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Purpose: This study aimed to compare the efficacy and safety of combining first-line chemoimmunotherapy with radiation therapy versus chemoimmunotherapy alone in patients with stage IVB esophageal squamous cell carcinoma (ESCC)., Methods and Materials: We retrospectively examined 409 patients with stage IVB ESCC who received first-line chemotherapy and anti-PD-1 antibody, with or without radiation therapy of ≥40 Gy radiation dose to primary lesion, from 4 academic cancer centers between October 2018 and December 2022. Propensity score matching was conducted to minimize the potential confounding effects., Results: In the overall cohort of 409 patients, the group that received additional radiation therapy had superior overall survival (OS) (hazard ratio [HR], 0.51; 95% CI, 0.39-0.66; P < .001) and progression-free survival (PFS) (HR, 0.52; 95% CI, 0.40-0.66; P < .001) compared to the group that received chemoimmunotherapy alone. After 1:1 propensity score matching, matching age, tumor location, and metastatic sites, a total of 250 patients were selected for further analysis. The results remained consistent and showed that the addition of radiation therapy significantly improved OS and PFS (median OS, 24.9 vs 14.6 months; P = .003; median PFS, 14.2 vs 10.6 months; P = .002). Multivariate Cox analysis including tumor location, T stage, metastatic sites, and treatment modality, revealed that radiation therapy was an independent prognostic factor for both OS (HR, 0.57; 95% CI, 0.41-0.81) and PFS (HR, 0.63, 95% CI, 0.47-0.86). Subgroup analyses revealed significant OS prolongation in patients with nonregional lymph node metastases only who received radiation therapy (HR, 0.49; 95% CI, 0.34-0.70). No OS survival benefit was observed in those with distant organ metastases (HR, 0.72; 95% CI, 0.46-1.13). Regarding safety, the group receiving additional radiation therapy had higher incidences of grade 3 to 4 lymphopenia (74.4% vs 17.7%, P < .001) and esophagitis (11.2% vs 2.4%, P = .006)., Conclusions: The addition of radiation therapy to chemoimmunotherapy improved the survival of stage IVB ESCC patients with nonregional lymph node metastasis., (Copyright © 2024. Published by Elsevier Inc.)

Background: Cancer stem cells (CSCs) play a significant role in the recurrence and drug resistance of esophageal carcinoma (ESCA). Ferroptosis is a promising anticancer therapeutic strategy that effectively targets CSCs exhibiting high tumorigenicity and treatment resistance. However, there is a lack of research on the combined role of ferroptosis-related genes (FRGs) and stemness signature in the prognosis of ESCA., Methods: The cellular compositions were characterized using single-cell RNA sequencing (scRNA-seq) data from 18 untreated ESCA samples. 50 ferroptosis-related stemness genes (FRSGs) were identified by integrating FRGs with stemness-related genes (SRGs), and then the cells were grouped by AUCell analysis. Next, functional enrichment, intercellular communication, and trajectory analyses were performed to characterize the different groups of cells. Subsequently, the stem-ferr-index was calculated using machine learning algorithms based on the expression profiles of the identified risk genes. Additionally, therapeutic drugs were predicted by analyzing the GDSC2 database. Finally, the expression and functional roles of the identified marker genes were validated through in vitro experiments., Results: The analysis of scRNA-seq data demonstrates the diversity and cellular heterogeneity of ESCA. Then, we identified 50 FRSGs and classified cells into high or low ferroptosis score stemness cells accordingly. Functional enrichment analysis conducted on the differentially up-regulated genes between these groups revealed predominant enrichment in pathways associated with intercellular communication and cell differentiation. Subsequently, we identified 9 risk genes and developed a prognostic signature, termed stem&#95;ferr&#95;index, based on these identified risk genes. We found that the stem-ferr-index was correlated with the clinical characteristics of patients, and patients with high stem-ferr-index had poor prognosis. Furthermore, we identified four drugs (Navitoclax, Foretinib, Axitinib, and Talazoparib) with potential efficacy targeting patients with a high stem&#95;ferr&#95;index. Additionally, we delineated two marker genes (STMN1 and SLC2A1). Particularly noteworthy, SLC2A1 exhibited elevated expression levels in ESCA tissues and cells. We provided evidence suggesting that SLC2A1 could influence the migration, invasion, and stemness of ESCA cells, and it was associated with sensitivity to Foretinib., Conclusion: This study constructed a novel ferroptosis-related stemness signature, identified two marker genes for ESCA, and provided valuable insights for developing more effective therapeutic targets targeting ESCA CSCs in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background/aim: The systemic immune-inflammation index (SII) is a calculated biomarker developed to predict the prognosis of malignant tumors. This study evaluated the influence of the SII in patients with esophageal cancer (EC) who underwent curative resection., Patients and Methods: Patients who underwent radical esophagectomy and lymph node dissection for EC were enrolled. The SII was calculated as follows: neutrophil count (cell/mm 3 ) × platelet count (cell/mm 3 ×10 3 )/lymphocyte count (cell/mm 3 ). The SII, patient characteristics, overall survival (OS), and recurrence-free survival (RFS) were assessed., Results: A total of 180 patients were included in this study. The cutoff value of the SII was set at 500 according to previous studies. Of the 180 patients, 100 were classified into the SII-high group and 80 into the SII-low group. The 3- and 5-year OS rates were 59.0% and 54.0%, respectively, in the SII-high group and 80.0% and 75.0%, respectively, in the SII-low group, showing significant differences between the groups (p=0.001). A multivariate analysis for the OS demonstrated that the SII was an independent prognostic factor (hazard ratio=2.333, 95% confidence interval=1.411-3.860, p<0.001), with similar results obtained for the RFS. Furthermore, hematological recurrence was significantly higher in the SII-high group than in the SII-low group (36.0% vs. 17.5%, p=0.006)., Conclusion: The preoperative SII was an independent prognostic factor for OS and RFS in patients with EC who underwent curative resection. Thus, the SII can be a useful marker for the treatment and management of EC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We hypothesized that the inflammatory burden index (IBI) is a promising biomarker for esophageal cancer (EC) treatment and management. To confirm our hypothesis, we evaluated the prognostic impact of IBI in patients with EC who received curative treatment., Patients and Methods: We conducted a retrospective review of medical records and collected data from consecutive patients with EC who underwent curative resection at Yokohama City University between 2005 and 2020. The IBI score was calculated as the C-reactive protein level multiplied by the neutrophil-to-lymphocyte ratio., Results: In total, 180 patients with EC were included in this study. The 3- and 5-year overall survival (OS) rates were 72.9% and 63.4%, respectively, in the IBI-low group, and 38.2% and 32.5% in the IBI-high group (p<0.001). In the multivariate analysis, IBI was identified as a significant prognostic factor for OS [hazard ratio (HR)=2.372; 95% confidence interval CI=1.478-3.806, p<0.001]. In addition, the 3- and 5-year recurrence-free survival (RFS) rates were 52.9% and 47.8%, respectively, in the IBI-low group, and 22.9% and 17.2% in the IBI-high group (p<0.001). In the multivariate analysis, IBI was identified as a significant prognostic factor for RFS (HR=2.484; 95%CI=1.373-4.494, p<0.001). When comparing the recurrence patterns between the IBI-high and IBI-low groups, there were significant differences in lymph node recurrence (46.0% vs. 26.2%, p=0.010) and hematological recurrence (52.0% vs. 18.5%, p<0.001)., Conclusion: IBI affects both the short- and long-term oncological outcomes. Thus, IBI may be a promising prognostic factor for the treatment and management of EC., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Homologous recombination deficiency (HRD) represents an impairment in the homologous recombination repair (HRR) pathway, crucial for repairing DNA double-strand breaks and contributing to genomic instability in cancer. The HRD score may be a more reliable biomarker than HRR-related gene mutations for identifying patients sensitive to poly(ADP-ribose) polymerase inhibitors. Despite its relevance in various cancers, the HRD score remains underexplored in esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed HRD scores in 96 ESCC patients, examining correlations with clinical characteristics and survival outcomes, and validated our findings using the TCGA dataset. Genomic sequencing utilized a custom superHRD next-generation sequencing panel, and HRD scores were calculated from 54,000 single-nucleotide polymorphisms using Kruskal-Wallis rank-sum tests and two cut-off points for analysis. Higher HRD scores correlated with advanced tumor stages, recurrence, and mutations in TP53 and ABCB1, while APC mutations were linked to lower HRD scores. Patients with high HRD scores had significantly shorter disease-free survival (p = 0.013) and a trend toward shorter overall survival (OS) (p = 0.005), particularly those not receiving adjuvant therapy. Conversely, HRD-high patients undergoing adjuvant therapy showed a trend toward longer OS (p = 0.015). Multivariate analysis identified HRD as an independent prognostic factor (hazard ratio = 2.814 for recurrence, p = 0.015). Validation with the TCGA dataset supported these findings. This study highlights the associations between HRD scores, clinical characteristics, and genomic mutations in ESCC, suggesting HRD as a potential prognostic biomarker. HRD assessment may aid in patient stratification and personalized treatment strategies, warranting further investigation to validate the therapeutic implications of HRD scores in ESCC., (© 2024 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

CXC chemokine receptor 4 (CXCR4) and ubiquitin specific protease 1 (USP1) have been reported to involve in the tumorigenesis of esophageal squamous-cell carcinoma (ESCC). Here, we investigated whether USP1 induced CXCR4 deubiquitination in regulating ESCC progression. MTT assay, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, transwell assay and ELISA analysis were used to detect cell oncogenic phenotypes, macrophage phenotypes, inflammatory cytokines production, the cytotoxicity of cytokine-induced killer (CIK) cells and CD8 + T cell apoptosis. Protein interaction was determined by immunoprecipitation assay. Cellular ubiquitination detected the ubiquitination effect on CXCR4. A mouse xenograft model was established for in vivo experiments. CXCR4 was highly expressed in ESCC tissues and cells. Functionally, CXCR4 silencing suppressed ESCC cell proliferation, invasion, and induced cell apoptosis. Moreover, CXCR4 deficiency suppressed cancer cell immune escape by suppressing macrophage M2 polarization, elevating inflammatory cytokines produced by PBMCs, enhancing the cytotoxicity of CIK cells, and suppressing CD8 + T cell apoptosis. A high USP1 expression was observed in ESCC, USP1 interacted with CXCR4 and enhanced its protein stability through deubiquitination. USP1 silencing suppressed ESCC cell proliferation, invasion, and immune escape, which were reversed by CXCR4 overexpression. In vivo assay showed that USP1 deficiency impeded tumor growth by regulating CXCR4. Besides, fused in sarcoma (FUS) was confirmed to bind to USP1 and stabilized its mRNA expression, and could regulate CXCR4 via USP1. In conclusion, USP1 stabilized CXCR4 by removing ubiquitination on CXCR4, thereby promoting ESCC cell proliferation, invasion, and immune escape in vitro, and tumor growth in vivo., (© 2024 Wiley Periodicals LLC.)

Background: Esophageal cancer poses a significant health burden globally. Endoscopic treatment has emerged as a viable option for patient ineligible for surgery or experiencing disease recurrence post-radiotherapy., Methods: Patients visiting the Department of Endoscopy at the Cancer Hospital of China Academy of Medical Sciences between March 2009 and March 2024 were retrospectively analyzed. Inclusion criteria encompassed patients with histologically confirmed esophageal cancer who had not undergone surgery, but received radiotherapy or CRT, and subsequently opted for endoscopic treatment. Data on demographics, treatment modalities, recurrence patterns, histopathological characteristics, and outcomes were collected. Statistical analysis was conducted using SPSS 27.0, employing Kolmogorov-Smirnov tests for data normality assessment., Results: Out of 25 included patients, the mean age was 60.29 years, with a predominance of males (88%). Most patients (64%) received chemoradiotherapy (CRT), while the rest underwent radiotherapy alone. The median follow-up duration was 50.92 months, with a median recurrence time of 38.92 months. Majority (56%) presented with a solitary lesion and 76% had negative margins. Histopathological analysis revealed various stages of cancer, with the most common being high-grade squamous epithelial neoplasia (64%). Survival analysis indicated a 72% overall survival rate, with 16% surviving beyond 5-year post-treatment. Approximately, 20% succumbed during the study, primarily due to non-esophageal causes (16%)., Conclusion: Endoscopic treatment shows promise as a therapeutic option for selected esophageal cancer patients, offering favorable outcomes in terms of survival and disease control. Further prospective studies are warranted to validate these findings and optimize patient selection criteria for endoscopic interventions in esophageal cancer management., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

CD44 is a type I transmembrane glycoprotein associated with poor prognosis in various solid tumors. Since CD44 plays a critical role in tumor development by regulating cell adhesion, survival, proliferation and stemness, it has been considered a target for tumor therapy. Anti‑CD44 monoclonal antibodies (mAbs) have been developed and applied to antibody‑drug conjugates and chimeric antigen receptor‑T cell therapy. Anti-pan‑CD44 mAbs, C 44 Mab‑5 and C 44 Mab‑46, which recognize both CD44 standard (CD44s) and variant isoforms were previously developed. The present study generated a mouse IgG 2a version of the anti‑pan‑CD44 mAbs (5‑mG 2a and C 44 Mab‑46‑mG 2a ) to evaluate the antitumor activities against CD44‑positive cells. Both 5‑mG 2a and C 44 Mab‑46‑mG 2a recognized CD44s‑overexpressed CHO‑K1 (CHO/CD44s) cells and esophageal tumor cell line (KYSE770) in flow cytometry. Furthermore, both 5‑mG 2a and C 44 Mab‑46‑mG 2a could activate effector cells in the presence of CHO/CD44s cells and exhibited complement-dependent cytotoxicity against both CHO/CD44s and KYSE770 cells. Furthermore, the administration of 5‑mG 2a and C 44 Mab‑46‑mG 2a significantly suppressed CHO/CD44s and KYSE770 xenograft tumor development compared with the control mouse IgG 2a . These results indicate that 5‑mG 2a and C 44 Mab‑46‑mG 2a could exert antitumor activities against CD44‑positive cancers and be a promising therapeutic regimen for tumors.

Background: The comparison of neoadjuvant chemoradiotherapy (nCRT) versus neoadjuvant chemotherapy (nCT) for locally advanced esophageal squamous cell carcinoma (ESCC) remains inconclusive, and the optimal regimen is still under investigation., Methods: Prospective randomized clinical trials were systematically searched in electronic databases from inception to Oct 2023. A graphical reconstructive algorithm was employed to extract time-to-event outcomes from Kaplan-Meier curves presented in the original studies. Using reconstructed individual patient data, summary overall survival (OS) and disease progression-free survival (DFS) for nCRT versus nCT, primarily doublet chemotherapy were recalculated. Hazard Ratios (HRs) of OS and DFS reported were also pooled by the fixed-effects model., Results: A total of 6 randomized clinical trials comprising 1162 patients were included in our analysis. In the individual patient data (IPD) pooled analysis, a significant OS benefit was found for nCRT in ESCC (HR=0.81, 95 %CI:0.67-0.98, p=0.029), compared with the treatment of nCT. The median overall survival time were 53 months (95 %CI:41.9-67.7 m) and 66 months(95 %CI:57.2-NA) respectively in the nCT and nCRT groups. Additionally, a significant improvement in PFS for nCRT compared to nCT in the IPD pooled analysis (HR=0.79,95 %CI:0.64-0.98; p=0.027). Consistent with above results, the pooled HRs of OS and DFS for nCRT versus nCT were 0.78 (95 % CI 0.65-0.92, p=0.004) and 0.79 (95 % CI: 0.65-0.97, p=0.02), respectively. Notably, no substantial heterogeneity across studies was observed., Conclusions: Our findings indicate that nCRT offers better survival outcomes for ESCC, at least when compared to neoadjuvant doublet chemotherapy.This evidence continues to support the clinical practice of employing nCRT in locally advanced resectable ESCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial., Methods: Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response., Results: Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability., Conclusions: Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning., (© 2024. Society of Surgical Oncology.)

Background: The upper mediastinum is the most common metastatic site of esophageal squamous cell carcinoma (ESCC), and complete dissection of this region is important for oncologic reasons. This study aimed to compare the oncologic outcomes and completeness of upper mediastinal dissection for ESCC patients undergoing the Ivor-Lewis (IL) or McKeown (MK) operations., Methods: Between 2013 and 2018, 680 patients (IL, 433; MK, 247) underwent upfront esophagectomy with two-field lymph node (LN) dissection for mid-to-lower ESCCs. Propensity score-matching (1:1 ratio) was performed to minimize the effects of confounding factors., Results: The mean age was 64.5 ± 8.8 years, and 635 (93.4%) of the patients were male. The median follow-up period was 71.66 months (interquartile range [IQR], 59.60-91.04 months). The IL group had a higher mean age, lower body mass index, higher proportion of advanced T and N, and higher adjuvant therapy rates, but these differences were well-balanced after propensity score-matching. The mean number of dissected LNs at the mediastinum and at the right recurrent laryngeal nerve (RLN) were similar between the two groups after matching, whereas the IL group exhibited a slightly greater number of dissected LNs at the left RLN. Among the matched patients, the IL and MK groups exhibited similar 5-year overall survival (OS: 75.1% vs 78.0%; p = 0.368). The multivariate model showed no differences in OS, disease-free survival, or recurrence-free survival for locoregional, upper mediastinum, or neck between the two groups., Conclusions: This study suggests that both the IL and MK operations are oncologically feasible for patients with mid-to-lower ESCC., (© 2024. Society of Surgical Oncology.)

Background: Despite trimodality treatment, 10% to 20% of patients with esophageal cancer experience interval metastases after surgery. Restaging may identify patients who should not proceed to surgery, as well as a subgroup with limited metastases for whom long-term disease-control can be obtained. This study aimed to determine the proportion of patients with interval metastases after neoadjuvant chemoradiotherapy (nCRT) and to evaluate treatment and survival., Methods: Patients who had cT2-4aN0-3M0 esophageal cancer treated with nCRT were identified from a trial database. Metastases detected up to 14 weeks after nCRT on 18 F-FDG-PET/CT or during surgery were categorized as oligometastases (≤3 lesions located in one single organ or one extra-regional lymph node station) or as non-oligometastases. The primary outcome was the proportion of patients with metastases after nCRT. The secondary outcomes were overall survival (OS) and the site and treatment of metastases., Results: Between 2013 and 2021, 973 patients received nCRT, and 10.3% had interval metastases. Of 100 patients, 30 (30%) had oligometastases, located mostly in non-regional lymph nodes (33.3%) or bones (26.7%). The median OS of this group was 13.8 months (95% confidence interval [CI] 9.2-27.1 months). Of 30 patients, 12 (40%) with oligometastases underwent potentially curative treatment, with a median OS of 22.8 months (95% CI 10.4-NA). The patients with non-oligometastases underwent mostly systemic therapy or BSC and had a median OS of 9 months (95% CI 7.4-10.9 months)., Conclusions: Interval metastases were detected in about 10% of patients after nCRT, underscoring the importance of re-staging with 18 F-FDG-PET/CT for those who proceed to surgery. A favorable survival might be accomplished for a subgroup of patients with oligometastases., (© 2024. The Author(s).)

Background: Although multiple treatment options exist for gastroesophageal junction (GEJ) cancer, surgery remains the mainstay for potential cure. Extended nodal dissection with a D2 lymphadenectomy (LAD) remains controversial for Siewert II GEJ cancer. Although D2 LAD may lead to a greater lymph node harvest, its effect on survival remains elusive. The authors hypothesized that additional D2 dissection in Siewert II GEJ cancer does not lead to increased survival., Methods: This study reviewed Siewert II patients who received a D1 or D2 LAD in addition to minimally invasive esophagectomy (MIE) after receiving neoadjuvant chemoradiation or perioperative chemotherapy (2012-2022). The patients were followed for up to 5 years. The outcomes measured were survival, number of nodes sampled, and operative time. The association between D1 or D2 LAD and overall survival was analyzed with Kaplan-Meier methods and a multivariable Cox regression model., Results: Among 155 patients, 74 % underwent D1 and 26 % underwent D2 LAD. The patients with D2 had more than 15 lymph nodes harvested more frequently than those who had D1 (83 % vs 48 %; p < 0.001), with no difference in positive nodes (2.8 ± 5.2 vs 2.1 ± 4.2; p = 0.4). The patients with D2 LAD had a longer median operative time than those who with D1 LAD (362 vs 244 min; p < 0.001). In Kaplan-Meier and multivariable Cox regression models, overall survival did not differ significantly between the patients undergoing D2 and those who had D1 (adjusted hazard ratio [aHR], 0.52; 95 % confidence interval [CI], 0.25-1.00; p = 0.067)., Conclusions: Little consensus exists regarding the optimal lymph node harvest for GEJ cancers. In Siewert II cancer, D2 LAD may not be mandatory and may lead to increased operative morbidity with no significant difference in survival., (© 2024. The Author(s).)

Definitive chemoradiotherapy (DCRT) is administered as standard treatment for patients with cT4 and/or M1Lym esophageal squamous cell carcinoma (ESCC); however, its long-term result is inadequate. Although several studies have reported that conversion surgery can improve the survival of these patients, none have identified significantly better long-term survival than that achieved by DCRT. Thus, enhancing DCRT seems important to improve the survival of these patients. A strategy of shrinking tumor volume before DCRT and providing consolidation chemotherapy for systemic control is expected to improve the survival of these patients. Pembrolizumab plus cisplatin and fluorouracil has demonstrated good local control and significant improvement in the survival of patients with advanced esophageal cancer. Based on these results, the following strategy is proposed: This protocol should be applied as induction for these patients; then, DCRT should be provided depending on the initial response; and finally, adjuvant chemotherapy with an immune checkpoint inhibitor should be given to all responders., (© 2024. The Author(s).)

Esophageal cancer (EC) is a familiar digestive tract tumor with highly lethal. The hypoxic environment has been demonstrated to be a significant factor in modulating malignant tumor progression and is strongly associated with the abnormal energy metabolism of tumor cells. Serine hydroxymethyl transferase 2 (SHMT2) is one of the most frequently expressed metabolic enzymes in human malignancies. The study was designed to investigate the biological functions and regulation mechanisms of SHMT2 in EC under hypoxia. We conducted RT-qPCR to assess SHMT2 levels in EC tissues and cells (TE-1 and EC109). EC cells were incubated under normoxia and hypoxia, respectively, and altered SHMT2 expression was evaluated through RT-qPCR, western blot, and immunofluorescence. The biological functions of SHMT2 on EC cells were monitored by performing CCK-8, EdU, transwell, sphere formation, glucose uptake, and lactate production assays. The SHMT2 protein lactylation was measured by immunoprecipitation and western blot. In addition, SHMT2-interacting proteins were analyzed by bioinformatics and validated by rescue experiments. SHMT2 was notably upregulated in EC tissues and cells. Hypoxia elevated SHMT2 protein expression, augmenting EC cell proliferation, migration, invasion, stemness, and glycolysis. In addition, hypoxia triggered lactylation of the SHMT2 protein and enhanced its stability. SHMT2 knockdown impeded the malignant phenotype of EC cells. Further mechanistic studies disclosed that SHMT2 is involved in EC progression by interacting with MTHFD1L. Hypoxia-induced SHMT2 protein lactylation and upregulated its protein level, which in turn enhanced MTHFD1L expression and accelerated the malignant progression of EC cells., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated., Methods: This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors., Results: Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1 months and overall survival was 14 months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4 months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7 months., Conclusions: Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding., (© 2024. Japanese Society of Gastroenterology.)

Background: Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited., Methods: ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician's choice of SOX (oral S-1 [tegafur-gimeracil-oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints-centrally assessed progression-free survival (PFS) and overall survival (OS)-and landmark analyses of OS among patients alive using 3-year follow-up data., Results: At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55-0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75-1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy., Conclusion: This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer., Trial Registration: NCT02746796., (© 2024. The Author(s).)

Purpose: Based on the comparison of ramucirumab monoclonal antibody with control treatments in randomized controlled trials, this study aims to elucidate the role of ramucirumab monoclonal antibody in cancer therapy and its potential side effects, providing scientific evidence for clinical treatment., Methods: PubMed, Embase, Cochrane, and Web of Science were searched systematically to obtain the trials on ramucirumab in the treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma up to April 13, 2023. We included randomized controlled trials (RCTs) evaluating the efficacy and safety of ramucirumab as monotherapy and in combination with other chemotherapy agents as interventions for treating gastric or gastroesophageal junction (GEJ) adenocarcinoma., Results: After screening 2200 studies, we finally included 8 eligible studies (involving a total of 3,283 participants). Meta-analysis results showed that compared to the control group, ramucirumab monotherapy significantly improved overall survival (OS) (hazard ratio [HR] = 0.77, 95% confidence interval [CI] [0.67, 0.89]) and progression-free survival (PFS) (HR = 0.48, 95% CI [0.40, 0.58]). Similar results were obtained for ramucirumab combined with paclitaxel. In the treatment combining ramucirumab with paclitaxel, compared to monotherapy, three severe adverse reactions (grade ≥ 3) were observed with significantly increased risks (OR > 2). These include proteinuria (OR = 5.37, 95% CI [1.22, 23.54]), hypertension (OR = 4.02, 95% CI [2.63, 6.14]), and gastrointestinal perforation (OR = 4.64, 95% CI [1.00, 21.60]). Subgroup analysis further indicated that ramucirumab is effective in both non-East Asian and East Asian populations, with East Asian patients more prone to developing proteinuria, while having a lower incidence of hypertension. Additionally, ramucirumab demonstrated comparable efficacy between first-line and second-line treatments, with a higher incidence of proteinuria observed in second-line therapy., Conclusion: Ramucirumab significantly improves the prognosis of patients with gastric or gastroesophageal junction adenocarcinoma. When used in combination with paclitaxel, close monitoring of adverse reactions such as proteinuria (especially in East Asian populations), hypertension (especially in non-East Asian populations), and gastrointestinal perforation is essential., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate the feasibility and accuracy of predicting locoregional recurrence (LR) in elderly patients with esophageal squamous cell cancer (ESCC) who underwent radical radiotherapy using a pairwise machine learning algorithm., Methods: The 130 datasets enrolled were randomly divided into a training set and a testing set in a 7:3 ratio. Clinical factors were included and radiomics features were extracted from pretreatment CT scans using pyradiomics-based software, and a pairwise naive Bayes (NB) model was developed. The performance of the model was evaluated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). To facilitate practical application, we attempted to construct an automated esophageal cancer diagnosis system based on trained models., Results: To the follow-up date, 64 patients (49.23%) had experienced LR. Ten radiomics features and two clinical factors were selected for modeling. The model demonstrated good prediction performance, with area under the ROC curve of 0.903 (0.829-0.958) for the training cohort and 0.944 (0.849-1.000) for the testing cohort. The corresponding accuracies were 0.852 and 0.914, respectively. Calibration curves showed good agreement, and DCA curve confirmed the clinical validity of the model. The model accurately predicted LR in elderly patients, with a positive predictive value of 85.71% for the testing cohort., Conclusions: The pairwise NB model, based on pre-treatment enhanced chest CT-based radiomics and clinical factors, can accurately predict LR in elderly patients with ESCC. The esophageal cancer automated diagnostic system embedded with the pairwise NB model holds significant potential for application in clinical practice., (© 2024. The Author(s).)

Recent research has revealed that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) constitutes a significant risk factor in the development of esophageal cancer. Several investigations have elucidated the beneficial impact of folic acid (FA) in safeguarding esophageal epithelial cells against MNNG-induced damage. Therefore, we hypothesized that FA might prevent MNNG-induced proliferation of esophageal epithelial cells by interfering with the PI3K/AKT/mTOR signaling pathway. In vivo experiments, we found that FA antagonized MNNG-induced proliferation of rat esophageal mucosal epithelial echinocytes and activation of the PI3K/AKT/mTOR signaling pathway. In our in vitro experiments, it was observed that acute exposure to MNNG for 24 h led to a decrease in proliferative capacity and inhibition of the PI3K/AKT/mTOR signaling pathway in an immortalized human normal esophageal epithelial cell line (Het-1A), which was also ameliorated by supplementation with FA. We successfully established a Het-1A-T-cell line by inducing malignant transformation in Het-1A cells through exposure to MNNG. Notably, the PI3K/AKT2/mTOR pathway showed early suppression followed by activation during this transition. Next, we observed that FA inhibited cell proliferation and activation of the PI3K/AKT2/mTOR signaling pathway in Het-1A-T malignantly transformed cells. We further investigated the impact of 740Y-P, a PI3K agonist, and LY294002, a PI3K inhibitor, on Het-1A-T-cell proliferation. Overall, our findings show that FA supplementation may be beneficial in safeguarding normal esophageal epithelial cell proliferation and avoiding the development of esophageal cancer by decreasing the activation of the MNNG-induced PI3K/AKT2/mTOR signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Tumor-associated macrophages (TAM), a major component of the tumor microenvironment, play key roles in tumor formation and progression; however, mechanisms underlying TAM-induced tumor progression are complex and not well known. We previously reported that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts., Methods: We examined ANGPTL2 expression in paraffin-embedded tumor samples from resected specimens of 221 patients with esophageal cancer. Patients were subdivided into four groups based on immunohistochemistry scores described above: ANGPTL2-low/TAM-low, ANGPTL2-low/TAM-high, ANGPTL2-high/TAM-low, and ANGPTL2-high/TAM-high groups. Gene expression datasets of esophageal cancer cell lines were obtained from the cancer cell line encyclopedia public database., Results: In this study, we demonstrate that TAM infiltration is associated with poor prognosis in patients with esophageal cancer whose tumor cells show relatively higher ANGPTL2 expression levels; however, TAM infiltration did not affect prognosis in patients with ANGPTL2-low-expressing esophageal cancer, suggesting that ANGPTL2 expression in esophageal cancer cells is required for TAM-induced tumor progression. Our analysis of public datasets indicates a potential positive correlation of ANGPTL2 expression levels with that of transforming growth factor (TGF)-β, a TAM-activating factor, in esophageal cancer cell lines., Conclusion: We conclude that ANGPTL2 signaling in tumor cells supports TAM-induced tumor progression and contributes to poor prognosis in patients with esophageal cancer. These findings overall provide novel insight into pro-tumor ANGPTL2 functions and illustrate the essential role of cancer cell/TAM crosstalk in cancer progression., (© 2024. Society of Surgical Oncology.)

Programmed cell death ligand-1 (PD-L1) is an ideal checkpoint for immunohistochemical detection. The method of obtaining PD-L1 expression through biopsy can impact the accurate assessment of PD-L1 expression due to the spatial and temporal heterogeneity of tumors. Because of the limited sample size, biopsies often give only a localized picture of the tumor. In this retrospective study, a total of 2,386 metabolic tumor volume (MTV) features were extracted from 18 F-FDG PET-CT images. A radiomics model was developed to holistically and non-invasively assess PD-L1 expression in patients with esophageal squamous cell carcinoma by identifying seven independent factors through feature screening. The radiomics model shows effective discrimination, with an area under the receiver operating characteristic curve of 0.888 [95% confidence interval (CI): 0.831-0.945] and 0.889 (95% CI: 0.706-1.000) for the training and validation cohorts, respectively. The results of the decision curve analysis demonstrated that utilizing the radiation model to forecast PD-L1 expression levels yielded more net benefits at threshold probabilities below 0.669. The clinical impact curves demonstrate that when the threshold probability is less than 0.501, the loss-to-benefit ratio is less than one in all cases., (© 2024. The Author(s).)

Objective: The purpose of the study is to develop a prognosis nomogram for esophageal squamous cell carcinoma (ESCC) patients with radical resection and to identify patients who may benefit from postoperative adjuvant radiotherapy/chemoradiotherapy through survival risk stratification., Methods: We retrospectively enrolled patients who underwent esophagectomy in the First Affiliated Hospital of Nanjing Medical University from July 2015 to June 2017. Patients with stage I-III esophageal squamous cell carcinoma who received radical R0 resection with or without postoperative adjuvant radiotherapy/chemoradiotherapy were included. Further, patients were randomly allocated into two groups (training and validation cohorts) with a distribution ratio of 7:3. The prognosis nomogram was constructed based on independent factors determined by univariate and multivariate Cox analyses. The area under the receiver operating characteristic curve (AUC) and calibration curve were adopted to evaluate the discriminative ability and reliability of the nomogram. The accuracy and clinical practicability were respectively assessed by C-index values and decision curve analysis (DCA), and further contrasted the nomogram model and the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system. In addition, survival risk stratification was further performed according to the nomogram, and the effect of postoperative adjuvant therapy on each risk group was appraised by the Kaplan-Meier survival analysis., Results: A total of 399 patients with esophageal squamous cell carcinoma were recruited in this study, including the training cohort (n = 280) and the validation cohort (n = 119). The nomogram-related AUC values ​​for 1, 3, and 5-year OS were 0.900, 0.795, and 0.802, respectively, and 0.800, 0.865, 0.829 in the validation cohort, respectively. The slope of the calibration curve for both cohorts was close to 1, indicating good consistency. The C-index value of the nomogram was 0.769, which was higher than that of the AJCC 8th TNM staging system by 0.061 (p < 0.001). Based on the prognosis nomogram, patients were stratified into three risk groups (low, medium, and high), and there were obvious differences in prognosis among the groups (p < 0.001). Furthermore, postoperative adjuvant therapy has been shown to enhance the 5-year survival rate by over 15% among patients classified as medium- and high-risk., Conclusion: The constructed nomogram as developed resulted in accurate and effective prediction performance in survival outcomes for patients with stage I-III esophageal squamous cell carcinoma who underwent radical R0 resection, which is superior to the AJCC 8th TNM staging system. The survival risk stratification had potential clinical application to guide further personalized adjuvant therapy., (© 2024. The Author(s).)

Dormant cancer stem cells (DCSCs) exhibit characteristics of chemotherapy resistance and immune escape, and they are a crucial source of tumor recurrence and metastasis. However, the underlying mechanisms remain unrevealed. We demonstrate that enriched Gzmk + CD8 + T cells within the niche of esophageal DCSCs restrict the outgrowth of tumor mass. Nonetheless, DCSCs can escape immune elimination by enhancing PD-L1 signaling, thereby maintaining immune equilibrium. Quiescent fibroblast-derived quiescin sulfhydryl oxidase 1 (QSOX1) promotes the expression of PD-L1 and its own expression in DCSCs by elevating the level of reactive oxygen species. Additionally, high QSOX1 in the dormant tumor niche contributes to the exclusion of CD8 + T cells. Conversely, blocking QSOX1 with Ebselen in combination with anti-PD-1 and chemotherapy can effectively eradicate residual DCSCs by reducing PD-L1 expression and promoting CD8 + T cell infiltration. Clinically, high expression of QSOX1 predicts a poor response to anti-PD-1 treatment in patients with esophageal cancer. Thus, our findings reveal a mechanism whereby QSOX1 promotes PD-L1 upregulation and T cell exclusion, facilitating the immune escape of DCSCs, and QSOX1 inhibition, combined with immunotherapy and chemotherapy, represents a promising therapeutic approach for eliminating DCSCs and preventing recurrence., Competing Interests: Competing interests statement:L.L. and J.-R.W. are inventors on a pending patent related to this work (patentee: Sun Yat-sen Memorial Hospital, 11 June 2024; Application No.: 202410743238.7). The other authors declare that they have no other competing interests.

Background: Esophageal Squamous Cell Carcinoma (ESCC) remains a predominant health concern in the world, characterized by high prevalence and mortality rates. Advances in single-cell transcriptomics have revolutionized cancer research by enabling a precise dissection of cellular and molecular diversity within tumors., Objective: This study aims to elucidate the cellular dynamics and molecular mechanisms in ESCC, focusing on the transcriptional influence of STAT3 (Signal Transducer and Activator of Transcription 3) and its interaction with LHPP, thereby uncovering potential therapeutic targets., Methods: Single-cell RNA sequencing was employed to analyze 44,206 cells from tumor and adjacent normal tissues of ESCC patients, identifying distinct cell types and their transcriptional shifts. We conducted differential gene expression analysis to assess changes within the tumor microenvironment (TME). Validation of key regulatory interactions was performed using qPCR in a cohort of 21 ESCC patients and further substantiated through experimental assays in ESCC cell lines., Results: The study revealed critical alterations in cell composition and gene expression across identified cell populations, with a notable shift towards pro-tumorigenic states. A significant regulatory influence of STAT3 on LHPP was discovered, establishing a novel aspect of ESCC pathogenesis. Elevated levels of STAT3 and suppressed LHPP expression were validated in clinical samples. Functional assays confirmed that STAT3 directly represses LHPP at the promoter level, and disruption of this interaction by promoter mutations diminished STAT3's repressive effect., Conclusion: This investigation underscores the central role of STAT3 as a regulator in ESCC, directly impacting LHPP expression and suggesting a regulatory loop crucial for tumor behavior. The insights gained from our comprehensive cellular and molecular analysis offer a deeper understanding of the dynamics within the ESCC microenvironment. These findings pave the way for targeted therapeutic interventions focusing on the STAT3-LHPP axis, providing a strategic approach to improve ESCC management and prognosis., (© 2024. The Author(s).)

Posterior thoracic para-aortic lymph node (TPAN) metastasis is a distant metastasis of esophageal cancer. Several case reports have shown that radical esophagectomy and lymphadenectomy for posterior TPAN improve the prognosis of patients with cStage IVB esophageal cancer and solitary posterior TPAN metastasis; however, the true value of this procedure is unclear. The primary objective of this study was to evaluate the short- and long-term outcomes of lymphadenectomy for posterior TPAN after induction chemotherapy in esophageal cancer. This study enrolled 15 patients who underwent radical esophagectomy for cStage IVB esophageal cancer with solitary posterior TPAN metastasis after induction chemotherapy between January 2013 and October 2022 at our hospital. The short- and long-term of radical esophagectomy and lymphadenectomy for posterior TPAN were retrospectively evaluated. All patients who underwent radical esophagectomy and lymphadenectomy for posterior TPAN achieved a pR0 in this study. The median operative time and intraoperative blood loss were 385 minutes and 164 ml, respectively. Four patients (26.7%) had postoperative complications of Clavien-Dindo grade II or more. The median postoperative hospital stay was 15 days. The 5-year overall survival and recurrence-free survival rates were 55.6% (95% confidence interval: 23.1-79.0) and 55.0% (95% confidence interval: 25.3-77.2), respectively. We showed that lymphadenectomy for posterior TPAN metastasis was associated with an improved prognosis of some patients with advanced esophageal cancer. This technique may serve as a viable treatment option for patients who respond well to induction chemotherapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Esophageal cancer presents a clinical challenge due to its high incidence and unfavorable prognosis. The prognostic role of the circumferential resection margin (CRM) remains highly controversial, potentially due to its temporal dynamics coupled with variability in follow-up durations across studies. We aimed to explore the time-dependent prognostic significance of CRM in T3 esophageal squamous cell carcinomas (ESCCs). We systematically reviewed literature from 1990 to 2023 to determine how follow-up duration influences the prognostic role of CRM in esophageal cancer. Concurrently, we performed a retrospective examination of 354 patients who underwent treatment at the National Cancer Center between 2015 and 2018. Integrating a time interaction term in the Cox regression analyses enabled us to not only identify independent risk factors affecting overall survival (OS) but also to specifically scrutinize the potential temporal variations in CRM's prognostic impact. Our literature review suggested that CRM's influence on prognosis diminishes with longer follow-up durations for both classifications, namely the Royal College of Pathologists (RCP) (β = -0.003, P < 0.001) and the College of American Pathologists (CAP) (β = -0.007, P < 0.001). Time-dependent multivariate Cox regression analysis emphasized the evolving nature of CRM's prognostic effect, and the inclusion of the time interaction term enhanced model accuracy. In conclusion, CRM is an independent prognostic factor for T3 thoracic ESCC patients. Its influence appears to decrease over extended follow-up periods, shedding light on the heterogeneity seen in previous studies. With the time interaction term, CRM becomes a more precise post-operative prognostic indicator for esophageal cancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Robotic esophagectomy has improved early outcomes and enhanced the quality of lymphadenectomy for esophageal cancer surgery. This study aimed to determine risk factors for long-term survival following robotic esophagectomy and the causes of long-term mortality. We included patients who underwent robotic esophagectomy at our institute between 2010 and 2022. Robotic esophagectomy was defined as a surgical procedure performed robotically in both the abdomen and thorax. Robotic esophagectomy was performed in patients at all stages, including advanced stages, even in patients with stage IV and supraclavicular lymph node metastasis. A total of 340 patients underwent robotic esophagectomy during the study period. Ivor-Lewis operation and McKeown operation were performed on 153 (45.0%) and 187 (55.0%) patients, respectively. The five-year survival rates based on clinical stages were as follows: 85.2% in stage I, 62.0% in stage II, 54.5% in stage III, and 40.3% in stage IV. Risk factors for long-term survival included body mass index, Charlson comorbidity index, clinical stages, and postoperative complications of grade 4 or higher. Among the cases of long-term mortality, recurrence accounted for 42 patients (61.7%), while non-cancer-related death occurred in 26 patients (38.2%). The most common cause of non-cancer-related death was malnutrition and poor general condition, observed in 11 patients (16.2%). Robotic esophagectomy has demonstrated the ability to achieve acceptable long-term survival rates, even in patients with cervical lymph node metastasis. However, addressing high-grade postoperative complications and long-term malnutrition remains crucial for further improving the long-term survival outcomes of patients with esophageal cancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The study aimed to describe the prevalence of lymph node metastases per lymph node station for esophageal squamous cell carcinoma (ESCC) after neoadjuvant treatment. Clinicopathological variables of ESCC patients were retrieved from the prospective database of the Surgical Esophageal Cancer Patient Registry in West China Hospital, Sichuan University. A two-field lymphadenectomy was routinely performed, and an extensive three-field lymphadenectomy was performed if cervical lymph node metastasis was suspected. According to AJCC/UICC 8, lymph node stations were investigated separately. The number of patients with metastatic lymph nodes divided by those who underwent lymph node dissection at that station was used to define the percentage of patients with lymph node metastases. Data are also separately analyzed according to the pathological response of the primary tumor, neoadjuvant treatment regimens, pretreatment tumor length, and tumor location. Between January 2019 and March 2023, 623 patients who underwent neoadjuvant therapy followed by transthoracic esophagectomy were enrolled. Lymph node metastases were found in 212 patients (34.0%) and most frequently seen in lymph nodes along the right recurrent nerve (10.1%, 58/575), paracardial station (11.4%, 67/587), and lymph nodes along the left gastric artery (10.9%, 65/597). For patients with pretreatment tumor length of >4 cm and non-pathological complete response of the primary tumor, the metastatic rate of the right lower cervical paratracheal lymph nodes is 10.9% (10/92) and 10.6% (11/104), respectively. For patients with an upper thoracic tumor, metastatic lymph nodes were most frequently seen along the right recurrent nerve (14.2%, 8/56). For patients with a middle thoracic tumor, metastatic lymph nodes were most commonly seen in the right lower cervical paratracheal lymph nodes (10.3%, 8/78), paracardial lymph nodes (10.2%, 29/285), and lymph nodes along the left gastric artery (10.4%, 30/289). For patients with a lower thoracic tumor, metastatic lymph nodes were most frequently seen in the paracardial station (14.2%, 35/247) and lymph nodes along the left gastric artery (13.1%, 33/252). The study precisely determined the distribution of lymph node metastases in ESCC after neoadjuvant treatment, which may help to optimize the extent of lymphadenectomy in the surgical management of ESCC patients after neoadjuvant therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The role of surgery in oligometastatic esophageal squamous cell carcinoma (ESCC) remains controversial. This study evaluated the oncological outcomes after esophagectomy in patients with ESCC with distant lymph node (LN) metastasis. Patients with ESCC and nodal metastasis treated with chemoradiotherapy or chemotherapy followed by esophagectomy between 2010 and 2020 were included. Overall survival (OS) and recurrence-free survival (RFS) were compared between patients with distant LN metastasis (dLN+) and exclusively regional LN metastasis (dLN-). The cohort comprised 69 dLN+ and 111 dLN- patients. Survival was significantly better in the dLN- group than in the dLN+ group (5-year OS, 51.9% vs. 25.5%, P < 0.001; RFS, 47.2% vs. 18.1%, P < 0.001). Stratified by the yp stage, 49 (44.1%) dLN- and 30 (43.5%) dLN+ patients achieved a pathological complete response (pCR). In the dLN- and dLN+ groups, the OS rates were significantly higher in the pCR group than in the non-pCR group (dLN-: 76.7% vs. 32.4%, P < 0.001; dLN+: 39.6% vs. 14.2%; P = 0.002). The dLN-/pCR group had the best OS, significantly outperforming the dLN-/non-pCR and dLN+/pCR groups. OS did not differ between the dLN-/non-pCR and dLN+/pCR groups. The dLN+/non-pCR group had the worst OS. The RFS analysis paralleled the OS findings. Patients with dLN+ disease had worse outcomes than their dLN- counterparts, irrespective of the pCR status. The survival rates were poor but comparable between the dLN+/pCR and dLN-/non-pCR groups. Adjuvant therapy may be required for dLN+ patients following systemic treatment and surgery, even after achieving pCR., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although esophageal cancers invading the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic resection (ER) are associated with a risk of lymph node metastasis, details of metastatic recurrence after additional treatment remain unknown. We aimed to identify the risk factors for metastatic recurrence and recurrence patterns in patients receiving additional treatment after ER for esophageal cancer. Between 2006 and 2017, patients with pT1a-MM/pT1b-SM esophageal cancer who underwent ER with additional treatment (esophagectomy, chemoradiotherapy [CRT], and radiation therapy) at 21 institutions in Japan were enrolled. We evaluated the risk factors for metastatic recurrence after ER with additional treatment. Subsequently, the rate and pattern (locoregional or distant) of metastatic recurrence were investigated for each additional treatment. Of the 220 patients who received additional treatment, 57, 125, and 38 underwent esophagectomy, CRT, and radiation therapy, respectively. In the multivariate analysis, lymphatic invasion was the sole risk factor for metastatic recurrence after additional treatment (hazard ratio, 3.50; P = 0.029). Although the risk of metastatic recurrence with additional esophagectomy was similar to that with CRT (hazard ratio, 1.01; P = 0.986), the rate of locoregional recurrence tended to be higher with additional esophagectomy (80.0% (4/5) vs. 36.4% (4/11)), leading to a better prognosis in patients with metastatic recurrence after additional esophagectomy than CRT (survival rate, 80.0% (4/5) vs. 9.1% (1/11)). Patients with lymphatic invasion have a high risk of metastatic recurrence after ER with additional treatment for pT1a-MM/pT1b-SM esophageal cancer. Additional esophagectomy may result in a better prognosis after metastatic recurrence., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy within the digestive system, characterized by high incidence and mortality rates. The biological role of REEP5 in ESCC progression remains poorly understood, despite its associations with various diseases, potentially accelerating tumor malignancy. We retrieved RNA-seq data and clinical information from 179 ESCC patients from the Gene Expression Omnibus (GEO) and 93 patients from The Cancer Genome Atlas (TCGA) databases. Bioinformatics analyses were conducted to explore the biological functions of REEP5 in ESCC, its role in the tumor microenvironment, and its prognostic value. Additionally, utilizing single-cell RNA-seq (scRNA-seq) data from 3 ESCC patients in the GEO database, we performed cluster analyses to investigate cell-specific expression differences of REEP5 between cancerous and adjacent non-cancerous tissues. Molecular biology experiments were also conducted to validate REEP5 expression disparities between tumor and non-tumor tissues. Compared to normal tissues, REEP5 was significantly enriched in ESCC tissues. High REEP5 expression was closely associated with poor prognosis in ESCC patients. Gene Ontology (GO) analysis revealed strong correlations between REEP5 and processes such as mRNA splicing and protein stabilization. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) indicated positive correlations between REEP5 and mRNA spliceosome assembly and disassembly. Pearson correlation analysis demonstrated positive associations between REEP5 and cancer-inhibitory immune checkpoints CTLA-4, TIM-3, and HVEM. Single-cell clustering and CIBERSORT analysis showed that REEP5 expression was closely related to T-cell infiltration in ESCC, with significant enrichment effects observed in CD8+ T-cell infiltration. REEP5 expression is closely correlated with the pathological and molecular pathology of ESCC, potentially playing a crucial role in Mast cell or T-cell-mediated immune responses in ESCC. Therefore, REEP5 holds promise as a novel therapeutic target for ESCC., (© 2024. The Author(s).)

Background: Neoadjuvant chemoimmunotherapy (nCIT) for locally advanced esophageal squamous cell cancer (ESCC) has shown short-term benefits, but long-term survival outcomes are unclear. This study compares nCIT and neoadjuvant chemotherapy (nCT) in resectable ESCC., Patients and Methods: A retrospective analysis was conducted on ESCC patients who underwent nCT or nCIT followed by esophagectomy. Propensity score matching (PSM) with a caliper of 0.02 was employed to minimize bias. The primary endpoints included disease-free survival (DFS) and overall survival (OS)., Results: A total of 131 comparable pairs of ESCC patients receiving nCT and nCIT were selected for the final analysis. The nCIT had higher rates of pathological complete response (pCR) and major pathological response (mPR) compared to nCT. Additionally, nCIT led to significant tumor down-staging, higher rates of R0 resection, and increased lymph node clearance during surgery. Patients who received nCIT exhibited improved disease-free survival (DFS) and overall survival (OS) at the 3-year follow-up. The incidence of distant and mixed relapses was lower in the nCIT group compared to the nCT group. However, the risk of locoregional relapse was comparable between the two groups. Subgroup analyses showed that the benefits of nCIT were generally observed across most patient subgroups. Interestingly, in patients without pCR or mPR, nCIT still demonstrated better survival benefits than nCT., Conclusion: nCIT demonstrated superior pathological response rates and improved 3-year DFS and OS compared to nCT alone in locally advanced ESCC, but long-term survival validation is needed., (© 2024. The Author(s).)

Purpose: With relatively few direct comparisons among treatment options for previously treated advanced gastric cancer or gastroesophageal junction (GEJ) cancer, network meta-analysis (NMA) may inform evidence-based decision-making. Ramucirumab plus paclitaxel (RAM + PTX) is a preferred regimen in guideline recommendations. NMA of key outcomes may further characterize the relative clinical value of RAM + PTX., Methods: A systematic literature review of randomized controlled trials of adult patients with previously treated advanced gastric/GEJ cancer informed a NMA which compared overall survival, progression-free survival, and discontinuations due to adverse events. Comparisons were reported relative to placebo/best supportive care (BSC) when possible, otherwise relative to RAM + PTX., Results: The base-case NMA focused on second-line treatment only, from 19 of 28 studies identified. For overall survival, seven of 16 regimens were favorable relative to placebo/BSC, with RAM + PTX as the most favorable. For progression-free survival, five of 14 regimens were unfavorable relative to RAM + PTX. For discontinuations due to adverse events, two of 13 regimens were similar to placebo/BSC: ramucirumab monotherapy and fluorouracil; relative to RAM-PTX, all regimens were similar except ramucirumab monotherapy which was favorable and irinotecan + cisplatin which was unfavorable., Conclusion: This NMA of trials of previously treated gastric/GEJ cancer suggests that RAM + PTX has one of the more favorable clinical profiles., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Currently, neoadjuvant chemoimmunotherapy (NCIT) is widely used in the perioperative treatment of esophageal squamous cell carcinoma (ESCC). However, the patterns of lymph node metastasis following this novel treatment approach remain poorly understood. The aim of this study was to elucidate the distribution and frequency of postoperative lymph node metastasis (LNM) after NCIT., Methods: We retrospectively analyzed cases from March 2020 to March 2023 in our hospital and selected patients who underwent NCIT followed by R0 resection for esophageal cancer. A total of 257 patients with clinical stage T3N0 or T1-3N + thoracic esophageal cancer were included. The distribution and frequency of metastatic lesions in each lymph node station were recorded according to the Japan Esophageal Society (JES) staging system. Additionally, we analyzed the patterns of lymph node metastasis based on the location of the thoracic tumor., Results: Among the 257 patients, 110 (42.8%) had pathologically positive lymph nodes postoperatively. Common sites of lymph node metastasis included station 107 (12.8%), station 106recR (11.7%), and station 7 (12.5%). The lymph node stations with lower metastasis rates were station 105, station 106tbL, and station 111, each with a metastasis rate of 2.3%. In upper thoracic (Ut) cases, station 106recR (23.7%) was the most common site of lymph node metastasis, while in middle thoracic (Mt) cases, station 107 (16.7%) had the highest metastasis rate, and in lower thoracic (Lt) cases, station 7 (17.6%) had the highest metastasis rate. Lymph node metastasis (LNM) was more likely to occur in station 101R in Ut and Mt cases than in Lt cases (13.2% and 8.6%; p < 0.01)., Conclusions: This study reveals the frequency and distribution patterns of lymph node metastasis following NCIT, highlighting the different patterns of lymph node metastasis based on tumor location. These findings can provide guidance for lymph node dissection during surgery., (© 2024. The Author(s).)

Introduction: Cachexia is strongly associated with digestive cancers, particularly oesogastric cancer. Mitochondria in adipose tissue are involved in the regulation of metabolism and physiopathology of cancer cachexia in animal studies. Chemotherapeutic regimens used to control tumour development could also alter mitochondrial function in adipose tissue. We hypothesise that cachexia induces an increase in adipose tissue mitochondrial energy metabolism and that chemotherapy can mitigate this. The purpose of the ChiFMeOE study is to identify adipocyte factors involved in the energy imbalance associated with the cachectic process and their response to chemotherapeutic treatments in patients with oesogastric cancer., Methods and Analysis: ChiFMeOE is a single-centre observational study that will prospectively include 60 patients referred to chemotherapy and surgery for oesophageal and gastro-oesophageal junction adenocarcinomas at the University Hospital of Clermont-Ferrand, France. Visceral and subcutaneous adipose tissue biopsies will be collected during surgery scheduled before and after neoadjuvant chemotherapy administration, as well as cachexia and nutritional assessment. The primary outcome is the maximum mitochondrial respiration rate (Vmax) measured by high-resolution respirometry. Secondary outcomes are other mitochondrial parameters (ie, enzymatic activities, proteins content and gene expression), tumour characteristics, nutritional status and body composition., Ethics and Dissemination: The study was approved by an independent institutional review board on June 2023 (Comité de protection des personnes Sud-Méditerranée V; 2023-A00582-43) and declared to the French regulatory authority for research. Written informed consent will be obtained prior to patient inclusion. The principal investigator will be notified of any changes in patient's health status requiring a modification of his management and/or treatment during the course of the protocol. Results will be published in peer-reviewed journals., Trial Registration Number: ClinicalTrials.gov, NCT05954117., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Long non-coding RNAs (lncRNAs), such as SNHG6, have been identified as crucial regulators in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). Although the role of SNHG6 in ESCC is not completely understood, our findings demonstrated that SNHG6 expression is upregulated in ESCC tissues compared to adjacent normal tissues. Furthermore, elevated levels of SNHG6 are significantly correlated with higher TNM stage and poorer clinical prognosis in ESCC patients. Functionally, both in vivo and in vitro experiments have shown that knocking down SNHG6 inhibits proliferation, invasion, and metastasis. Luciferase reporter assays and Ago2-RIP assay confirm that SNHG6 functions as a competing endogenous RNA (ceRNA) by sponging miR-26b-5p to modulate ITGB1 expression in ESCC. Given that ITGB1 is instrumental in EMT and metastasis, we assessed the expression of EMT-related proteins. The findings suggest that miR-26b-5p and reduced ITGB1 expression can reverse the EMT induced by lncRNA SHNG6, as demonstrated through rescue analysis. Overall, this study aims to elucidate the molecular mechanisms through which SNHG6 promotes EMT and metastasis in ESCC, providing a novel theoretical foundation for understanding ESCC progression and identifying new targets for improving outcomes in metastatic ESCC., (© 2024. The Author(s).)

Background: Neoadjuvant chemoradiotherapy combined with immunotherapy (NICRT) is a new neoadjuvant treatment approach that has raised concerns regarding potential challenges in surgery and postoperative complications. This study aimed to compare the efficacy and safety of neoadjuvant chemoradiotherapy (NCRT) and NICRT for the treatment of resectable locally advanced esophageal squamous cell carcinoma (ESCC)., Methods: We retrospectively analyzed 291 patients with locally advanced ESCC who underwent neoadjuvant therapy and esophagectomy at three centers between January 2019 and September 2023 and added the data from PALACE-1 for the analysis, Among these patients, 248 and 61 patients received NCRT and NICRT, respectively. Propensity score matching (PSM) was used to balance the potential bias., Results: After the PSM,the rate of a pathological complete response (pCR) in the NCRT group was not significantly different from that in the NICRT group (46.90% vs 36.36%, P = 0.180). There were no significant differences in the tumor regression grade (TRG) and positive lymph node pCR rates between the two groups (P = 0.233 and P = 0.354, respectively). Treatment-related toxicities and postoperative complications were not significantly different between the NCRT group and the NICRT group (P = 0.199, P = 0.284)., Conclusion: Compared with NCRT, NICRT did not lead to the better treatment efficacy. There were no significant differences was observed in the incidence of treatment-related toxicities and postoperative complications., (© 2024. The Author(s).)

Cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment and significantly contribute to the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). Our previous study established a direct co-culture system of human bone marrow-derived mesenchymal stem cells (progenitors of CAFs) and ESCC cell lines, which facilitates the generation of CAF-like cells and enhances malignancy in ESCC cells. In this study, we further elucidated the mechanism by which CAFs promote ESCC progression using cDNA microarray analysis of monocultured ESCC cells and those co-cultured with CAFs. We observed an increase in the expression and secretion of amphiregulin (AREG) and the expression and phosphorylation of its receptor EGFR in co-cultured ESCC cells. Moreover, AREG treatment of ESCC cells enhanced their survival and migration via the EGFR-Erk/p38 MAPK signaling pathway. Immunohistochemical analysis of human ESCC tissues showed a positive correlation between the intensity of AREG expression at the tumor-invasive front and the expression level of the CAF marker FAP. Bioinformatics analysis confirmed significant upregulation of AREG in ESCC compared with normal tissues. These findings suggest that AREG plays a crucial role in CAF-mediated ESCC progression and could be a novel therapeutic target for ESCC.

Despite the success of immune checkpoint blockade (ICB) therapy for esophageal squamous cell cancer, the key immune cell populations that affect ICB efficacy remain unclear. Here, imaging mass cytometry of tumor tissues from ICB-treated patients identifies a distinct cell population of CD39 + PD-1 + CD8 + T cells, specifically the TCF1 + subset, precursor exhausted T (CD39 + Tpex) cells, which positively correlate with ICB benefit. CD39 + Tpex cells are predominantly in the stroma, while differentiated CD39 + exhausted T cells are abundantly and proximally within the parenchyma. Notably, CD39 + Tpex cells are concentrated within and around tertiary lymphoid structure (TLS). Accordingly, tumors harboring TLSs have more of these cells in tumor areas than tumors lacking TLSs, suggesting Tpex cell recruitment from TLSs to tumors. In addition, circulating CD39 + Tpex cells are also increased in responders following ICB therapy. Our findings show that this unique subpopulation of CD39 + PD-1 + CD8 + T cells is crucial for ICB benefit, and suggest a key role in TLS-mediated immune responses against tumors., (© 2024. The Author(s).)

Esophageal squamous cell carcinoma (ESCC) is highly heterogeneous. Our understanding of full molecular and immune landscape of ESCC remains limited, hindering the development of personalised therapeutic strategies. To address this, we perform genomic-transcriptomic characterizations and AI-aided histopathological image analysis of 120 Chinese ESCC patients. Here we show that ESCC can be categorized into differentiated, metabolic, immunogenic and stemness subtypes based on bulk and single-cell RNA-seq, each exhibiting specific molecular and histopathological features based on an amalgamated deep-learning model. The stemness subgroup with signature genes, such as WFDC2, SFRP1, LGR6 and VWA2, has the poorest prognosis and is associated with downregulated immune activities, a high frequency of EP300 mutation/activation, functional mutation enrichment in Wnt signalling and the highest level of intratumoural heterogeneity. The immune profiling by transcriptomics and immunohistochemistry reveals ESCC cells overexpress natural killer cell markers XCL1 and CD160 as immune evasion. Strikingly, XCL1 expression also affects the sensitivity of ESCC cells to common chemotherapy drugs. This study opens avenues for ESCC treatment and provides a valuable public resource to better understand ESCC., (© 2024. The Author(s).)

Background: To compare the performance between one-slice two-dimensional (2D) and whole-volume three-dimensional (3D) computed tomography (CT)-based radiomics models in the prediction of lymphovascular invasion (LVI) status in esophageal squamous cell carcinoma (ESCC)., Methods: Two hundred twenty-four patients with ESCC (158 LVI-absent and 66 LVI-present) were enrolled in this retrospective study. The enrolled patients were randomly split into the training and testing sets with a 7:3 ratio. The 2D and 3D radiomics features were derived from the primary tumors' 2D and 3D regions of interest (ROIs) using 1.0 mm thickness contrast-enhanced CT (CECT) images. The 2D and 3D radiomics features were screened using inter-/intra-class correlation coefficient (ICC) analysis, Wilcoxon rank-sum test, Spearman correlation test, and the least absolute shrinkage and selection operator, and the radiomics models were built by multivariate logistic stepwise regression. The performance of 2D and 3D radiomics models was assessed by the area under the receiver operating characteristic (ROC) curve. The actual clinical utility of the 2D and 3D radiomics models was evaluated by decision curve analysis (DCA)., Results: There were 753 radiomics features from 2D ROIs and 1130 radiomics features from 3D ROIs, and finally, 7 features were retained to construct 2D and 3D radiomics models, respectively. ROC analysis revealed that in both the training and testing sets, the 3D radiomics model exhibited higher AUC values than the 2D radiomics model (0.930 versus 0.852 and 0.897 versus 0.851, respectively). The 3D radiomics model showed higher accuracy than the 2D radiomics model in the training and testing sets (0.899 versus 0.728 and 0.788 versus 0.758, respectively). In addition, the 3D radiomics model has higher specificity and positive predictive value, while the 2D radiomics model has higher sensitivity and negative predictive value. The DCA indicated that the 3D radiomics model provided higher actual clinical utility regarding overall net benefit than the 2D radiomics model., Conclusions: Both 2D and 3D radiomics features can be employed as potential biomarkers to predict the LVI in ESCC. The performance of the 3D radiomics model is better than that of the 2D radiomics model for the prediction of the LVI in ESCC., (© 2024. The Author(s).)

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68 + PD-L1 + PD-1 + macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC., (© 2024. The Author(s).)

In this phase II study, 47 patients with locally advanced, resectable esophageal squamous cell carcinoma (ESCC) received three cycles of pembrolizumab plus chemotherapy, followed by Da Vinci robot-assisted surgery. The primary endpoints were safety and major pathological response (MPR). Key secondary endpoints included complete pathological response (pCR) and survival. No grade ≥3 adverse events or surgical delays occurred during neoadjuvant therapy. Among 46 patients studied for efficacy, the MPR and pCR rates were 72% and 41%, respectively. After a median follow-up of 27.2 months, the 2-year overall survival (OS) and disease-free survival (DFS) rates were 91% and 89%, respectively. Expansion of TRGC2 + NKT cells in peripheral blood correlated with neoadjuvant treatment effectiveness, which was validated by in vitro organoid experiments and external cancer datasets, and its functional classification and mechanism of action were further explored. These findings show preoperative pembrolizumab plus chemotherapy is a promising therapeutic strategy for resectable ESCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Serum fibrinogen and albumin play important roles in systemic inflammation and are implicated in tumor progression. The fibrinogen-to-albumin ratio (FAR) has shown a prognostic impact in several malignancies. This study aims to assess the prognostic value of the pretherapeutic FAR in patients with adenocarcinoma of the gastroesophageal junction (AEG) who underwent upfront resection., Methods: Consecutive patients who underwent surgical resection at the Department of Surgery at the Medical University of Vienna between 1992 and 2014 were included into this study. Optimal cut-off values were determined with the receiver-operating characteristic (ROC) curve, uni- and multivariate analyzes were calculated by the Cox proportional hazard regression model for overall survival (OS)., Results: Among 135 included patients, the majority were male (79.26%), with a mean age of 66.53 years. Elevated FAR correlated significantly (p = 0.002) with shorter OS in univariate analysis, also confirmed as independent prognostic factor (p = 0.005) in multivariable analysis. The ROC curve of FAR (AUC = 0.744) outperformed fibrinogen (AUC = 0.738) and albumin (AUC = 0.378) in predicting OS for AEG patients., Conclusion: The FAR serves as an independent prognostic factor for OS in patients undergoing primarily resection for AEG. Given its routine availability and ease of calculation, FAR could help in diagnosis and treatment selection for AEG patients. Further validation studies are warranted to confirm these findings conclusively., (© 2024. The Author(s).)