Impact of weekday of esophageal cancer surgery on long-term oncological outcomes.

BACKGROUND: Studies about the influence of weekday of esophagectomy on survival are limited and show conflicting results. This study aimed to explore whether weekday of esophagectomy affects patient's survival outcomes. METHODS: Patients who underwent esophagectomy in a grade-A tertiary hospital from January 2015 to December 2016 were enrolled. The primary outcome was 5-year overall survival (OS). The secondary outcomes were 5-year disease-free survival (DFS) and days of hospitalization. The impact of weekday surgery on 5-year OS and DFS were evaluated with Cox regression, and impact on days of hospitalization was assessed using logistic regression. Propensity score matching (PSM) analysis was used to balance the confounding factors. RESULTS: A total of 1478 patients were included. The 5-year OS and DFS were 63.77% and 59.26% respectively. Multivariate analyses adjusted for covariables indicated that weekday was not significantly associated with OS (P = 0.076), nor days of hospitalization (P = 0.824), but it appeared to be associated with DFS (P = 0.044). Additionally, PSM analysis showed no significant effect of weekday on the 5-year OS, nor DFS and days of hospitalization. CONCLUSION: In patients diagnosed with squamous esophageal cancer, the survival outcome of patients was not influenced by weekday.

Neoadjuvant Chemotherapy or Adjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma.

BACKGROUND: Chemotherapy and chemoradiation have become essential adjuncts to improve the survival of patients with resectable esophageal squamous cell carcinoma (ESCC) in the perioperative period. Although preoperative treatment plus surgery is commonly used, controversy remains regarding the optimal treatment strategy for patients with locally advanced ESCC. METHODS: A retrospective review of clinical stage II and III ESCC patients who underwent esophagectomy at Henan Cancer Hospital between October 2014 and October 2017 was performed. The patients were divided into a neoadjuvant chemotherapy (NAC) group and an adjuvant chemotherapy (AC) group. Propensity score matching (PSM) was used to exclude confounders. Survival was estimated using Kaplan‒Meier analysis and compared by the log-rank test. The Cox proportional hazards regression model was used for both the univariate and multivariate analyses. RESULTS: A total of 684 patients were enrolled, including 365 (53.4%) patients in the NAC group. After PSM, 294 pairs of patients were left. NAC prolonged the OS (not reached versus 57.3 months, P = 0.002) and DFS (57.2 vs. 36.4 months, P = 0.010) and decreased the total rate of recurrence (50.1% vs. 59.2%, P = 0.025) and local recurrence (27.9% vs. 36.7%, P = 0.022) compared with AC. The multivariable analyses showed that NAC plus surgery modality was an independent predictor for improved OS (HR: 0.582, 95% CI: 0.467-0.786, P = 0.001). CONCLUSION: NAC plus surgery prolonged OS and DFS, and significantly decreased the total rate of recurrence compared with surgery plus AC in patients with clinical stage II and III ESCC.

A multicenter randomized, controlled clinical trial of adjuvant sintilimab for esophageal squamous cell carcinoma.

No adjuvant treatment has been established for patients who remain at high risk of recurrence and incidental pathologic lymph node metastasis for esophageal squamous cell carcinoma (ESCC). In this open-label, multicenter, phase III, randomized controlled trial, ESCC patients who did not achieve pathologic complete response after neoadjuvant chemotherapy plus surgery and clinical T1-2 N0 patients with incidental pathologic lymph node metastasis following initial surgery were randomized at a 2:1 ratio to receive either a sintilimab regimen or observational management (NCT05495152). The primary end point was disease-free survival for all randomized patients. The results of this randomized controlled trial addressed controversy regarding the survival benefits of adjuvant sintilimab treatment for patients with resected locally advanced ESCC. Clinical Trial Registration: NCT05495152 (ClinicalTrials.gov).

Patterns and Influence of Lymph Nodal Metastases After Neoadjuvant Chemotherapy and Surgery for Thoracic Esophageal Squamous Cell Carcinoma.

PURPOSE: The purpose of this retrospective study was to define the pattern of lymph nodal metastases in patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemotherapy (NCT) followed by esophagectomy and to evaluate its influence on prognosis. METHODS: A total of 398 patients with clinical stage T3N0 or T1-3N+ ESCC who underwent NCT and radical esophagectomy with two-field lymphadenectomy were included. The distribution and frequency of metastases were counted separately for each lymph node station. The ypN stage, number of positive lymph node stations and lymph node stations with a metastasis rate greater than 5% were analyzed by using univariate Cox regression, followed by separate multivariable Cox regression analyses after adjusting for various clinical factors. RESULTS: Lymph node metastases were most frequently observed in the right upper paratracheal (16.8%) and left gastric artery (13.1%) stations. Multivariable models controlling for clinical factors showed that ypN stage remained a significant independent predictor of survival (N1 vs. N0: hazard ratio [HR], 2.30, 95% confidence interval [CI] 1.38-3.83, P < 0.001; N2 vs. N0: HR, 3.76, 95% CI 2.21-6.38, P < 0.001; N3 vs. N0: HR, 7.14, 95% CI 3.78-13.48, P < 0.001). The model from the multivariable analysis with the highest c-index score, indicating superior discriminatory preference, was ypN stage (c-index, 0.72). CONCLUSIONS: The pattern and influence of lymph node metastases after NCT will provide guidance on the extent of lymphadenectomy. Common positive lymph node stations for thoracic ESCC after NCT include the paratracheal, subcarinal, paraesophageal, paracardial, and left gastric artery stations.

Treatment outcomes of surgery and chemotherapy for pulmonary metastases from non-lung cancers: a propensity score-matched analysis.

Background: The optimal treatment for pulmonary metastases has not been determined, and the survival benefit of surgical resection in selected patients remains controversial. The purpose of this retrospective study was to explore whether surgery can prolong survival in patients with pulmonary metastases compared with chemotherapy, and to analyze the factors that may affect the long-term survival of patients with pulmonary metastases. Methods: We retrospectively analyzed the medical records of patients with pulmonary metastases from June 2012 to June 2019. Propensity score matching (PSM) was used to balance factors that might affect survival between the two groups. The data were analyzed by Kaplan-Meier survival analysis and Cox proportional hazards models to compare the survival of the surgery group and the chemotherapy group. Results: A total of 202 patients with pulmonary metastases were enrolled in the study, with 43 patients in the surgery group and 43 in the chemotherapy group after screening and PSM. After PSM, patients in the surgery group had better survival than those in the chemotherapy group, with 5-year overall survival (OS) rates of 75.1% and 48.0%, respectively (P=0.017). Univariate analysis of the two groups of patients found that the treatment method, the number of metastases, and the total diameter of metastases were prognostic factors, but multivariate analysis did not find independent prognostic factors. In the surgical group, univariate analysis found that disease-free interval (DFI), the number of metastases, surgical methods, resection scope and surgical route were prognostic factors, and multivariate analysis showed that only DFI was an independent prognostic factor. In the chemotherapy group, DFI and the response of metastases to chemotherapy were found to be prognostic factors in univariate analysis, but no independent prognostic factors were found in multivariate analysis. Conclusions: Surgery does not provide a significant survival advantage. For patients undergoing surgery, longer DFI predicts better survival.

Left compared with right thoracic approach thoracotomy in esophageal cancer: a retrospective cohort study.

BACKGROUND: Esophagectomy is regarded as one of the optimal treatments for resectable esophageal cancer. However, the impact of surgical approach on the long-term prognosis of esophageal cancer remains controversial. This study attempted to compare the long-term survival outcomes of patients receiving left and right thoracic esophagectomy for esophageal cancer. METHODS: A total of 985 patients underwent esophagectomy (including 453 left and 532 right thoracic approach) for esophageal cancer in Henan Cancer Hospital from January 2015 to December 2016 were enrolled. Their 5 year overall survival (OS) and disease-free survival (DFS) were retrospectively collected. Cox regression was performed to compare OS and DFS in patients who underwent left and right thoracic esophagectomy. Propensity score matching (PSM) analysis was used to balance confounding factors. RESULTS: The 5 year OS rates were 60.21% in the left and 51.60% in the right thoracic esophagectomy, respectively (P = 0.67). The 5 year DFS rates were 56.73% in the left and 47.93% and in the right thoracic esophagectomy, respectively (P = 0.36). Cox regression analysis showed there was no significant difference in long-term survival between patients with left and right surgical access (OS: HR = 0.95, 95% CI 0.77-1.18; DFS: HR = 0.91, 95% CI 0.74-1.12). In the cohort of patients obtained by PSM, Cox regression analysis yielded the similar results. CONCLUSION: For patients with resectable esophageal cancer, the surgical treatment through left thoracic approach can achieve the same long-term survival outcomes as the right thoracic approach.

Initial experience with modified en bloc robot-assisted minimally invasive oesophagectomy for thoracic oesophageal squamous cell carcinoma.

BACKGROUND: The feasibility and safety of en bloc robot-assisted minimally invasive oesophagectomy (RAMIE) need to be verified. METHODS: Forty-seven patients who received conventional RAMIE and 31 who received modified en bloc RAMIE at Henan Cancer Hospital were included in the study cohort. We compared the perioperative outcomes of conventional RAMIE and modified en bloc RAMIE. RESULTS: Compared with the conventional RAMIE group, the en bloc RAMIE group yielded a higher total number of lymph nodes (p = 0.001), especially thoracic lymph nodes (p = 0.025) and left recurrent laryngeal nerve (RLN) lymph nodes (p = 0.005). No notable differences were found in the rate of total complications (p = 0.663) or RLN injury (p = 0.891) between the two groups. The preoperative and postoperative serological indicators were comparable between the two groups. CONCLUSIONS: Modified en bloc RAMIE was safe and feasible for patients with oesophageal squamous cell carcinoma and improved lymph node dissection, especially thoracic and left RLN lymph node dissection.

Survival impact of the number of lymph nodes dissection in patients receiving neoadjuvant chemotherapy for esophageal squamous cell carcinoma.

This study aimed to investigate the survival impact of the number of lymph nodes dissection (LND) in patients receiving neoadjuvant chemotherapy (NCT) for esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed the clinical pathological data and survival of 407 ESCC patients who underwent esophagectomy after NCT between January 2015 and December 2016. The relationship between the number of LNDs and 5-year overall survival (OS) or disease-free survival (DFS) was plotted by using restricted cubic spline analysis. A Cox proportional hazards regression model was used to identify prognostic factors of OS and DFS. We observed an obvious non-linear relationship between LND and the hazard ratios (HRs) for OS (P = 0.0015) and DFS (P < 0.001) of all the patients. In the multivariate analysis of OS and DFS, the number of LNDs (greater than 28 and less than 46) had a significant protective effect on survival (OS: HR: 0.61, 95% CI: 0.42-0.88, P = 0.007; DFS: HR: 0.50, 95% CI: 0.36-0.70, P < 0.001). For patients with nodal metastases, it was also an independent prognostic factor for OS (HR, 0.56, 95% CI, 0.35-0.90, P = 0.017) and DFS (HR, 0.42, 95% CI, 0.28-0.65, P < 0.001). Some degree of lymphadenectomy after NCT was beneficial in improving 5-year OS and DFS for ESCC patients with nodal metastases. For patients with nodal negativity, more extended lymphadenectomy did not improve patient survival.

Perioperative Outcomes and Learning Curve of Robot-Assisted McKeown Esophagectomy.

BACKGROUND: This study aimed to evaluate the perioperative outcomes of patients undergoing robot-assisted McKeown esophagectomy (RAME) and the learning curves of surgeons performing RAME at a single center. METHODS: Perioperative outcomes of RAME and video-assisted McKeown esophagectomy (VAME) were compared after eliminating confounding factors by propensity score matching (PSM). The cumulative sum (CUSUM) method was used to evaluate the learning curves of RAME for a single surgical team. RESULTS: In general, a total of 198 patients with esophageal cancer (RAME: 45 patients, VAME: 153 patients) were included in this study, and 43 pairs of patients receiving RAME or VAME were matched using 1:1 PSM analysis. Those in the RAME group had more lymph nodes dissected in the total lymph nodes (median 29.0 vs. 26.0, P = 0.011) and the upper mediastinum (median 8.0 vs. 6.0, P < 0.001), especially the left recurrent laryngeal nerve (RLN) lymph node (median 4.0 vs. 2.0, P = 0.001). According to the trend of the CUSUM plot, the learning curve was divided into two stages at the 20th RAME procedure. After mastering the learning curve, RAME harvested a significantly higher number of upper mediastinal lymph nodes (median 9.0 vs. 6.0, P = 0.001), left RLN lymph nodes (median 5.0 vs. 3.5, P = 0.003), and right RLN lymph nodes (median 4.0 vs. 2.0, P = 0.002). Meanwhile, the incidence of postoperative pneumonia in the proficiency phase was significantly lower than that in the learning phase (4.0% vs. 25.0%, P = 0.04). CONCLUSIONS: RAME improved left RLN lymph node dissection. Surgeons with extensive VAME experience need at least 20 cases to achieve early proficiency in RAME.

ß-Carboline Alkaloids From the Deep-Sea Fungus Trichoderma sp. MCCC 3A01244 as a New Type of Anti-pulmonary Fibrosis Agent That Inhibits TGF-ß/Smad Signaling Pathway.

Pulmonary fibrosis is a scarring disease of lung tissue, which seriously threatens human health. Treatment options are currently limited, and effective strategies are still lacking. In the present study, 25 compounds were isolated from the deep-sea fungus Trichoderma sp. MCCC 3A01244. Among them, two ß-carboline alkaloids, trichocarbolines A (1) and C (4) are new compounds. The chemical structures of these compounds were elucidated based on their HRESIMS, 1D and 2D NMR spectra, optical rotation calculation, and comparisons with data reported in the literature. Trichocarboline B [(+)- and (-)-enantiomers] had previously been synthesized, and this is its first report as a natural product. Their anti-pulmonary fibrosis (PF) activity and cytotoxicity were investigated. Compounds 1, 11, and 13 strongly inhibited TGF-ß1-induced total collagen accumulation and showed low cytotoxicity against the HFL1 cell line. Further studies revealed compound 1 inhibited extracellular matrix (ECM) deposition by downregulating the expression of protein fibronectin (FN), proliferating cell nuclear antigen (PCNA), and α-smooth muscle actin (α-SMA). Mechanistic study revealed that compound 1 decreased pulmonary fibrosis by inhibiting the TGF-ß/Smad signaling pathway. As a newly identified ß-carboline alkaloid, compound 1 may be used as a lead compound for developing more efficient anti-pulmonary fibrosis agents.

Predictive model of postoperative pneumonia after neoadjuvant immunochemotherapy for esophageal cancer.

Background: Postoperative pneumonia (PP) is the most common pulmonary complication of esophagectomy. It is of great importance to identify any high-risk factors and prevent pulmonary complications to improve the prognosis of patients with esophageal cancer undergoing esophagectomy. Thus, we established a predictive model of PP in patients with neoadjuvant immunochemotherapy for resectable esophageal squamous cell carcinoma (ESCC), and provide suggestions for the best strategy for the perioperative period of the patients. Method: We retrospectively analyzed 78 patients who underwent esophagectomy for squamous cell carcinoma after neoadjuvant immunochemotherapy between September 2019 and August 2021.We used the "glmnet" language package in R to perform least absolute shrinkage and selection operator (LASSO) regression to screen the best predictors of PP, and nomograms predicting PP were constructed utilizing screened factors. The performance of nomograms was internally validated by calibration curves, concordance index (C-index), and the Brier score for overall performance. Results: Twenty-six patients (33.3%) had postoperative pneumonia. After LASSO regression, the factors that were independently associated with PP were diffusing capacity of the lungs for carbon monoxide (DLCO) (P=0.0002), white blood cell (WBC) difference before vs. after neoadjuvant immunochemotherapy (P=0.0133). We constructed a prediction model, plotted the nomogram, and verified its accuracy. Its Brier score was 0.147, its calibration slope was 0.98, and its C-index was 0.85 (95% CI: 0.75-0.95). Internal validation demonstrated a good discrimination power that the actual probability corresponds closely with the predicted probability. Conclusions: Our prediction model can predict the possibility of PP in patients with neoadjuvant immunochemotherapy for resectable esophageal squamous cell carcinoma and may facilitate physicians' efforts to reduce the incidence of postoperative pneumonia.

Identification of a seven-cell cycle signature predicting overall survival for gastric cancer.

While genetic alterations in several regulators of the cell cycle have a significant impact on the gastric carcinogenesis process, the prognostic role of them remains to be further elucidated. The TCGA-STAD training set were downloaded and the mRNA expression matrix of cell cycle genes was extracted and corrected for further analysis after taking the intersection with GSE84437 dataset. Differentially expressed mRNAs were identified between tumor and normal tissue samples in TCGA-STAD. Univariate Cox regression analysis and lasso Cox regression model established a novel seven-gene cell cycle signature (including GADD45B, TFDP1, CDC6, CDC25A, CDC7, SMC1A and MCM3) for GC prognosis prediction. Patients in the high-risk group shown significantly poorer survival than patients in the low-risk group. The signature was found to be an independent prognostic factor for GC survival. Nomogram including the signature shown some clinical net benefit for overall survival prediction. The signature was further validated in the GSE84437 dataset. In tissue microarray, CDC6 and MCM3 protein expression were significant differences by the immunohistochemistry-based H-score between tumor tissues and adjacent tissues, and CDC6 is an independent prognostic factor for GC. Interestingly, our GSEA revealed that low-risk patients were more related to cell cycle pathways and might benefit more from therapies targeting cell cycle. Our study identified a novel robust seven-gene cell cycle signature for GC prognosis prediction that may serve as a beneficial complement to clinicopathological staging. The signature might provide potential biomarkers for the application of cell cycle regulators to therapies and treatment response prediction.

Adjuvant Chemotherapy for Node-positive Esophageal Squamous Cell Carcinoma Improves Survival.

BACKGROUND: The aim of this study was to evaluate the survival benefits of adjuvant chemotherapy in patients with positive lymph nodes after esophagectomy for esophageal squamous cell carcinoma. METHODS: Patients who underwent esophagectomy for esophageal cancer in the Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital) in Zhengzhou, China from 2013 to 2017 were selected for this retrospective cohort study. Patients with positive lymph nodes were grouped into the surgery alone group or the adjuvant chemotherapy group. Propensity score matching (1:1) was used to minimize baseline differences. RESULTS: Among the 5118 patients who underwent esophagectomy, 792 patients were enrolled in the study. After matching, 253 (of 476) patients (adjuvant chemotherapy group) and 253 (of 316) patients (surgery alone group) were included. The median overall survival was significantly prolonged in the adjuvant chemotherapy group (54.0 months; 95% CI, 41.1-66.9 months) compared with the surgery alone group (28.0 months; 95% CI, 22.4-33.6 months) (P < .001). A significant difference was also observed in median disease-free survival between the 2 groups (adjuvant chemotherapy group, 33.0 months [95% CI, 20.8-45.2 months] compared with the surgery alone group, 22.0 months [95% CI, 17.0-27.0 months]; P = .007). In a multivariable analysis, receiving adjuvant chemotherapy (P < .001) was significantly associated with a reduced risk of death, and dissection of more than 6 lymph node stations (P = .05) was marginally associated with a reduced risk of death. CONCLUSIONS: Postoperative adjuvant chemotherapy improves the overall survival and disease-free survival of patients with resected esophageal squamous cell carcinoma with positive lymph nodes.

Weighted gene co-expression network-based approach to identify key genes associated with anthracycline-induced cardiotoxicity and construction of miRNA-transcription factor-gene regulatory network.

BACKGROUND: Cardiotoxicity is a common complication following anthracycline chemotherapy and represents one of the serious adverse reactions affecting life, which severely limits the effective use of anthracyclines in cancer therapy. Although some genes have been investigated by individual studies, the comprehensive analysis of key genes and molecular regulatory network in anthracyclines-induced cardiotoxicity (AIC) is lacking but urgently needed. METHODS: The present study integrating several transcription profiling datasets aimed to identify key genes associated with AIC by weighted correlation network analysis (WGCNA) and differentially expressed analysis (DEA) and also constructed miRNA-transcription factor-gene regulatory network. A total of three transcription profiling datasets involving 47 samples comprising 41 rat heart tissues and 6 human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) samples were enrolled. RESULTS: The WGCNA and DEA with E-MTAB-1168 identified 14 common genes affected by doxorubicin administrated by 4 weeks or 6 weeks. Functional and signal enrichment analyses revealed that these genes were mainly enriched in the regulation of heart contraction, muscle contraction, heart process, and oxytocin signaling pathway. Ten (Ryr2, Casq1, Fcgr2b, Postn, Tceal5, Ccn2, Tnfrsf12a, Mybpc2, Ankrd23, Scn3b) of the 14 genes were verified by another gene expression profile GSE154603. Importantly, three key genes (Ryr2, Tnfrsf12a, Scn3b) were further validated in a hiPSCMs-based in-vitro model. Additionally, the miRNA-transcription factor-gene regulatory revealed several top-ranked transcription factors including Tcf12, Ctcf, Spdef, Ebf1, Sp1, Rcor1 and miRNAs including miR-124-3p, miR-195-5p, miR-146a-5p, miR-17-5p, miR-15b-5p, miR-424-5p which may be involved in the regulation of genes associated with AIC. CONCLUSIONS: Collectively, the current study suggested the important role of the key genes, oxytocin signaling pathway, and the miRNA-transcription factor-gene regulatory network in elucidating the molecular mechanism of AIC.