Prognostic factors for patients with pathologic T1-T2N+ esophageal squamous cell carcinoma: A retrospective study with external validation.

BACKGROUND: Lymph node metastasis is significantly associated with a worse prognosis in patients with localized early-stage esophageal squamous cell carcinoma. This study aimed to explore the prognostic factors and develop a nomogram for predicting survival in patients with pathologic T1-2N+ esophageal squamous cell carcinoma. METHODS: Between 2014 and 2022, patients with pT1-2N+ esophageal squamous cell carcinoma who underwent esophagectomy with lymphadenectomy at 2 institutes were reviewed and assigned to training and external validation cohorts. Independent prognostic factors were identified via univariate and multivariate Cox regression analyses. The nomogram model was developed and evaluated by the area under the receiver operating characteristic curve and calibration curve. RESULTS: In total, 268 patients with a median age of 65 years (range, 40-82) were included and assigned to training (n = 190) and external validation (n = 78) cohorts. The Cox proportional hazards model demonstrated that body mass index (P = .031), surgical approach (P < .001), T stage (P = .015), and Clavien-Dindo classification (P < .001) were independent prognostic factors in the training cohort. The nomogram showed good discrimination, with an area under the receiver operating characteristic curve for 1-year, 3-year, and 5-year of 0.810, 0.789, and 0.809 in the training cohort and 0.782, 0.679, and 0.698 in the validation cohort. The calibration curve showed that the predicted survival probability was in good agreement with the actual survival probability. CONCLUSION: Lower body mass index, left surgical approach, T2 stage, and Clavien-Dindo classification grade III to V were related to worse prognosis in patients with pT1-T2N+ esophageal squamous cell carcinoma. The developed nomogram may predict individual survival accurately.

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.

The application of radiomics in esophageal cancer: Predicting the response after neoadjuvant therapy.

Esophageal cancer (EC) is one of the fatal malignant neoplasms worldwide. Neoadjuvant therapy (NAT) combined with surgery has become the standard treatment for locally advanced EC. However, the treatment efficacy for patients with EC who received NAT varies from patient to patient. Currently, the evaluation of efficacy after NAT for EC lacks accurate and uniform criteria. Radiomics is a multi-parameter quantitative approach for developing medical imaging in the era of precision medicine and has provided a novel view of medical images. As a non-invasive image analysis method, radiomics is an inevitable trend in NAT efficacy prediction and prognosis classification of EC by analyzing the high-throughput imaging features of lesions extracted from medical images. In this literature review, we discuss the definition and workflow of radiomics, the advances in efficacy prediction after NAT, and the current application of radiomics for predicting efficacy after NAT.

The minimum number of examined lymph nodes for accurate nodal staging and optimal survival of stage T1-2 esophageal squamous cell carcinoma: A retrospective multicenter cohort with SEER database validation.

BACKGROUND: The extent of lymphadenectomy during esophagectomy remains controversial for patients with T1-2 ESCC. The aim of this study was to identify the minimum number of examined lymph node (ELN) for accurate nodal staging and overall survival (OS) of patients with T1-2 esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Patients with T1-2 ESCC from three institutes between January 2011 and December 2020 were retrospectively reviewed. The associations of ELN count with nodal migration and OS were evaluated using multivariable models, and visualized by using locally weighted scatterplot smoothing (LOWESS). Chow test was used to determine the structural breakpoints of ELN count. External validation in the SEER database was performed. RESULTS: In total, 1537 patients were included. Increased ELNs was associated with an increased likelihood of having positive nodal disease and incremental OS. The minimum numbers of ELNs for accurate nodal staging and optimal survival were 14 and 18 with validation in the SEER database (n = 519), respectively. The prognostic prediction ability of N stage was improved in the group with ≥14 ELNs compared with those with fewer ELNs (iAUC, 0.70 (95%CI 0.66-0.74) versus 0.61(95%CI 0.57-0.65)). The higher prognostic value was found for patients with ≥18 ELNs than those with <18 ELNs (iAUC, 0.78 (95%CI 0.74-0.82) versus 0.73 (95%CI 0.7-0.77)). CONCLUSION: The minimum numbers of ELNs for accurate nodal staging and optimal survival of stage T1-2 ESCC patients were 14 and 18, respectively.

Preoperative Clinical Characteristics Predict Recurrent Laryngeal Nerve Lymph Node Metastasis and Overall Survival in Esophageal Squamous Cell Carcinoma: A Retrospective Study With External Validation.

Background: Recurrent laryngeal nerve (RLN) lymph node metastasis (LNM) is not rare in patients with esophageal squamous cell carcinoma (ESCC). We aimed to develop and externally validate a preoperative nomogram using clinical characteristics to predict RLN LNM in patients with ESCC and evaluate its prognostic value. Methods: A total of 430 patients with ESCC who underwent esophagectomy with lymphadenectomy of RLN LNs at two centers between May 2015 and June 2019 were reviewed and divided into training (center 1, n = 283) and external validation cohorts (center 2, n = 147). Independent risk factors for RLN LNM were determined by multivariate logistic regression, and a nomogram was developed. The performance of the nomogram was assessed in terms of discrimination, calibration, clinical usefulness, and prognostic value. The nomogram was internally validated by the bootstrap method and externally validated by the external validation cohort. Results: Multivariate analysis indicated that clinical T stage (P <0.001), endoscopic tumor length (P = 0.003), bioptic tumor differentiation (P = 0.004), and preoperative carcinoembryonic antigen level (P = 0.001) were significantly associated with RLN LNM. The nomogram had good discrimination with the area under the curve of 0.770 and 0.832 after internal and external validations. The calibration curves and decision curve analysis confirmed the good calibration and clinical usefulness of this model. High-risk of RLN LNM predicted by the nomogram was associated with worse overall survival in the external validation cohort (P <0.001). Conclusion: A nomogram developed by preoperative clinical characteristics demonstrated a good performance to predict RLN LNM and prognosis for patients with ESCC.

Bear bile powder attenuates senecionine-induced hepatic sinusoidal obstruction syndrome in mice.

Hepatic sinusoidal obstruction syndrome (HSOS) via exposure to pyrrolizidine alkaloids (PAs) is with high mortality and there is no effective treatment in clinics. Bear bile powder (BBP) is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis, inflammation, and fibrosis. Here, we aim to evaluate the protective effect of BBP against HSOS induced by senecionine, a highly hepatotoxic PA compound. Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently, which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells, alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells, as well as decreased conventional serum liver function indicators. In addition, BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts, two well-known markers positively associated with the severity of PA-induced HSOS. Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules. BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines, in which tauroursodeoxycholic acid played an important role. What's more, BBP treatment also decreased the accumulation of hydrophobic bile acids, such as cholic acid, taurocholic acid, glycocholic acid, as well. We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis, preventing liver fibrosis, and alleviating liver inflammation. Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.

Risk factors for lymph node metastasis in T1 esophageal squamous cell carcinoma: A systematic review and meta-analysis.

BACKGROUND: Lymph node metastasis (LNM) affects the application and outcomes of endoscopic resection in T1 esophageal squamous cell carcinoma (ESCC). However, reports of the risk factors for LNM have been controversial. AIM: To evaluate risk factors for LNM in T1 ESCC. METHODS: We searched Embase, PubMed and Cochrane Library to select studies related to LNM in patients with T1 ESCC. Included studies were divided into LNM and non-LNM groups. We performed a meta-analysis to examine the relationship between LNM and clinicopathologic features. Odds ratio (OR), mean differences and 95% confidence interval (CI) were assessed using a fixed-effects or random-effects model. RESULTS: Seventeen studies involving a total of 3775 patients with T1 ESCC met the inclusion criteria. After excluding studies with heterogeneity based on influence analysis, tumor size (OR = 1.93, 95%CI = 1.49-2.50, P < 0.001), tumor location (OR = 1.46, 95%CI = 1.17-1.82, P < 0.001), macroscopic type (OR = 3.17, 95%CI = 2.33-4.31, P < 0.001), T1 substage (OR = 6.28, 95%CI = 4.93-8.00, P < 0.001), differentiation (OR = 2.11, 95%CI = 1.64-2.72, P < 0.001) and lymphovascular invasion (OR = 5.86, 95%CI = 4.60-7.48, P < 0.001) were found to be significantly associated with LNM. Conversely, sex, age and infiltrative growth pattern were not identified as risk factors for LNM. CONCLUSION: A tumor size > 2 cm, lower location, nonflat macroscopic type, T1b stage, poor differentiation and lymphovascular invasion were associated with LNM in patients with T1 ESCC.

Clinical nomogram for lymph node metastasis in pathological T1 esophageal squamous cell carcinoma: a multicenter retrospective study.

BACKGROUND: Endoscopic resection is increasingly used to treat pathological T1 (pT1) esophageal cancer (EC) patients. However, the procedures are limited by lymph node metastasis (LNM) and remain controversial. We aimed to construct a nomogram to predict the risk of LNM in patients with pT1 esophageal squamous cell carcinoma (ESCC). METHODS: A total of 243 patients with pT1 ESCC who underwent esophagectomy and lymph node dissection at two different institutes between February 2013 and June 2019 were analyzed retrospectively. Patients were categorized into the negative group and the positive group according to whether there was LNM. Risk factors for LNM were evaluated by univariate and multivariate analyses. The nomogram was used to estimate the individual risk of LNM. RESULTS: Forty-six (18.9%) of the 243 patients with pT1 ESCC exhibited LNM. The LNM rate in patients with stage T1a disease was 5.7% (5/88), and the rate in patients with stage T1b disease was 26.5% (41/155). Multivariable logistic regression analysis showed that tumor differentiation [odds ratio (OR) =1.942, 95% confidence interval (CI): 1.067-3.536, P=0.030], the T1 sub-stage (OR =4.750, 95% CI: 1.658-13.611, P=0.004), the preoperative alanine aminotransferase/aspartate aminotransferase ratio (LSR) (OR =5.371, 95% CI: 1.676-17.210, P=0.005), and the high-density lipoprotein cholesterol (HDL-C) level (OR =5.894, 95% CI: 1.917-18.124, P=0.002) were independent risk factors for LNM. The nomogram had relatively high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.803 (95% CI: 0.732-0.873). The calibration curve showed that the predicted probability of LNM was in good agreement with the actual probability. CONCLUSIONS: Clinicopathological and hematological parameters of tumor differentiation, the T1 sub-stage, the preoperative LSR, and the HDL-C level may predict the risk of LNM in T1 ESCC. The risk of LNM can be predicted by the nomogram.

[Quantification of hepatotoxic pyrrolizidine alkaloid adonifoline in traditional Chinese medicine preparations containing Senecionis Scandentis Herba].

Pyrrolizidine alkaloids(PAs) are a kind of natural toxins, which can cause severe hepatotoxicity, pulmonary toxicity, genotoxicity, neurotoxicity, embryotoxicity and even death. Therefore, international organizations and countries such as World Health Organization have paid great attention to herbal medicines and preparations containing PAs. PAs are widely distributed in Chinese herb medicines and contained in hundreds of traditional Chinese medicine preparations. The content of adonifoline, the main PAs in Senecionis Scandentis Herba, shall be less than 0.004% in herbal medicines as described in Chinese pharmacopeia. However, there is no guidance in preparations which contain Senecionis Scandentis Herba. In this study, 14 preparations were analyzed by an UPLC-MS method. Among them, 8 preparations were found to contain adonifoline much higher than the content limits of such countries as Germany, Netherlands and New Zealand. And the highest contents of adonifoline were found in Qianbai Biyan Tablets and Qianbai Biyan Capsules, which are officially recorded in Chinese Pharmacopeia. The contents of adonifoline varied in different batches of the same preparations. The highest content was 156.10 µg·g~(-1) Qianbai Biyan Tablets, whose daily intake of adonifoline was up to 1 030.26 µg according to the recommended dosage of the preparation. Our results showed the potential risk of these preparations, and the content limit of adonifoline shall be inspected Chinese medicine preparations containing Senecionis Scandentis Herba.

Depth of Invasion into the Circular and Longitudinal Muscle Layers in T2 Esophageal Squamous Cell Carcinoma Does Not Affect Prognosis or Lymph Node Metastasis: A Multicenter Retrospective Study.

BACKGROUND: Although a greater depth of tumor invasion is correlated with a poorer prognosis in esophageal squamous cell carcinoma (ESCC), it remains controversial whether T2 ESCC should be subclassified by circular and longitudinal muscle invasion. We conducted a multicenter retrospective study to evaluate the relationship between the depth of invasion and long-term outcome and to identify the clinical significance of subclassifying T2 ESCC. METHODS: Patients with T2 ESCC who underwent esophagectomy at two different institutes between January 2009 and December 2017 were analyzed retrospectively. ESCC with circular and longitudinal muscle invasion was defined as T2 circular and T2 longitudinal ESCC, respectively. Survival outcomes and risk factors for lymph node metastasis (LNM) were evaluated by univariate and multivariate analyses. In addition, data from stage T1b ESCC cases during the same period were retrieved for use as a comparison cohort to evaluate the prognostic significance of the T2 substage. RESULTS: A total of 536 T2 ESCC patients were eligible, and 192 (36%) patients developed LNM. No significant difference was found in general characteristics between the T2 circular and T2 longitudinal ESCC groups (n = 219 and n = 317, P > 0.05), except for tumor location (P = 0.02). The T2 substage was not significantly correlated with survival on univariate or multivariate analysis (P = 0.30 and P = 0.34, respectively). Multivariate analysis also indicated that the T2 substage was not an independent risk factor for LNM (P = 0.15). When patients with stage T1b ESCC were considered, their survival time was significantly different from that of patients with T2 circular and T2 longitudinal disease (P = 0.01). CONCLUSIONS: The depth of tumor invasion into the circular and longitudinal muscle layers in T2 ESCC does not affect the prognosis or risk of LNM.

Author Correction: Investigation of Dietary Factors and Esophageal Cancer Knowledge: Comparison of Rural Residents in High- and Low-incidence Areas.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Investigation of Dietary Factors and Esophageal Cancer Knowledge: Comparison of Rural Residents in High- and Low-incidence Areas.

To compare the differences in dietary status and knowledge of esophageal cancer (EC) between residents of high- and low-incidence areas. We investigated dietary conditions and EC knowledge among residents in high- and low-EC incidence areas (Yanting and Qingzhen counties). Residents in Yanting consumed more pickled vegetables, salted meat and barbecued food (P < 0.05). Analysis of the past ten-year trend in Yanting consumed fresh vegetables/fruits, beans, sauerkraut, hot food, and barbecued food had gradually increased, and the trend was less than that in Qingzhen County. However, the gradual increasing trend in consumption of pickled vegetables, pickled meat, and spicy food over the past 10 years was greater (P < 0.05). Drinking water in Yanting County was healthier than that in Qingzhen County (P < 0.05). In terms of EC knowledge, the proportions of residents in Yanting who had a clear understanding, knowledge or had heard of EC or knew the common causes, primary symptoms, therapeutic measures, preventive measures, and government interventions for EC were all higher than in Qingzhen (P < 0.05). Residents in Yanting had greater EC knowledge but more harmful dietary habits than those in Qingzhen.