Background and study aims Radial incision and cutting (RIC) was established to improve refractory esophageal anastomotic strictures but its efficacy and safety for nonsurgical refractory strictures remain unclear. To evaluate the usefulness of RIC in nonsurgical refractory strictures, we retrospectively compared outcomes between nonsurgical and surgical strictures. Patients and methods We retrospectively studied 54 consecutive patients who were initially treated with RIC for refractory benign esophageal stricture. The study variables included dysphasia score improvement rate, frequency of repeated RIC, cumulative patency rate, cumulative stricture improved rate, and adverse events(AEs), which were compared between nonsurgical (n = 21) and surgical (n = 33) stricture groups. Results Immediately after RIC, 90.5% of patients in the nonsurgical group and 84.8% of patients in the surgical group had improvement in dysphagia (P = 0.69). The frequency of intervening repeated RIC was 42.9% in the nonsurgical group and 42.4% in the surgical group (P = 0.98). During median follow-up of 22.3 months (range, 1.0–175.0), the cumulative patency rate (P = 0.23) and cumulative stricture improvement rate (P = 0.14) but there was not statistical difference between the two groups. Despite a low cumulative stricture improvement rate (9.5%) at 6 months after the first RIC in the nonsurgical group, 57.7% of patients no longer required endoscopic balloon dilatation at 2 years. The cumulative stricture improvement rate was significantly lower in patients with a history of radiation therapy. No severe AEs were observed in the nonsurgical group. Conclusions RIC for nonsurgical refractory benign esophageal stricture is an effective and safe treatment option.

Barrett’s esophagus (BE) is a common precancerous lesion that can progress to esophageal adenocarcinoma (EAC). There are significant alterations in the esophageal microbiome in the progression from healthy esophagus to BE to EAC, including an increased abundance of a variety of lactate-producing bacteria and an increase of lactate in the tumor microenvironment, as predicted by metabolic modeling. The role of bacterial lactate in EAC is unknown. Here, we utilize patient-derived organoid (PDO) models of EAC and demonstrate that lactate inhibits the growth and proliferation of EAC PDOs through alterations in the tumor NADH/NAD+ redox state. Further RNA sequencing of EAC PDOs identifies ID1 and RSAD2 as potential regulatory molecules crucial in mediating lactate’s ability to suppress glycolysis and proliferation. Gene ontology analysis also identifies the activation of inflammatory and immunological pathways in addition to alterations in the metabolic pathways in EAC PDOs exposed to lactate, suggesting a multi-faceted role for lactate in the pathogenesis of EAC.

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single‐strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin‐dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho‐histone H3 (p‐hH3)‐positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p‐hH3‐positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine‐mediated DNA damage, namely DNA double‐strand breaks, as shown by increased γ‐H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC‐derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.

The transcription factor STAT3 plays broad roles in epithelial biology, yet its function in human esophageal development remains undefined. Using 2D and 3D human induced pluripotent stem cell (hiPSC)-derived platforms, we investigated how STAT3 regulates esophageal epithelial differentiation. We find that STAT3 is dispensable for definitive endoderm and anterior foregut endoderm specification but becomes essential during the transition to esophageal progenitor cells (EPCs). Inhibition of STAT3, via CRISPR-mediated knockout or siRNA, impairs the expression of key EPC and differentiation markers, including TP63 , and disrupts 3D organoid formation. These defects are accompanied by reduced epithelial proliferation. Notably, STAT3 is highly expressed in human fetal esophageal tissues and hiPSC-derived organoids, while its deletion in the developing mouse esophagus does not affect epithelial architecture, highlighting species-specific differences. Together, these findings identify STAT3 as a critical determinant of basal cell identity and epithelial morphogenesis, revealing a developmental checkpoint in early human esophageal lineage commitment.

TP53 and other DNA damage response-related gene mutations in human esophageal squamous cell carcinomas.