Dysregulation of MiR-199a/IL8 pathway in chronic Cr (VI)-induced tumor growth and angiogenesis.

Hexavalent chromium [Cr(VI)] is a well-known environmental carcinogen. Recent studies revealed that chronic exposure of human bronchial epithelial cells (BEAS-2B, B2B) to Cr(VI) activated several signaling pathways and induced cell malignant transformation and tumor growth. However, new mechanisms of Cr(VI) in inducing carcinogenesis remains to be elucidated. This study showed that miR-199a expression levels were significantly lower in Cr(VI)-transformed Cr-T cells. By using the mouse model, the expression levels of miR-199a were significantly decreased in blood samples and lung tissues of mice intranasally exposed to Cr(VI) for 12 weeks compared to the solvent exposure control. Overexpression of miR-199a inhibited tube formation and angiogenesis. C-X-C motif chemokine ligand 8 (CXCL8, IL8) levels were significantly higher in blood samples of Cr (VI)-exposed workers compared to normal workers, and forced expression of miR-199a in the cells suppressed IL8 levels. miR-199a suppression induced expression of hypoxia-inducible factor 1α (HIF-1α) and nuclear factor kappa B (NF-κB) p65 to increase IL8 expression. With animal experiment, the results showed that miR-199a overexpression inhibited tumor growth and angiogenesis through inhibiting IL8, HIF-1α and NF-κB p65 expression in vivo. These results show that miR-199a/IL8 pathway is important in Cr(VI)-induced carcinogenesis and angiogenesis.

Reconstruction of upper mediastinal pleura reduces postoperative complications in enhanced recovery surgery system after esophagectomy: A propensity score matching study.

OBJECTIVES: This study aimed to explore the effect of suturing upper mediastinum pleura on postoperative complications, surgery-related mortality, and hospital stay. METHODS: Four hundred and thirty-eight patients with esophageal cancer who underwent esophagectomy were identified. Patients were divided into two groups: those in the test group who received reconstruction of upper mediastinal pleura, those in the conventional group who did not. The incidence of postoperative complications, surgery-related mortality, and hospital stay were compared. To reduce the impact of confounding factors, a propensity score matching (PSM) method was performed. RESULTS: A total of 273 patients were treated with suturing upper mediastinal pleura and 165 were not. After PSM, compared with the conventional group, the incidence of atelectasis (7.2% vs. 1.4%, p = 0.035), anastomotic leakage (5.8% vs. 0.7%, p = 0.036), and delayed gastric emptying (10.8% vs. 3.6%, p = 0.034) were significantly lower in the test group. And suturing the upper mediastinal pleura could reduce the severity of leakage (p = 0.045), consistent with the results before PSM. Moreover, there were no significant differences in the incidence of other complications, postoperative hospital stay, and 30-day mortality (all p > 0.05). CONCLUSIONS: In this study, suturing the upper mediastinal pleura can reduce the incidence of atelectasis, anastomotic leakage, and delayed gastric emptying, and the severity of leakage, without increasing the incidence of other complications, surgery-related death, and postoperative hospital stay.

Sarcopenia and Short-Term Outcomes After Esophagectomy: A Meta-analysis.

BACKGROUND: This meta-analysis aimed to investigate the value of preoperative sarcopenia in predicting complications after esophagectomy. Clinicopathologic characteristics of sarcopenia patients, which may support sarcopenia management, also were studied. METHODS: This study searched for articles describing an association between sarcopenia and short-term outcomes after esophagectomy using PubMed, EMBASE, and the Cochrane Library. Mantel-Haenszel and inverse variance models were used for the meta-analyses of end points. RESULTS: The meta-analysis included 14 studies comprising a total of 2387 patients. Sarcopenia was significantly associated with advanced age (weighted mean difference [WMD], 3.48; 95% confidence interval [CI], 2.22-4.74), lower body mass index (WMD - 2.22; 95% CI - 2.65 to - 1.79), squamous cell carcinoma (odds ratio [OR], 2.78; 95% CI 1.72-4.47), advanced clinical tumor stage (OR 1.65; 95% CI 1.28-2.15), and neoadjuvant therapy (OR 1.87; 95% CI 1.38-2.53). The sarcopenia patients showed lower preoperative albumin levels (WMD - 0.11; 95% CI - 0.19 to - 0.04) than the nonsarcopenia patients. Sarcopenia was significantly predictive of pneumonia (OR 2.58; 95% CI 1.75-3.81) and overall complications (OR 1.52; 95% CI 1.07-2.15) after esophagectomy. The sarcopenia patients also showed nonsignificant increases in the risks of anastomotic leakage (OR 1.29; 95% CI 0.99-1.67), vocal cord palsy (OR 2.03; 95% CI 0.89-4.64), and major complications (≥ Clavien-Dindo grade III; OR 1.30; 95% CI 0.95-1.79) but not increased operation time, blood loss, or mortality. CONCLUSIONS: Preoperative sarcopenia assessment showed considerable potential for predicting postoperative complications for esophageal cancer patients. To realize this potential, more effective diagnostic criteria and severity classifications for sarcopenia are warranted.

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.

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.

Complete Mitochondrial Genome of a Tongue Worm Armillifer agkistrodontis.

Armillifer agkistrodontis (Ichthyostraca: Pantastomida) is a parasitic pathogen, only reported in China, which can cause a zoonotic disease, pentastomiasis. A complete mitochondrial (mt) genome was 16,521 bp comprising 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes, and 1 non-coding region (NCR). A phylogenetic tree drawn with the concatenated amino acid sequences of the 6 conserved PCGs (atp6, cox1-3, and nad2) showed that A. agkistrodontis and Armillifer armillatus constituted a clade Pentastomida which was a sister group of the Branchiura. The complete mt genome sequence of A. agkistrodontis provides important genetic markers for both phylogenetic and epidemiological studies of pentastomids.

[Preliminary Genetic and Functional Analyses of Schistosoma japonicum Chymotrypsin-like Protease].

OBJECTIVE: To investigate the gene expression, localization and potential functions of Schistosoma japonicum chymotrypsin-like protease (SjCTRL) in the host, and evaluate its potential immune-protection efficacy against S. japonicum infection in mice. METHODS: The physicochemical properties of SjCTRL and its phylogenetic relationship with homologous genes from other species were analyzed with bioinformatic software. The distribution of SjCTRL transcripts in 26-day-old worms was investigated using whole-mount in situ hybridization. The transcriptional levels of SjCTRL in male and female worms at four development stages (14, 18, 22, and 26 days after infection) were measured with quantitative real-time PCR. The SjCTRL-dsRNA was prepared and used to induce RNA interference (RNAi) in 26-day-old worms via soaking in vitro, and confocal microscopy was used to observe the morphological changes of worms after RNAi. Primers were designed to amplify the encoding sequence (excluding the transmembrane region) from the S. japonicum cDNA. The truncated gene was subcloned into the pET-28a plasmid, transformed into E. coli BL21 (DE3) for expression. Mice were immunized with the purified recombinant protein and challenged with cercariae. The worms and mouse liver were collected on day 35 after the challenge, and the worm-reduction rate and egg-reduction rate were calculated. RESULTS: The in situ hybridization results showed that SjCTRL mRNA was located in the posterior segment of intestinal tract of female worms, and having abundence only in 26-day-old female worms. After RNAi with SjCTRL-dsRNA, the mRNA expression was reduced to 25.7% (P< 0.05), without significant morphological changes. Using the recombinant plasmid pET-28a/SjCTRL, expression of insoluble SjCTRL protein was induced. Mice immunized with this protein gained a worm-reduction rate of 25.4% and an egg-reduction rate of 80.5% in liver after being challenged with cercariae. CONCLUSION: This study proves a high transcriptional level of SjCTRL in the posterior segment of intestinal tract in 26-day-old female worms, which can be reduced by RNAi treatment in vitro. Immunization with the SjCTRL protein can reduce adult worms and liver eggs.

Neoadjuvant chemotherapy combined with immunotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

BACKGROUND: To date, few studies have compared effectiveness and survival rates of neoadjuvant chemotherapy combined with immunotherapy (NACI) and conventional neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). The present study was conducted to compare therapeutic response and survival between NACI and NCRT. METHODS: The study cohort comprised patients with locally advanced ESCC treated with either NACI or NCRT followed by surgery between June 2018 and March 2021. The 2 groups were compared for treatment response, 3-year overall survival (OS), and disease-free survival (DFS). Survival curves were created using the Kaplan-Meier method, differences were compared using the log-rank test, and potential imbalances were corrected for using the inverse probability of treatment weighting (IPTW) method. RESULTS: Among 202 patients with locally advanced ESCC, 81 received NACI and 121 received conventional NCRT. After IPTW adjustment, the R0 resection rate (85.2% vs 92.3%; P = .227) and the pathologic complete response (pCR) rate (27.5% vs 36.4%; P = .239) were comparable between the 2 groups. Nevertheless, patients who received NACI exhibited both a better 3-year OS rate (91.7% vs 79.8%; P = .032) and a better 3-year DFS rate (87.4% vs 72.8%; P = .039) compared with NCRT recipients. CONCLUSIONS: NACI has R0 resection and pCR rates comparable to those of NCRT and seems to be correlated with better prognosis than NCRT. NACI followed by surgery may be an effective treatment strategy for locally advanced ESCC.

Dissecting Plant Gene Functions Using CRISPR Toolsets for Crop Improvement.

The CRISPR-based gene editing technology has become more and more powerful in genome manipulation for agricultural breeding, with numerous improved toolsets springing up. In recent years, many CRISPR toolsets for gene editing, such as base editors (BEs), CRISPR interference (CRISPRi), CRISPR activation (CRISPRa), and plant epigenetic editors (PEEs), have been developed to clarify gene function and full-level gene regulation. Here, we comprehensively summarize the application and capacity of the different CRISPR toolsets in the study of plant gene expression regulation, highlighting their potential application in gene regulatory networks' analysis. The general problems in CRISPR application and the optimal solutions in the existing schemes for high-throughput gene function analysis are also discussed. The CRISPR toolsets targeting gene manipulation discussed here provide new solutions for further genetic improvement and molecular breeding of crops.

Development and validation of a nomogram model for the prediction of 4L lymph node metastasis in thoracic esophageal squamous cell carcinoma.

Objectives: The left tracheobronchial (4L) lymph nodes (LNs) are considered as regional LNs for esophageal squamous cell carcinoma (ESCC), but there is a controversy about routine prophylactic 4L LN dissection for all resectable ESCCs. This study aimed to develop a nomogram for preoperative prediction of station 4L lymph node metastases (LNMs). Methods: A total of 522 EC patients in the training cohort and 370 in the external validation cohort were included. The prognostic impact of station 4L LNM was evaluated, and multivariable logistic regression analyses were performed to identify independent risk factors of station 4L LNM. A nomogram model was developed based on multivariable logistic regression analysis. Model performance was evaluated in both cohorts in terms of calibration, discrimination, and clinical usefulness. Results: The incidence of station 4L LNM was 7.9% (41/522) in the training cohort. Patients with station 4L LNM exhibited a poorer 5-year overall survival rate than those without (43.2% vs. 71.6%, p < 0.001). In multivariate logistic regression analyses, six variables were confirmed as independent 4L LNM risk factors: sex (p = 0.039), depth of invasion (p = 0.002), tumor differentiation (p = 0.016), short axis of the largest 4L LNs (p = 0.001), 4L conglomeration (p = 0.006), and 4L necrosis (p = 0.002). A nomogram model, containing six independent risk factors, demonstrated a good performance, with the area under the curve (AUC) of 0.921 (95% CI: 0.878-0.964) in the training cohort and 0.892 (95% CI: 0.830-0.954) in the validation cohort. The calibration curve showed a good agreement on the presence of station 4L LNM between the risk estimation according to the model and histopathologic results on surgical specimens. The Hosmer-Lemeshow test demonstrated a non-significant statistic (p = 0.691 and 0.897) in the training and validation cohorts, which indicated no departure from the perfect fit. Decision curve analysis indicated that the model had better diagnostic power for 4L LNM than the traditional LN size criteria. Conclusions: This model integrated the available clinical and radiological risk factors, facilitating in the precise prediction of 4L LNM in patients with ESCC and aiding in personalized therapeutic decision-making regarding the need for routine prophylactic 4L lymphadenectomy.

Clinical significance of left tracheobronchial lymph node dissection in thoracic esophageal squamous cell carcinoma.

OBJECTIVE: The left tracheobronchial lymph nodes are considered as regional lymph nodes for esophageal squamous cell carcinoma, but routine prophylactic left tracheobronchial lymph node dissection for all resectable esophageal squamous cell carcinoma has been controversial. This study aimed to evaluate the prognostic impact of left tracheobronchial lymph node dissection and left tracheobronchial lymph node metastases in thoracic esophageal squamous cell carcinoma and to analyze the risk factors of left tracheobronchial lymph node metastases. METHODS: A total of 3522 patients with esophageal squamous cell carcinoma undergoing esophagectomy were included. Overall survival was calculated by a Kaplan-Meier method and compared using the log-rank test. Propensity score matching was conducted to adjust confounding factors. Univariable and multivariable logistic regression analyses were used to identify independent risk factors of left tracheobronchial lymph node metastases. RESULTS: In this study, 608 patients underwent left tracheobronchial lymph node dissection and 45 patients had left tracheobronchial lymph node metastases (7.4%). After propensity score matching, the 5-year overall survival in patients receiving left tracheobronchial lymph node dissection was better than in patients who did not (68.2% vs 64.6%, P = .012). In patients receiving left tracheobronchial lymph node dissection, patients with left tracheobronchial lymph node metastases had a significantly poorer survival than patients without (5-year overall survival: 40.5% vs 62.2%, P = .029). Multivariable logistic analyses showed that clinical T stage and tumor differentiation were independent risk factors for left tracheobronchial lymph node metastases. CONCLUSIONS: In thoracic esophageal squamous cell carcinoma, station left tracheobronchial lymph node metastases indicate a poor prognosis and left tracheobronchial lymph nodes dissection seems to be associated with a more favorable prognosis. Clinical T stage and tumor differentiation were independent risk factors for left tracheobronchial lymph node metastases. For patients with high risk, routine prophylactic left tracheobronchial lymph node dissection should be performed.

99m Tc bone scintigraphy does not affect preoperative workup for patients with potentially resectable esophageal squamous cell carcinoma.

BACKGROUND: 99m Tc bone scintigraphy (BS) is the mainstay and most widely used technique in evaluation of bone metastasis (BM) in China. This study aimed to investigate the value of 99m Tc BS in preoperative workup for patients with potentially resectable (cT1-4a N0-3 ) esophageal squamous cell carcinoma (ESCC). METHODS: This prospective cross-section clinical trial (ChiCTR1800020304) enrolled a total of 385 patients with ESCC diagnosed at thoracic surgery clinic from October 2018 to September 2020. All patients were diagnosed with stage cT1-4a N0-3 and were potential candidates for surgical resection. BS was performed preoperatively and the treatment strategy was changed after confirmation of BM. The primary endpoint was the rate of change of the treatment regimen because of BM, while the secondary endpoint was the rate of positive BS findings. RESULTS: Out of the 385 patients, only two (0.5%) changed their treatment regimen because of BM. The rate of positive BS findings was 1%, while two patients (0.5%) had false-positive or false-negative results. The BS diagnostic performance for BM was sensitivity 50%, specificity 99.5%, positive predictive value 50%, negative predictive value 99.5%, and accuracy 99.0%. There was no significant difference in BM in relation to age, sex, tumor location or clinical stage. CONCLUSION: Our data demonstrated that 99m Tc bone scintigraphy does not significantly affect the preoperative workup in patients with potentially resectable ESCC, especially in early clinical stage patients.

Pathologic responses and surgical outcomes after neoadjuvant immunochemotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

Background: Currently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC. Methods: Of 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors. Results: After adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (P<0.001) and higher major pathological response (MPR) rate (64.7% vs. 53.6%, P=0.001) compared to those receiving NICT. However, NICT brought a higher pCR rate of metastatic LNs than conventional NCRT (53.9% vs. 37.1%, P<0.001). The rates of type I/II/III/IV regression patterns were 44.6%, 6.8%, 11.4% and 37.1% in the NICT group, 16.9%, 8.2%, 18.3% and 56.6% in the NCRT group, indicating a significant difference (P<0.001). Moreover, there were no significant differences in the incidence of total postoperative complications (35.8% vs. 39.9%, P=0.189) and 30-d mortality (0.0% vs. 1.1%, P=0.062). Conclusion: For patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.

Application of four nutritional risk indexes in perioperative management for esophageal cancer patients.

PURPOSE: The Prognostic Nutritional Index (PNI), Nutritional Risk Index (NRI), Geriatric Nutritional Risk Index (GNRI), and Controlling Nutritional Status (CONUT) score were devised for quantifying nutritional risk. This study evaluated their properties in detecting compromised nutrition and guiding perioperative management of esophageal cancer patients. METHODS: A prospective institutional database of esophageal cancer patients was reviewed and analyzed. Compromised nutritional status was defined as PNI < 50, NRI < 97.5, GNRI < 92, or CONUT score ≥ 4, respectively. The malnutrition diagnosis consensus established by the European Society of Clinical Nutrition and Metabolism (ESPEN 2015) was selected as reference. Multivariable logistic regression and receiver operating characteristic curve analysis were used. External validation was conducted. RESULTS: After reviewing the 212-patient database, 192 patients were finally included. Among the four nutritional indexes, the GNRI < 92 showed highest sensitivity (72.0%), specificity (78.9%), and consistency (AUC 0.754, 95% CI 0.672-0.836) with malnutrition diagnosed by ESPEN 2015. The GNRI < 92 showed comparable performance with ESPEN 2015 in recognizing decreased fat mass, fat-free mass, and skeletal muscle mass (all P < 0.01). Both the GNRI < 92 and ESPEN 2015 showed good property in predicting major complications, infectious complications, overall complications and delayed hospital discharge (all P < 0.01), better than PNI < 50, NRI < 97.5, and CONUT score ≥ 4. Regarding the external validation, a retrospective analysis of 155 esophageal cancer patients confirmed the better performance of GNRI < 92 in predicting perioperative morbidities than other 3 nutritional indexes. CONCLUSION: The GNRI was optimal in perioperative management of esophageal cancer patients among the four nutritional indexes and was an appropriate alternative to ESPEN 2015 for simplifying nutritional assessment.

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.

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.

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.

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.