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Let R k = F q u 1 , u 2 , ⋯ , u k / < u i 2 = α i u i , u i u j = u j u i = 0 > , where q = p m , p is an odd prime, α i is a unit over F q , and i , j = 1,2 , ⋯ , k . In this article, we define a Gray map from R k n to F q k + 1 n , we study the structure of skew ϱ - λ -constacyclic codes over R k , and then we give the necessary and sufficient conditions for skew ϱ - λ -constacyclic codes over R k to satisfy dual containing. Further, we have obtained some new nonbinary quantum codes from skew ϱ - λ -constacyclic over R k by using the CSS construction.

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.

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.

Cervical anastomotic leakages may manifest either cervically or intrathoracically. We retrospectively investigated the management strategies and clinical outcomes of patients who developed anastomotic leakages after McKeown esophagectomy and the spectrum of its clinical manifestations.Patients with esophageal cancer who underwent McKeown esophagectomy with cervical anastomosis (n = 749) between January 2015 and December 2018 were included.Cervical anastomosis leakage was diagnosed in 53/749 (7.3%) patients. The leakage was primarily limited to cervical region in 16 (30.2%) patients, whereas intrathoracic spread was present in 37 (69.8%) patients. Intrathoracic manifestations were more commonly accompanied by fever (75.7% vs. 18.8%, P 0.001) and leukocytosis than cervical manifestations (81.1% vs. 25.0%, P 0.001). Compared to patients with cervical manifestations, those with intrathoracic manifestations had a longer duration of hospital stay (median; 58 vs. 40 days, P = 0.006) and higher incidence of tracheal fistula (21.6% vs. 0%, P = 0.045). Drainage through the neck wound was effective in all patients with cervical manifestations. Patients with intrathoracic manifestations who had transnasal inner drain or mediastinal drain placed intraoperatively achieved satisfactory drainage (27/37, 73.0%). Subsequent healing of anastomotic leaks was observed in 50 (94.3%) patients. There was no mortality associated with complications related to anastomotic leakage.Intrathoracic manifestations of cervical anastomotic leakage are common in patients after McKeown esophagectomy. However, they are diagnosed later and are associated with more severe clinical consequences than cervical manifestations. Thus, a high index of suspicion and an early intervention policy for such anastomotic leaks should be adopted and strengthened to decrease the incidence of adverse clinical outcomes.

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.

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.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).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.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.

Chest wall tumors are a relatively uncommon disease in clinical practice. Most of the published studies about chest wall tumors are usually single-center retrospective studies, involving few patients. Therefore, evidences regarding clinical conclusions about chest wall tumors are lacking, and some controversial issues have still to be agreed upon. In January 2019, 73 experts in thoracic surgery, plastic surgery, science, and engineering jointly released the Chinese Expert Consensus on Chest Wall Tumor Resection and Chest Wall Reconstruction (2018 edition). After that, numerous experts put forward new perspectives on some academic issues in this version of the consensus, pointing out the necessity to further discuss the points of contention. Thus, we conducted a survey through the administration of a questionnaire among 85 experts in the world. Consensus has been reached on some major points as follows. (I) Wide excision should be performed for desmoid tumor (DT) of chest wall. After excluding the distant metastasis by multi-disciplinary team, solitary sternal plasmacytoma can be treated with extensive resection and adjuvant radiotherapy. (II) Wide excision with above 2 cm margin distance should be attempted to obtain R0 resection margin for chest wall tumor unless the tumor involves vital organs or structures, including the great vessels, heart, trachea, joints, and spine. (III) For patients with chest wall tumors undergoing unplanned excision (UE) for the first time, it is necessary to carry out wide excision as soon as possible within 1-3 months following the previous surgery. (IV) Current Tumor Node Metastasis staging criteria (American Joint Committee on Cancer) of bone tumor and soft tissue sarcoma are not suitable for chest wall sarcomas. (V) It is necessary to use rigid implants for chest wall reconstruction once the maximum diameter of the chest wall defect exceeds 5 cm in adults and adolescents. (VI) For non-small cell lung cancer (NSCLC) invading the chest wall, wide excision with neoadjuvant and/or adjuvant therapy are recommended for patients with stage T3-4N0-1M0. As clear guidelines are lacking, these consensus statements on controversial issues on chest wall tumors and resection could possibly serve as further guidance in clinical practice during the upcoming years. ispartof: TRANSLATIONAL LUNG CANCER RESEARCH vol:10 issue:11 pages:4057-4083 ispartof: location:China status: published

Background: Multimodal therapies, such as perioperative chemotherapy and neoadjuvant chemoradiotherapy together with surgical advances, have improved the outcomes of patients with resectableesophageal cancer (EC).However, the 5-year survival of these patients remains below 50%. The advent of immunotherapy has resulted in novel approaches to advanced or metastatic disease, but the role of immunotherapy in the neoadjuvant settings has not yet to be established. In this single-arm study, the efficacy and safetyofneoadjuvant pembrolizumab plus chemotherapy were evaluatedin patients with resectableesophageal squamous cell carcinoma (ESCC).Methods: This study was conducted at 2 hospitals(in Xi'an and Tianjin)and included patients with ESCC of clinical stage II–IVAwho underwent surgery within 4 to 6 weeks after completing treatment withpembrolizumab(200mg) combined with a conventional chemotherapy regimen (3 cycles). The efficacy and safety of this combination treatment were evaluated as primary endpointsof the study. This study was retrospectively registered (Registration number: ChiCTR2100048917).Results:A total of 22 patients (including 18 men) were enrolled, of whom 17 patients progressed to surgery,4 patients refused surgery due to tumor regression and symptomatic relief, and 1 patient had progressive disease. As determinedby the Response Evaluation Criteria in Solid Tumors(RECIST,version 1.1), 7 patients (31.8%) had a partial response and 4 (18.2%) patients hada complete response, which translated to an objective response rate of 50%. The symptom remission rate was 90.9% according to the Stooler classification. Five patients (22.7%) experienced serious treatment-related adverse events of grade 3–4 (including anorexia, vomiting, fatigue, alopecia and hypoadrenalism). Postoperative pathology revealed a major pathological response in 14 cases (82.3%) and a complete pathological response in 8 cases (47.1%). Programmed death-ligand 1expression in pretreatment specimens was not significantly associated with the percentage of residual viable tumor (RVT)(r=-0.55, p=0.08). Changes in counts of CD68+ macrophage between pre- and post-treatment specimens wereweakly correlated with RVT(r=0.71; p=0.07), while a positive correlation was observed between postoperative Foxp3+T cells/CD4+Tcellsratios and RVT(r=0.84, p=0.03).Conclusion: The combination of neoadjuvantimmunotherapy and chemotherapy for ESCC is associated with a high pathological response and immunologic effects in the tumor microenvironment. It has acceptable toxicity and great efficacy, suggesting a strong rationale for its further evaluation in randomized clinical trials.Trial registration: ChiCTR, ChiCTR2100048917. Registered 19 July 2021 - Retrospectively registered, https://www.chictr.org.cn/edit.aspx?pid=130073&htm=4

Programmed cell death ligand 1 (PD‐L1) is a major immunosuppressive checkpoint protein expressed by tumor cells to subvert anticancer immunity. Recent studies have shown that ionizing radiation (IR) upregulates the expression of PD‐L1 in tumor cells. However, whether an IR‐induced DNA damage response (DDR) directly regulates PD‐L1 expression and the functional significance of its upregulation are not fully understood. Here, we show that IR‐induced upregulation of PD‐L1 expression proceeds through both transcriptional and post‐translational mechanisms. Upregulated PD‐L1 was predominantly present on the cell membrane, resulting in T‐cell apoptosis in a co‐culture system. Using mass spectrometry, we identified PD‐L1 interacting proteins and found that BCLAF1 (Bcl2 associated transcription factor 1) is an important regulator of PD‐L1 in response to IR. BCLAF1 depletion decreased PD‐L1 expression by promoting the ubiquitination of PD‐L1. In addition, we show that CMTM6 is upregulated in response to IR and participates in BCLAF1‐dependent PD‐L1 upregulation. Finally, we demonstrated that the ATM/BCLAF1/PD‐L1 axis regulated PD‐L1 stabilization in response to IR. Together, our findings reveal a novel regulatory mechanism of PD‐L1 expression in the DDR., IR‐induced PD‐L1 upregulation expression proceeded through post‐translational mechanisms. We identified BCLAF1 as a new PD‐L1 stabilization regulator in response to IR.

Background In recent years, diagnosis of early squamous cell carcinoma of the esophagus has been increasingly emphasized. The application of endoscopic submucosal dissection (ESD) has enabled safe resection of esophageal lesions. Minimally invasive esophagectomy (MIE) is also safe and feasible for early stages of the cancer. This study aimed to compare the therapeutic effects of early esophageal carcinoma treatment, and find the best predictive factor for the selection of treatment for T1a patients. Methods We performed a retrospective study of early‐stage patients admitted to Tianjin Medical University Cancer Institute and Hospital between January 2015 and December 2018. A total of 128 patients underwent MIE, while 78 patients underwent ESD. The depth of the tumor invasion, lymph node metastasis, and complications were compared between the two groups. Results In the ESD group, 76.92% of the patients were stage T1a, while 34.38% in the MIE group were stage T1a. The lymph node metastasis rate was 16.41% in the MIE group (6.98% in T1a stage), which related to tumor differentiation, tumor length (≥37.5 mm), depth of invasion, and angiolymphatic invasion. However, the R0 resection rate was only 73.08% in the ESD group. Comprehensive analysis of all T1 patients in the two groups revealed that the positive margin was related to tumor differentiation, tumor width (≥13.5 mm), and depth of invasion (≥3.25 mm). Conclusion For early‐stage cases, lymph node metastasis and positive margins are risk factors affecting long‐term survival. Efficient predictive factors mentioned in our study would provide a proper indication for treatment strategy selection.

Background Most human solid tumors are aneuploid; at the same time, polyploid cancer cells are found to be resistant to radiotherapy and chemotherapy and have a poor prognosis. The transforming growth factor beta induction (TGFBI) protein plays important roles in the development of tumors, depending on the cancer of origin. Methods In this study, we established polyploid clones of breast cancer treated with nocodazole. The drug sensitivity was measured by MTT assay. Western blot analysis was used to detect the expression of TGFBI protein in polyploid clones. The effects of paclitaxel on apoptosis, cell cycle and DNA ploidy were analyzed by flow cytometry. TGFBI protein expression was performed in samples from patients with epithelial ovarian tumors by immunohistochemical staining. Results We found that compared with the MDA-MB-231 cell line, the expression of TGFBI in the HGF1806 cell line was relatively higher. In addition, compared with its parental cells, TGFBI showed relatively low expression in the polyploid breast cancer cell line T-MDA-MB-231. Compared with the empty vector, under paclitaxel treatment, the over-expression of TGFBI in MDA-MB-231 and T-MDA-MB-231 both showed a higher growth inhibition rate. After nocodazole treatment, the over-expression of TGFBI in MDF-MB-231 cells proved that the expression of tetraploid cells was lower compared to the control. The positive rate of TGFBI expression in ovarian cancer specimens before chemotherapy was 33.3% (5/15), which was higher than the positive rate of TGFBI expression in ovarian cancer specimens matched with relapsed specimens after treatment (0%, 0/15). Conclusions TGFBI can increase the sensitivity of paclitaxel in polyploid cancer cells and participate in the formation of polyploidy in MDA-MB-231 induced by nocodazole. This newly recognized role of TGFBI provides further insight into the pathogenesis of polyploid cancer and identifies potential new therapeutic targets.

Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m2] plus docetaxel [25 mg/m2] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9–24.5), OS and PFS time ranged from 8.2–28.5 and 4.0–28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c+ dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that seriously affects quality of life. Quinine is a bitter taste receptor agonist that exhibits antimalarial effects. The aim of the present study was to examine the therapeutic effects of quinine in AD-like mice. AD was induced with 2,4-dinitrochlorobenzene, and the mice were treated with 10 mg/kg quinine for 1, 4 and 7 days. A total of 60 BALB/c mice were divided into the following groups: Healthy, AD-like, AD-like + quinine and healthy + quinine, with 1, 4 and 7 days groups for each treatment. Blood was extracted from all mice and ELISA was performed to detect immunoglobulin E (IgE) levels. H&E-stained tissue sections were prepared from skin lesions on the backs of the mice and pathological changes were observed. Cytokines were detected via ELISA, and the filaggrin (FLG) and kallikrein-7 (KLK7) proteins were detected via western blotting and immunohistochemistry. IKKα and NF-κB mRNA were analyzed via reverse transcription-quantitative PCR. Quinine ameliorated skin damage in the AD-like mice, reduced IgE expression in the blood, inhibited expression of IKKα and NF-κB, reduced cytokine secretion, reduced KLK7 expression, reduced scratching frequency, increased FLG expression and repaired the skin barrier. These results suggested that quinine exhibited therapeutic effects in AD-like mice.

Background: The development of minimally invasive surgery has initiated many changes in the surgical treatment of esophageal cancer (EC) patients. The aim of this study was to compare the short-term outcomes of robotic-assisted minimally invasive esophagectomy (RAMIE), video-assisted minimally invasive esophagectomy (VAMIE), and open esophagectomy (OE). Methods: Our study included patients who had undergone McKeown esophagectomy at Tianjin Medical University Cancer Institute and Hospital between January 2016 and December 2018. We analyzed clinical baseline data, as well as perioperative and pathological outcomes. Results: A total of 312 cases met the inclusion criteria (OE: 77, VAMIE: 144, RAMIE: 91). The OE group had a greater number of late-stage patients as well as those who received the neo-adjuvant therapy, compared with the other two groups (P=0.001). The procedure time in the OE group was also shorter by approximately 20 minutes (P=0.021). Total blood loss was significantly lower in the two MIE groups (P=0.004) than in the OE group. There were no differences in the total number of dissected lymph nodes between the three groups (OE: 24.09±10.77, VAMIE: 23.07±10.18, RAMIE: 22.84±8.37, P=0.680). Both the lymph node number (P=0.155) and achievement rate (P=0.190) in the right recurrent laryngeal nerve (RLN) area were comparable between the three groups. However, in the left RLN area, minimally invasive approaches resulted in a higher number of harvested lymph nodes (P=0.032) and greater achievement rate (P=0.018). Neither MIE procedure increased the incidence of postoperative complications. Conclusions: Minimally invasive surgery could guarantee the quality of bilateral RLN lymphadenectomy without increasing postoperative complications, especially in RAMIE patients. The rational choice of different surgical approaches would improve both safety and oncological outcomes for patients.

Background: CirRNA Circ_0058063 has been proven as an oncogene in bladder cancer, while its involvement in esophageal squamous-cell carcinomas (ESCC) is unknown. This study aimed to investigate the role of Circ_0058063 in ESCC. Methods: Paired ESCC and non-tumor tissues were collected from ESCC patients and gene expression was analyzed by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Gene interactions were analyzed by overexpression experiment. Glucose uptake was analyzed by glucose uptake assay. Cell proliferation was analyzed by cell proliferation assay. Results: We found that Circ_0058063 was upregulated in ESCC and positively correlated with GLUT1 mRNA. It is known that GLUT1 plays critical roles in glucose transportation and glucose supports the Warburg Effect as the major metabolic precursor. In ESCC cells, Circ_0058063 and GLUT1 overexpression both promoted glucose uptake. In ECSS cells, Circ_0058063 overexpression resulted in the upregulated, while Circ_0058063 knockdown resulted in downregulated GLUT1. In cell proliferation assay, Circ_0058063 and GLUT1 overexpression resulted in the increased, while Circ_0058063 knockdown resulted in the decreased rate of ESCC cell proliferation. Moreover, GLUT1 overexpression reduced the effects of Circ_0058063 knockdown. Conclusions: Circ_0058063 upregulates GLUT1 expression and promotes glucose-uptake in ESCC to promote cell proliferation.

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/m(2)) on day 2, and cisplatin (20 mg/m(2)) 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).

Growing evidence indicates that systemic inflammation response and malnutrition status are correlated with survival in certain types of solid tumors. The aim of this study is to evaluate the association between the systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) and overall survival (OS) in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. A consecutive series of 655 patients with resected ESCC who underwent esophagectomy were enrolled in the retrospective study. The preoperative SII was defined as platelet × neutrophil/lymphocyte counts. The PNI was calculated as albumin concentration (g/L) + 5 × total lymphocyte count (109 /L). The optimal cut-off values of SII, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and PNI were determined by receiver operating characteristic analysis. Survival analysis was performed using the Kaplan-Meier method with a log-rank test, followed by a multivariate Cox proportional hazards model. A high SII was significantly related to tumor size, histological type, invasion depth, and TNM stage (p < 0.05). A low PNI was significantly associated with age, tumor size, invasion depth, lymph node metastasis, and TNM stage (p < 0.05). Univariate analysis revealed that age, smoking history, tumor size, invasion depth, lymph node metastasis, SII, NLR, PLR, and PNI were predictors of OS (p < 0.05). Multivariate analysis identified age (p = 0.041), tumor size (p = 0.016), invasion depth (p < 0.001), lymph node metastasis (p < 0.001), SII (p = 0.033), and PNI (p = 0.022) as independent prognostic factors correlated with OS. There was a significant inverse relationship between the SII and PNI (r = 0.309; p < 0.001). The predictive value increased when the SII and PNI were considered in combination. Our results demonstrate that the preoperative high SII and low PNI are powerful indicators of aggressive biology and poor prognosis for patients with ESCC. The combination of SII and PNI can enhance the accuracy of prognosis.

// Zhao Ma 1, * , Xianxian Wu 1, *, # , Bo Xu 2 , Hongjing Jiang 1 , Peng Tang 1 , Jie Yue 1 , Mingquan Ma 1 , Chuangui Chen 1 , Hongdian Zhang 1 and Zhentao Yu 1 1 Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Prevention and Therapy of Tianjin, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center of Cancer, Tianjin, China 2 Department of Molecular Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China * These authors have contributed equally to this work # Co-first author Correspondence to: Zhentao Yu, email: yuzhtao@hotmail.com Keywords: esophageal squamous cell cancer; lymph node metastasis; biomarker; risk prediction; squamous cell carcinoma antigen Abbreviations: Esophageal squamous cell carcinoma (ESCC), Lymph node metastasis (LNM), Japanese Esophageal Society (JES), A receiver operating characteristic (ROC), The area under the ROC curve (AUC) Received: June 27, 2017 Accepted: October 12, 2017 Published: November 11, 2017 ABSTRACT The number and range of lymph node metastasis (LNM) are critical prognostic factors in esophageal squamous cell carcinoma (ESCC). Preoperative serum biomarkers are reported to be associated with LNM. However, whether these markers can precisely predict the extent of LNM is not known. The aim of this study was to evaluate the predictive value of preoperative serum SCC-Ag, Cyfra21-1, CEA, CA19-9 and CA72-4 for LNM number and range by retrospectively investigating 577 ESCC patients undergone esophagectomy from 2007-2010. In this study, the positive rate of SCC-Ag and CA19-9 were associated with pN stage. Significant differences were found in CEA and CA19-9 between pN0-1 stage patients and pN2-3 stage patients. However, in subgroup analysis (patients with pN0-1), significant difference was found only in SCC-Ag between pN0 and pN1 stage patients ( P =0.003). Middle thoracic ESCC patients were Chosen to analyze the correlation between the range of LNM and biomarkers. SCC-Ag was correlated with paraesophageal and paracardial lymph nodes, but not correlated with subcarinal and left gastric artery lymph nodes. Interestingly, the results of CEA were opposite to that of SCC-Ag. CA19-9 was associated with subcarinal and paracardial LNM ( P =0.000, P =0.038). Based on the results, a model incorporated SCC-Ag, CEA and CA19-9 was constructed. The rate of patients with pN2-3 stage was 15.4% and 54.4% in group 1 and 4 of our model. In summary, SCC-Ag was associated with early lymph node metastatic stage, and CEA and CA19-9 have a close relationship with advanced lymph node metastatic stage. The model combining SCC-Ag, CEA and CA19-9 might help identify the preoperative extent of LNM for a subgroup of ESCC patients that can be benefited from neoadjuvant therapy.

Background Neoadjuvant chemoradiation is not recommended as an approach for treatment of esophageal squamous cell carcinoma due to its significant postoperative mortality. However, it is assumed the combination of neoadjuvant chemoradiation with minimally invasive esophagectomy (MIE) may reduce postoperative mortality, which can revive preoperative chemoradiation. No randomized controlled studies comparing neoadjuvant chemoradiation plus MIE with neoadjuvant chemotherapy plus MIE have been performed so far. The present trial is initiated to obtain valid information whether neoadjuvant chemoradiation plus MIE yields better survival without worse postoperative morbidity and mortality in the treatment of locally advanced resectable esophageal squamous cell carcinoma(cT3-4aN0-1M0). Methods/design CMISG1701 is a multicenter, prospective, randomized, phase III clinical trial, investigating the safety and efficacy of neoadjuvant chemoradiation plus MIE compared with neoadjuvant chemotherapy plus MIE. Patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) are eligible for the study. A total of 264 patients are randomly assigned to neoadjuvant chemoradiation (arm A) or neoadjuvant chemotherapy (arm B) with a 1:1 allocation ratio. The primary outcome is overall survival assessed with a minimum follow-up of 36 months. Secondary outcomes are progression-free survival, recurrence-free survival, postoperative pathologic stage, treatment-related complications, postoperative mortality as well as quality of life. Discussion The objective of this trial is to identify the superior protocol with regard to patient survival, treatment morbidity/mortality and quality of life between neoadjuvant chemoradiation plus MIE and neoadjuvant chemotherapy plus MIE. Trial registration NCT03001596 (December 17, 2016). Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3446-7) contains supplementary material, which is available to authorized users.

BACKGROUND To compare the lymph node dissection with the right transthoracic Ivor-Lewis (IL) procedure to that with the left transthoracic (LT) approach for Siewert type II adenocarcinoma of the esophagogastric (AEG) junction. METHODS In this study, 136 patients with Siewert type II AEG who met the inclusion criteria underwent surgical resection were divided into the IL (47 cases) and LT (89 cases) groups. The number and frequency of the dissected lymph nodes in each station were compared between the two groups. RESULTS The IL group had a longer proximal surgical margin (P = 0.000) and more total (P = 0.000), thoracic (P = 0.000), and abdominal lymph nodes (P = 0.000) dissected than the LT group. In general, the IL group had a higher dissection rate in each thoracic lymph node station (P

Background After neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer, high pathologically complete response (pCR) rates are being achieved especially in patients with squamous cell carcinoma (SCC). An active surveillance strategy has been proposed for SCC patients with clinically complete response (cCR) after nCRT. To justify omitting surgical resection, patients with residual disease should be accurately identified. The aim of this study is to assess the accuracy of response evaluations after nCRT based on the preSANO trial, including positron emission tomography with computed tomography (PET-CT), endoscopy with bite-on-bite biopsies and endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) in patients with potentially curable esophageal SCC. Methods Operable esophageal SCC patients who are planned to undergo nCRT according to the CROSS regimen and are planned to undergo surgery will be recruited from four Asian centers. Four to 6 weeks after completion of nCRT, patients will undergo a first clinical response evaluation (CRE-1) consisting of endoscopy with bite-on-bite biopsies. In patients without histological evidence of residual tumor (i.e. without positive biopsies), surgery will be postponed another 6 weeks. A second clinical response evaluation (CRE-2) will be performed 10–12 weeks after completion of nCRT, consisting of PET-CT, endoscopy with bite-on-bite biopsies and EUS with FNA. Immediately after CRE-2 all patients without evidence of distant metastases will undergo esophagectomy. Results of CRE-1 and CRE-2 as well as results of the three single diagnostic modalities will be correlated to pathological response in the resection specimen (gold standard) for calculation of sensitivity, specificity, negative predictive value and positive predictive value. Discussion If the current study shows that major locoregional residual disease (> 10% residual carcinoma or any residual nodal disease) can be accurately (i.e. with sensitivity of 80.5%) detected in patients with esophageal SCC, a prospective trial will be conducted comparing active surveillance with standard esophagectomy in patients with a clinically complete response after nCRT (SINO trial). Trial registration The preSINO trial has been registered at ClinicalTrials.gov as NCT03937362 (May 3, 2019).

Importance Safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) vs neoadjuvant chemotherapy (nCT) for treatment of locally advanced esophageal squamous cell carcinoma (ESCC) remain uncertain given lack of high-level clinical evidence. Objective To compare safety and long-term survival of nCRT followed by minimally invasive esophagectomy (MIE) with that of nCT followed by MIE for patients with locally advanced ESCC. Design, Setting, and Participants A prospective, multicenter, open-label, randomized clinical trial that compared safety and efficacy of nCRT vs nCT followed by MIE for patients with locally advanced ESCC. From January 1, 2017, to December 31, 2018, 264 patients with ESCC of clinical stages from cT3 to T4aN0 to 1M0 were enrolled. Analysis was performed on an intention-to-treat basis from January 1, 2017, to August 30, 2020. Interventions Eligible patients were randomized to the nCRT group (n = 132) or the nCT group (n = 132) by a computer-generated random system. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while 40 Gy of concurrent radiotherapy was added for the nCRT group. At about 6 weeks after neoadjuvant therapy, MIE via thoracoscopy and laparoscopy was performed for the patients in both groups. Main Outcomes and Measures The primary outcome was 3-year overall survival. Secondary outcomes included postoperative complications, mortality, postoperative pathologic outcome, recurrence-free survival time, and quality of life. Results Among 264 patients (226 men [85.6%]; mean [SD] age, 61.4 [6.8] years), postoperative morbidity was 47.4% in the nCRT group (54 of 114) and 42.6% in the nCT group (46 of 108), with no significant difference between groups (difference, 4.8%; 95% CI, −8.2% to 17.5%;P = .48). Distribution of the severity of complications was similar between the 2 groups based on Clavien-Dindo classification. The 90-day perioperative mortality rate was 3.5% for the nCRT group (4 of 114) and 2.8% for the nCT group (3 of 108) (P = .94). The R0 resection rates were similar between groups (109 of 112 [97.3%] vs 100 of 104 [96.2%];P = .92). However, patients in the nCRT group had a higher pathologic complete response (residual tumor, 0%) rate (40 of 112 [35.7%] vs 4 of 104 [3.8%];P Conclusions and Relevance Initial results of the trial showed that nCRT followed by MIE has similar safety to and better histopathologic outcome than nCT followed by MIE for treatment of locally advanced ESCC. Trial Registration ClinicalTrials.gov Identifier:NCT03001596

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.

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-β 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.

// Hongdian Zhang 1,* , Xiaobin Shang 1,* , Chuangui Chen 1 , Yongyin Gao 2 , Xiangming Xiao 3 , Peng Tang 1 , Xiaofeng Duan 1 , Mingjian Yang 1 , Hongjing Jiang 1 and Zhentao Yu 1 1 Department of Esophageal Cancer, Tianjin Medical University, Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, China 2 Department of Cardiopulmonary Function, Tianjin Medical University, Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, China 3 Department of General Surgery, Weifang People’s Hospital, Shandong, China * These authors have contributed equally to this work Correspondence to: Zhentao Yu, email: // Keywords : adenocarcinoma of the esophagogastric junction; lymph node metastasis; metastatic lymph node ratio; tumor-N-ratio-metastasis (TrNM) staging system; prognosis Received : March 14, 2016 Accepted : July 27, 2016 Published : August 10, 2016 Abstract This study aimed to assess the prognostic value of the hypothetical tumor-N-ratio (rN)-metastasis (TrNM) staging system in adenocarcinoma of the esophagogastric junction (AEG). The clinical data of 387 AEG patients who received surgical resection were retrospectively reviewed. The optimal cut-off point of rN was calculated by the best cut-off approach using log-rank test. Kaplan-Meier plots and Cox regressions model were applied for univariate and multivariate survival analyses. A TrNM staging system based on rN was proposed. The discriminating ability of each staging was evaluated by using an adjusted hazard ratio (HR) and a −2log likelihood. The prediction accuracy of the model was assessed by using the area under the curve (AUC) and the Harrell’s C-index. The number of examined lymph nodes (LNs) was correlated with metastatic LNs (r = 0.322, P 0.05). The optimal cut-points of rN were calculated as 0, 0~0.3, 0.3~0.6, and 0.6~1.0. Univariate analysis revealed that pN and rN classifications significantly influenced patients’ RFS and OS ( P < 0.001). Multivariate analysis adjusted for significant factors revealed that rN was recognized as an independent risk factor. A larger HR, a smaller −2log likelihood and a larger prediction accuracy were obtained for rN and the modified TrNM staging system. Taken together, our study demonstrates that the proposed N-ratio-based TrNM staging system is more reliable than the TNM staging system in evaluating prognosis of AEG patients after curative resection.

Introduction The aim of this study is to investigate the number of negative lymph nodes (NLNs) as a prognostic factor for survival in patients with resected esophageal squamous cell carcinoma. Methods A total of 381 esophageal squamous cell carcinoma patients who had underwent surgical resection as the primary treatment was enrolled into this retrospective study. The impact of number of NLNs on patient's overall survival was assessed and compared with the factors among the current tumor-nodes-metastasis (TNM) staging system. Results The number of NLNs was closely related to the overall survival, and the 5-year survival rate was 45.4% for number of NLNs of >20 (142 cases) and 26.4% for NLNs ≤ 20 (239 cases) (P = 0.001). In multivariate survival analysis, the number of NLNs remained an independent prognostic factor (P = 0.002) as did the other current TNM factors. For subgroup analysis, the predictive value of number of NLNs was significant in patients with T3 or T4 disease (P = 0.001) and patients with N1 and N2–3 disease (P = 0.025, 0.043), but not in patients with T1 or T2 disease or patients with N0 disease. Conclusions The number of NLNs, which represents the extent of lymphadenectomy for esophageal squamous cell carcinoma, could impact the overall survival of patients with resected esophageal squamous cell carcinoma, especially among those with nodal-positive disease and advanced T-stage tumor.

Cervical cancer is the third-most common cause of female cancer-related mortality worldwide. In cervical cancer, aberrant activation of nuclear factor (NF)-κB signaling is widely reported. However, the transcriptional regulation of NF-κB signaling remains unclear. The present study aimed to explore the underlying mechanism in which NF-κB signaling was activated in cervical cancer cells. Initially, the expression of p65 was demonstrated to be markedly enhanced in grade II, III or IV cervical cancer tissues compared with that of normal cervical tissues, indicating that p65 expression was correlated with tumor grade. In HeLa and CaSki cells, overexpression of p65 markedly enhanced cervical cancer cell invasion and migration. Further experiments demonstrated that p65 overexpression significantly increased the phosphorylation levels of protein kinase B (AKT) and p38. Dual luciferase reporter and chromatin immunoprecipitation assays demonstrated that USF1 was able to bind the promoter region of p65, thereby enhancing the transcriptional activation of p65. Notably, when p65 was silenced, the phosphorylation levels of AKT and p38 were suppressed even in cells transfected with adenovirus vectors expressing upstream transcription factor 1 (USF1). These data indicated that USF1 prompted cervical cancer progression primarily by transcriptionally activating p65. In conclusion, the present study demonstrated that USF1 was able to activate the transcription of p65, thereby enhancing the malignancy of cervical cancer cells.

Purpose Clinical tools are unavailable for accurate prediction of pathologic responses to chemoradiation therapy (CRT) among patients with esophageal squamous cell carcinoma (ESCC) before surgery. We evaluated tumor remission and tumor-infiltrating lymphocytes (TILs) during CRT as predictors of pathologic response and prognostic markers for patients with locally advanced ESCC treated with neoadjuvant CRT (neo-CRT) or definitive CRT. Methods and Materials We analyzed patients with locally advanced ESCC (N = 164) who underwent neo-CRT (N = 48) or definitive CRT (N = 116). Patients underwent endoscopic ultrasonography and biopsies when induction CRT finished. Tumor remission characteristics were designated minor (–/+) to excellent remission (ER) (+++). TILs were determined in 10% increments. Tumor remission, TILs, or both were associated with pathologic complete response (pCR) and survival in the neo-CRT group and then analyzed in the definitive CRT group. Results ER and lymphocyte-predominant ESCC (LPE; ≥60% TILs) were identified according to the pCR rate and disease-free survival. We built a prediction model for pCR incorporating ER and LPE. The area under the receiver operating characteristic curve was 0.877, and sensitivity and specificity were 86.7% and 90.9%, respectively. Furthermore, this model identified pathologic response with an excellent calibration. Disease-free survival of patients with ER and LPE tumors was significantly longer than that of other patients. Conclusions When we included tumor remission and TILs during CRT, our model predicted pCR with high probability and helped stratify prognostic subgroups, thereby guiding future therapy decisions for patients with locally advanced ESCC. Validation of this model in larger, prospective, multicenter studies is essential.

As a mitotic spindle checkpoint gene, baculoviral IAP repeat containing 5 (BIRC5) serves pivotal roles in the development of various types of malignant tumors. In the present study, the expression of BIRC5 in patients with different stages of esophageal squamous cell cancer (ESCC) was investigated. The effect of BIRC5 on the migratory and invasive abilities of different ESCC cell lines was analyzed. Additionally, the effect of BIRC5 on the angiogenesis-associated factor vascular endothelial growth factor, brain-specific angiogenesis inhibitor 1 and methyl-CpG binding domain protein 2 was examined. In addition, the interaction between BIRC5 and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was analyzed. It was determined that BIRC5 is able to inhibit the migration and invasion of tumor cells, and regulate the expression of angiogenesis-associated factors. In addition, the PI3K/Akt signaling pathway is able to regulate the expression of BIRC5, which affects the development of ESCC.

Patients undergoing lobectomy are at significantly increased risk of lung injury. One-lung ventilation is the most commonly used technique to maintain ventilation and oxygenation during the operation. It is a challenge to choose an appropriate mechanical ventilation strategy to minimize the lung injury and other adverse clinical outcomes. In order to understand the available evidence, a systematic review was conducted including the following topics: (I) protective ventilation (PV); (II) mode of mechanical ventilation [e.g., volume controlled (VCV) versus pressure controlled (PCV)]; (III) use of therapeutic hypercapnia; (IV) use of alveolar recruitment (open-lung) strategy; (V) pre-and post-operative application of positive end expiratory pressure (PEEP); (VI) Inspired Oxygen concentration; (VII) Non-intubated thoracoscopic lobectomy; and (VIII) adjuvant pharmacologic options. The recommendations of class II are non-intubated thoracoscopic lobectomy may be an alternative to conventional one-lung ventilation in selected patients. The recommendations of class IIa are: (I) Therapeutic hypercapnia to maintain a partial pressure of carbon dioxide at 50–70 mmHg is reasonable for patients undergoing pulmonary lobectomy with one-lung ventilation; (II) PV with a tidal volume of 6 mL/kg and PEEP of 5 cmH 2 O are reasonable methods, based on current evidence; (III) alveolar recruitment [open lung ventilation (OLV)] may be beneficial in patients undergoing lobectomy with one-lung ventilation; (IV) PCV is recommended over VCV for patients undergoing lung resection; (V) pre- and post-operative CPAP can improve short-term oxygenation in patients undergoing lobectomy with one-lung ventilation; (VI) controlled mechanical ventilation with I:E ratio of 1:1 is reasonable in patients undergoing one-lung ventilation; (VII) use of lowest inspired oxygen concentration to maintain satisfactory arterial oxygen saturation is reasonable based on physiologic principles; (VIII) Adjuvant drugs such as nebulized budesonide, intravenous sivelestat and ulinastatin are reasonable and can be used to attenuate inflammatory response.