Learning Curve of Robot-Assisted Lymph Node Dissection of the Left Recurrent Laryngeal Nerve: A Retrospective Study of 417 Patients.

OBJECTIVE: Left recurrent laryngeal nerve (no.106recL) lymph node dissection is a challenging procedure, and robotic-assisted minimally invasive esophagectomy (RAMIE) may have some advantages. This study aimed to determine the learning curve of no.106recL lymph node dissection. METHODS: The data of 417 patients who underwent McKeown RAMIE between June 2017 and June 2022 were retrospectively analyzed. The lymph node harvest of no.106recL was used to determine the learning curve, and the cumulative sum (CUSUM) method was employed to obtain the inflection point. RESULTS: A total of 404 patients (404/417, 96.9%) underwent robotic surgery. Based on the number of no.106recL lymph nodes harvested, the CUSUM learning curve was mapped and divided into three phases: phase I (1‒75 cases), phase II (76‒240 cases), and phase III (241‒404 cases). The median (IQR) number of no.106recL lymph node harvests were 1 (4), 3 (6,) and 4 (4) in each phase (p < 0.001). The lymph node dissection rate gradually increased from 62.7% in phase I to 82.9% in phase III (p = 0.001). The total and thoracic lymph node harvest gradually increased (p < 0.001), whereas operation time (p = 0.001) and blood loss gradually decreased (p < 0.001). Moreover, the incidence of total complication (p = 0.020) and recurrent laryngeal nerve injury (p = 0.001) significantly decreased, and the postoperative hospital stay gradually shortened (p < 0.001). CONCLUSION: Robotic no.106recL lymph node dissection has some advantages for patients with esophageal cancer. In this study, perioperative and clinical outcomes were significantly improved over the learning curve. However, further prospective studies are required to confirm our results.

CXCR4 promotes the growth and metastasis of esophageal squamous cell carcinoma as a critical downstream mediator of HIF-1α.

C-X-C motif chemokine receptor 4 (CXCR4) belongs to the CXC chemokine receptor family, which mediates the metastasis of tumor cells and promotes the malignant development of cancers. However, its biological role and regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we found that CXCR4 expression was associated with lymph node metastasis and a poor prognosis. In vitro and in vivo studies demonstrated that CXCR4 overexpression promoted ESCC cell proliferation, migration, invasion, and survival, whereas silencing CXCR4 induced the opposite effects. Mechanically, HIF-1α transcriptionally regulates CXCR4 expression by binding to a hypoxia response element in its promoter. HIF-1α-induced ESCC cell migration and invasion were reversed by CXCR4 knockdown or treatment with MSX-122, a CXCR4 antagonist. Collectively, these data revealed that the HIF-1α/CXCR4 axis plays key roles in ESCC growth and metastasis and indicated CXCR4 as a potential target for ESCC treatment.

A nomogram to predict lymph node metastasis risk for early esophageal squamous cell carcinoma.

BACKGROUND: A nomogram was developed to predict lymph node metastasis (LNM) for patients with early-stage esophageal squamous cell carcinoma (ESCC). METHODS: We used the clinical data of ESCC patients with pathological T1 stage disease who underwent surgery from January 2011 to June 2018 to develop a nomogram model. Multivariable logistic regression was used to confirm the risk factors for variable selection. The risk of LNM was stratified based on the nomogram model. The nomogram was validated by an independent cohort which included early ESCC patients underwent esophagectomy between July 2018 and December 2019. RESULTS: Of the 223 patients, 36 (16.1%) patients had LNM. The following three variables were confirmed as LNM risk factors and were included in the nomogram model: tumor differentiation (odds ratio [OR] = 3.776, 95% confidence interval [CI] 1.515-9.360, p = 0.004), depth of tumor invasion (OR = 3.124, 95% CI 1.146-8.511, p = 0.026), and tumor size (OR = 2.420, 95% CI 1.070-5.473, p = 0.034). The C-index was 0.810 (95% CI 0.742-0.895) in the derivation cohort (223 patients) and 0.830 (95% CI 0.763-0.902) in the validation cohort (80 patients). CONCLUSIONS: A validated nomogram can predict the risk of LNM via risk stratification. It could be used to assist in the decision-making process to determine which patients should undergo esophagectomy and for which patients with a low risk of LNM, curative endoscopic resection would be sufficient.

Lymph node dissection around left recurrent laryngeal nerve: robot-assisted vs. video-assisted McKeown esophagectomy for esophageal squamous cell carcinoma.

OBJECTIVE: This study investigated the advantages of robot-assisted McKeown esophagectomy (RAME) for extensive superior mediastinal lymph node dissection (LND) versus video-assisted McKeown esophagectomy (VAME). METHODS: The cases of 184 consecutive esophageal squamous cell carcinoma (ESCC) patients who underwent minimally invasive McKeown esophagectomy (109 with RAME, 75 with VAME) performed by a single surgical group between June 2017 and December 2019 were retrospectively reviewed. RESULTS: Overall, 59.8% (110/181) patients (70 treated with RAME, 40 treated with VAME; 64.2% vs. 53.3%, respectively, p = 0.139) underwent complete LND around the left recurrent laryngeal nerve (RLN) by pathological assessment. Cumulative sum plots showed increased numbers of LND around the left RLN (3.6 ± 2.0 vs. 5.4 ± 2.7, p = 0.008) and a decreased incidence of recurrent nerve injury (27.9% vs. 7.4%, p = 0.037) after RAME learning curve. Despite similar overall LND results (30.6 ± 10.2 vs. 28.1 ± 10.2, p > 0.05), RAME yielded more LND (5.4 ± 2.7 vs. 4.4 ± 2.2, p = 0.016) and a greater proportion of lymph node metastases (37.0% vs. 7.5%) around the left RLN but induced a lower proportion of recurrent nerve injuries (7.4% vs. 22.5%, p = 0.178) compared with VAME. Further analysis revealed that the complete LND around the left RLN was associated with recurrent nerve injury in the RAME (20.0% vs. 5.1%, p = 0.035) and VAME (22.5% vs. 5.7%, p = 0.041) groups but did not affect other clinical outcomes including surgical duration, intraoperative blood loss, postoperative intensive care unit stay, hospital stay, and other complications. CONCLUSIONS: For patients with ESCC, RAME has great advantages in LND around the left RLN and recurrent nerve protection after learning curve of robotic esophagectomy.

Safety and Efficacy of Apatinib Monotherapy for Unresectable, Metastatic Esophageal Cancer: A Single-Arm, Open-Label, Phase II Study.

LESSONS LEARNED: Patient compliance with the oral dosage treatment was good, with no need for hospitalization. Patients with tracheal and esophageal fistulas can take crushed apatinib by nutrient tube, with the same bioavailability and efficacy. Apatinib may be an effective and safe second- or further-line treatment for advanced esophageal cancer. BACKGROUND: Apatinib is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2), which is thought to play a role in esophageal cancer progression. Our goal was to evaluate the efficacy and safety of apatinib in patients with unresectable esophageal cancer and to examine whether VEGFR2 expression influenced the clinical response. METHODS: This single-arm, open-label, investigator-initiated phase II study enrolled patients with advanced squamous cell carcinoma (SCC) or adenocarcinoma of the esophagus or esophagogastric junction who were admitted to Tianjin Medical University Cancer Institute and Hospital between August 2017 and January 2019. Apatinib monotherapy (500 mg/day) was given orally or via an enteral tube until disease progression, unacceptable toxicity, withdrawal, or death. Patients were followed until treatment was discontinued or death. The main endpoints were tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs). RESULTS: Among 32 patients screened for inclusion, 30 were included in the safety and survival analyses (i.e., received apatinib), and 26 were included in the efficacy analysis (at least one imaging follow-up). Median follow-up time and exposure to apatinib were 5.34 months and 72 days, respectively. Among 26 patients included in the efficacy analysis, 2 had a partial response (PR; 7.7%) and 14 had stable disease (SD; 53.8%). The overall response rate (ORR) was 7.7%, and the disease control rate (DCR) was 61.5%. Median PFS and OS were 4.63 months (95% confidence interval, 2.11-7.16 months) and 6.57 months (4.90 months to not estimable), respectively. Fifteen patients (50.0%) experienced treatment-related AEs, most commonly hypertension (26.7%), diarrhea (20.0%), and hand-foot-skin reaction (10.0%). No patients had grade ≥4 treatment-related AEs. CONCLUSION: Apatinib was effective as second- or further-line treatment for advanced esophageal cancer.

Influence of Induction Therapy on Robot-Assisted McKeown Esophagectomy for Esophageal Squamous Cell Carcinoma.

BACKGROUND: The present study was to investigate the influence of induction therapy on robot-assisted McKeown esophagectomy (RAME) with radical superior mediastinal lymph node dissection for esophageal squamous cell carcinoma in a high-volume cancer center. METHODS: A consecutive patient cohort who underwent RAME from January 2017 to May 2019 were reviewed. The perioperative outcomes of patients with induction therapy were compared with those who had surgery alone. RESULTS: In total, 118 patients underwent RAME during the study period. The average age was 59.1 ± 7.5 years, including 100 male and 18 female patients. Thirty patients (25.4%) had induction therapy, and 88 patients did not receive induction therapy. The average age of the patients treated with induction therapy was younger than those received surgery alone (56.8 ± 6.1 vs. 59.5 ± 7.6 years, p = 0.039). There were no statistically significant differences in the mean operative time and estimated blood loss between both groups. Complications occurred in 46 (39.0%) patients. There were no statistically significant differences in the rates of any complications between both groups (p = 0.951). There were no deaths in either group. The hospital stay was prolonged in patients with induction therapy than those in the surgery-alone group (20.8 ± 8.9 vs. 16.8 ± 6.0, p = 0.048). There was no statistically significant difference in the average number of dissected lymph nodes in total and both recurrent laryngeal nerve stations between both groups. CONCLUSION: For patients with esophageal squamous cell carcinoma, induction therapy has no influence on RAME with radical superior mediastinal lymph node dissection.

Krüppel-Like Factor 4 Enhances Sensitivity of Cisplatin to Esophageal Squamous Cell Carcinoma (ESCC) Cells.

BACKGROUND The aim of this study was to elucidate the role of Krüppel-Like factor 4 (KLF4) in cisplatin resistance in esophageal squamous cell carcinoma (ESCC) cells, which may eventually help to improve the treatment efficacy. MATERIAL AND METHODS Human esophageal squamous cell carcinoma (ESCC) cell line CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30 were selected to detect their sensitivity to cisplatin. 5-Azacytidine-2'-deoxycytidine (5'-Aza-CdR) treatment and methylation-specific PCR (MS-PCR) were used to detect the methylation status for KLF4. Cell viability, apoptosis, and cell cycle were measured using methyl thiazolyl tetrazolium (MTT) assay, Annexin V affinity assay, and flow cytometry, respectively. RESULTS The sensitivity to cisplatin was different in the seven ESCC cell lines, with TE-1 having the lowest sensitivity and KYSE140 having the highest sensitivity. Interestingly, the level of KLF4 was relatively low in TE-1 cells; while it was high in KYSE140 cells. These results suggested that KLF4 may be involved in cisplatin resistance. The promoter region was mostly unmethylated in KYSE140 cells; while it was hypermethylated in TE-1 cells. After treatment with demethylation reagent 5-Aza-CdR, cisplatin sensitivities were significantly increased after upregulation of KLF4, as the IC50 values were significantly decreased in the TE-1 cell treated with 5-Aza-CdR. Furthermore, upregulation of KLF4 induced cell apoptosis and cell cycle arrest at S phase. CONCLUSIONS KLF4 enhances the sensitivity of cisplatin to ESCC cells through apoptosis induction and cell cycle arrest. Our data provided a novel insight to the mechanism of cisplatin resistance; overexpression of KLF4 may be a potential therapeutic strategy for cisplatin resistance in human ESCC.

[Clinical features and risk factors of anastomotic leakage after radical esophagectomy].

OBJECTIVE: To analyze the clinical features and risk factors of anastomotic leakage after radical esophagectomy of esophageal carcinoma. METHODS: The clinical data of 547 esophageal cancer patients underwent radical esophagectomy in Tianjin Medical University Cancer Hospital from January 2012 to December 2013 was analyzed retrospectively. There were 421 male and 126 female patients, with a median age of 65 years (ranging from 29 to 82 years). There were 155 cases of upper esophageal carcinoma, 340 cases of middle esophageal carcinoma and 52 cases of lower esophageal carcinoma. The surgical procedures included 41 cases completed through Sweet, 145 cases completed through McKeown, 279 cases completed through Ivor Lewis, 82 cases completed through minimally invasive esophagectomy. Moreover, 24 of 547 cases underwent preoperative neoadjuvant radiochemotherapy. χ² test and Cox's proportional hazards regression model were used for univariate analysis and multivariate analysis of the risk factors of postoperative anastomotic leakage. RESULTS: Twenty-seven of 547 cases with esophagectomy occurred anastomotic leakage and the incidence rate was 4.94% (27/547). One of 27 cases died and the mortality rate was 3.70% (1/27). The time of anastomotic leakage found was 4 to 45 days, with a median time of 10 days. There were 0 case of early leakage, 20 cases of mid-term leakage, 7 cases of late leakage. Three of 27 cases with anastomotic leakage had tracheoesophageal fistula, while 3 cases had contralateral pleural fistula. As to the incidence rate of anastomotic leakage, there was statistically significant difference between cervical anastomotic leakage (8.14%, 18/221) and intrathoracic anastomotic leakage (2.76%, 9/326) (χ² =7.41, P=0.000), among Sweet (4.88%, 2/41), McKeown (9.66%, 14/145), Ivor Lewis (2.51%, 7/279) and MIE (4.88%, 4/82) (χ² =21.48, P=0.000), and between with (16.67%, 4/24) and without (4.40%, 23/523) neoadjuvant radiochemotherapy (χ² =9.20, P=0.000). The multivariate analysis showed that anastomotic site (HR=2.594, P=0.048), surgical approach (HR=5.689, P=0.003) and preoperative neoadjuvant radiochemotherapy (HR=3.604, P=0.027) are independent risk factors for anastomotic leakage after esophagectomy. CONCLUSIONS: The mid-term anastomotic leakage after esophagectomy occurs higher. McKeown is a main surgical procedure and neoadjuvant radiochemotherapy is an important factor for the anastomotic leakage.

[Characteristics and risk factors of lymph node metastasis in pN1 stage esophageal squamous cell carcinoma].

OBJECTIVE: To analyze the pattern and the clinicopathologic risk factors of lymph node metastasis (LNM) in pN1 stage esophageal squamous cell carcinoma. METHODS: Clinical data of 181 patients (154 male and 27 female patients, aging from 38 to 84 years) who underwent esophagectomy during January 2005 and December 2008 were reviewed, including 69 cases through left thoracotomy and 112 cases through right thoracotomy. All patients underwent systematic lymphadenectomy. The risk factors related to lymph node metastasis were analyzed by χ² test and Logistic regression analysis. RESULTS: The relatively highest LNM site were middle and lower thoracic paraesophageal (38.4%), right and left cardiac (35.3%) and the left gastric artery (38.8%). The LNM of middle and lower thoracic paraesophageal was correlated with T stage (χ² =11.754, P=0.009). A correlation was also found among the LNM of upper mediastinum and the location of tumor (P=0.039). The T stage (χ² =8.694, P=0.034) and TNM stage (χ² =6.906, P=0.032) were the risk factors of the LNM of middle and lower mediastinum. The risk factors of the LNM of abdomen were the location of tumor, the length of tumor, T stage and TNM stage (χ² =5.713 to 16.749, P>0.05). Multivariate analysis showed that the location of tumor is the independent risk factors for the abdominal lymph node metastasis. CONCLUSIONS: The relatively highest LNM sites are correlated with the location of tumor, T stage, the length of tumor and TNM stage. According to the risk factors of LNM, the relatively highest LNM sites should be mainly swept.

[Effect of number of metastatic lymph nodes and metastatic lymph node ratio on the prognosis in patients with adenocarcinoma of the esophagogastric junction after curative resection].

OBJECTIVE: To analyze the effects of number of positive lymph nodes and metastatic lymph node ratio (LNR) in evaluation of recurrence risk and overall survival in patients with adenocarcinoma of the esophagogastric junction (AEG) after curative resection. METHODS: Clinical data of 337 AEG patients who underwent curative resection in our hospital were retrospectively reviewed. The pN stage was categorized based on the number of metastatic lymph nodes and LNR stage, and was determined by the best cutoff approach at log-rank test. Univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model were used to analyze the effects of pN and LNR on recurrence-free survival and overall survival of these patients. Receiver operating characteristic (ROC) curves were plotted to compare the accuracy of prognosis prediction with pN and LNR. RESULTS: The 5-year recurrence-free survival rate and overall survival rate for all patients were 25.5% and 29.9%, respectively. The 5-year recurrence-free survival rates were 47.6%, 23.2%, 17.1% and 5.7% for pN0, pN1, pN2, and pN3, respectively, (P < 0.001) and the 5-year overall survival rates were 53.3%, 28.9%, 18.9% and 7.3%, respectively (P < 0.001). The 5-year recurrence-free survival rates were 47.6%, 24.3%, 11.4% and 2.0% for LNR0, LNR1, LNR2, and LNR3, respectively (P < 0.001), and the 5-year overall survival rates were 53.3%, 28.5%, 15.0%, 2.6%, respectively (P < 0.001). Univariate analysis showed that tumor size, macroscopic type, degree of differentiation, pT, pN, LNR and TNM stage were significantly associated with RFS and OS (P < 0.05). Cox multivariate analysis showed that either pN or LNR was independent risk factor for RFS and OS (P < 0.001). When pN and LNR were entered into the Cox hazard ratio model as covariates at the same time, LNR remained as an independent prognosis factor for RFS and OS (P < 0.001), but pN was not (P > 0.05). ROC curves showed that the area under the curve of LNR stage was larger than that of pN stage in prediction of both RFS and OS, however the differences were not statistically significant (P > 0.05). CONCLUSIONS: LNR is an independent risk factor associated with the prognosis of AEG patients. The value of LNR in prediction of recurrence hazard and overall survival was better than that of pN stage. It offers some helpful suggestions for AEG patients risk classification, allowing clinicians to develop a reasonable treatment.

Clinical outcomes of the robot-assisted Ivor Lewis procedure for adenocarcinoma of the esophagogastric junction with semi-instrument overlap intrathoracic anastomosis.

Background: The main difficulty of minimally invasive Ivor Lewis (IL) procedure for adenocarcinoma of the esophagogastric junction (AEGJ) is the intrathoracic esophagogastric anastomosis (IEA). We aimed to assess the safety and feasibility of the IL procedure with the da Vinci surgical system for treatment of AEGJ with semi-mechanical intrathoracic IEA. Methods: The cohort included 72 patients with AEGJ who received treatment at the Department of Minimally Invasive Esophagus Surgery of the Tianjin Medical University Cancer Institute and Hospital from August 2020 to March 2023. Of these 72 patients, 17 received neoadjuvant chemo-immunotherapy. The robot-assisted minimally invasive IL procedure was performed using a linear stapler for overlap side-to-side intrathoracic anastomosis and the stapler defect was closed with double full-layer continuous sutures by robotic hand-sewn (semi-mechanical) IEA. Results: Of the 72 AEGJ patients, 2 were converted to exploration, 7 were converted to laparotomy and thoracotomy for circular-stapled intrathoracic anastomosis, and 6 were converted to thoracotomy for circular-stapled anastomosis, which included 2 cases of extensive pleural adhesion and 4 cases of overlap anastomosis failure, whereas 57 underwent the robot-assisted minimally invasive IL procedure with semi-mechanical IEA. Among the 9 patients converted to laparotomy, the laparotomy rate was closely related to the Siewert classification (P<0.005) and preoperative use of neoadjuvant therapy (P<0.05). Among the 57 patients who underwent the robot-assisted minimally invasive IL procedure with semi-mechanical IEA, there were 2 cases of anastomotic leakages (2/57, 3.5%), no case of anastomotic stricture, 5 cases of postoperative pneumonia (5/57, 8.77%), 2 cases of intensive care unit admission (2/57, 3.5%), and 1 case of readmission within 30 days (1/57, 1.75%). None of the patients died within 30 days after surgery. Conclusions: The robot-assisted minimally invasive IL procedure with semi-mechanical IEA is both safe and feasible for AEGJ. However, caution is advised for patients with Siewert type III AEGJ and those who have already received preoperative neoadjuvant therapy.

Exosome-Delivered EGFR Induced by Acidic Bile Salts Regulates Macrophage M2 Polarization to Promote Esophageal Adenocarcinoma Cell Proliferation.

Purpose: Chronic gastroesophageal reflux disease (GERD) causes the abnormal reflux of acid and bile salts, which would induce Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EGFR, as one of main components of the exosome, plays an important role in cancer progression. Here, we investigated the role of acidic bile salts (ABS)-induced exosomal EGFR in EAC cell proliferation. Methods: Electronic microscopic examination and Western blot were used to identify exosomes. Western blot, siRNA transfection, enzyme-linked immunosorbent assay, qRT-PCR, cell viability detection, mouse xenograft tumor models, and immunohistochemical staining were performed to study the function of ABS-induced exosomal EGFR in cell proliferation. Results: We found that ABS improved the exosomal EGFR level of normal human esophageal epithelial cells, BE cells, and BE-associated adenocarcinoma cells. The results were confirmed in the serum-derived exosomes from healthy persons and patients suffering from GERD, BE with or without GERD, and EAC with or without GERD. Moreover, cell line-derived exosomal EGFR was found to promote macrophage M2 polarization through the PI3K-AKT pathway. The co-incubation medium of macrophages and exosomes improved cell proliferation and tumor growth, which depended on the exosomal EGFR level. CCL18 was identified as the most effective component of the co-incubation medium to promote EAC cell proliferation by binding to its receptor PITPNM3 in vitro and in vivo. Conclusion: Our findings demonstrate that ABS-induced exosomal EGFR regulates macrophage M2 polarization to promote EAC proliferation. This study provides an important insight into the role of ABS in EAC development.

Neoadjuvant chemoimmunotherapy was associated with better short-term survival of patients with locally advanced esophageal squamous cell carcinoma compared to neoadjuvant chemoradiotherapy.

INTRODUCTION: The chemotherapy and immunotherapy combination is currently the primary strategy to treat metastatic esophageal squamous cell carcinoma (ESCC). Neoadjuvant chemoimmunotherapy (NCIT) is being intensively investigated for treating locally advanced ESCC. OBJECTIVE: We compared the efficacy and safety of NCIT and neoadjuvant chemoradiotherapy (NCRT) to treat locally advanced ESCC. METHODS: We included 214 locally advanced ESCC patients who were administered neoadjuvant therapy from May 2014 to April 2022. The patients were grouped according to two neoadjuvant protocols (NCIT and NCRT) routinely used at our institution. Perioperative findings, pathological results, and survival data were compared between the two groups by conducting unmatched and 1:1 propensity score matching (PSM) analyses. RESULTS: Following 1:1 PSM analysis of the confounders, 66 patients were allocated to each of the two groups. Time span between neoadjuvant therapy completion and esophagectomy was significantly longer after NCRT than that after NCIT (47.1 ± 13.2 days vs. 34.7 ± 8.8 days; p < 0.001). The NCIT group exhibited significantly greater number of harvested lymph nodes than the NCRT group (33.6 ± 12.7 vs. 21.7 ± 10.2; p < 0.001). The pathological complete response and major pathological response rates were similar between the two groups [NCIT group: 25.8% (17/66) and 62.1% (41/66), respectively; NCRT group: 27.3% (18/66) and 56.1% (37/66), respectively (p > 0.05)]. The overall incidence of pneumonia, anastomotic leakage, or postoperative complications did not differ significantly between the two groups. The 2-year cumulative overall survival rates and the 2-year disease-free survival rates of the NCIT and NCRT groups were 80.2% and 62.2%, respectively (p = 0.029) and 70.0% and 50.8%, respectively (p = 0.023). CONCLUSION: In locally advanced ESCC patients, short-term survival after NCIT is superior to that after NCRT, with similar perioperative and pathological outcomes.

Extranodal metastasis is a powerful prognostic factor in patients with adenocarcinoma of the esophagogastric junction.

BACKGROUND AND OBJECTIVES: The purpose of this study is to estimate the effect of extranodal metastasis (EM) on recurrence and survival in patients with adenocarcinoma of the esophagogastric junction (AEG) after curative resection. METHODS: Clinical data from 284 node-positive AEG patients who underwent curative resection were reviewed. Univariate and multivariate analyses were conducted to elucidate the effect of EM on recurrence-free survival (RFS) and overall survival (OS). RESULTS: EM was detected in 70 (24.6%) of the 284 cases. It had a significant correlation with tumor size, Lauren type, histopathological grading, depth of tumor invasion, number of metastatic nodes, lymph node ratio, and TNM stage. The 5-year RFS and OS rates were 22.2% and 24.3%, respectively. Patients with EM had a significantly decreased RFS (16 vs. 36 months, P < 0.001) and OS (23 vs. 41 months, P < 0.001) compared with those without EM. Multivariate analyses identified EM as an independent prognostic factor (P = 0.003 and 0.001, respectively). CONCLUSION: The presence of EM increases recurrence probability and reduces OS probability of AEG patients with lymph node metastasis. EM is a powerful prognostic factor reflecting a particularly aggressive biological behavior. Better understanding of EM status can help clinicians with regard to treatment decision and prognosis evaluation.

Acetylcysteine and budesonide for the treatment of refractory Mycoplasma pneumoniae pneumonia in children: a clinical observation.

BACKGROUND: To examine the clinical impact of bronchoscope alveolar lavage (BAL) combination with budesonide, ambroxol + budesonide, or acetylcysteine + budesonide in the treatment of refractory Mycoplasma pneumoniae pneumonia (RMPP). METHODS: Eighty-two RMPP patients admitted to Pediatrics at The First People's Hospital of Zhengzhou were retrospectively evaluated between August 2016 and August 2019. All patients were administered BAL in addition to intravenous Azithromycin, expectoration, and nebulizer inhalation. The medications added to the BLA separated the patients into the Budesonide group, Ambroxol + budesonide group, and acetylcysteine + budesonide group. Analyzed were the variations in laboratory examination indices, improvement in lung imaging, overall effective rate, and adverse responses in the three groups. RESULTS: The laboratory test indices of patients in all three groups improved significantly relative to pre-treatment levels, and the results were statistically significant. After therapy, there were no significant differences between the three groups in terms of white blood cell (WBC), C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR). Serum lactate dehydrogenase (LDH) and serum ferritin (SF) varied significantly across the three groups (P < 0.05). In the acetylcysteine + budesonide group, the absorption rate of lung imaging lesions and clinical efficacy were superior to those of the other two groups. There were no significant differences between the three groups in the occurrence of adverse events (P > 0.05). CONCLUSIONS: BLA-coupled acetylcysteine + budesonide was superior to the other two groups in enhancing the effectiveness of RMPP in children, which might increase lung opacity absorption and minimize lung inflammation.

Comparison of lymph node metastasis pattern from esophagogastric junction adenocarcinoma versus very low thoracic esophageal squamous cancer: a propensity-matched analysis.

Background: The anatomical locations of esophagogastric junction adenocarcinoma (AEG) and very low thoracic esophageal squamous cell carcinoma (ESCC) are similar. This study aimed to evaluate the difference in lymph node metastasis (LNM) distribution between AEG and very low thoracic ESCC. Methods: Data from 156 Siewert I-II AEG patients and 120 ESCC patients with proximal edges located within 5 cm of the esophagogastric junction (EGJ) and underwent curative surgery from 2010 to 2015 were retrospectively analyzed using propensity score matching (PSM). Five or six baseline variables were included in PSM separately. All patients underwent curative transthoracic surgery and systematic lymphadenectomy. After PSM, LNM rates of major stations were compared using the chi-squared test or Fisher's exact test. Results: After PSM was performed with covariates (age, sex, T stage, grade, tumor length), 60 pairs of patients were included. The lower mediastinal and total thoracic LNM rates of ESCC were significantly higher than those of AEG (18.3% vs. 3.3%, P=0.019; 25% vs. 3.3%, P=0.002). After further addition of the N stage as a variant to the previous PSM model, we found that the paracardial LNM distribution was significantly different between ESCC and AEG patients (36.1% vs. 19.7%, P=0.043). Among all tumor characteristics, only the T stage was positively correlated with paracardial LNM in ESCC (P=0.010), but not in AEG. In AEG, the median survival was poor for patients with thoracic LNM. Conclusions: Patients with very low thoracic ESCC exhibit stronger metastatic ability in the lower mediastinal and paracardial nodes than Siewert I-II AEG. However, the pathological metastasis of AEG in thoracic nodes was associated with poor survival outcomes.

[Effect of HMGB1 on the VEGF-C expression and proliferation of esophageal squamous cancer cells].

OBJECTIVE: To explore the effect of HMGB1 on the VEGF-C expression and proliferation of esophageal squamous cancer cells as well as its possible mechanism. METHODS: A cassette encoding siRNA targeting HMGB1 mediated by rAAV was constructed, the rAAV-siHMGB1-hrGFP, and a vector encoding siRNA mismatching HMGB1 was constructed, the rAAV-miHMGB1-hrGFP. This experiment in vitro included three groups, namely, the blank control group (group A) of KYSE150 cells transfected by rAAV-hrGFP, negative mismatch control group (group B) of KYSE150 cells transfected with rAAV-miHMGB1-hrGFP, and RNA interference group (group C) of KYSE150 cells transfected with rAAV-siHMGB1-hrGFP. We examined the expression of HMGB1 mRNA and protein in the three group cells by real-time PCR and Western blot after 24 h and 48 h, respectively. Then, VEGF-C expression and cell proliferation in the three group cells with or without sRAGE, as an inhibitor of RAGE signal pathway, were assayed by ELISA and MTT after 24 h. RESULTS: The expression of HMGB1 mRNA and protein in KYSE150 cells in vitro in the group C transfected with rAAV-siHMGB1-hrGFP at the final concentration of 2×10(6) v.g/cell was significantly lower than that of the group A or B after 24 h and 48 h (P < 0.01). The VEGF-C expression of KYSE150 cells was (502.43 ± 13.10) pg/ml in the group C, significantly reduced in comparison with that of the group A (686.40 ± 10.94) pg/ml or group B (682.31 ± 9.61) pg/ml after 24 h (P < 0.05). At the same time, the proliferation of KYSE150 cells in the group C was significantly inhibited compared with that of groups A and B after 24 h (P < 0.01). Moreover, sRAGE at the final concentration of 0.2 µg/ml inhibited the VEGF-C expression and proliferation of KYSE150 cells compared with the corresponding group without sRAGE after 24 h (P < 0.01 or P < 0.05). However, there was no significant difference of the VEGF-C expression and proliferation of KYSE150 cells with sRAGE in the group C compared with that of cells with sRAGE of the group A or group B after 24 h (P > 0.05). CONCLUSIONS: In esophageal squamous cell carcinoma, HMGB1 can promote the VEGF-C expression and proliferation of the cancer cells through RAGE signal pathway, and HMGB1-RAGE may become a potential target for cell proliferation and lymph node metastasis of this cancer.

Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage III) esophageal squamous cell carcinoma: a study protocol for a prospective, single-arm, single-center, open-label, phase-II trial (Keystone-001).

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most refractory malignant tumors. Esophageal cancer (EC) is a malignant tumor with a high incidence worldwide, and over 50% of EC cases occur in China. Under the National Comprehensive Cancer Network (NCCN) guidelines, concurrent chemoradiotherapy is the only standard neoadjuvant treatment for locally advanced ESCC. In the first-line treatment of advanced ESCC, the efficacy of immune checkpoint inhibitors (ICIs) combined with systemic chemotherapy is significantly better than that of chemotherapy alone. Paclitaxel and cisplatin (TP), as one of the neoadjuvant chemotherapy regimens for locally advanced ESCC, have been widely used in China in recent years. ICIs combined with TP as neoadjuvant therapy seems promising. Methods: This is an open-label, single-arm, single-center, phase-II trial. Locally advanced resectable (stage III) ESCC patients who have not undergone previous systemic treatments will be enrolled in this study. All the subjects will intravenously receive 3 cycles of pembrolizumab (200 mg) on day 1, paclitaxel (135 mg/m2) on day 2, and cisplatin (20 mg/m2) on days 2-4, every 3 weeks. After an efficacy evaluation, the subjects will undergo Da Vinci robot-assisted radical resection. If the postoperative pathologic results do not reveal a complete response, pembrolizumab will be administrated for at least 6 cycles as an adjuvant therapy with the same usage as before. The primary endpoints are the major pathological response and safety. The secondary endpoints include the objective response rate (ORR), overall survival (OS), disease-free survival (DFS), the R0 resection rate, and perioperative complications. The exploratory endpoint is to examine the correlation between related biomarkers and tumor responses to this neoadjuvant treatment regimen. Discussion: This trial is the first enrolled study to evaluate the safety and efficacy of pembrolizumab combined with TP as neoadjuvant therapy for locally advanced ESCC. Currently, under the NCCN guidelines, neoadjuvant chemoradiotherapy (nCRT) is the only recommended treatment for locally advanced ESCC. This phase-II study will provide preliminary evidence of the efficacy of pembrolizumab combined with TP as novel neoadjuvant therapy for patients with locally advanced ESCC. Trial Registration: Clinicaltrials.gov (Identifier: NCT04389177).

Pembrolizumab Combined With Neoadjuvant Chemotherapy Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Locally Advanced Oesophageal Squamous Cell Carcinoma: Protocol for a Multicentre, Prospective, Randomized-Controlled, Phase III Clinical Study (Keystone-002).

Background: To compare the efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy (neoCT) versus neoadjuvant chemoradiotherapy (neoCRT) followed by surgery for locally advanced resectable oesophageal squamous cell carcinoma (ESCC). Methods: This study is a multicentre, prospective, randomized-controlled, phase III clinical study. Eligible ESCC (staging: cT1N2M0 or cT2-3N0-2M0 (stage II/III, high-risk lesions in T2N0M0)) patients will be randomly assigned to either the experimental group (pembrolizumab with neoCT, n = 228) or the control group (neoCRT, n = 114) at a ratio of 2:1. Within 4-6 weeks after preoperative therapy, the McKeown procedure will be performed. Patients in the experimental group will also receive pembrolizumab alone as adjuvant therapy after surgery until 1 year or until the radiographically confirmed PD or other condition indicated for premature termination is observed. The primary endpoint is event-free survival (EFS). The secondary endpoints are 1-, 3-, and 5-year overall survival (OS) and disease-free survival (DFS), short-term outcomes, and quality of life. Discussion: This is the first prospectively randomized controlled trial designed to compare pembrolizumab plus chemotherapy and chemoradiotherapy as neoadjuvant therapy for resectable ESCC. According to our hypothesis, preoperative pembrolizumab combined with chemotherapy will result in a better tumour response and prolong the survival of patients, with acceptable toxicity. This study started in December 2021, and the enrolment time is estimated to be 2 years. Trial Registration: This prospective study has been registered at ClinicalTrials.gov (NCT04807673), March 2021.