Abstract Topic Esophageal Cancer: Surgical Treatment of Esophageal Cancer – long term outcomes Background Given the limited integration of nodal count and spatial distribution in current esophageal cancer N staging, we sought to develop and validate a newN staging system that incorporates both dimensions. Methods We used prospectively maintained, retrospective databases from three centers (2008–2022). The primary endpoint was overall survival (OS). We constructed a Target–Ring Burden framework by computing Spearman correlations from station-involvement proportions across primary-tumor locations, mapping stations via multidimensional scaling to a 0–5 radial distance, then discretizing this distance into rings 0–3 and flagging cross-compartment spread (cervical, thoracic, abdominal). At the patient level, nodal burden, maximal ring distance, and cross-compartment indicators were aggregated; a Cox model generated a risk score, and survival-driven cut points were applied to classify N+ cases into newN (N1–N3; N0 defined as no nodal metastasis). Discrimination was evaluated using Kaplan–Meier with log-rank, Cox, and time-dependent ROC at 12/36/60 months. Results We analyzed 5,261 consecutive patients. Overall distribution was N0 2,976 (56.6%); by AJCC, N1 1,418 (27.0%), N2 688 (13.1%), N3 179 (3.4%); by newN, N1 1,338 (25.4%), N2 596 (11.3%), N3 351 (6.7%). Regarding risk gradients (multivariable Cox, vs N0), hazard ratios for AJCC N1/N2/N3 were 1.52/2.05/1.90, whereas for newN they were 1.50/1.93/2.25 (all P <0.05), showing a more orderly stepwise pattern with a more pronounced highest-risk group. In multivariable Cox models restricted to N+ patients, time-dependent AUC at 12/36/60 months were 0.642/0.681/0.698 for AJCC and 0.652/0.690/0.708 for newN. Conclusion In this multicenter cohort, the newN staging that integrates nodal count and spatial spread outperformed the current N staging, with clearer survival gradients and higher time-dependent AUC at 12/36/60 months. It also identified poorer-prognosis subgroups within current N1–N2, supporting incorporation of both nodal burden and anatomic/cross-compartment information into clinical stratification and postoperative decision-making.

Supplementary Table S1. RATIONALE-213 ethics approval. Supplementary Table S2. Representativeness of study participants. Supplementary Table S3. Summary of treatment exposure to tislelizumab. Supplementary Table S4. Summary of treatment exposure to chemotherapy. Supplementary Table S5. Summary of treatment exposure to radiotherapy. Supplementary Table S6. Baseline characteristics of surgical and nonsurgical patients by PET response status. Supplementary Table S7. Summary of surgery (safety analysis set). Supplementary Table S8. Subgroup analyses of pathological response by baseline clinical characteristics. Supplementary Table S9. Analysis of pathological response assessed by local pathologist by baseline PD-L1 status (efficacy-evaluable analysis set). Supplementary Table S10. Analysis of disease response by investigator per RECIST v1.1 (safety analysis set with measurable disease at baseline). Supplementary Table S11. Disease recurrence by PET response status. Supplementary Table S12. TRAEs with ≥10% incidence (safety analysis set). Supplementary Table S13. Summary of surgery-relevant adverse events (efficacy-evaluable analysis set). Supplementary Table S14. Summary of all deaths (safety analysis set). Supplementary Table S15. Baseline demographic and clinical characteristics (efficacy- and GEP-evaluable populations).

OBJECTIVES:The role of adjuvant therapy in ypT0-2N0M0 oesophageal squamous cell carcinoma (OSCC) remains controversial. This study aimed to assess the impact of adjuvant therapy on overall survival (OS) and disease-free survival (DFS) and to develop prognostic nomogram models. METHODS:Patients with ypT0-2N0M0 followed by radical oesophagectomy between 2011 and 2024 were reviewed. Propensity score matching (PSM) was applied to adjust for baseline imbalances between treatment groups. OS and DFS were estimated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model, and nomogram models were developed. RESULTS:A total of 363 patients were enrolled in the study, of whom 67 received adjuvant therapy. Patients who received adjuvant therapy had significantly poorer OS and DFS compared with those who did not, both before and after PSM (P < .05). Multivariate analyses identified adjuvant therapy as an independent adverse prognostic factor for OS and DFS (P < .05). The nomogram demonstrated good discrimination for OS, with time-dependent areas under the receiver operating characteristic curve (AUCs) of 0.729 (95% CI, 0.623-0.835) and 0.716 (95% CI, 0.642-0.790) at 1 and 3 years, respectively, and acceptable discrimination for DFS, with corresponding AUCs of 0.673 (95% CI, 0.596-0.751) and 0.659 (95% CI, 0.589-0.728). CONCLUSIONS:In patients with ypT0-2N0M0 OSCC, adjuvant therapy may not be associated with improved OS or DFS. The developed nomogram models demonstrated good performance in predicting individualized OS and DFS.

Background Extralobar pulmonary sequestration is a rare congenital malformation characterized by nonfunctional lung tissue lacking communication with the tracheobronchial tree and receiving systemic arterial supply. Because of its unusual location and nonspecific imaging appearance, it may occasionally mimic a mediastinal tumor. Case presentation A 66-year-old woman was referred after an asymptomatic left lower thoracic mass was incidentally detected during routine screening. Contrast-enhanced computed tomography revealed a 3.3 × 2.5 cm paravertebral soft-tissue lesion located near the left cardiophrenic angle adjacent to the descending thoracic aorta. Three-dimensional computed tomographic angiography demonstrated an aberrant systemic feeding artery originating from the descending thoracic aorta and venous drainage into a branch of the azygos vein. Uniportal video-assisted thoracoscopic surgery was performed. Intraoperatively, the lesion was identified in the para-aortic region and was completely separated from the normal lung parenchyma. The aberrant feeding artery and draining vein were divided using an endoscopic stapling device, and the lesion was completely resected. Histopathological examination confirmed extralobar pulmonary sequestration. The postoperative course was uneventful, and the patient remained asymptomatic at 6-month follow-up. Conclusions Para-aortic extralobar pulmonary sequestration is rare and may mimic a posterior mediastinal tumor. Preoperative three-dimensional computed tomographic angiography is essential for identifying aberrant systemic vessels and facilitating safe thoracoscopic resection.

The clinical efficacy of immunotherapy in advanced esophageal squamous cell carcinoma (ESCC) remains suboptimal, as most patients eventually develop drug resistance and experience disease progression. Here, we identify Collagen Triple Helix Repeat Containing 1 (CTHRC1) as a critical mediator of immunotherapy resistance in ESCC. Elevated CTHRC1 expression was observed in tumors unresponsive to immune checkpoint blockade and was associated with enhanced platelet activity and infiltration of megakaryocytes (MKs) into the tumor microenvironment. Mechanistically, CTHRC1 facilitated MK activation and recruitment, fostering an immunosuppressive niche that impaired cytotoxic T-cell activity and promoted cell exhaustion. To therapeutically target this axis, we developed a lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding CTHRC1. In preclinical ESCC models, the CTHRC1-mRNA-LNP vaccine elicited robust antitumor immunity. Notably, the combination of CTHRC1-mRNA vaccination with anti–PD-1 therapy induced synergistic intratumoral T-cell infiltration, depletion of MKs, reversal of immunosuppression, and durable tumor regression. Collectively, these findings uncover an unrecognized immunoregulatory function of CTHRC1 in ESCC and highlight its therapeutic targeting as a promising strategy to enhance the efficacy of immune checkpoint blockade. CTHRC1 directly engages integrin αIIbβ3 and to drive megakaryocyte and activates the TLR4–NF-κB-IL-8 axis to promote megakaryocyte/platelet infiltration, promoting an immunosuppressive ESCC TME and T-cell dysfunction. Administration of a CTHRC1 mRNA–LNP vaccine elicits potent antigen-specific humoral and cellular immunity, dismantles megakaryocyte-mediated immune exclusion, converts a cold TME into an inflamed state, and restores sensitivity to PD-1 blockade.

Background:Gustave Roussy Immune Score (GRIm-Score), a new prognostic index based on nutritional and inflammatory status, acts as an adverse prognostic factor in patients diagnosed with esophageal cancer (EC). However, the clinical prognostic significance of the GRIm-Score in these patients after receiving neoadjuvant chemoradiotherapy (nCRT) remains unclear. The aim of the study was to evaluate the prognostic value of GRIm-Score in patients with EC following nCRT. Methods:A retrospective study was conducted involving 432 patients with EC who had undergone surgical resection. The GRIm-Score of each enrolled patient was calculated on the basis of three key parameters: lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR), and albumin (ALB). Overall survival (OS) and disease-free survival (DFS) were set as the primary study endpoints, which were analyzed utilizing Cox proportional hazards regression analysis, the Kaplan-Meier method, and propensity score matching (PSM). Results:The study cohort comprised 359 male patients (83.1%) and 73 female patients (16.9%), with a mean age of 62.1±7.7 years and an age range of 39 to 80 years. Following the implementation of PSM, the matched research cohort was divided into a high GRIm-Score group and a low GRIm-Score group, with 55 patients in each group respectively. Patients with a high GRIm-Score exhibited inferior OS (cohort: P<0.001; PSM: P=0.009) and DFS (cohort: P<0.001; PSM: P=0.01). Before PSM, the GRIm-Score was confirmed as an independent prognostic factor for OS (P=0.02) in multivariate regression analyses, while none of the individual indicators of NLR, LDH, and ALB exhibited such prognostic significance. However, after PSM, the GRIm-Score acted as a powerful independent prognostic factor for both OS (P=0.03) and DFS (P=0.04) in these multivariate analyses. Further subgroup analyses demonstrated that the GRIm-Score could effectively identify pT3-4 stage EC patients with inferior OS or DFS, which suggests that the GRIm-Score plays a complementary role in the clinical decision-making for adjuvant therapy in EC patients. Conclusions:In patients with EC who underwent nCRT followed by surgical resection, the GRIm-Score was verified as an independent prognostic factor. Additionally, this study constitutes the first investigation to elucidate the prognostic significance of the GRIm-Score in EC patients after receiving nCRT.

BACKGROUND:Lymph node metastasis is a crucial factor in predicting the prognosis of patients with pathologic T1-2 esophageal squamous cell carcinoma, but the optimal extent of lymphadenectomy remains unclear. This study aims to determine the prognostic significance of high-risk lymph node stations and identify risk factors for high-risk lymph node station involvement. METHODS:Patients with pathologic T1-2 esophageal squamous cell carcinoma who underwent esophagectomy with lymph node dissection were enrolled between January 2014 and December 2019. The incidence of metastasis at each regional lymph node station was assessed, and the efficacy index was calculated to evaluate the therapeutic value of dissection. RESULTS:In total, 695 patients with T1-2 esophageal squamous cell carcinoma were included. Lymph node stations 2, 7, 8, 16, and 17 were defined as high-risk stations, with metastasis rates of 6.47%, 4.17%, 11.37%, 5.90%, and 7.34%, respectively, which were greater than those of the other stations. Patients with high-risk lymph node station metastasis exhibited elevated efficacy index values (1.67-5.44) and significantly worse overall survival (P < .001). High-risk lymph node station metastasis was an independent prognostic factor (hazard ratio, 1.986; 95% confidence interval, 1.452-2.716, P < .001). Logistic regression identified body mass index, tumor differentiation, tumor size, and tumor location as independent risk factors for high-risk lymph node station involvement. CONCLUSION:Lymph node stations 2, 7, 8, 16, and 17 were high-risk stations associated with poor prognosis and high therapeutic value. Identification of these high-risk lymph node stations may guide a more tailored lymphadenectomy strategy in patients with T1-2 esophageal squamous cell carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies with high morbidity and mortality. Exploring the molecular pathogenesis of ESCC is of pivotal importance to improve patients' prognosis. Lactate-mediated lysine lactylation (Kla) is a novel post-translational modification and critical for cancer progression. However, the role and mechanism of Kla in ESCC metastasis are poorly defined. Methods: A comparative lactylome analysis was carried out to assess proteins with significantly different lactylation between ESCC patients with and without lymph node metastasis (LNM). Furthermore, key findings of liquid chromatography-tandem mass spectrometry (LC-MS/MS) were verified using ESCC cell lines and primary ESCC specimens. Results: Global lactylome profiling revealed that many proteins were lactylated in ESCC samples. Substantial upregulation of Kla was observed in ESCC tissues with LNM compared to tissues without LNM. Forty-eight Kla sites in 29 proteins were substantially downregulated, whereas 91 Kla sites in 60 proteins were markedly upregulated in ESCC tissues with LNM compared to tissues without LNM. It was observed that about 46.07% of the differentially expressed lactylated proteins were localized in the cytoplasm, indicating that many non-histone proteins were lactylated in ESCC samples and Kla involvement in ESCC metastasis via multiple tumorigenic processes. We verified that the enolase 1 (ENO1) protein's Kla level in ESCC cells was positively correlated with cell migration ability. Using tyramide signal amplification (TSA) multiplex immunofluorescence staining, it was demonstrated that ESCC-LNM tissues had higher ENO1 Kla levels than ESCC-non-LNM tissues. Conclusions: The study found a positive correlation between Kla and ESCC metastasis. Furthermore, ENO1-Kla potentially promotes esophageal cancer (EC) metastasis and it may be a promising treatment target and a predictive biomarker of ESCC metastasis.

Siewert type II adenocarcinoma of the esophagogastric junction (AEG) is characterized by complex, bidirectional lymph node metastasis. This retrospective study evaluates recurrence and mortality risks associated with varying extents of mediastinal lymph node dissection. A retrospective analysis was conducted on 221 Siewert type II AEG patients who underwent radical surgery (McKeown or Left Thoracotomy [LT] approach) between June 2016 and October 2023. Patients were grouped according to the extent of lymphadenectomy: complete mediastinal and abdominal lymph node dissection (CMAD) or middle/lower mediastinal and abdominal lymph node dissection (MLMAD). To ensure comparability, patients in the CMAD group were matched 1:1 with those in the MLMAD group using propensity score matching (PSM). Prognostic outcomes were analyzed using Kaplan–Meier curves, and Cox regression analysis was performed to identify risk factors. CMAD was associated with significantly improved overall survival (OS) (HR = 0.37, 95

Supplementary Figure S4. Kaplan–Meier plot of OS (safety analysis set).

Esophageal leiomyoma, the most common benign esophageal tumor, has transitioned from invasive thoracotomy to minimally invasive techniques. Endoscopic mucosal resection (EMR) for small tumors, thoracoscopic/laparoscopic approaches for larger lesions, and Robotic-assisted techniques have shown promising preliminary results in selected case series, with early evidence suggesting potential benefits in reducing postoperative morbidity and hospitalization; however, these findings require validation through larger prospective studies. The data sources of this review included multicenter findings for EMR, endoscopic submucosal dissection (ESD), submucosal tunneling endoscopic resection (STER), and robotic techniques. The review also highlights clinical innovations, including carbon dioxide (CO₂) insufflation to reduce the risk of mediastinal emphysema, intraoperative endoscopy to prevent esophageal leakage or mucosal injury during enucleation, and postoperative enhanced recovery (ERAS) protocols to shorten hospital stays. We emphasize tailored approaches based on tumor characteristics, with dynamic growth monitoring for asymptomatic lesions. By integrating novel decision algorithms, this review presents a practical management framework for the evolving therapeutic landscape. This review further provides a novel evidence-based decision algorithm that integrates tumor size, morphology, growth dynamics, and anatomical location, alongside a GRADE-informed assessment of evidence quality across techniques. We critically compare the latest 2024–2025 evidence, including the largest robotic series to date and multi-center endoscopic cohorts, to identify key knowledge gaps—particularly the paucity of long-term comparative data and cost-effectiveness analyses—thereby guiding future research priorities and refining personalized surgical selection.

Supplementary Figure S5. Comparison of immune-related and tumor-intrinsic signatures at baseline between PET responders and PET nonresponders (A) and indicated signatures between patients with and without pathological response in (B, C) PET responders and (D, E) PET nonresponders.

Supplementary Figure S2. Distribution of residual viable tumor percentages in non-pCR patients by PET response status

OBJECTIVE:Pathologic complete response (pCR) after neoadjuvant therapy predicts favorable outcomes in esophageal squamous cell carcinoma (ESCC). In this era of neoadjuvant immunochemotherapy (nICT), the prognosis of patients achieving nICT-induced pCR remains unclear. This study aimed to characterize recurrence patterns and identify prognostic factors in this population. METHODS:A multicenter retrospective cohort study was conducted across 26 Chinese centers from 2019 to 2023. Patients with ESCC who underwent surgery after nICT and achieved pCR were included. Prognostic factors for recurrence-free survival (RFS) and overall survival (OS) were evaluated using Cox regression analysis. RESULTS:Among 2135 patients receiving nICT, 474 (22.2%) achieved pCR. After a median follow-up of 32.8 months, 60 patients (12.7%) experienced recurrence, with a median interval of 17.8 months (interquartile range, 8.7-26.7) after surgery. Most recurrences (75%) occurred within 2 years, predominantly as distant metastases (63.3%), with the lung being the most common site. The 2-year RFS and OS were 89.6% and 92.1%, respectively. Advanced clinical nodal stage (cN2-3) was identified as an independent prognostic factor for inferior RFS (adjusted hazard ratio, 1.83; 95% CI, 1.10-3.05; P = .02) but not OS, whereas adjuvant treatment was not associated with improved survival (adjusted hazard ratio, 1.29; 95% CI, 0.69-2.42; P = .42). CONCLUSIONS:Patients with ESCC achieving pCR after nICT exhibited excellent short-term survival but a persistent risk of distant recurrence. Advanced clinical nodal stage is associated with higher recurrence risk, which warrants further validation. Risk-adapted postoperative management may be preferable to routine adjuvant treatment.