Jing Wen

Evidence is limited on long‐term prognosis, and little is known about the immunotranscriptome in esophageal squamous cell carcinoma (ESCC) patients with different tumor regression grades (TRGs) after neoadjuvant chemoradiotherapy (NCRT) followed by surgery. Herein, the prognostic analysis of 300 ESCC patients treated with NCRT and surgery revealed that the TRG0/1 group (good responders) had significantly longer disease‐free survival (DFS) and overall survival (OS) than the TRG2/3 group. Integrating TRG and pathological N‐stage, we developed a tumor regression grade and lymph node (TRGN) staging system, which demonstrated superior prognostic stratification and distinct recurrence patterns. Transcriptome analysis showed that compared to the TRG2/3 group, the TRG0/1 group exhibited higher scores in immune checkpoint blockade (ICB) response‐related signatures, greater similarity to ICB responder samples, and increased T‐cell receptor clonality, suggesting enhanced immunotherapy sensitivity. Integrating scRNA‐seq and RNA‐seq, we identified B cell, CD8+ T cell, and NK cell subsets associated with better NCRT responses, within which a tight cell communication network potentially mediating antitumor immunity was formed. Multiplexed immunohistochemistry confirmed that the spatial relationship between CD8+ T/NK cells and tumor cells improved the NCRT response. These findings confirmed the prognostic value of TRGs and can help guide surveillance and treatment strategies in ESCC.

Microbiomes within the tumor microenvironment (TME) are intricately linked to the modulation of cancer cell properties and the prognoses of various types of cancer, including esophageal squamous cell carcinoma (ESCC). However, their contribution to the onset and advancement of ESCC is still not fully elucidated. We adopted single‐cell RNA sequencing to investigate the effects of esophageal commensal bacteria during the development of mice's spontaneous ESCCs. By analyzing the single‐cell transcriptomes of 54,562 cells across different ESCC pathological stages, commensal bacteria were observed to display a cellular heterogeneous distribution in the ESCC TME. These bacteria were associated with the malignant transformation of epithelial cells and the formation of inflammatory fibroblasts, contributing to a chronic inflammatory microenvironment. However, after depriving commensal bacteria with an antibiotic cocktail (ABX), infiltrations of inflammatory fibroblasts and anti‐bacteria macrophages were lower than those in the control H ₂ O group, while the infiltration of regulatory Cd4 ⁺ T (Treg) cells was higher. Interactions between inflammatory fibroblasts and Treg cells were intensified in the ABX group, which exacerbated the immunosuppressive state in the TME and developed more invasive carcinomas. This study demonstrates the significant role of commensal bacteria in ESCC tumorigenesis and sheds light on the potential clinical applications of adjusting commensal bacteria for the prevention and treatment of ESCC.

Background Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear. Methods Here, 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. Results A 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. Conclusion Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, the evolution of genome and immunogenome in ESCCs driven by NCRT remains incompletely elucidated. We performed whole‐exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. Clonal analysis identified clonal extinction in 13 ESCC patients wherein all pre‐NCRT clones disappeared after NCRT, and clonal persistence in 9 patients wherein clones endured following NCRT. The clone‐persistent patients showed higher pre‐NCRT genomic intratumoral heterogeneity and worse prognosis than the clone‐extinct ones. In contrast to the clone‐extinct patients, the clone‐persistent patients demonstrated a high proportion of subclonal neoantigens within pre‐treatment specimens. Transcriptome analysis revealed increased immune infiltrations and up‐regulated immune‐related pathways after NCRT, especially in the clone‐extinct patients. The number of T cell receptor–neoantigen interactions was higher in the clone‐extinct patients than in the clone‐persistent ones. The decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especially in the clone‐extinct patients. In conclusion, we identified two prognosis‐related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge of the ESCC genome and immunogenome evolutions driven by NCRT.

Background Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, evolution of genome and immunogenome in ESCCs driven by NCRT remain incompletely elucidated. Methods We performed whole-exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. Results Clonal analysis identified clonal extinction in 13 ESCC patients wherein all pre-NCRT clones disappeared after NCRT, and clonal persistence in 9 patients wherein clones endured following NCRT. Clone-persistent patients showed higher pre-NCRT genomic intratumoral heterogeneity and worse prognosis than clone-extinct ones. In contrast to clone-extinct patients, clone-persistent patients demonstrated a high proportion of subclonal neoantigens within pre-treatment specimens. Transcriptome analysis revealed increased immune infiltrations and up-regulated immune-related pathways after NCRT, especially in clone-extinct patients. The number of T cell receptor-neoantigen interactions were higher in clone-extinct patients than clone-extinct ones. Decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especifically in clone-extinct patients. Conclusions We identified two prognosis-related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge in the field of ESCC genome and immunogenome evolutions driven by NCRT.

Many controversies still exist concerning the optimal extent of lymphadenectomy during esophagectomy in esophageal squamous cell carcinoma (ESCC). The objective of this study was to explore the characteristics of 4R metastasis and evaluate the clinical value of 4R node dissection in ESCC. A total of 736 ESCC patients who underwent radical esophagectomy between 2005 and 2013 were retrospectively collected, among which 393 ones underwent 4R dissection. Propensity score matching (PSM) method was applied to reduce the effects of confounding variables between the 4R dissection and non-dissection groups to analyze overall survival. Patients showed a low 4R metastasis rate of 5.1% (20/393) (5.2%, 5.8%, and 1.8% for upper, middle, and lower tumors, respectively). Correlation analyses identified that 4R metastasis was significantly associated with station 2R metastasis (p < 0.001) and pathologic tumor-node-metastasis (pTNM) stage (p < 0.001). All 4R metastases were observed in stages IIIB and IVA. Moreover, patients with station 4R dissection failed to achieve significantly improved overall survival compared with those without 4R dissection, regardless of tumor stage (overall: p = 0.696; stage 0-IIIA: p = 0.317; stage IIIB-IVA: p = 0.619). 4R metastasis is likely to be associated with more aggressive disease, and routine 4R node dissection might not be necessary for ESCC patients.

Background: Endometrial carcinoma (EC) is the second most common gynecological malignancy, and the differences between different pathological types are not entirely clear. Here, we retrospectively collected eligible EC patients to explore their differences regarding clinical characteristics and prognosis. Methods: Five hundred seventy EC patients from the First Affiliated Hospital of Zhengzhou University were included. Prognostic factors were measured using the univariate/multivariate Cox models. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively. Results: In total, 396 patients with uterine endometrioid carcinoma (UEC), 106 patients with uterine serous carcinoma (USC), 34 patients with uterine mixed carcinoma (UMC), and 34 patients with uterine clear cell carcinoma (UCCC) were included. Comparison of baseline characteristics revealed patients diagnosed with UEC were younger, had more early clinical stage, and had lower incidence of menopause and lymph node metastasis. Compared to UEC, other pathological EC obtained more unfavorable OS (UCCC: HR = 12.944, 95%CI = 4.231–39.599, P < 0.001; USC: HR = 5.958, 95%CI = 2.404–14.765, P < 0.001; UMC: HR = 1.777, 95%CI = 0.209–15.114, P = 0.599) and PFS (UCCC: HR = 8.696, 95%CI = 1.972–38.354, P = 0.004; USC: HR = 4.131, 95%CI = 1.243–13.729, P = 0.021; UMC: HR = 5.356, 95%CI = 0.935–30.692, P = 0.060). Compared with UEC patients, the OS of UCCC patients in stage I–II and USC patients in stage III–IV were significantly worse, while UMC patients in stage I–II favored poorer PFS. The OS of UCCC patients receiving no postoperative adjuvant therapy or chemotherapy alone were significantly worse. Conclusions: The baseline characteristics of UEC and other rare EC types varied greatly, and the prognostic significance of different pathological types on EC patients depended on clinical tumor stages and therapeutic options.

Background: After radical surgery, patients with esophageal cancer should undergo long-term surveillance of disease relapse. However, the optimal follow-up strategy remains to be explored. Method: A total of 4688 patients were recruited. Recursive partition analysis was applied to develop recurrence risk stratification for patients. The follow-up strategies of each stratification were developed based on monthly recurrence probability and validated by bootstrap validation and an external dataset. A Markov decision-analytic model was constructed to evaluate the cost-effectiveness of the follow-up strategies. Results: Patients were stratified into four groups according to four pathological features. The authors applied a random survival forest to calculate the monthly recurrence probability of each group. Based on the temporal distribution of recurrences, the authors further established surveillance strategies for four groups. The strategies were validated as optimal protocols by bootstrap resampling and another dataset. Markov cost-effective analysis indicated that our recommended strategies outperformed the mainstream protocols from guidelines. Using less than 12 visits across the first 5 years on average, our follow-up strategies were more efficient than the NCCN recommended strategies (14 visits average). Our results also supported the computerized tomography from the neck to the upper abdomen as a routine examination and PETCT of distant metastasis for some groups with high risks. Conclusion: Our study provided data-driven evidence of personalized and economic follow-up strategies for esophageal cancer patients and shed light on follow-up optimization for other cancer types.

Background: The overall prognosis of primary mediastinal germ cell tumors (PMGCTs) is poor and the associated prognostic factors are not fully understood. Our goal was to investigate the prognostic factors of PMGCTs and to develop a validated prognostic prediction model. Materials and Methods: A total of 114 PMGCTs with specific pathological types were included in this study. Clinicopathological characteristics of nonseminomatous PMGCTs and mediastinal seminomas were compared using the χ ² or Fisher’s exact test. Independent prognostic factors of nonseminomatous PMGCTs screened using the univariate and multivariate Cox regression analysis were then used to generate a nomogram. The predictive performance of the nomogram was evaluated using the concordance index, decision curve, and the area under the receiver operating characteristic curve (AUC) and validated by bootstrap resampling. The Kaplan–Meier curves of independent prognostic factors were analyzed. Results: This study included 71 cases of nonseminomatous PMGCTs and 43 cases of mediastinal seminomas. The 3-year overall survival rates for nonseminomatous PMGCTs and mediastinal seminomas patients were 54.5 and 97.4%, respectively. The overall survival prognostic nomogram for nonseminomatous PMGCTs was established by integrating independent prognostic factors, including the Moran-Suster stage, white blood cell, hemoglobin, and platelet-lymphocyte ratio. The nomogram demonstrated good performance with a concordance index of 0.760 and the 1-year and 3-year AUC values of 0.821 and 0.833, respectively. These values were better than those of the Moran-Suster stage system. The bootstrap validation had an AUC of 0.820 (0.724–0.915) and showed a well-fitting calibration curve. Besides, patients with mediastinal seminomas showed favorable clinical outcomes and all the nine patients received neoadjuvant therapy and postoperative surgery achieved pathological complete response. Conclusion: A nomogram based on staging and blood routine examination results was established to accurately and consistently predict the prognosis of patients with nonseminomatous PMGCTs.