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.

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.

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.

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.

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.

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.

Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by surgery in patients with locally advanced esophageal squamous cell carcinoma who achieved clinical complete response when induction chemoradiation finished: A phase II random.

BACKGROUND AND PURPOSE: More than 40% of patients with esophageal squamous cell carcinoma (ESCC) exhibit pathological complete responses (pCR) after neoadjuvant chemoradiotherapy (nCRT), and theoretically, these patients may be cured by CRT and omit surgery. This prospectively randomized pilot study compared definitive chemoradiotherapy (dCRT) with nCRT in patients with locally advanced ESCC who achieved clinical complete responses (cCRs) to nCRT. MATERIALS AND METHODS: Single center, randomized, open phase 2 study of 256 patients with locally advanced ESCC enrolled between April 2016 and November 2018. Immediately when nCRT finished, patients enrolled underwent response evaluations within 1 week. Patients with cCR were randomly allocated to undergo surgery (arm A) or complete CRT up to the definitive radiation dose (arm B). The primary end point was 3-year disease-free survival (DFS). RESULTS: Finally, 71 patients were randomly assigned to the nCRT (n = 36) and dCRT (n = 35) arms. The median observation time was 35.7 months. The 3-year DFS rate was 56.43 % in arm A versus 54.73 % in arm B (hazard ratio [HR] = 0.862, 95 % confidence interval [CI] = 0.452 to 1.645, P = 0.652). The 3-year overall survival (OS) rates in arms A and B were 69.5 % and 62.3 % (HR = 0.824, 95 % CI = 403-1.688, P = 0.597), respectively. CONCLUSIONS: According to our treatment response evaluation criteria, survival of the patients with cCR after nCRT was not significant different between nCRT group and dCRT group. An optimized response evaluation strategy soon after nCRT may guide next therapy decisions for patients with locally advanced ESCC.

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.

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).

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.

EMT Participates in the Regulation of Exosomes Secretion and Function in Esophageal Cancer Cells.

Epithelial-mesenchymal transition (EMT) is a key step in tumor invasion and distant metastasis. Abundant evidence has documented that exosomes can mediate EMT of tumor cells and endow them with the ability of invasion and migration. However, there are few studies focusing on whether EMT can reverse the secretion of exosomes. In this study, 2 esophageal cancer cells (FLO-1 and SK-GT-4) were selected to compare the migration ability and EMT activation, and to further analyze the secretion ability of exosomes of the 2 cell lines. According to the results, inhibited activation of EMT in FLO-1 cells with relatively high migration ability could effectively reduce the secretion of exosomes. Besides, in SK-GT-4 cells, EMT activation induced by TGF-ß could promote the secretion of exosomes. FLO-1 cell derived exosomes exhibited a paracrine effect of promoting the migration of SK-GT-4 cells, and the use of EMT inhibitors could weaken this ability. Furthermore, inhibition of EMT could change the relative content of some miRNAs in exosomes, with a particularly significant downregulation in the expression of miR-196-5p, miR-21-5p and miR-194-5p. Significantly, artificial transfection of the 3 miRNAs into exosomes by electroporation resulted in the recovery of migration-promoting effect of exosomes. Subsequent experiments further revealed that the effect of EMT on these miRNAs could be explained by the intracellular transcription level or the specific sorting mechanism of exosomes. To sum up, our study undoubtedly reveals that EMT has a regulatory effect on exosomes in the quantity and contents in esophageal cancer cells. Significantly, findings in our study provide experimental evidence for the interaction of EMT with the secretion and sorting pathway of exosomes, and also give a new direction for the further study of tumor metastasis.

Genomic Heterogeneity and Clonal Evolution in Gastroesophageal Junction Cancer Revealed by Single Cell DNA Sequencing.

Gastroesophageal junction (GEJ) cancer is a tumor that occurs at the junction of stomach and esophagus anatomically. GEJ cancer frequently metastasizes to lymph nodes, however the heterogeneity and clonal evolution process are unclear. This study is the first of this kind to use single cell DNA sequencing to determine genomic variations and clonal evolution related to lymph node metastasis. Multiple Annealing and Looping Based Amplification Cycles (MALBAC) and bulk exome sequencing were performed to detect single cell copy number variations (CNVs) and single nucleotide variations (SNVs) respectively. Four GEJ cancer patients were enrolled with two (Pt.3, Pt.4) having metastatic lymph nodes. The most common mutation we found happened in the TTN gene, which was reported to be related with the tumor mutation burden in cancers. Significant intra-patient heterogeneity in SNVs and CNVs were found. We identified the SNV subclonal architecture in each tumor. To study the heterogeneity of CNVs, the single cells were sequenced. The number of subclones in the primary tumor was larger than that in lymph nodes, indicating the heterogeneity of primary site was higher. We observed two patterns of multi-station lymph node metastasis: one was skip metastasis and the other was to follow the lymphatic drainage. Taken together, our single cell genomic analysis has revealed the heterogeneity and clonal evolution in GEJ cancer.

Risk factors for lymph node metastasis of the left recurrent laryngeal nerve in patients with esophageal squamous cell carcinoma.

BACKGROUND: The factors for left recurrent laryngeal nerve (RLN) lymph node (LN) metastasis have important guiding significance for whether the left RLN LNs should be dissected in patients with esophageal squamous cell carcinoma (ESCC), but few studies are currently available. To analyze the risk factors of LN metastasis of the left RLN area and to assess which LNs should be dissected in ESCC. METHODS: This was a retrospective study of patients who underwent McKeown minimally invasive esophagectomy (MIE) (no neoadjuvant therapy) at Tianjin Medical University Cancer Institute and Hospital (from January 2016 to December 2019). The detection of left RLN LNs using enhanced computed tomography (CT) was compared with the pathological examination. RESULTS: Of the total 94 participants, 43 had LN metastasis. The metastatic LNs were mainly located next to left (18.1%) and right (14.9%) RLN, and the left gastric artery (13.8%). Tumor size, LN size, tumor invasion (T stage), N stage, and tumor node metastasis (TNM) stage were associated with left RLN LNs metastasis, while LN size was the only independently associated factor [odds ratio (OR) =1.569, 95% confidence interval (CI): 0.259-1.956, P=0.0012]. The area under receiver operating characteristic (ROC) curve (AUC) reached 0.877, with 64% sensitivity and 75% specificity using a cutoff of 5.5 mm LN size. CONCLUSIONS: The size of left RLN LN is independently associated with metastasis. Left RLN LNs >5.5 mm at CT examination are more likely to be positive and should probably be dissected.

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.

The assessment of intraoperative technique-related risk factors and the treatment of anastomotic leakage after esophagectomy: a narrative review.

Anastomotic leakage, including cervical anastomotic leakage and intrathoracic anastomotic leakage, is a serious complication of esophageal cancer and a leading cause of death after esophagectomy. In fact, anastomotic leakage after esophagectomy can be caused by numerous factors in the preoperative, intraoperative, and postoperative periods. Intraoperative technique-related risk factors, including surgical methods, anastomosis sites, anastomosis methods, the type of gastric tube, and reconstruction routes, are the key causes of its occurrence. Anastomotic leakage treatments include both surgical and non-surgical treatments, while surgical treatment has high risks, many complications, and high mortality. Actually, non-surgical methods including naso-leakage drainage, stent, negative pressure therapy, and so on, are also very critical in the treatment of anastomotic leakage. So, the selection of correct and appropriate treatment methods plays an important role in alleviating the suffering of patients, shortening hospitalization time, and reducing mortality. This study undertook a systematic review in which data in the PubMed database were searched and analyzed to assess the safety and efficacy of surgical technique-related factors in esophagectomy, and appropriate treatment of anastomotic leakage after esophagectomy. In conclusion, gastric tube, posterior mediastinal route and stapled anastomosis are safe among esophagectomy surgical techniques, and non-surgical treatment of anastomotic leakage such as naso-leakage drainage is feasible in the majority of cases.

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.

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.

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.

Tumor marker index based on preoperative SCC and CYFRA 21-1 is a significant prognostic factor for patients with resectable esophageal squamous cell carcinoma.

OBJECTIVE: The aim of this study was to evaluate the prognostic value of a novel tumor marker index (TMI) based on preoperative serum levels of squamous cell carcinoma antigen (SCC) and cytokeratin 19 fragment (CYFRA 21-1) for patients with resectable esophageal squamous cell carcinoma (ESCC). METHODS: A total of 315 ESCC patients who had underwent curative surgery between 2008 and 2012 were retrospectively included in this study. The TMI was defined as the geometric mean of normalized SCC and CYFRA21-1 levels. Univariate and multivariate survival analyses were performed to confirm the clinical and prognostic significance of preoperative SCC and CYFRA 21-1 levels and TMI. RESULTS: Elevated preoperative SCC was associated with histological grade, pT status, lymph node status and TNM stage. Elevated preoperative CYFRA 21-1 was correlated with tumor size, lymph node status and TNM stage. The overall survival of patients with elevated SCC and CYFRA 21-1 levels was significantly poorer than that of patients with normal levels. Multivariate survival analysis identified that preoperative SCC (P= 0.353) and CYFRA 21-1 (P= 0.139) were not independent prognostic factors. The cut-off value of TMI based on SCC and CYFRA 21-1 was 0.531, and the patients were subdivided into high and low TMI groups. The 5-year survival rate of patients with high TMI was 30.9%, which was significantly lower than that of patients with low TMI (50.4%, P< 0.05). Multivariate analysis identified the TMI (HR 1.371; 95% CI 1.024-1.836; P= 0.034) as an independent prognostic factor. CONCLUSIONS: Elevated preoperative SCC and CYFRA 21-1 levels were associated with aggressive cancer behavior in ESCC. The TMI based on preoperative SCC and CYFRA 21-1 might serve as a novel marker that can be used to predict the prognosis of ESCC patients.