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BackgroundGenome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear.MethodsHere, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041.ResultsA two-gene (AHNAK and AHNAK2) mutation signature was identified to define the “AHNAK1/2-mutant” cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-β and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients.ConclusionOur study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.

Background Previous studies indicated that over-dissection of lymph nodes might impair the efficacy of immunotherapy. This study aims to explore the prognostic value of ypN  + status and the impact of lymph node dissection (LND) on survival after neoadjuvant immunochemotherapy (NICT) for esophageal squamous cell cancer (ESCC). Methods This double-center retrospective study enrolled 206 consecutive ESCC patients who underwent NICT followed by esophagectomy between 2018 and 2024. Overall survival (OS) and disease-free survival (DFS) were compared based on ypN / ypT status and LND count. Cutoff values for LND were determined by restricted cubic spline (RCS) analysis based on Cox regression models. Results ypN  + status was significantly associated with worse OS (3-year OS: 69.3% vs. 92.8%, p  = 0.0063) and DFS (3-year DFS: 52.4% vs. 85.3%, p  < 0.001) compared to ypN 0. Multivariate Cox analysis confirmed ypN status ( ypN 2: OS HR = 8.510, p  < 0.001; DFS HR = 8.162, p  < 0.001. ypN 3 DFS HR = 18.82, p  = 0.001) as a stronger independent prognostic factor than ypT status. RCS curves identified the cutoff values of 32 and 48 for  LND . Patients with 32 < LND ≤ 48 had the best OS and DFS. LND > 48 was associated with significantly worse OS ( p  = 0.033) and DFS ( p  = 0.025) compared to 32 < LND ≤ 48. Although not statistically significant, the LND > 48 group had higher rates of total complications (52.3% vs. 42.6%; p  = 0.330). Conclusions ypN status is a more powerful prognostic factor than ypT status in ESCC patients treated with NICT and surgery. LND exceeding 48 nodes is associated with diminished survival. An optimal LND range of 32 to 48 nodes is recommended to balance accurate staging, therapeutic benefit, and preservation of immune function.

Backgrounds While adjuvant immunotherapy (AIT) is recommended for non-pathological complete response (non-pCR) patients, its role in ypStage I esophageal cancer (EC) patients with low tumor burden remains unclear. The study aims to evaluate the necessity of AIT for esophageal cancer patients achieving ypStage I following neoadjuvant immunochemotherapy (NICT) and surgery. Methods This retrospective study analyzed 157 ypStage I (ypT0-2N0M0) EC patients treated with NICT followed by surgery in Sun Yat-sen University Cancer Center between 2019 and 2024. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) adjusted for baseline imbalances between the none adjuvant therapy (NAT, n = 121)  group and AIT (n = 36) group. Survival outcomes analyses and Cox regression analyses were performed. Results In the unmatched cohorts, 3-year overall survival (3-y OS) was 93.53% (NAT) versus 87.68% (AIT) ( p  = 0.76), and 3-year disease-free survival (3-y DFS) was 86.38% versus 84.17% ( p  = 0.60). Post-PSM (OS: 91.95% vs. 87.68%, p  = 0.81 and DFS: 88.58% vs. 84.17%, p  = 0.45) and IPTW-adjusted analyses (OS: 93.74% vs. 87.76%, p  = 0.76 and DFS: 87.96% vs. 79.08%, p  = 0.60) confirmed no survival advantage for AIT. Cox regression revealed no significant prognostic value of AIT for OS (unmatched cohorts: HR = 1.29, p  = 0.757; PSM: HR = 1.270, p  = 0.810; and IPTW: HR = 1.760, p  = 0.536) or DFS (unmatched cohorts: HR = 1.320, p  = 0.597; PSM: HR = 1.720, p  = 0.459; and IPTW: HR = 2.230, p  = 0.207). Conclusions Patients with ypStage I EC following NICT and surgery might not benefit from AIT. This study provides a hint for the risk–benefit balance of prolonged immunotherapy exposure in ypStage I patients while preserving clinical efficacy. Further studies are warranted.

ObjectiveTo evaluate the outcome following the strategy of endoscopic R0 resection (ER) plus adjuvant treatment (AT) versus esophagectomy for esophageal squamous cell cancer in T1a invading muscularis mucosa (M3)-T1b stage.MethodsWe evaluated the outcomes of 46 esophageal squamous cell cancer (ESCC) patients with T1aM3-T1b stage who underwent ER + AT from the Esophageal Cancer Endoscopic Therapy Consortium (ECETC) and compared these outcomes to 92 patients who underwent esophagectomy. Propensity score matching (1:2) was used, with overall survival (OS) and relapse-free survival (RFS) being compared between the two groups.ResultsDuring a median follow-up of 32 months, there were no statistical differences (P = 0.226) in OS between the two groups. The 1-, 2-, and 3-year overall survival in the esophagectomy group was 95%, 91%, and 84%, respectively. There were no mortalities within three years in the ER + AT group. The RFS between the two groups was also not significantly different (P = 0.938). The 1-, 2-, and 3-year RFS of patients in the esophagectomy group was 90%, 90%, and 83%, respectively, while it was 97%, 94%, and 74% in the ER + AT group, respectively. The local recurrence rates between the two groups were not significantly different (P = 0.277).ConclusionsThis first multicenter analysis showed similar outcomes were found regarding OS and RFS between the two groups in T1aM3-T1b stage patients. ER + AT may be considered in high-risk patients or for those who refuse esophagectomy.

Background Glutathione S-transferase mu 3 (GSTM3) plays a crucial role in tumor progression in various cancers. However, the relationship between GSTM3 expression and the clinical prognosis of esophageal squamous cell carcinoma (ESCC) has not been studied to date. We aimed to characterize the role of GSTM3 in predicting postoperative prognosis of ESCC patients. Methods In the retrospective study, GSTM3 mRNA levels in 184 ESCC tissues and matched 43 adjacent nontumorous tissues were measured by quantitative real-time PCR. GSTM3 protein levels in 247 ESCC tissues were measured by immunohistochemistry. Results Downregulation of GSTM3 occurred in 62.8 % of primary ESCC tissues compared with their nontumor counterparts. Patients with low GSTM3 expression tended to exhibit an increased rate of poor differentiation in both the mRNA cohort ( p  = 0.024) and protein cohort ( p  = 0.004). In the mRNA cohort, low GSTM3 expression was associated with unfavorable 3-year disease-free survival (DFS) (39.2 % vs. 57.4 %) and 5-year DFS (26.8 % vs. 45.1 %) ( p  = 0.023). The result was confirmed in the protein cohort. Patients with low GSTM3 expression had unfavorable 3-year disease-free survival (DFS) (18.7 % vs. 33.5 %) and 5-year DFS (5.3 % vs. 30.5 %) ( p  = 0.006). Cox multivariate analysis revealed that GSTM3 expression was an independent prognostic factor. Conclusions The findings of the present study provide evidence that GSTM3 may function as a tumor suppressor in ESCC and represents a potential novel prognostic biomarker for disease-free survival for resected ESCC patients.

Purpose To determine risk factors, treatment outcomes, and prognostic factors for esophageal fistula (EF) in patients with esophageal squamous cell carcinoma (ESCC) during radiotherapy. Methods Between 2010 and 2018, 109 patients with EF during radiotherapy were retrospectively collected. A controlled cohort including 416 patients who received definitive chemoradiotherapy without EF was used to compare risk factors and survival outcomes. Univariate and multivariate logistic regression analyses were performed to identify predictors of EF. Propensity score matching (PSM) was applied to adjust for potential confounding factors. Results Multivariate analysis demonstrated that sex, body mass index, alcohol history, esophageal ulceration, primary tumor length, T stage, and absolute lymphocyte count were independent risk factors for EF. After PSM, patients with EF showed remarkably worse prognosis than those without EF (median overall survival: 13.0 versus 20.5 months; P  = 0.009). For patients with EF, serum albumin level (≥ 35 g/L), subsequent radiotherapy, and fistula closure were associated with significantly prolonged survival. In addition, esophageal-mediastinum fistula and subsequent radiotherapy were positive predictors for fistula closure. Conclusions We identified risk factors for radiotherapy-related EF and its unfavorable prognosis in patients with ESCC. Of them, patients with serum albumin level of ≥ 35 g/L, subsequent radiotherapy after EF, and fistula closure had a more favorable survival.

Cigarette smoking is reported to decrease survival and induce chemotherapy resistance in patients with various cancers. However, the impact of cigarette smoking on patients with esophageal squamous cell carcinoma (ESCC) remains unknown. A total of 1,084 ESCC patients were retrospectively enrolled from a southern Chinese institution. Patients were divided into two groups according to their treatment modalities: the SC group (surgery with chemotherapy) (n = 306) and the S group (surgery without chemotherapy) (n = 778). Smoking status was quantified as smoking history (non-smoker, ex-smoker, and current smoker) and cumulative smoking (0, between 0 and 20, and greater than 20 pack-years). The association between cigarette smoking and overall survival (OS) was evaluated using the Kaplan-Meier method and univariate/multivariate regression analysis. Among 1,084 patients, 702 (64.8%) reported a cigarette smoking history, and the 5-year OS for non-smokers and smokers was 45.8% and 37.3%, respectively. In the SC group, compared with non-smoker, the adjusted HRs of ex-smoker and current smoker were 1.540 (95% CI, 1.1-2.2) and 2.110 (95% CI, 1.4-3.1), respectively; there is a correlative trend of decreased OS with increased cigarette smoking (Ptrend = 0.001). These associations were insignificant in the S group. In subgroup analysis of the SC group, the lower OS conferred by smoking was not significantly modified by age, gender, body mass index, alcohol drinking, or chemotherapy method (chemotherapy and chemoradiotherapy). Our results suggest that smoking may affect treatment outcome in patients with resected ESCC who received chemotherapy.

Alcohol is a well‐established cause of esophageal carcinoma, but its effect on survival is little known and contradictory. To clarify whether drinking is an independent predictor of survival in esophageal carcinoma, 2151 Chinese patients, receiving surgical resection from January 1997 to December 2008, were followed until March 2014. Cox proportional hazards analysis was applied to evaluate the prognostic effect of alcohol consumption. The median follow‐up was 64 months. The median overall survival (OS; 42 months) and disease‐free survival (DFS; 33 months) for never‐drinkers were significantly higher than ever‐drinkers (27 and 22 months, respectively). In the multivariate Cox model that was adjusted for age, weight loss, stage according to criteria set by the American Joint Committee on Cancer, radicality of surgery, adjuvant treatment, smoking status, and gender, the hazard ratios of ever‐drinking were 1.22 (1.06–1.41, P = 0.005) on OS, and 1.16 (1.01–1.34, P = 0.037) on DFS. The hazardous effect on OS and DFS of drinking grew statistically significantly in a dose‐dependent manner with increasing amount of alcohol consumption per day (both P‐value for trend < 0.05). The predictive effect of drinking on OS (P = 0.596) or DFS (P = 0.207) was not significant in the subgroup with esophageal adenocarcinoma (n = 195). The current study revealed that the survival is shortened, of those patients who consume alcohol before diagnosis of esophageal squamous cell carcinoma, which are not attributable to differences in stage, smoking status, and gender. Alcohol control should be emphasized to reduce mortality of esophageal carcinoma, and further outcome studies should include alcohol as a potential prognosticator. Alcohol drinking is independently associated with decreased survival in patients with esophageal squamous cell carcinoma, and the hazardous effects grew significantly with the increase of alcohol consumption amount. Nevertheless, alcohol consumption might be not a prognostic factor of patients with esophageal adenocarcinoma.

Histone deacetylase 6 (HDAC6) exerts enzymatic deacetylation activity on histones and on non-histone substrates and plays a key role in microtubule dynamics and chaperone activities. In addition, previous studies have demonstrated its role in cancer progression. However, its clinical significance in esophageal squamous cell cancer (ESCC) has not been elucidated. We investigated the correlation of HDAC6 expression and clinical outcome in a group of T3N1-3M0 surgically resected ESCCs. Tissue microarrays were conducted on 209 surgically resected T3N1-3M0 ESCC tumors, including 163 pairs of primary tumors (PTs) and their corresponding metastatic lymph nodes (MLNs). Immunohistochemistry was utilized to evaluate HDAC6 protein levels. The relationship between patient outcomes and HDAC6 expression was analyzed statistically. The level of HDAC6 expression in ESCC MLNs was found to be significantly lower than that in PTs ( <0.001). Patients with lower MLN HDAC6 expression demonstrated improved overall survival ( =0.011) and disease-free survival ( =0.012) than those with higher HDAC6 expression. HDAC6 expression levels in PTs revealed no prognostic significance. Multivariate analysis showed that the MLN HDAC6 expression level was an independent prognostic factor for both overall survival (HR 1.456, =0.029) and disease-free survival (HR 1.432, =0.033). High expression of HDAC6 in MLNs but not in PTs suggests a poor prognosis for patients with resected T3N1-3M0 ESCC. We should take into account the protein expression of MLNs when assessing prognosis in patients with lymph-node involvement.