Search Results (1,293)

Immune checkpoint inhibitors have improved outcomes in esophageal cancer across settings, yet clinical benefit remains heterogeneous, with current host-derived biomarkers incompletely predicting response. This mini review evaluates recent studies that integrate gut or intratumoral microbial features with host immune, molecular, or metabolic assessment in esophageal cancer. We classify the evidence using a four-level hierarchy of host-microbiome integration: ecological association, functional association, mechanistic integration, and clinical predictive integration. Tissue studies reveal compartment-specific relationships between microbial diversity or individual taxa and immune architecture, whereas treatment cohorts identify bacterial and fungal signatures associated with pathological or immunotherapy response. Mechanistic studies offer the strongest biological evidence, most notably the Lactobacillus salivarius-indole-3-lactic acid-AhR/NF-κB axis, which drives CD8-positive T-cell exhaustion and resistance to anti-PD-1 therapy. However, biological integration is substantially more advanced than clinical response prediction. Small cohorts, heterogeneous regimens, contamination of low-biomass samples, coarse taxonomic (rather than functional) resolution, confounding by histology, multi-omic layers measured in different patients, and lack of external validation currently jeopardize integration of microbiome to guide treatment. Future studies should use longitudinal, multicenter, compartment-matched sampling and test whether microbial genes or metabolites improve patient selection and predict clinical response beyond established clinical and host biomarkers. Full article

Esophageal cancer is a common malignancy of the upper gastrointestinal tract that is associated with high incidence and mortality rates. Radiotherapy constitutes a cornerstone therapeutic modality for esophageal cancer. In radiotherapy, ionizing radiation is used to eliminate tumor cells through direct DNA damage and indirect reactive oxygen species (ROS)-mediated effects. However, clinical outcomes are frequently limited by interpatient heterogeneity and intrinsic tumor radioresistance. This review systematically describes the determinants of radiosensitivity in esophageal cancer within the established radiobiological framework of the “6Rs”: DNA damage repair (Repair), which is mediated by γ-H2AX phosphorylation, PARP family enzymes, and nonhomologous end joining (NHEJ) and homologous recombination (HR) pathways; cell cycle redistribution (Redistribution), which is regulated by G1/S and G2/M checkpoint dynamics; tumor repopulation (Repopulation), which is driven by cancer stem cell activity during fractionated treatment; reoxygenation (Reoxygenation), which is modulated through HIF-1α signaling and ROS homeostasis; intrinsic radiosensitivity (Radiosensitivity), which reflects interindividual and histopathological variability; and reactivation of antitumor immune responses (Reactivation), which enhances efficacy by remodeling the tumor immune microenvironment. Furthermore, regulated cell death mechanisms, including ferroptosis, autophagy, and apoptosis, significantly modulate radiotherapeutic responses. Elucidating these interconnected mechanisms provides a robust theoretical foundation for developing targeted interventions, identifying predictive biomarkers, and advancing precision radiotherapy strategies to optimize clinical outcomes for patients with esophageal cancer. Full article

Chronic kidney disease (CKD) may reduce physiologic reserve among patients with esophageal cancer, but evidence beyond postoperative cohorts is limited. Using the TriNetX Global Collaborative Network, we studied adults with esophageal cancer diagnosed during 2010–2023. CKD stages 3–5 were defined by diagnostic codes plus estimated glomerular filtration rate < 60 mL/min/1.73 m² within 6 months before or on the index date; dialysis-dependent patients were excluded. Non-CKD patients served as comparators. Prespecified outcomes from day 1 to up to 3 years included all-cause mortality, subsequent recorded metastatic diagnosis, pneumonia, sepsis, blood transfusion, and major adverse cardiovascular events. Propensity score matching produced 832 pairs. All-cause mortality was not significantly higher in the overall cohort with CKD stages 3–5 than in the non-CKD cohort (HR, 1.13; 95% CI, 0.98–1.31; p = 0.099), whereas CKD stages 4–5 were associated with higher mortality in the stage-specific analysis (HR, 1.46; 95% CI, 1.03–2.06; p = 0.031). CKD stages 3–5 were also associated with higher risks of blood transfusion (HR, 1.45; 95% CI, 1.04–2.01; p = 0.025) and MACEs (HR, 1.22; 95% CI, 1.02–1.47; p = 0.027), and with a lower risk of subsequent recorded metastatic diagnosis (HR, 0.80; 95% CI, 0.65–0.99; p = 0.036). These findings suggest that the associations of CKD with post-diagnostic outcomes varied by outcome type, with higher mortality observed in the separate CKD stages 4–5 analysis. Full article

Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for detecting minimal residual disease (MRD) and predicting recurrence after curative treatment, yet evidence in esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric cancer has largely been examined within individual tumor types. In this scoping review, we mapped this evidence across all three malignancies and clarified key methodological and clinical considerations. Following the PRISMA-ScR guidelines, we searched PubMed, Scopus, and the Cochrane Library (3 April 2026) for studies linking ctDNA to disease-free, recurrence-free, or overall survival after curative-intent treatment. Twenty-seven studies (1746 patients; 10 ESCC, 4 EAC, 8 gastric, and 5 mixed) were included. Across every tumor type, postoperative ctDNA MRD was the most informative timepoint, with independent multivariable hazard ratios for disease-free, recurrence-free, or event-free survival of 2.8 to 21.8, whereas preoperative ctDNA was seldom prognostic. Serial monitoring further improved performance and flagged recurrence 78 to 278 days before imaging. Tumor-informed assays showed higher sensitivity than tumor-agnostic ones (80% vs. 35%), though direct comparisons were limited; correction for clonal hematopoiesis was essential for tumor-agnostic assays, and blood-based assays performed poorly in diffuse-type and peritoneal disease. Postoperative ctDNA MRD is a consistent, independent prognostic biomarker across upper gastrointestinal cancers that adds prognostic information beyond conventional staging and pathological response, supporting prospective interventional trials of ctDNA-guided management. Full article

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies. Full article

The African esophageal squamous cell carcinoma (ESCC) corridor extends from Ethiopia to the Eastern Cape and contains some of the highest age-standardized ESCC incidence rates reported anywhere, with five-year survival below 5%. The corridor’s heterogeneous incidence (sex ratios from 1:1 to 7:1; tenfold variation between adjacent populations) has resisted single-factor explanation through more than half a century of investigation. We synthesize the multicenter evidence accumulated since the IARC 2018 Group 2A classification of very hot beverages (>65 °C), with particular attention to the African Esophageal Cancer Consortium (ESCCAPE) outputs and to whole-genome sequencing. We argue, on the convergent evidence of animal toxicology, human in vitro mucosa, and population genomics, that thermal exposure acts as a tumor promoter rather than an initiator. On this reading, the corridor’s heterogeneous burden reflects heterogeneous chemical co-exposure profiles operating against a shared thermal-promoter substrate. Extending the comparative margin-of-exposure (MOE) methodology to esophageal squamous carcinogenesis, we present an MOE framework distinguishing genotoxic compounds (within-mode-of-action additive) from thermal exposure (separate companion figure) and apply it to two corridor scenarios. The framework supports a four-lever prevention strategy combining tobacco control, alcoholic-strength reduction in unrecorded spirits, clean-cookstove deployment, and graduated thermal-exposure reduction. Full article

Objective: To evaluate the feasibility of sentinel lymph node (SLN) identification in distal esophageal and esophagogastric junction (EGJ) adenocarcinoma and determine whether the SLN concept applies to this disease. Methods: Patients undergoing esophagectomy for clinical stage I-IVA esophageal and EGJ adenocarcinoma underwent SLN mapping by near-infrared detection of indocyanine green (ICG) injected via endoscopy before esophagectomy. Lymphatic drainage patterns were recorded, and the first identified nodes (SLNs) were harvested. Standard esophagectomy and lymphadenectomy were performed. SLN status was compared with overall nodal status. Results: Of 90 included patients, 77 received ICG; SLN mapping was successful in 64 (83%). Ten patients had two SLN stations identified; the remainder had one. The most common SLN location was along the left gastric artery (36/74 [48%]), followed by the paracardial (17/74 [23%]) and periesophageal (15/74 [20%]) stations. Seven patients had SLNs positive for metastasis (in one, the SLN was the only positive node; in the rest, metastatic nodes were identified in the same or other stations). Of the 57 patients with negative SLNs, 11 (19%) had ≥1 positive node in the same or different nodal station. The false-negative rate was 61.1%. Conclusions: SLN mapping with ICG is feasible in patients with distal esophageal and EGJ adenocarcinoma, with a high rate of successful node identification. Occult nodal metastasis in patients with negative SLNs limits the reliability of SLN assessment as a determinant for selective lymphadenectomy. Full article

Background: Squamous cell carcinomas (SCCs) share squamous differentiation and may engage the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway, although their causes, biology, and treatment differ by anatomical site. We evaluated tumor response, short-term survival, and grade 3–4 adverse events after neoadjuvant immune-checkpoint blockade, with or without chemotherapy, followed by surgery. Methods: A comprehensive search of PubMed, Embase, the Cochrane Library, and clinical trial registries was conducted from inception to October 2024. Prospective and retrospective studies evaluating neoadjuvant immunotherapy, with or without chemotherapy, before surgery in patients with SCC were included. In mixed-histology studies, data were eligible only when SCC outcomes could be extracted separately. Pooled proportions and 95% confidence intervals (CIs) were estimated with random-effects models. Results: A total of 44 studies involving 2586 patients with six anatomical SCC groups were included. The pooled objective response rate (ORR) was 0.70 (95% CI, 0.59–0.80), clinical complete response (cCR) rate was 0.17 (95% CI, 0.10–0.28), and pathological complete response (pCR) rate was 0.30 (95% CI, 0.27–0.34). The pooled 1-year progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS) rates were 0.82 (95% CI, 0.79–0.86), 0.86 (95% CI, 0.75–0.92), and 0.92 (95% CI, 0.90–0.93), respectively. The pooled incidence of grade 3–4 adverse events was 0.18 (95% CI, 0.14–0.23). Because the PD-L1 subgroup contained only one study for most outcomes, checkpoint-target subgroup findings were considered exploratory. Conclusions: Existing predominantly single-arm evidence suggests antitumor activity of neoadjuvant immune-checkpoint blockade, with or without chemotherapy, in selected patients with resectable SCC. Because esophageal SCC accounted for most studies and clinical heterogeneity was substantial, these pooled proportions should not be interpreted as comparative effects or as evidence of uniform benefit across SCC sites. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis, highlighting the urgent need to elucidate its molecular mechanisms to develop targeted therapies. Long non-coding RNAs (lncRNAs) play a critical role in cancer progression. However, the majority of lncRNAs involved in ESCC progression remain to be elucidated. Methods: We integrated bioinformatic analyses of the TCGA and GEO datasets to identify differentially expressed lncRNAs in ESCC, and the biological functions of the candidate lncRNA LINC01446 were investigated using loss-of-function assays in ESCC cell lines, including colony formation, wound healing, Transwell invasion, C11-BODIPY staining, malondialdehyde (MDA) quantification, and glutathione (GSH) evaluation. A nude mouse xenograft model was established for in vivo validation, and the underlying molecular mechanism was explored through RNA sequencing, fluorescence in situ hybridization (FISH), dual-luciferase reporter assays, AGO2-RIP, and rescue experiments. Results: LINC01446 was significantly upregulated in ESCC tissues and cell lines. Based on univariate analysis, high expression of LINC01446 was associated with poorer overall survival (OS). Functional studies showed that LINC01446 knockdown suppressed ESCC cell proliferation, migration, and invasion, promoted ferroptosis-related changes in vitro and was associated with increased lipid peroxidation and possible ferroptosis-related changes in vivo. Mechanistic analyses supported a regulatory relationship in which LINC01446 may function as a competing endogenous RNA (ceRNA) for miR-338-3p, thereby contributing to the upregulation of its downstream target, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1), in ESCC cells. Moreover, APEX1 was found to be overexpressed in ESCC and associated with poor OS. Conclusions: This study suggests that the LINC01446/miR-338-3p/APEX1 regulatory axis may contribute to ESCC progression and ferroptosis-related regulation. Additionally, LINC01446 and APEX1 represent promising prognostic biomarkers and therapeutic targets for ESCC. Full article

Background/Objectives: This study aimed to analyze the effect of diabetes prevalence on mortality levels from gastrointestinal cancers. Methods: The study utilized mortality data for Türkiye from the World Health Organization (WHO) Mortality Database, covering deaths from stomach, colon and rectum, liver, and pancreas cancers, as well as diabetes prevalence data, between 2009 and 2023. Health expenditure and life expectancy data from the World Bank were used as control variables. Results: Diabetes prevalence was significantly correlated with colon and rectum cancer mortality (r = 0.929; p < 0.01), pancreas cancer mortality (r = 0.978; p < 0.01), life expectancy (r = 0.941; p < 0.01), and health expenditure (r = −0.635; p < 0.01). Correlations of diabetes prevalence with esophagus, stomach, and liver cancer mortality were statistically insignificant (p > 0.05). According to generalized linear model analysis results, there was an effect of diabetes prevalence on colon and rectum cancer mortality (B = 383.108; p < 0.01) and pancreas cancer mortality (B = 330.415; p < 0.01). Effects of diabetes prevalence on esophagus, stomach, and liver cancer mortality were statistically insignificant (p > 0.05). Conclusions: Diabetes prevalence was significantly associated with mortality levels for colon and rectal cancer and pancreatic cancer; however, it did not have a significant effect on mortality levels for esophageal, gastric, and liver cancers. Although there is a close relationship between diabetes and the digestive system, a similar relationship between cancer mortality levels of digestive system organs and diabetes is not valid for every organ. We believe that the effect of diabetes on gastrointestinal cancers has a tissue- or organ-specific mechanism of action rather than a digestive mechanism. Full article

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent malignancy worldwide. Moreover, ESCC remains poorly characterized at the molecular level, which contributes to limited therapeutic options and an overall poor prognosis. In this context, HMGA family members, which are overexpressed in tumors but almost absent in healthy adult tissues, seem to represent promising therapeutic targets. These proteins act by binding to AT-hook DNA-binding motifs and may regulate the expression of several genes associated with tumor progression. Therefore, integrating in silico, translational, and in vitro approaches, we investigated the functional consequences of blocking HMGA2–DNA interaction in ESCC tumor progression by using netropsin, a site-specific ligand for AT-rich DNA regions. Our results demonstrate that netropsin treatment significantly reduced cell viability, migration, and cell cycle progression, thereby promoting apoptosis. Furthermore, netropsin treatment was capable of partially reverting Epithelial–Mesenchymal Transition (EMT) activation associated with HMGA2 expression, by downregulating EMT activators, such as Slug and Twist. Finally, the netropsin treatment sensitizes ESCC cells to chemotherapeutic treatment with 5-Fluorouracil. Taken together, our findings highlight that AT binding-specific blockade could be correlated with the inhibition of HMGA2 and may reveal a promising approach to better understand ESCC progression. Full article

Proximal gastrectomy preserves gastric function; however, reconstruction choice influences reflux control and quality of life (QOL), and the comparative efficacy of available techniques remains unclear. A PRISMA-guided search of PubMed and Web of Science Core Collection (January 2000–April 2025) identified studies reporting reflux or QOL outcomes after proximal gastrectomy. Eligible studies included adult gastric cancer cohorts with original clinical data. Two reviewers independently screened articles, extracted predefined variables, and performed a narrative synthesis. The protocol was archived on the OSF. Thirty-two studies (2958 patients) met inclusion criteria. Simple esophagogastrostomy (EG) consistently demonstrated the poorest reflux control and widest range of stricture rates. Double-tract reconstruction (DTR) showed a generally favorable balance among reflux control, low leakage rates, and acceptable stricture rates, suggesting that it may represent a practical and broadly applicable reconstruction option. Jejunal interposition and pouch variants were reported in small, heterogeneous series, limiting their generalizability. Among valve-forming methods, the double-flap technique was associated with very low rates of endoscopic reflux in two Los Angeles–graded cohorts, though a 4–6% stricture rate remained a concern. Evidence for the side overlap with fundoplication by Yamashita, both original and modified, was sparse and inconsistent. Global QOL, assessed using PGSAS-45/37 and EORTC instruments, did not differ consistently between reconstruction types, although specific domains—such as appetite loss, nausea, and weight maintenance—varied sporadically. Available evidence suggests that DTR may be considered a practical and broadly applicable reconstruction option following proximal gastrectomy, whereas the double-flap technique appears to provide strong reflux control but may be associated with a risk of anastomotic stricture. Simple EG may was associated with higher reflux rates across studies and may be less favorable for reflux control. Larger multicenter studies using standardized, nutrition-sensitive QOL measures and physiological reflux testing are needed to optimize reconstruction choice. However, substantial heterogeneity and the limited quality of the available evidence preclude definitive conclusions regarding the superiority of any single reconstruction method. Full article

Background: Ki-67 is a pivotal biomarker of tumor proliferative activity in esophageal cancer, yet its clinical application is hindered by reliance on invasive biopsy. Radiomics offers a non-invasive alternative, but conventional methods may be confounded by inter-individual baseline variations. This exploratory study aims to develop a radiomics-based biomarker for predicting Ki-67 expression. Methods: This single-center retrospective study included 59 patients with esophageal cancer. Delta-radiomics features were derived from preoperative CT images by calculating the difference between radiomic features from the tumor and paired normal esophageal tissue. Feature selection (mRMR, k = 3) was nested within leave-one-out cross-validation (LOOCV) to prevent data leakage. A Random Forest model was compared with Logistic Regression and Support Vector Machine across three feature types, five Ki-67 thresholds, and clinical variables. SHAP analysis was used for interpretability. Results: The Random Forest model achieved an AUC of 0.643 (95% CI: 0.483–0.792). Delta radiomics outperformed esotarget (AUC = 0.546) and eso (AUC = 0.514) models. The combined model (AUC = 0.619) did not outperform delta radiomics alone. SHAP analysis identified GrayLevelVariance and SmallAreaEmphasis as the most influential features. Conclusions: This exploratory study demonstrates that delta radiomics provides moderate discriminatory performance for predicting Ki-67 expression. External validation in independent multi-center cohorts is required before clinical application. Full article

Robotic-assisted minimally invasive esophagectomy (RAMIE) has emerged as an increasingly utilized approach for the surgical management of esophageal malignancies, offering potential advantages over conventional minimally invasive esophagectomy (MIE) and open esophagectomy (OE). Advances in robotic technology, enhanced visualization, instrument articulation, and surgeon ergonomics have facilitated wider adoption of RAMIE in thoracic surgical oncology. This review summarizes contemporary evidence regarding intraoperative, postoperative, oncologic, and patient-centered outcomes associated with RAMIE while highlighting emerging technologies and future directions in the field. Current literature, including randomized controlled trials, meta-analyses, propensity-matched studies, and international registry data, suggests that RAMIE is associated with reduced blood loss, improved lymph node harvest, and lower pulmonary morbidity compared with OE, while demonstrating outcomes comparable or favorable to conventional MIE. Oncologic outcomes, including R0 resection rates and overall survival, appear equivalent across approaches in most contemporary studies. In addition, robotic platforms may facilitate recurrent laryngeal nerve lymphadenectomy and complex mediastinal dissection. Despite these advantages, RAMIE is frequently associated with longer operative times and remains dependent on institutional expertise, surgeon experience, and resource availability. Current evidence is promising but remains limited by heterogeneity of surgical techniques, institutional expertise, and a relative scarcity of long-term randomized data. Emerging innovations including fluorescence-guided imaging, perfusion assessment technologies, artificial intelligence integration, augmented reality, and advanced robotic platforms may further enhance precision, safety, and personalization of esophageal cancer surgery. As robotic technology and perioperative systems continue to evolve, ongoing prospective investigation and long-term oncologic evaluation will remain essential to define the optimal role of RAMIE within multidisciplinary esophageal cancer care. Full article

Chimeric antigen receptor (CAR)-T therapy has achieved partial therapeutic efficacy in solid tumors, but its overall effectiveness remains limited. IL-21-armored CD276.CAR-T (IL21.CD276.CAR-T) represents a promising strategy to enhance anti-tumor activity against esophageal squamous cell carcinoma (ESCC). However, resistance mechanisms remain unclear. We generated IL21.CD276.CAR-T cells and evaluated their cytotoxicity in vitro and in B-NDG xenograft models. Poliovirus receptor (PVR) expression on ESCC cells was analyzed, and shRNA-mediated PVR knockdown was performed to validate its role in resistance. IL-21R expression on ESCC cells was examined to exclude direct IL-21 signaling. IL-21 enhances the cytotoxicity of CD276.CAR-T cells against ESCC. Although IL21.CD276.CAR-T exhibited potent cytotoxicity in vitro, it failed to achieve complete tumor regression, and resistant cells still emerged. Mechanistically, resistance was not caused by CD276 antigen loss or IL-21R expression, but by upregulation of PVR on cancer cell membrane after IL21.CAR-T exposure. PVR knockdown restored CAR-T sensitivity in vitro, enhanced the anti-tumor capacity of IL21.CD276.CAR-T cells, and partially improved anti-tumor efficacy in vivo without systemic toxicity. PVR may act as a mediator of resistance to IL21.CD276.CAR-T in ESCC. Targeting PVR represents a novel strategy to overcome IL21.CAR-T resistance and improve therapeutic outcomes in ESCC. Full article