CircRNA CircZMYM4 inhibits the growth and metastasis of lung adenocarcinoma via the miR-587/ODAM pathway.

Circular RNAs (circRNAs) are known to regulate tumorigenesis. In this study, circRNAs microarray was used to analyze the circRNA expression in lung adenocarcinoma (LUAD) tissues, and CircRNA zinc finger MYM-type containing 4(circZMYM4) was selected for further analysis. In this study, we detected circZMYM4 expression in LUAD specimens and cell lines using RT-PCR. The expression of circZMYM4 was further verified in the GEO datasets and TCGA datasets. Gain-of-function and loss-of-function experiments were used to analyze the effects of circZMYM4 on LUAD in vivo and in vitro. The relationship between miR-587 and circZMYM4 or ODAM was predicted by bioinformatics tools and confirmed using dual-luciferase reporter assays and RNA-pull down. We found that circZMYM4 was distinctly down-regulated in LUAD tissues and cell lines. Functional assays revealed that circZMYM4 overexpression suppressed LUAD cell proliferation, metastasis and suppressed apoptosis, while miR-587 overexpression could weaken these effects. Importantly, circZMYM4 upregulated ODAM expression via sponging miR-587 to suppress LUAD progression. ODAM knockdown could reverse the repressive effect of circZMYM4 overexpression on cell proliferation, migration and invasion abilities. Overall, circZMYM4 regulates the miR-587/ODAM axis to suppress LUAD progression, which may become a potential biomarker and therapeutic target.

A phase III study on neoadjuvant chemotherapy versus neoadjuvant toripalimab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: Henan Cancer Hospital Thoracic Oncology Group 1909 (HCHTOG1909).

BACKGROUND: Neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACR) are the standard treatments for esophageal squamous cell carcinoma (ESCC). However, the 5-year overall survival (OS) rate is still far from satisfactory. In recent years, immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of ESCC. More than 20 phase II clinical trials have been launched to explore combinations of ICIs in the neoadjuvant setting for ESCC. Based on our phase II clinical trial, a two-arm phase III trial was launched in Henan Cancer Hospital. ICIs combined with NAC may usher in a new era and may benefit locally advanced, resectable ESCC patients. METHODS: A two-arm phase III trial was launched in April 2020 in Henan Cancer Hospital. Patient recruitment will be completed within 18 months. The primary endpoint is event-free survival (EFS). The secondary endpoints include pathologic complete response (pCR), disease-free survival (DFS) rate, overall response rate (ORR), R0 resection rate, major pathologic response (MPR), adverse events (AEs), complication rate and quality of life (QOL). A biobank of pretreatment, resected tumor tissue and paired blood samples will be built for translational research in the future. DISCUSSION: This RCT directly compares NAC with neoadjuvant toripalimab plus chemotherapy in terms of EFS for locally advanced ESCC. The results may usher in a new era of resectable ESCC treatment. TRIAL REGISTRATION: NCT04280822 (https://www.clinicaltrials.gov/ct2/show/NCT04280822). Registered title: "A Phase III, Randomized Controlled Study of Neo-adjuvant Toripalimab (JS001) in Combination with Chemotherapy versus Neo-adjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma". Version 1.0/Nov. 21, 2019.

Highlighting sarcopenia management for promoting surgical outcomes in esophageal cancers: Evidence from a prospective cohort study.

BACKGROUND: Studies have provided controversial and limited knowledge regarding the impact of sarcopenia on surgical outcomes in esophageal cancers due to retrospective study designs and single muscle-mass assessment. This prospective cohort study aimed to resolve these issues. METHODS: Bioelectrical impedance analysis, handgrip strength measurement, and the 4-m walking test were conducted before surgery. Sarcopenia was diagnosed as low appendicular skeletal muscle mass index (<7.0 kg/m2 in men and <5.7 kg/m2 in women) plus low handgrip strength (<26 kg in men and <18 kg in women) and/or low gait speed (<0.8 m/s). Presarcopenia was diagnosed as either: (1) solely low muscle mass index; or (2) solely low handgrip strength and/or gait speed. Endpoints included perioperative biochemical indicators, postoperative complications, and the recovery of postoperative quality of life (QOL). RESULTS: In total, 212 patients were enrolled, including 55 (25.9%) and 60 (28.3%) patients diagnosed with sarcopenia and presarcopenia, respectively. The presarcopenic and normal patients showed a similar risk of postoperative complications and were combined. Despite similar baseline levels, sarcopenic patients (vs. non-sarcopenic) showed decreased prealbumin on postoperative day (POD) 1, decreased albumin on PODs 1, 3, and 5, and delayed recovery of lymphocyte counts (all P < 0.05). The levels of C-reactive protein in sarcopenic patients was lower than in non-sarcopenic patients on POD 1 (P = 0.010) but higher on POD 5 (P = 0.001). Multivariate analyses demonstrated the independent predictive value of sarcopenia for overall complications (P < 0.001), major complications (Clavien-Dindo grade ≥ III, P = 0.001), and delayed hospital discharge (>12 days, P < 0.001). Sarcopenia was demonstrated as a risk factor for deteriorated global QOL (P = 0.001), physical (P = 0.001) and role functions (P = 0.006), and severe fatigue (P = 0.004) at four weeks after surgery. CONCLUSIONS: Sarcopenia was associated with poor metabolic stress and immune responses surrounding esophagectomy and was a potential target for reducing complications and promoting recovery of QOL.

Clinical evaluation of right recurrent laryngeal nerve nodes in thoracic esophageal squamous cell carcinoma.

BACKGROUND: The accuracy of clinical N staging of esophageal squamous cell carcinoma is suboptimal. As an important station of lymph node metastasis, station C201 (right recurrent laryngeal nerve nodes) has rarely been evaluated alone. We aimed to explore an effective way to evaluate the right recurrent laryngeal nerve nodes in thoracic esophageal squamous cell carcinoma. METHODS: We retrospectively analyzed 628 thoracic esophageal squamous cell carcinoma patients who underwent radical resection without neoadjuvant therapy from two Chinese cancer centers. The diameter of the short axis of the largest right recurrent laryngeal nerve node (DC201) was measured on contrast-enhanced multi-slice computed tomography (MSCT). Right recurrent laryngeal nerve nodes were examined by postoperative pathologic results. The receiver operating characteristic (ROC) curve was generated to assess the diagnostic capabilities of DC201 to determine the right recurrent laryngeal nerve nodes status. RESULTS: ROC curve analysis revealed that the optimal cut-off point of DC201 was 6 mm, with an area under curve (AUC), sensitivity, specificity, and Youden index of 0.896, 71.9%, 88.8%, and 0.607 respectively. When the cut-off point of DC201 was set to 10 mm, sensitivity, specificity and the Youden index were 14.1%, 99.6% and 0.137 respectively. Among 128 patients with right recurrent laryngeal nerve node metastasis, 71 and 108 patients had the largest right recurrent laryngeal nerve node located above the suprasternal notch level and in the tracheoesophageal groove respectively. CONCLUSIONS: When DC201 ≥6.0 mm instead of DC201 ≥10 mm was used to dictate the right recurrent laryngeal nerve nodes metastasis, contrast-enhanced MSCT could evaluate the status of right recurrent laryngeal nerve nodes with high sensitivity and specificity. The largest right recurrent laryngeal nerve nodes were mainly located in the tracheoesophageal groove and/or above the suprasternal notch.

Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for locally advanced oesophageal squamous cell carcinoma: a single-Centre, open-label, randomized, controlled, clinical trial (HCHTOG1903).

BACKGROUND: Neoadjuvant therapy plus oesophagectomy has been accepted as the standard treatment for patients with potentially curable locally advanced oesophageal cancer. No completed randomized controlled trial (RCT) has directly compared neoadjuvant chemotherapy and neoadjuvant chemoradiation in patients with oesophageal squamous cell carcinoma (ESCC). The aim of the current RCT is to investigate the impact of neoadjuvant chemotherapy plus surgery and neoadjuvant chemoradiotherapy plus surgery on overall survival for patients with resectable locally advanced ESCC. METHODS: This open label, single-centre, phase III RCT randomized patients (cT2-T4aN + M0 and cT3-4aN0M0) in a 1:1 fashion to receive either the CROSS regimen (paclitaxel 50 mg/m2; carboplatin (area under the curve = 2), q1w, 5 cycles; and concurrent radiotherapy, 41.4 Gy/23 F, over 5 weeks) or neoadjuvant chemotherapy (paclitaxel 175 mg/m2; and cisplatin 75 mg/m2, q21d, 2 cycles). Assuming a 12% 5-year overall survival difference in favour of the CROSS regimen, 80% power with a two-sided alpha level of 0.05 and a 5% dropout each year for an estimated 3 years enrolment, the power calculation requires 456 patients to be recruited (228 in each group). The primary endpoint is 5-year overall survival, with a minimum 5-year follow-up. The secondary endpoints include 5-year disease-free survival, toxicity, pathological complete response rate, postoperative complications, postoperative mortality and quality of life. A biobank of pre-treatment and resected tumour tissue will be built for translational research in the future. DISCUSSION: This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies. TRIAL REGISTRATION: NCT04138212, date of registration: October 24, 2019.

LncRNA SNHG1 Regulates the Progression of Esophageal Squamous Cell Cancer by the miR-204/HOXC8 Axis.

OBJECTIVE: Long noncoding RNA small nucleolar RNA host gene 1 (SNHG1) has been reported to be aberrantly expressed and plays an important role in human cancers, including esophageal squamous cell cancer. However, the regulatory mechanism underlying SNHG1 in the progression of esophageal squamous cell cancer is poorly defined. MATERIALS AND METHODS: Fifty-three esophageal squamous cell cancer patients were recruited and overall survival was analyzed. EC9706 and KYSE150 cells were cultured for study in vitro. The expression levels of SNHG1, microRNA (miR)-204 and homeobox c8 (HOXC8) were detected by quantitative real-time polymerase chain reaction and Western blot. Cell cycle distribution, apoptosis, migration and invasion were determined by flow cytometry and transwell assays, respectively. The target interaction among SNHG1, miR-204 and HOXC8 was validated by luciferase reporter assay and RNA immunoprecipitation. Xenograft model was established to investigate the role of SNHG1 in vivo. RESULTS: High expression of SNHG1 was exhibited in esophageal squamous cell cancer and indicated poor outcomes of patients. SNHG1 silence led to cell cycle arrest at G0-G1 phase, inhibition of migration and invasion and increase of apoptosis. miR-204 was validated to sponge by SNHG1 and target HOXC8 in esophageal squamous cell cancer cells. miR-204 knockdown or HOXC8 restoration reversed the inhibitive role of SNHG1 silence in the progression of esophageal squamous cell cancer cells. Furthermore, inhibiting SNHG1 decreased xenograft tumor growth by regulating miR-204 and HOXC8. CONCLUSION: SNHG1 knockdown suppresses migration and invasion but induces apoptosis of esophageal squamous cell cancer cells by increasing miR-204 and decreasing HOXC8.

Impact of an Early Oral Feeding Protocol on Inflammatory Cytokine Changes After Esophagectomy.

BACKGROUND: The aim of the current study was to investigate the impact of early oral feeding (EOF) on inflammatory cytokine levels after McKeown minimally invasive esophagectomy (MIE) for cancer. METHODS: This study was based on a randomized controlled trial (NCT01998230). Patients with esophageal cancer who received McKeown MIE were randomly allocated into a group that started oral feeding on postoperative day (POD) 1 (EOF group) or a second group that received nil by mouth until 7 days after operation (late oral feeding [LOF] group). We chose 86 patients, 46 patients in the EOF group and 40 patients in the LOF group, in which to analyze inflammatory cytokine levels (interleukin [IL]-6, IL-8, tumor necrosis factor-a [TNF-α], and monocyte chemotactic protein-1 [MCP-1]). RESULTS: The EOF and LOF groups exhibited similar preoperative IL-6, IL-8 TNF-α, and MCP-1 levels. The levels of the four inflammatory cytokines at PODs 1 and 3 were significantly higher than the preoperative levels (all p < 0.001). At POD 5 the levels of all four inflammatory cytokines were decreased compared with those at PODs 1 and 3. At PODs 3 and 5 the levels of IL-6, IL-8, and TNF-α were significantly lower in the EOF group than in the LOF group (all p < 0.05). At POD 3 the MCP-1 levels in the EOF group were significantly lower than those in the LOF group (all p < 0.05). CONCLUSIONS: Compared with conventional rehabilitation programs the EOF protocol may decrease stress response after McKeown MIE.

Is laryngeal mask airway general anesthesia feasible for minimally invasive esophagectomy?

Minimally invasive esophagectomy (MIE) has been identified as an oncological method with lower mortality and morbidity. This procedure is usually performed under general anesthesia using double endotracheal tube intubation and one-lung ventilation for a good visualization like other video-assisted thoracoscopic surgery (VATS). However, it is difficult to differentiate weather the postoperative hoarseness is caused by intubation or by recurrent laryngeal nerve injury during operation, and some complications related to intubation also are the focus of thoracic surgeons. Recently, VATS without tracheal intubation were reported to be feasible and safe in a series of VATS procedures, including management of pneumothorax, wedge resection of pulmonary tumors, excision of mediastinal tumors, lung reduction surgery and lobectomy. However, there is no report about its use in MIE. In December of 2012, we successfully applied nonintubated laryngeal mask airway (LMA) general anesthesia in MIE for three patients with esophageal cancer. Here, we retrospectively report the tentative results.

Early Oral Feeding Following McKeown Minimally Invasive Esophagectomy: An Open-label, Randomized, Controlled, Noninferiority Trial.

OBJECTIVE: Our objective was to evaluate the impact of early oral feeding (EOF) on postoperative cardiac, respiratory, and gastrointestinal (CRG) complications after McKeown minimally invasive esophagectomy for esophageal cancer. SUMMARY BACKGROUND DATA: Nil-by-mouth with enteral tube feeding is routinely practiced after esophagectomy. METHODS: Patients were randomly allocated to receive oral feeding on the first postoperative day (EOF group) or late oral feeding (LOF group) 7 days after surgery. The primary endpoint was the occurrence of postoperative CRG complications, and the secondary outcomes included bowel function recovery and short-term quality of life (QOL). RESULTS: Between February 2014 and October 2015, 280 patients were enrolled in this study. There were 140 patients in the EOF group and 140 patients in the LOF group. EOF was noninferior to LOF for CRG complications (30.0% in the EOF group vs. 32.9% in the LOF group; 95% confidence interval of the difference: -13.8% to 8.0%). Compared with the LOF group, the EOF group showed significantly shorter time to first flatus (median of 2 days vs. 3 days, P = 0.001) and bowel movement (median of 3 vs. 4 days, P < 0.001). Two weeks after the operation, patients in the EOF group reported higher global QOL and function scores and lower symptom scores than patients in the LOF group. CONCLUSIONS: In patients after McKeown minimally invasive esophagectomy is noninferior to the standard of care with regard to postoperative CRG complications. In addition, patients in the EOF group had a quicker recovery of bowel function and improved short-term QOL.

Embedded Three-Layer Esophagogastric Anastomosis Reduces Morbidity and Improves Short-Term Outcomes After Esophagectomy for Cancer.

BACKGROUND: There exists great controversy regarding the use of esophagogastric anastomotic techniques in the treatment of esophageal cancer. The aim of this study was to compare two types of cervical esophagogastric anastomoses with respect to the reduction of postoperative anastomotic leaks, stenosis, and gastroesophageal reflux. METHODS: From June 2010 to September 2013, 339 patients who underwent two different cervical esophagogastric anastomotic procedures after thoracolaparoscopic esophagectomy for esophageal cancer were identified. RESULTS: A total of 166 patients with esophageal cancer were treated using an embedded three-layer anastomosis (embedded group), and 173 were treated using a conventional two-layer anastomosis (conventional group). The rates of anastomotic leak (2.4% [4 of 166] versus 7.5% [13 of 173], p = 0.031) and benign anastomotic stricture (4.8% [8 of 166] versus 12.7% [22 of 173], p = 0.010) were significantly lower in the embedded group compared with the conventional group. The mean reflux scores were significantly higher among the patients in the conventional group compared with the patients in the embedded group at 1 month (25.2 versus 19.0, p = 0.001), 3 months (27.8 versus 21.4, p = 0.001), and 6 months (23.4 versus 17.8, p < 0.001) of follow-up. The mean scores for dysphagia were significantly lower among the patients in the embedded group compared with the patients in the conventional group at both 3 months (22.7 versus 29.8, p = 0.012) and 6 months (16.0 versus 21.3, p = 0.008) of follow-up. CONCLUSIONS: The new embedded three-layer esophagogastric anastomosis offers several advantages and reduces the incidence of postoperative complications such as anastomotic leak, stricture, and gastroesophageal reflux.

Early oral feeding following thoracolaparoscopic oesophagectomy for oesophageal cancer.

OBJECTIVES: Nil-by-mouth with enteral tube feeding is widely practised for several days after resection and reconstruction of oesophageal cancer. This study investigates early changes in postoperative gastric emptying and the feasibility of early oral feeding after thoracolaparoscopic oesophagectomy for patients with oesophageal cancer. METHODS: Between January 2013 and August 2013, gastric emptying of liquid food and the feasibility of early oral feeding after thoracolaparoscopic oesophagectomy was investigated in 68 patients. Sixty-five patients previously managed in the same unit who routinely took liquid food 7 days after thoracolaparoscopic oesophagectomy served as controls. RESULTS: The mean preoperative half gastric emptying time (GET1/2) was 66.4 ± 38.4 min for all 68 patients, and the mean GET1/2 at postoperative day (POD) 1 and POD 7 was statistically significantly shorter than preoperative GET1/2 (23.9 ± 15.7 min and 24.1 ± 7.9 min, respectively, both P-values <0.001). Of the 68 patients who were enrolled to analyse the feasibility of early oral feeding, 2 (3.0%) patients could not take food as early as planned. The rate of total complication was 20.6% (14/68) and 29.2% (19/65) in the early oral feeding group and the late oral feeding group, respectively (P = 0.249). Compared with the late oral feeding group, time to first flatus and bowel movement was significantly shorter in the early oral feeding group. CONCLUSIONS: Compared with preoperative gastric emptying, early postoperative gastric emptying for liquid food after oesophagectomy is significantly faster. Postoperative early oral feeding in patients with thoracolaparoscopic oesophagectomy is feasible and safe.