Robot-assisted versus thoracolaparoscopic oesophagectomy for locally advanced oesophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy.

INTRODUCTION: Robot-assisted oesophagectomy (RAE) and thoracolaparoscopic oesophagectomy (TLE) are surgical techniques for the treatment of oesophageal cancer. This study aimed to compare the perioperative and mid-term outcomes of RAE versus TLE for patients with locally advanced oesophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoradiotherapy (nCRT). METHODS: Consecutive patients receiving nCRT plus RAE or TLE were retrospectively included in this single-institution study from January 2016 to January 2021. Perioperative outcomes were compared and survival analysis was performed. RESULTS: This study enrolled 251 patients, 80 (31.9%) in RAE and 171 (68.1%) in TLE. The conversion rate was equivalent in RAE versus TLE (3.8% vs 2.9%, P = 1). Median operative time in RAE was significantly shorter than that in TLE (254 vs 289 min, P < 0.001). Compared to TLE, RAE harvested more lymph nodes along the recurrent laryngeal nerve [4 (3-6) vs 3 (1-5), P < 0.001]. Overall complications were similar in RAE compared to TLE (38.8% vs 38.0%, P = 0.911). No statistically significant difference in disease-free survival (log-rank P = 0.721) or overall survival (log-rank P = 0.325) was found between groups. CONCLUSIONS: Compared to TLE, RAE could achieve shorter operative duration and better lymph nodes dissection along the bilateral RLN for locally advanced ESCC after nCRT, with comparable short-term outcomes. A long-term survival remains to be verified.

Clonal relationship and alcohol consumption-associated mutational signature in synchronous hypopharyngeal tumours and oesophageal squamous cell carcinoma.

BACKGROUND: The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading. METHOD: Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients. RESULTS: All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (p = 0.013) and public data set (n = 165, p = 0.003). This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival. CONCLUSIONS: Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis.

A population-based predictive model predicting candidate for primary tumor surgery in patients with metastatic esophageal cancer.

BACKGROUND: The survival benefit of primary tumor surgery for metastatic esophageal cancer (mEC) patients has been observed, but methods for discriminating which individual patients would benefit from surgery have been poorly defined. Herein, a predictive model was developed to test the hypothesis that only certain metastatic patients would gain a survival benefit from primary tumor surgery. METHODS: Clinical data for patients with mEC were extracted from the Surveillance, Epidemiology and End Results (SEER) database [2004-2016] and then divided into surgery and no-surgery groups according to whether surgery was performed on the primary tumor. Propensity-score-matching (PSM) was performed to balance the confounding factors. We hypothesized that the patients who had undergone surgery and lived longer than the median cancer-specific-survival (CSS) of the no-surgery group could benefit from surgery. We constructed a nomogram to predict surgery benefit potential based on multivariable logistic-regression analysis using preoperative factors. The predictive performance of the nomogram was evaluated by the area under the receiver operating characteristic (AUC) and calibration curves. The clinical application value of the nomogram was estimated with decision curve analysis (DCA). RESULTS: A total of 5,250 eligible patients with mEC were identified, and 9.4% [492] received primary tumor surgery. After PSM, CSS for the surgery group was significantly longer [median: 19 vs. 9 months; hazard ratio (HR) 0.52, P<0.001] compared with the no-surgery group. Among the surgery group, 69.3% [327] survived >9 months (surgery-beneficial group). The prediction nomogram showed good discrimination both in training and validation sets (AUC: 0.72 and 0.70, respectively), and the calibration curves indicated a good consistency. DCA demonstrated that the nomogram was clinically useful. According to this nomogram, surgery patients were classified into two groups: no-benefit-candidate and benefit-candidate. The benefit-candidate group was associated with longer survival than the no-benefit-candidate group (median CSS: 19 vs. 6.5 months, P<0.001). Additionally, there was no difference in survival between the no-benefit-candidate and no-surgery groups (median CSS: 6.5 vs. 9 months, P=0.070). CONCLUSIONS: A predictive model was created for the selection of candidates for surgical treatment among mEC patients. This predictive model might be used to select patients who may benefit from primary tumor surgery.

Assessment of Quality Outcomes and Learning Curve for Robot-Assisted Minimally Invasive McKeown Esophagectomy.

BACKGROUND: This study aimed to identify the results of the quality assessment and the learning curve of robot-assisted minimally invasive McKeown esophagectomy (RAMIE-MK). METHODS: The study retrospectively reviewed the data of 400 consecutive patients with esophageal cancer who underwent RAMIE-MK by a single surgeon from November 2015 to March 2019. Cumulative summation analysis of the learning curve was performed. The patients were divided into decile cohorts of 40 cases to minimize demographic deviations and to maximize the power of detecting statistically significant changes in performance. RESULTS: The 90-day mortality rate for all the patients was 0.5% (2 cases). The authors' experience was divided into the ascending phase (40 cases), the plateau phase (175 cases), and the descending phase (185 cases). After 40 cases, significant improvements in operative time (328 vs. 251 min; P = 0.019), estimated blood loss (350 vs. 200 ml; P = 0.031), and conversion rates (12.5% vs. 2.5%; P < 0.001) were observed. After 80 cases, a decrease in the rates of anastomotic leakage (22.5% vs. 8.1%; P = 0.001) and vocal cord palsy (31.3% vs. 18.4%; P = 0.024) was observed. The number of harvested lymph nodes increased after 40 cases (13 vs. 23; P < 0.001), especially for lymph nodes along the recurrent laryngeal nerve (3.0 vs. 6.0; P < 0.001). CONCLUSIONS: The learning phase of RAMIE-MK consists of 40 cases, and quality outcomes can be improved after 80 procedures. Several turning points related to the optimization of surgical outcomes can be used as benchmarks for surgeons performing RAMIE-MK.

Risk Factors for Anastomotic Complications After Radical McKeown Esophagectomy.

BACKGROUND: Surgical resection with esophagogastric anastomosis is the preferred treatment for patients with esophageal cancer. This study aimed to investigate independent risk factors for anastomotic leakage and stricture in patients undergoing radical McKeown esophagectomy. METHODS: This single-institution study retrospectively included 1300 patients who had undergone radical McKeown esophagectomy between March 2014 and July 2019. Univariable and multivariable regression analyses were performed to identify independent risk factors of anastomotic leakage and stricture. A point system for leakage was set up on the basis of multivariable regression model. RESULTS: Leakage occurred in 135 (10.4%) of the patients. Multivariable analyses showed that sex (male vs female, odds ratio [OR] 2.619), age (OR 1.038), preoperative albumin (OR 0.916), and width of gastric tube (5 cm vs 3 cm, OR 2.063) were associated with the risk of leakage. Stricture was noted in 335 (28.4%) of the 1178 patients and included grade I (258, 21.9%) and grade II (77, 6.5%). Multivariable analyses identified grade II (OR 2.195) or III (OR 12.001) leakage as an independent risk factor for stricture. A point system for risk factors was set up and associated with theoretical risk of leakage from 0.016 to 0.245 (c-statistic = 0.659). CONCLUSIONS: Male sex, older age, lower preoperative albumin, and 5-cm-wide gastric tube increased the risk for leakage development with cervical anastomosis. The grade of leakage was significantly associated with the formation of stricture. Valuing these factors could improve the perioperative strategy to prevent anastomotic complications.

The mechanism of ABL1 upregulating the expression of PD-L1 and the therapeutic effect of PD-L1 and STAT3 inhibitors in lung adenocarcinoma.

The upregulation of programmed cell death-ligand 1 (PD-L1) and continuous mutation of EGFR could induce chemoresistance in somatic cancers, however, the molecular mechanism of oncogene ABL1 in regulating the expression of PD-L1 in lung adenocarcinoma (LAD) remains unclear. In addition, the therapeutic effect of STAT3 and PD-L1 inhibitors in LAD is not fully understood. The ABL1 lentiviruses were used to transfect LAD cell lines (H1975, PC-9) with different EGFR mutation subtypes. Next, the expression of the JAK/STAT3 and PD-L1 pathway was detected followed by the treatment with STAT3 and PD-L1 inhibitors. Lastly, we observed the apoptosis and expression of STAT3 and PD-L1 before and after treatments in transfected and knocked down cell lines. The expression of ABL1 was upregulated by more than 3.71-fold and the expression of PD-L1 increased by 4.85-fold in lung cancer tissues compared with para-cancer tissues (both p<0.01), the ABL1 could induce upregulation of PD-L1 in LAD cell lines. Furthermore, the STAT3 inhibitor might induce more apoptosis than the PD-L1 inhibitor in both H1975 and PC-9 cell lines (both p<0.01) The STAT3 inhibitor combined with PD-L1 inhibitor had a synergistic effect on the PC-9 cell line, and the antagonistic effect was observed on the H1975 cell line. Furthermore, the expression of PD-L1 decreased almost equally after the PD-L1 inhibitor combined with a STAT3 inhibitor, or the STAT3 inhibitor alone (p>0.05). In addition, the STAT3 and PD-L1 decreased significantly after the STAT3 inhibitor compared with other treatments on the H1975 cell line (both p<0.01). To conclude, the EGFR mutation subtypes might influence the therapeutic efficacy in the treatment with PD-L1 inhibitor combined with STAT3 inhibitor on LAD cell lines.

Near-Infrared Fluorescent Image-Guided Lymphatic Mapping in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Recently, the feasibility of near-infrared (NIR) image-guided sentinel lymph node (SLN) mapping has been tested in patients with gastrointestinal cancer. The aim of this study is to investigate whether SLN mapping can be used to identify mediastinal lymph node metastases during minimally invasive esophagectomy and explore the lymphatic drainage pattern of esophageal squamous cell carcinoma (ESCC) using NIR fluorescent imaging. PATIENTS AND METHODS: A total of 21 patients diagnosed with cT1-3 stage ESCC were enrolled. Patients received submucosal injection of indocyanine green diluted with sodium chloride (0.9%) at the start of the esophagectomy procedure followed by NIR mapping. RESULTS: Thoracoscopic-assisted McKeown esophagectomy with NIR imaging was successfully performed in all patients. The detection rate and number of NIR+ lymph nodes were 95.2% (20/21) and 4.0 (2.0-6.5), respectively. The accuracy, false-negative rates, and negative predictive value were 100% (10 of 10 cases), 0% (0 of 4), and 100% (6 of 6), respectively, for pT1/T2 diseases; and 80.0% (8 of 10), 40% (2 of 5), and 71.4% (5 of 7), respectively, for pT3 diseases. The NIR+ region was the most commonly detected in the right recurrent laryngeal nerve (80%), and the NIR+ region was identified in the upper mediastinal zone in 20 patients. CONCLUSIONS: Evaluation of the lymphatic drainage pattern and the application of sentinel lymph node in ESCC with real-time NIR imaging could be effective, especially in pT1/2 disease. NIR imaging-guided SLN navigation appears to be a clinically beneficial less-invasive method for treating ESCC.

The value of enhanced CT scanning for predicting lymph node metastasis along the right recurrent laryngeal nerve in esophageal squamous cell carcinoma.

BACKGROUND: The right recurrent laryngeal nerve (RRLN) is the region most prone to lymph node metastasis in esophageal squamous cell carcinoma (ESCC). Nodal involvement may be underestimated by traditional imaging prediction criteria, such as a short axis diameter of 10 mm. The purpose of this study was to determine a more accurate imaging criterion to guide clinical treatment strategy selection. METHODS: The clinical data of 307 patients with thoracic ESCC who underwent surgery at Shanghai Chest Hospital between January 2018 and December 2018 were retrospectively analyzed. Utilizing 1-mm layer thickness enhanced computed tomography (CT), the RRLN lymph node short diameter (LNSD) size was measured. Univariate and multivariate analyses were performed to determine the risk factors for lymph node metastasis along the RRLN. RESULTS: In our study, RRLN lymph node metastasis occurred in 60 (19.5%) patients and general lymph node metastasis occurred in 150 (48.9%) patients. Of the resected lymph nodes along the RRLN, 14.5% (121/832) were positive. Multivariate analysis identified LNSD [odds ratio (OR), 1.236] as an independent risk factor for RRLN lymph node metastasis. In CT evaluation, a short diameter of 6.5 mm in the RRLN lymph nodes is a critical predictor of metastasis at this site (sensitivity =50%, specificity =83.4%) and a larger short diameter was associated with a higher risk of metastasis (P<0.001). CONCLUSIONS: A 6.5 mm cutoff in LNSD can be applied to clinically predict lymph node metastasis in the RRLN region for patients with ESCC.