Mapping of lymph node metastasis from esophageal squamous cell carcinoma after neoadjuvant treatment: a prospective analysis from a high-volume institution in China.

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.

Impact of deep muscle invasion on nodal status and survival in patients with pT2 esophageal squamous cancer.

BACKGROUND: Whether T2 esophageal squamous cell carcinoma should be subclassified remains controversial. We aimed to investigate the impact of the depth of muscularis propria invasion on nodal status and survival outcomes. METHODS: We identified patients with pT2 esophageal squamous cell carcinoma who underwent primary surgery from January 2009 to June 2017. Clinical data were extracted from prospectively maintained databases. Tumor muscularis propria invasion was stratified into superficial or deep. Binary logistic regression was used to determine risk factors for lymph node metastases. The impact of the depth of muscularis propria invasion on survival was investigated using Kaplan‒Meier analysis and a Cox proportional hazard regression model. RESULTS: A total of 750 patients from three institutes were investigated. The depth of muscularis propria invasion (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 2.46-6.35; p < 0.001) was correlated with lymph node metastases using logistic regression. T substage (hazard ratio [HR]: 1.37, 95% CI: 1.05-1.79; p < 0.001) and N status (HR: 1.51, 95% CI: 1.05-2.17; p < 0.001) were independent risk factors in multivariate Cox regression analysis. The deep muscle invasion was associated with worse overall survival (HR: 1.52, 95% CI: 1.19-1.94; p = 0.001) than superficial, specifically in T2N0 patients (HR: 1.38, 95% CI: 1.08-1.94; p = 0.035). CONCLUSIONS: We found that deep muscle invasion was associated with significantly worse outcomes and recommended the substaging of pT2 esophageal squamous cell carcinoma in routine pathological examination.

Increased resected lymph node stations improved survival of esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) and surgery have been recommended as the standard treatments for locally advanced esophageal squamous cell carcinoma (ESCC). In addition, nodal metastases decreased in frequency and changed in distribution after neoadjuvant therapy. This study aimed to examine the optimal strategy for lymph node dissection (LND) in patients with ESCC who underwent nCRT. METHODS: The hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were calculated using the Cox proportional hazard model. To determine the minimal number of LNDs (n-LNS) or least station of LNDs (e-LNS), the Chow test was used. RESULTS: In total, 333 patients were included. The estimated cut-off values for e-LNS and n-LNS were 9 and 15, respectively. A higher number of e-LNS was significantly associated with improved OS (HR: 0.90; 95% CI 0.84-0.97, P = 0.0075) and DFS (HR: 0.012; 95% CI: 0.84-0.98, P = 0.0074). The e-LNS was a significant prognostic factor in multivariate analyses. The local recurrence rate of 23.1% in high e-LNS is much lower than the results of low e-LNS (13.3%). Comparable morbidity was found in both the e-LNS and n-LND subgroups. CONCLUSION: This cohort study revealed an association between the extent of LND and overall survival, suggesting the therapeutic value of extended lymphadenectomy during esophagectomy. Therefore, more lymph node stations being sampled leads to higher survival rates among patients who receive nCRT, and standard lymphadenectomy of at least 9 stations is strongly recommended.

Impact of Skeletal Muscle Loss and Sarcopenia on Outcomes of Locally Advanced Esophageal Cancer during Neoadjuvant Chemoradiation.

BACKGROUND: The impact of changes in skeletal muscle and sarcopenia on outcomes during neoadjuvant chemoradiotherapy (NACR) for patients with esophageal cancer remains controversial. PATIENTS AND METHODS: We retrospectively analyzed the data of patients with locally advanced esophageal squamous cell cancer who received NACR followed by esophagectomy between June 2013 and December 2021. The images at third lumbar vertebra were analyzed to measure the cross-sectional area and calculate skeletal muscle index (SMI) before and after NACR. SMI less than 52.4 cm2/m2 for men and less than 38.5 cm2/m2 for women were defined as sarcopenia. The nonlinearity of the effect of percent changes in SMI (ΔSMI%) to survival outcomes was assessed by restricted cubic splines. RESULTS: Overall, data of 367 patients were analyzed. The survival outcomes between sarcopenia and non-sarcopenia groups had no significant differences before NACR. However, patients in post-NACR sarcopenia group showed poor overall survival (OS) benefit (P = 0.016) and poor disease-free survival (DFS) (P = 0.043). Severe postoperative complication rates were 11.9% in post-NACR sarcopenia group and 5.0% in post-NACR non-sarcopenia group (P = 0.019). There was a significant non-linear relationship between ΔSMI% and survival outcomes (P < 0.05 for non-linear). On the multivariable analysis of OS, ΔSMI% > 12% was the independent prognostic factor (HR 1.76, 95% CI 1.03-2.99, P = 0.039) and significant difference was also found on DFS analysis (P = 0.025). CONCLUSIONS: Patients with post-neoadjuvant chemoradiotherapy sarcopenia have worse survival and adverse short-term outcomes. Moreover, greater loss in SMI is associated with increased risks of death and disease progression during neoadjuvant chemoradiotherapy, with maximum impact noted with SMI loss greater than 12%.

Vitamin D receptor induces oxidative stress to promote esophageal squamous cell carcinoma proliferation via the p53 signaling pathway.

Background: Esophageal squamous cell carcinoma (ESCC) is a common pathological esophageal cancer with poor prognosis. Vitamin D deficiency reportedly occurs in ESCC patients, and this is related to single nucleotide polymorphism of vitamin D receptor (VDR). Objective: We investigated the effect of VDR on ESCC proliferation, invasion, and metastasis and its potential mechanism. Methods: ESCC and normal tissues were collected from 20 ESCC patients. The ESCC tissue microarray contained 116 pairs of ESCC and normal tissues and 73 single ESCC tissues. VDR expression and its clinicopathological role were determined by real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry staining. sh-VDR and VDR overexpression were used to validate the effect of VDR on ESCC cell phenotype, and tandem mass tag-based quantitative proteomics and bioinformatics methods identified differential VDR-related proteins. The downstream pathway and regulatory effect were analyzed using ingenuity pathway analysis (IPA). Differentially expressed proteins were verified through parallel reaction monitoring and Western blot. In vivo imaging visualized subcutaneous tumor growth following tail vein injection of VDR-deficient ESCC cells. Results: High VDR expression was observed in ESCC tissues and cells. Gender, T stage, and TNM stage were related to VDR expression, which was the independent prognostic factor related to ESCC. VDR downregulation repressed ESCC cell proliferation, invasion, and migration in vitro and subcutaneous tumor growth and lung metastases in vivo. The cell phenotype changes were reversed upon VDR upregulation, and differential proteins were mainly enriched in the p53 signaling pathway. TP53 cooperated with ABCG2, APOE, FTH1, GCLM, GPX1, HMOX1, JUN, PRDX5, and SOD2 and may activate apoptosis and inhibit oxidative stress, cell metastasis, and proliferation. TP53 was upregulated after VDR knockdown, and TP53 downregulation reversed VDR knockdown-induced cell phenotype changes. Conclusions: VDR may inhibit p53 signaling pathway activation and induce ESCC proliferation, invasion, and metastasis by activating oxidative stress.

Pararespiratory and paradigestive lymph node metastases in esophageal squamous cell carcinoma: predicting survival and refining the N staging system.

BACKGROUND: The site of lymph node metastasis (LNM) may affect the prognosis of patients with esophageal squamous cell carcinoma (ESCC). To investigate the prognoses of pararespiratory and paradigestive LNM and to propose a novel N (nN) staging system that integrates both the LNM site and count. METHODS: This study was a multicenter, large-sample, retrospective cohort study that included ESCC patients with LNM between January 2014 and December 2019 from three Chinese institutes. Patients were set into training (two institutes) and external validation (one institute) cohorts. The primary outcomes were survival differences in LNM site and the development of novel nodal staging system. The overall survival (OS) of patients with pararespiratory LNM only (Group A), paradigestive LNM only (Group B), and both sites (Group C) was evaluated by Kaplan-Meier. Cox proportional hazards models were used to identify the independent prognostic factors. An nN staging system considering both the LNM site and count was developed and evaluated by the area under the receiver operating characteristic curve (AUC). RESULTS: In total, 1313 patients were included and split into training (n = 1033) and external validation (n = 280) cohorts. There were 342 (26.0%), 568 (43.3%) and 403 (30.7%) patients in groups A, B and C, respectively. The OS of patients with pararespiratory and patients with paradigestive LNM presented significant differences in the training and validation cohorts (P < 0.050). In the training cohort, LNM site was an independent prognostic factor (hazard ratio: 1.58, 95% confidence intervals: 1.41-1.77, P < 0.001). The nN staging definition: nN1 (1-2 positive pararespiratory/paradigestive LNs), nN2 (3-6 pararespiratory LNs or 1 pararespiratory with 1paradigestive LN), nN3 (3-6 LNs with ≥ 1 paradigestive LN), nN4 (≥ 7 LNs). Subsets of patients with different nN stages showed significant differences in OS (P < 0.050). The prognostic model of the nN staging system presented higher performance in the training and validation cohorts at 3-year OS (AUC, 0.725 and 0.751, respectively) and 5-year OS (AUC, 0.740 and 0.793, respectively) than the current N staging systems. CONCLUSIONS: Compared to pararespiratory LNM, the presence of paradigestive LNM is associated with worse OS. The nN staging system revealed superior prognostic ability than current N staging systems.

Efficacy and safety of PD-1/PD-L1 inhibitor combined with chemotherapy versus chemotherapy alone in the treatment of advanced gastric or gastroesophageal junction adenocarcinoma: a systematic review and meta-analysis.

Background: There is increasing evidence that immunotherapy (programmed cell death-1 (PD-1) inhibitor) combined with chemotherapy is superior to chemotherapy alone in neoadjuvant therapy for patients with previously untreated, unresectable advanced, or metastatic esophageal adenocarcinoma (EAC)/gastric/gastroesophageal junction adenocarcinoma (GEA). However, the results of recent studies have been contradictory. Therefore, the aim of this article is to evaluate the efficacy and safety of PD-1 inhibitors combined with chemotherapy in neoadjuvant therapy through meta-analysis. Method: We comprehensively reviewed the literature and clinical randomized controlled trials (RCTs) by February 2022 by searching Medical Subject Headings (MeSH) and keywords such as "esophageal adenocarcinoma" or "immunotherapy" in several databases, including the Embase, Cochrane, PubMed, and ClinicalTrials.gov websites. Two authors independently selected studies, extracted data, and assessed the risk of bias and quality of evidence by using standardized Cochrane Methods procedures. The primary outcomes were 1-year overall survival (OS) and 1-year progression-free survival (PFS), estimated by calculating the 95% confidence interval (CI) for the combined odds ratio (OR) and hazard ratio (HR). Secondary outcomes estimated using OR were disease objective response rate (DORR) and incidence of adverse events. Results: Four RCTs with a total of 3,013 patients researching the efficacy of immunotherapy plus chemotherapy versus chemotherapy alone on gastrointestinal cancer were included in this meta-analysis. The results showed that immune checkpoint inhibitor plus chemotherapy treatment was associated with an increased risk of PFS (HR = 0.76 [95% CI: 0.70-0.83]; p < 0.001), OS (HR = 0.81 [95% CI: 0.74-0.89]; p < 0.001), and DORR (relative ratio (RR) = 1.31 [95% CI: 1.19-1.44]; p < 0.0001) when compared with chemotherapy alone in advanced, unresectable, and metastatic EAC/GEA. However, immunotherapy combined with chemotherapy increased the incidence of adverse reactions such as alanine aminotransferase elevation (OR = 1.55 [95% CI: 1.17-2.07]; p = 0.003) and palmar-plantar erythrodysesthesia (PPE) syndrome (OR = 1.30 [95% CI: 1.05-1.63]; p = 0.02). Nausea (OR = 1.24 [95% CI: 1.07-1.44]; p = 0.005) and white blood cell count decreased (OR = 1.40 [95% CI: 1.13-1.73]; p = 0.002), and so on. Fortunately, toxicities were within acceptable limits. Meanwhile, for patients with a combined positive score (CPS) ≥1, compared with chemotherapy alone, immunotherapy combined with chemotherapy had a better overall survival rate (HR = 0.81 [95% CI: 0.73-0.90]; p = 0.0001). Conclusion: Our study shows that immunotherapy plus chemotherapy has an obvious benefit for patients with previously untreated, unresectable advanced, or metastatic EAC/GEA when compared with chemotherapy alone. However, a high risk of adverse reactions may occur during immunotherapy plus chemotherapy, and more studies focusing on the treatment strategies of untreated, unresectable advanced, or metastatic EAC/GEA are warranted. Systematic review registration: www.crd.york.ac.uk, identifier CRD42022319434.

Identification of m6a-related signature genes in esophageal squamous cell carcinoma by machine learning method.

Background: We aimed to construct and validate the esophageal squamous cell carcinoma (ESCC)-related m6A regulators by means of machine leaning. Methods: We used ESCC RNA-seq data of 66 pairs of ESCC from West China Hospital of Sichuan University and the transcriptome data extracted from The Cancer Genome Atlas (TCGA)-ESCA database to find out the ESCC-related m6A regulators, during which, two machine learning approaches: RF (Random Forest) and SVM (Support Vector Machine) were employed to construct the model of ESCC-related m6A regulators. Calibration curves, clinical decision curves, and clinical impact curves (CIC) were used to evaluate the predictive ability and best-effort ability of the model. Finally, western blot and immunohistochemistry staining were used to assess the expression of prognostic ESCC-related m6A regulators. Results: 2 m6A regulators (YTHDF1 and HNRNPC) were found to be significantly increased in ESCC tissues after screening out through RF machine learning methods from our RNA-seq data and TCGA-ESCA database, respectively, and overlapping the results of the two clusters. A prognostic signature, consisting of YTHDF1 and HNRNPC, was constructed based on our RNA-seq data and validated on TCGA-ESCA database, which can serve as an independent prognostic predictor. Experimental validation including the western and immunohistochemistry staining were further successfully confirmed the results of bioinformatics analysis. Conclusion: We constructed prognostic ESCC-related m6A regulators and validated the model in clinical ESCC cohort as well as in ESCC tissues, which provides reasonable evidence and valuable resources for prognostic stratification and the study of potential targets for ESCC.

Safety and feasibility of a modularized procedure for trans-subxiphoid robotic extended thymectomy.

BACKGROUND: The purpose of this study was to introduce an "eight-step modularized procedure (M-RET)" for trans-subxiphoid robotic extended thymectomy for patients with myasthenia gravis (MG). Its safety and feasibility were further verified in this study. MATERIALS AND METHODS: This retrospective study included 87 consecutive MG patients who underwent trans-subxiphoid robotic extended thymectomy at our institution between September 2016 and August 2021. According to different resection models, patients were divided into two groups: traditional trans-subxiphoid robotic extended thymectomy group (T-RET group) and eight-step modularized technique group (M-RET group). Baseline demographic characteristics and operation-related parameters were collected and compared between the two groups. RESULTS: There were 41 (47.1%) patients in the M-RET group and 46 (52.9%) patients in the T-RET group. The M-RET group resected a greater amount of mediastinal adipose tissues and required more dissection time (median and interquartile range: 135.0, 125.0 to 164.0 v. 120.0, 105.0 to 153.8, P = 0.006) compared with the T-RET group. There were no statistically significant differences in terms of the intraoperative blood loss, duration of chest drainage, length of hospital stay, and postoperative complications between the two groups. There was no mortality or conversion in each of the two groups and all patients recovered well upon discharge. CONCLUSION: The eight-step modularized technique of trans-subxiphoid robotic extended thymectomy was verified to be a safe, effective, radical procedure, which offers unique superiority over ectopic thymic tissue resection.

Longer Time Interval from Neoadjuvant Chemoradiation to Surgery is Associated with Poor Survival for Patients Without Clinical Complete Response in Oesophageal Cancer.

BACKGROUND: The optimal interval between neoadjuvant therapy and oesophagectomy for oesophageal cancer remains controversial. METHODS: Patients with locally advanced oesophageal squamous cell carcinoma (ESCC) who received neoadjuvant chemoradiotherapy followed by oesophagectomy between June 2017 and December 2020 were prospectively enrolled and retrospectively analysed. Patients were divided into two groups: timely (group A; < 10 weeks) and delayed (group B; ≥ 10 weeks) surgery groups. Survival was the primary outcome, and tumour response and post-operative complications were the secondary outcomes. RESULTS: Overall, 224 patients were recruited; 116 patients (51.8%) underwent timely surgery within 10 weeks (group A), and 108 patients (49.2%) underwent delayed surgery over 10 weeks (group B) after chemoradiotherapy. In patients with clinical complete response (cCR), two groups had no significant difference of survival benefit (P = 0.618). However, in patients without cCR, delayed surgery was associated with poor survival (P = 0.035) and cancer progression (P = 0.036). A total of 40 patients (34.5%) in group A and 54 patients (50.0%) in group B achieved pCR (P = 0.019). pCR rates were significantly different across the four groups and increased over time (P = 0.006). CONCLUSIONS: Patients with a prolonged time interval from neoadjuvant chemoradiation to surgery had higher pCR rates. For patients with cCR to neoadjuvant chemoradiation, the time interval to surgery can be safely prolonged for at least 10 weeks. However, for patients with non-cCR to neoadjuvant chemoradiation, delayed surgery is associated with poor survival, and surgery should be performed within 10 weeks of neoadjuvant chemoradiation.

The prognostic impact of preoperative body mass index changes for patients with esophageal squamous cell carcinoma who underwent esophagectomy: A large-scale long-term follow-up cohort study.

Background: This study aims to investigate the relationship between preoperative body mass index changes (ΔBMI) and prognosis in patients with esophageal squamous cell carcinoma who underwent esophagectomy. Methods: We identified 1,883 patients with esophageal squamous cell carcinoma who underwent curative resection in our department between January 2005 and December 2013. Patients were grouped into a stable body mass index (ΔBMI = 0) group and a decreased body mass index (ΔBMI < 0) group. Risk factors for ΔBMI were assessed using logistic regression analysis. The impact of ΔBMI on survival was investigated using Kaplan-Meier curves and Cox regression. A nomogram for survival prediction was constructed and validated. Results: The results showed that T stage (OR: 1.30, 95% CI: 1.16-1.45, P < 0.001) and N stage (OR: 1.24, 95% CI: 1.11-1.38, P < 0.001) were independent risk factors for ΔBMI. The ΔBMI < 0 group had worse overall survival than the stable body mass index group (HR: 1.25, 95% CI: 1.08-1.44, P = 0.002). When stratified by stage, ΔBMI had the greatest prognostic impact in stage I tumors (HR: 1.82, 95%: 1.05-3.15, P = 0.033). In addition, multiple comparisons showed that decreasing ΔBMI correlated with worse prognosis. The ΔBMI-based nomogram presented good predictive ability with a C-index of 0.705. Conclusion: This study demonstrates that ΔBMI < 0 had an adverse impact on the long-term survival of patients with esophageal squamous cell carcinoma undergoing esophagectomy. These results may support further investigation of preoperative nutrition support.

Is Tumor Regression Grade Sufficient to Predict Survival in Esophageal Cancer with Trimodal Therapy?

BACKGROUND: This study aimed to assess the predictive value of tumor regression grade (TRG) and nodal status on survival in esophageal carcinoma with neoadjuvant chemoradiotherapy (nCRT). METHODS: Tumor pathologic regression and nodal status were assessed. Differences in survival stratified by TRG or nodal status were analyzed using the Kaplan-Meier method and log-rank test. The prognostic value of TRG and nodal status were analyzed using univariate and multivariate Cox proportional hazards methods. RESULTS: From July 2016 to June 2019, 253 patients with esophageal cancer underwent nCRT followed by surgery. Significant differences were presented in survival according to nodal status but not TRG. Multivariate analysis showed that nodal status and not TRG was the only independent predicter for overall survival (HR: 3.550, 95% CI: 2.264-5.566, P < 0.001) and disease-free survival (HR: 2.801, 95% CI: 1.874-4.187, P < 0.001). The modified TRG system combining tumor regression with nodal status stratified patients survival with good discrimination. CONCLUSIONS: Lymph node status impacts more importantly than TRG on survival for patients with esophageal cancer undergoing nCRT plus esophagectomy. The modified TRG system may facilitate postoperative treatment decisions and survival surveillance.

Effect of circumferential resection margin status on survival and recurrence in esophageal squamous cell carcinoma with neoadjuvant chemoradiotherapy.

Background: The aim of this study was to investigate whether circumferential resection margin (CRM) status has an impact on survival and recurrence in esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy. Methods: We screened patients with esophageal squamous cell carcinoma who underwent esophagectomy from January 2017 to December 2019. The CRM was reassessed. Patients were grouped into a CRM of 1 mm or less (0 < CRM ≤ 1 mm) and a CRM greater than 1 mm (CRM>1 mm). The impact of CRM on survival was investigated using Kaplan-Meier analysis and Cox regression modeling. The optimal CRM cut point was evaluated using restricted cubic spline curve. Results: A total of 89 patients were enrolled in this study. The CRM status was an independent risk factor for the prognosis (HR: 0.35, 95% CI: 0.16-0.73). Compared with a CRM of 1 mm or less, a CRM greater than 1 mm had better overall survival (HR: 0.35, 95% CI: 0.16-0.73, log-rank P = 0.011), longer disease-free survival (HR: 0.51, 95% CI: 0.27-0.95, log-rank P = 0.040), and less recurrence (HR: 0.44, 95% CI: 0.23-0.85, log-rank P = 0.015). We visualized the association between CRM and the hazard ratio of survival and identified the optimal cut point at 1 mm. Conclusions: A CRM greater than 1 mm had better survival and less recurrence compared to a CRM of 1 mm or less. A more radical resection with adequate CRM could benefit survival in patients with esophageal squamous cell carcinoma after neoadjuvant therapy.