esophageal squamous cell carcinoma (ESCC), a lethal disease, and its underlying molecular mechanisms.

Differentially expressed genes between ESCC mouse oesophageal cancer tissues and normal tissues were analysed via RNA-seq; among them, SENP5 expression was upregulated, and this gene was selected for further analysis. Immunohistochemistry and western blotting were then used to validate the increased protein level of SENP5 in both mouse and human ESCC samples. The Kaplan‒Meier method and multivariate analysis were used to analyse the relationship between SENP5 expression and ESCC prognosis. Stable SENP5-knockdown (KD) cell lines and conditional knockout (cKO) mice were established to verify the biological function of SENP5. Further RNA-seq comparisons between short hairpin SENP5 (shSENP5)- and short hairpin negative control (shNC)-transfected ESCC cell lines were conducted, and the nuclear factor kappa B (NF-κB)-SLC1A3 axis was identified through bioinformatics analysis. The correlation of SENP5 with signalling pathway components was validated via real-time quantitative PCR (qPCR), western blotting (WB), and immunoprecipitation.

Our study revealed that SENP5 was upregulated in human and mouse ESCC samples, and clinical data analysis revealed a correlation between high SENP5 expression and poor patient prognosis. SENP5 knockdown inhibited tumorigenesis and growth in vivo and suppressed the proliferation, migration, and invasion of ESCC cell lines in vitro. Our study also revealed that SENP5 knockdown enhanced the SUMO1-mediated SUMOylation of NF-kappa-B inhibitor alpha (IκBα), thereby inhibiting the activation of the NF-κB-SLC1A3 axis, which subsequently suppresses ESCC cell energy metabolism and impedes ESCC progression.

Suppression of SENP5 slows the development of ESCC by inhibiting the NF-κB‒SLC1A3 axis through SUMO1-mediated SUMOylation of IκBα. Our research suggests that SENP5 could serve as a prognostic indicator and a target for therapeutic intervention for ESCC patients.

Esophageal cancer (EC) is a major global health issue characterized by high morbidity and mortality rates, with a notably low five-year survival rate. Comprehensive analyses of the global burden of EC remain limited and outdated, despite its global significance. This study aimed to systematically assess the global burden and trends of esophageal cancer across diverse populations.

Data on the burden of EC were collected from the Global Burden of Disease (GBD) 2021 study, including estimates of incidence, mortality, and disability-adjusted life years (DALYs), as well as risk factors, spanning 204 countries and territories. Age-standardized rates (ASRs) were calculated to allow comparisons across populations. The study further explored the relationship between EC burden and socioeconomic development by utilizing the Socio-demographic Index (SDI), aggregating data by regions. The Bayesian age-period-cohort model was applied to project future trends until 2050.

In 2021, there were 576,529 new esophageal cancer cases, with an age-standardized incidence rate (ASIR) of 6.65 per 100,000, reflecting a 24.87% decrease since 1990. The global number of deaths reached 538,602, with an age-standardized death rate (ASDR) of 6.25 per 100,000, representing a 30.67% decline. DALYs totaled 12,999,264, corresponding to an estimated annual percentage change (EAPC) of a 1.73% decrease in the age-standardized DALYs rate. East Asia accounted for nearly two-thirds of global EC cases and deaths, while Central Sub-Saharan Africa recorded the highest ASIR and ASDR. Central Asia experienced the largest reductions, whereas Western Sub-Saharan Africa showed increasing trends. Middle-SDI countries, such as Malawi and Lesotho, had disproportionately high burdens, while high-SDI countries, including Tunisia and Kuwait, had lower burdens. Males had higher incidence and mortality rates across all age groups. By 2050, the ASIR is projected to decrease to 6.17 per 100,000, and the ASDR to 5.23 per 100,000, though the absolute number of cases and deaths is expected to rise.

The global burden of EC remains significant, with ongoing challenges in regions such as Africa and East Asia. These findings highlight the need for sustained and targeted prevention efforts, particularly in high-risk populations, to address the increasing absolute number of cases and deaths.

Esophageal cancer is a predominantly male disease. However, the sex differences associated with esophageal cancer have not been thoroughly investigated. This study aimed to evaluate the differences between esophageal cancer in males and females in the Korean population.

We assessed patients diagnosed with esophageal cancer between 2005 and 2015 at a tertiary referral center. The clinical features of patients, histopathologic characteristics of tumors, and treatment and survival outcomes were compared between male and female patients.

We enrolled 2,068 patients, comprising 1,924 (93.0%) males and 144 (7.0%) females. The median age at diagnosis was younger for females than males (65 vs. 63 years, p=0.004). Squamous cell carcinoma was the predominant pathological type (99.0% in males and 93.1% in females); however, the proportion of adenocarcinoma cases was higher in females than males (0.8% vs. 5.6%, p<0.001). Multivariate analysis indicated favorable overall survival for female patients (hazard ratio [HR], 0.685; 95% confidence interval [CI], 0.548-0.857) and patients with high body mass index (≥25 kg/m², HR, 0.432; 95% CI, 0.355-0.526), and in early tumor stage (Stage 4, HR, 12.684; 95% CI, 7.451-21.591). The 5-year overall survival (44.8% vs. 53.5%, p=0.016) and recurrence-free survival rates (74.0% vs. 84.3%, p=0.036) were higher in females than in males.

We found significant sex differences in esophageal cancer among the Korean population, with female patients demonstrating distinct clinical characteristics and more favorable survival outcomes compared to male patients. These findings underscore the importance of considering sex-specific factors in the management and prognosis of esophageal cancer.

This study aimed to explore the causal relationship between concentrations of various insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) and esophageal cancer (ESC), addressing the gap in understanding the genetic link between IGF1 and ESC. A two-sample Mendelian randomization (MR) analysis was conducted using single nucleotide polymorphisms linked to IGFs/IGFBPs and ESC from the IEU Open GWAS Project. This analysis included ESC GWAS data from 1996 individuals of European descent and genetic variant data from 3310 individuals of European ancestry. Various methods, such as inverse variance weighting, weighted median, weighted mode, and MR-Egger regression, were applied for analysis, with sensitivity assessments including MR-PRESSO, Cochran Q, and leave-one-out analysis to ensure the robustness of results and detect biases. The genetic predictions indicated no significant association between IGFs/IGFBPs and ESC. When ESC was the outcome measure, the odds ratios with 95% confidence intervals were as follows: IGF1 = 1.00 (0.89-1.12, P = .936), IGF1R = 1.07 (0.90-1.27, P = .453), IGFBP3 = 1.00 (0.79-1.26, P = .975), and IGFBPL1 = 0.91 (0.75-1.12, P = .372). MR-Egger regression confirmed the absence of horizontal pleiotropy, and no outliers were identified by MR-PRESSO. Leave-one-out analysis supported the stability of the results. The study did not find a causal connection between IGFs/IGFBPs and ESC. These results suggest the need for further validation and potentially highlight the complex interplay of factors involved in the development of ESC.

Tumor mutation burden (TMB) has been considered a biomarker for utilization of immune checkpoint inhibitors(ICIs), but whole exome sequencing(WES) and cancer gene panel(CGP) based on next generation sequencing for TMB detection are costly. Here, we use transcriptome data of TCGA to construct a model for TMB prediction in gastrointestinal tumors.

Transcriptome data, somatic mutation data and clinical data of four gastrointestinal tumors from TCGA, including esophageal cancer (ESCA), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ). Using R, we performed visual analysis of somatic mutation data, differentially expressed genes (DEGs) function enrichment analysis, gene set enrichment analysis (GSEA), and estimated TMB value in clinic. Finally, a deep neural network (DNN) model was constructed for TMB prediction.

Visualization of somatic mutation data summarized the classification of mutation, frequency of each mutation type, and top-mutated genes. GSEA showed the enrichment of CD4+/CD8+ T cells in the high TMB group and the activation of tumor suppressing pathways. Single-sample GSEA (ssGSEA) manifested that the high-TMB group had higher level of multiple immune cells infiltration. In addition, distribution of TMB was related to clinical parameters. Like age, M stage, N stage, AJCC stage, and overall survival(OS). After model optimization using genetic algorithm, in the training set, validation set, and testing set, the Pearson relevance coefficient r between predicted values and actual values reaches 0.98, 0.82, and 0.92, respectively; the coefficient of determination R2 is 0.95, 0.82, and 0.7, respectively.

TMB correlates with clinicopathological parameters in gastrointestinal carcinoma, and patients with high TMB have higher levels of immune infiltration. In addition, the DNN model based on 31 genes predicts TMB of gastrointestinal tumors in a high accuracy.

Background and Objectives: The Esophageal Adenocarcinoma Study Group Europe (EACSGE) recently proposed a granular histologic classification of esophageal-esophago-gastric junctional adenocarcinomas (EA-EGJAs) based on the study of naïve surgically resected specimens that, when combined with the pTNM stage, is an efficient indicator of prognosis, molecular events, and response to treatment. In this study, we compared histologic classes of endoscopic biopsies taken before surgical resection with those of the surgical specimen, to evaluate the potential of the EACSGE classification at the initial diagnostic workup. Methods: A total of 106 EA-EGJA cases with available endoscopic biopsies and matched surgical resection specimens were retrieved from five Italian institutions. Histologic classification was performed on all specimens to identify well-differentiated glandular adenocarcinoma (WD-GAC), poorly differentiated glandular adenocarcinoma (PD-GAC), mucinous muconodular carcinoma (MMC), infiltrative mucinous carcinoma (IMC), diffuse desmoplastic carcinoma, diffuse anaplastic carcinoma (DAC), and mixed subtypes. Related risk subgroups (low-risk versus high-risk) were also assessed. The correlations of histologic classes and risk subgroups between diagnostic biopsies and surgical resection specimens were explored with Spearman's correlation test. Sensitivity, specificity, accuracy, positive predictive value, negative predictive value, true positives, true negatives, false positives, and false negatives were also calculated. Results: A strong positive correlation between biopsies and surgical specimens occurred for both histologic classes (coefficient: 0.75, p < 0.001) and risk subgroups (coefficient: 0.65, p < 0.001). The highest sensitivities and specificities were observed for MMC, IMC, and DAC (100% and 99% for all), followed by WD-GAC (sensitivity 91%, specificity 79%) and PD-GAC (sensitivity 722%, specificity 86%). The low-risk and high-risk groups presented a sensitivity and specificity of 89% and 76% (low-risk) and 76% and 89% (high-risk). Conclusions: The EACSGE histologic classification of EA-EGJAs and associated prognostic subgroups can be reliably assessed on pre-operative diagnostic biopsies. Further studies on larger and more representative cohorts of EA-EGJAs will allow us to validate our findings and confirm if the EA-EGJA biopsy histomorphology and clinical TNM staging will be as efficient as the surgical specimen histomorphology and pTNM in predicting patient prognoses and tailoring personalized therapeutic approaches.

The first step towards developing a screening strategy for Barrett's esophagus (BE) is the identification of individuals in the community. Currently available tools include endoscopy, less-invasive non-endoscopic devices, and non-invasive risk stratification models. We evaluated the cost of potential strategies for identification of BE as a first step towards screening.

Two hypothetical cohorts of the general population aged ≥ 50 years with BE prevalence rates of 1.9% and 6.8% were modeled. Four potential screening tools were evaluated: (i) risk stratification based on non-weighted clinical factors according to US/European guidelines, (ii) weighted risk stratification using algorithmic models, (iii) less-invasive devices such as Cytosponge + trefoil factor 3 (TFF3), and (iv) endoscopy. Using a decision-analytic model, the cost per BE case identified and the cost-effectiveness were compared for six potential BE screening strategies based on combinations of the four screening tools; (i) + (iv), (ii) + (iv), (iii) + (iv), (i) + (iii) + (iv), (ii) + (iii) + (iv), and only (iv).

The cost per BE case identified was lowest for the weighted risk stratification followed by Cytosponge-TFF3 then endoscopy strategy at both 1.9% and 6.8% BE prevalences (US$9282 and US$3406, respectively) although it was sensitive to the cost of less-invasive devices. This strategy was also most cost-effective for a BE prevalence of 1.9%. At BE prevalence of 6.8%, the Cytosponge-TFF3 followed by endoscopy strategy was most cost-effective.

Incorporating weighted risk stratification and less-invasive devices such as Cytosponge-TFF3 into BE screening strategies has a potential to cost-effectively identify BE in the community although device cost and the community prevalence of BE will impact the optimal strategy.

The objective of this systematic review and dose‒response meta-analysis was to assess the associations between the dietary consumption of nitrate and nitrite and the risk of gastric and esophageal cancer.

MEDLINE, Scopus, Embase, Web of Science, Proquest, and Google Scholar were searched until April 1, 2024. Articles were selected by two independent researchers on the basis of the inclusion and exclusion criteria. Data regarding the study design, type of exposure and outcomes, intervals of intake of nitrate or nitrite in each layer, OR/RR/HR of the relationship for each layer of intake, total sample size, and number of cases of gastric or esophageal cancer were extracted. The certainty of the evidence was rated via the GRADE method. The pooled odds ratios, risk ratios, and dose‒response analyses were calculated via Stata version 17.0. The best-fit dose‒response model was assessed by the P value for linearity and nonlinearity. Study heterogeneity was assessed via the I2 and Q tests.

We found 2124 nonredundant studies, 234 of which were potentially relevant. Eighteen articles met the inclusion criteria and were included in the review. The results of the meta-analysis revealed a significant positive association between nitrite intake and gastric cancer in both case‒control studies (OR = 1.29, 95 % CI = 1.09-1.52, P value = 0.001, I2 = 1.91 %) and cohort studies (RR = 1.17, 95 % CI = 1.00-1.37, P value = 0.04, I2 = 0.00 %). In addition, case‒control studies revealed a nonsignificant inverse association between nitrate intake and gastric cancer incidence (OR = 0.71, 95 % CI = 0.50-1.01, P value = 0.06, I2 = 74.89 %), and cohort studies (RR = 0.89, 95 % CI = 0.73-1.09, P value = 0.27, I2 = 0.00 %). Case‒control studies also revealed no significant correlation between nitrite intake and esophageal cancer incidence (OR = 1.48, 95 % CI = 0.91 to 2.42, P value = 0.12, I2 = 0.001 %). Nitrites correlated linearly with gastric cancer (linearity P value = 0.001). The most appropriate fit models for the relationship between nitrate and gastric cancer were both piecewise linear and natural polynomial regression (quadratic) models (P values = 0.003 and 0.005, respectively). There was no significant publication bias.

According to this meta-analysis, high consumption of nitrites was associated with an increased risk of gastric cancer in case‒control and cohort studies with a linear regression model, and dietary nitrate intake was not associated with the risk of gastric cancer in either case‒control or cohort studies. These findings are inconclusive and require confirmation in future prospective studies with robust methodologies and adjustments for potential confounders.

Esophageal cancer is one of the most prevalent malignant tumors and the sixth largest cause of tumor-associated death worldwide. Squamous cell carcinoma (ESCC) accounts for 85 % of all esophageal cancer cases. ESCC treatment remains to be significantly difficult. Corynoxine (Cory) is a tetracyclic hydroxyindole alkaloid isolated from Uncaria macrophylla. It is unclear whether Cory has an anti-tumor effect on ESCC.

To determine the anti-tumor activity of Cory and the associated mechanisms in ESCC.

Cory's effects on proliferation, apoptosis, migration, and invasion, as well as the underlying molecular causes were assessed using two ESCC cell lines, KYSE150 and TE-1. A xenograft mouse model was then applied to evaluate the anti-tumor activity of Cory in vivo.

Western blot, assays including CCK-8, colony formation, EdU staining, TUNEL staining, cell scratch and Transwell, and a xenograft mouse model were used in this study.

Cory suppressed cell growth, provoked cell apoptosis, and hindered cell migration and invasion of ESCC cells. DUSP5 knockdown reduced the Cory-induced cell death and restored cell migration and invasion through ERK1/2 activation. Further analyses showed that Cory promoted DUSP5 expression via inhibiting EZH2 expression, leading to inactivation of ERK1/2 signaling and the subsequent cell growth inhibition of ESCC. In vivo experiments disclosed that Cory suppressed tumor growth of ESCC through upregulating DUSP5 expression.

Cory plays an anti-tumor role in ESCC by regulating EZH2-DUSP5-ERK1/2 signaling pathway. Cory may be promising to be a novel therapy for treating ESCC.

Esophageal adenocarcinoma (EAC) was the predominant subtype of esophageal cancer in the Western population. However, an updated and comprehensive analysis of epidemiologic, clinical, and prognostic characteristics of esophageal adenocarcinoma is lacking.

This was a population-based cohort study using the Surveillance Epidemiology and End-Results (SEER) Database. Patients diagnosed with EAC between 1988 and 2020 were included. Incidence trends, clinical characteristics, treatment patterns, and relative survival were systematically analyzed.

The overall age-standardized incidence rate of EAC significantly increased from 1.7 per 100000 persons in 1988 to 3.6 per 100000 persons in 2020. There were no significant changes in the distribution of age group, sex, and primary site of EAC over time. However, the proportion of EAC clinically staged as I or II decreased from 35.1 % to 27.9 %. Over time, palliative chemotherapy in metastatic EAC increased from 26.7 % to 41.3 %, combination therapy was still the main treatment strategy for nonmetastatic EAC. Despite the 5-year survival rate was less than 20 %, 1-year survival has experienced a moderate increase from 46.7 % to 53.7 %. Specifically, 1-year survival rate for nonmetastatic EAC undergoing surgery only experienced a significant increase from 80.2 % in 2004-2006 to 94.7 % in 2019-2020. For metastatic EAC, obvious improvement in 1-year survival rate was observed in those treated with systematic therapy (from 26.6 % in 2004-2006 to 41.2 % in 2019-2020). In the multivariable analysis, older age, male sex, lower household income, living without a partner, advanced TNM stage, and receiving no cancer treatment were significantly associated with poor survival.

In summary, this population-based study of EAC patients in the US showed an increase in incidence, a shift in treatment modalities for metastatic EAC, and moderately improved 1-year survival. The search for more effective surveillance and treatment strategies should be continued in the future.

Esophageal cancer (EC) is one of the most common malignant tumors worldwide. Exosomes are a type of extracellular vesicles produced by eukaryotic cells and present in all body fluids. Recent studies have revealed that exosomes can be used as a tool for cell signaling and have great potential in cancer diagnosis and treatment strategies. This article reviews the research progress of exosomes in EC in recent years, mainly including the mechanism of action, diagnostic markers, therapeutic targets, and drug carriers. The challenges faced are discussed to provide guidelines for further research in future.

Barrett esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC). We aimed to assess performance, safety, and tolerability of the EsoGuard (EG) assay on samples collected nonendoscopically with the EsoCheck (EC) device (EG/EC) for BE detection in the intended-use population meeting American College of Gastroenterology guideline criteria (chronic gastroesophageal reflux disease and 3+ additional risk factors).

We performed a prospective, multicenter study (NCT04293458) to assess EG performance (primary endpoint) on cells collected with EC, for detection of BE and EAC using esophagogastroduodenoscopy (EGD) and biopsies as the comparator. Twenty-four sites across the United States and Spain participated. EC safety and usability were assessed as secondary endpoints.

180 male subjects aged >50 years with chronic gastroesophageal reflux disease met eligibility criteria, of which 163 (90.6%) had EGD and successful EC administration. Mean age was 60.5 years, 34.4% were obese, 56.7% had tobacco history, and 3.9% had a 1st degree relative with BE or EAC. Of 122 samples analyzed, 93 contributed to the primary endpoint analysis. Eight subjects (8.6%) in the Primary Analysis Population had BE on EGD, none with dysplasia. Sensitivity of EG for BE was 87.5% (95% confidence interval [CI] 47.4-99.7), specificity was 81.2% (95% CI 71.2-88.8), positive predictive value was 30.4% (95% CI 13.2-52.9), and negative predictive value was 98.6% (95% CI 92.3-99.96). Mild esophageal abrasions were observed in 1.5%; no serious adverse events were reported.

This study in the intended-use population suggests that EG/EC is promising for BE screening. While future work is necessary to define its performance characteristics with more precision, this approach may provide a safe, accurate, and well-tolerated nonendoscopic alternative in high-risk patients.

Oesophageal cancer is the seventh leading cause of cancer mortality worldwide. Two major pathological subtypes exist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Epidemiological studies in the last decade have shown a gradual increase in the incidence of oesophageal adenocarcinoma worldwide. The prognosis of oesophageal cancer has greatly improved due to breakthroughs in screening, surgical procedures, and novel treatment modalities. The success achieved with combined modality therapies, including surgery, chemotherapy, and radiotherapy, to treat locally advanced oesophageal cancer is particularly notable. Immunotherapy has become a crucial treatment for oesophageal cancer, with immune checkpoint inhibitor-based therapies now established as the standard of care in adjuvant and metastatic first-line settings. This Seminar provides an overview of advances in the screening, diagnosis, and treatment of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, with a particular focus on neoadjuvant therapies for locally advanced oesophageal cancer and immune checkpoint inhibitor-based therapies.

Cisplatin (CDDP) serves as a vital component in the chemotherapeutic approach to treat esophageal squamous cell carcinoma (ESCC). However, prolonged CDDP application frequently culminates in resistance, compromising therapeutic outcomes. Through genome-wide CRISPR library screening, our study elucidates the mechanisms underlying this resistance, pinpointing CYFIP2 as a pivotal mediator. Notably, the involvement CYFIP2 is characterized by pronounced autophagic activity and the modulation of multiple cellular pathways. Empirical validation was achieved by treating ESCC cell lines with CDDP, which resulted in an upsurge of CYFIP2 expression. The functional impact of CYFIP2 was further delineated through knockdown experiments, where a marked suppression in cell proliferation was observed, alongside a discernible decline in reactive oxygen species levels. This was complemented by a suite of assays and microscopic techniques, including GFP-LC3, mRFP-GFP-LC3, electron microscopy and western blot, which collectively affirmed the inhibitory effect of CYFIP2 knockdown on autophagic processes, particularly impeding autophagosome formation and their subsequent fusion with lysosomes. In vivo studies have also confirmed that CYFIP2 knockdown limits tumor progression and increases CDDP efficacy. Conclusively, our findings introduce CYFIP2 as a novel contributor to CDDP resistance in ESCC, underscoring its potential as a therapeutic target. This revelation not only deepens our understanding of resistance mechanisms but also paves the way for novel oncotherapeutic strategies, promising enhanced treatment efficacy against ESCC.