Diagnosis of Esophageal Squamous Cell Carcinoma by High-Performance Serum Metabolic Fingerprints: A Retrospective Study.

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy, and timely diagnosis of ESCC contributes to an increased cancer survival rate. However, current detection methods for ESCC mainly rely on endoscopic examination, limited by a relatively low participation rate. Herein, ferric-particle-enhanced laser desorption/ionization mass spectrometry (FPELDI MS) is utilized to record the serum metabolic fingerprints (SMFs) from a retrospective cohort (523 non-ESCC participants and 462 ESCC patients) to build diagnostic models toward ESCC. The PFELDI MS achieved high speed (≈30 s per sample), desirable reproducibility (coefficients of variation < 15%), and high throughput (985 samples with ≈124 200 data points for each spectrum). Desirable diagnostic performance with area-under-the-curves (AUCs) of 0.925-0.966 is obtained through machine learning of SMFs. Further, a metabolic biomarker panel is constructed, exhibiting superior diagnostic sensitivity (72.2-79.4%, p < 0.05) as compared with clinical protein biomarker tests (4.3-22.9%). Notably, the biomarker panel afforded an AUC of 0.844 (95% confidence interval [CI]: 0.806-0.880) toward early ESCC diagnosis. This work highlighted the potential of metabolic analysis for accurate screening and early detection of ESCC and offered insights into the metabolic characterization of diseases including but not limited to ESCC.

Efficacy and safety of esophagectomy via left thoracic approach versus via right thoracic approach for middle and lower thoracic esophageal cancer: a multicenter randomized clinical trial (NST1501).

Background: Left thoracic approach (LTA) has been a favorable selection in surgical treatment for esophageal cancer (EC) patients in China before minimally invasive esophagectomy (MIE) is popular. This study aimed to demonstrate whether right thoracic approach (RTA) is superior to LTA in the surgical treatment of middle and lower thoracic esophageal squamous cell carcinoma (TESCC). Methods: Superiority clinical trial design was used for this multicenter randomized controlled two-parallel group study. Between April 2015 and December 2018, cT1b-3N0-1M0 TESCC patients from 14 centers were recruited and randomized by a central stratified block randomization program into LTA or RTA groups. All enrolled patients were followed up every three months after surgery. The software SPSS 20.0 and R 3.6.2. were used for statistical analysis. Efficacy and safety outcomes, 3-year overall survival (OS) and disease-free survival (DFS) were calculated and compared using the Kaplan-Meier method and the log-rank test. Results: A total of 861 patients without suspected upper mediastinal lymph nodes (umLN) were finally enrolled in the study after 95 ineligible patients were excluded. 833 cases (98.7%) were successfully followed up until June 1, 2020. Esophagectomies were performed via LTA in 453 cases, and via RTA in 408 cases. Compared with the LTA group, the RTA group required longer operating time (274.48±78.92 vs. 205.34±51.47 min, P<0.001); had more complications (33.8% vs. 26.3% P=0.016); harvested more lymph nodes (LNs) (23.61±10.09 vs. 21.92±10.26, P=0.015); achieved a significantly improved OS in stage IIIa patients (67.8% vs. 51.8%, P=0.022). The 3-year OS and DFS were 68.7% and 64.3% in LTA arm versus 71.3% and 63.7% in RTA arm (P=0.20; P=0.96). Conclusions: Esophagectomies via both LTA and RTA can achieve similar outcomes in middle or lower TESCC patients without suspected umLN. RTA is superior to LTA and recommended for the surgical treatment of more advanced stage TESCC due to more complete lymphadenectomy. Trial Registration: ClinicalTrials.gov NCT02448979.

Real-World Efficacy and Safety of Sintilimab-Based Regimens against Advanced Esophageal Cancer: A Single-Center Retrospective Observational Study.

This study is aimed at assessing the sintilimab-based regimens' safety and efficacy for advanced esophageal cancer (EC) treatment in the real world. Cases of advanced EC treated with sintilimab-based regimens in the Anyang Tumor Hospital between 1 January 2020 and 1 August 2021 were retrospectively examined. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), objective response rate (ORR), and adverse events (AEs) were evaluated. Among the 50 included patients, the median PFS was 11.3 months (95% CI: 5.0-17.6 months), and the 1-year PFS rate was 49.2%. The median OS was not reached, and the 1-year OS rate was 67.1%. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were seen in 14% (n = 7), 46% (n = 23), 32% (n = 16), and 8% (n = 4) of the 50 patients, respectively. Therefore, the ORR and DCR were 60% (30/50) and 92% (46/50), respectively. The CR rate of patients with radiotherapy was higher than that without radiotherapy (25% vs. 3.8%, P = 0.031). The 1-year OS rate was higher in patients with radiotherapy than in patients without radiotherapy (85.9% vs. 53.2%, P = 0.020). The most observed AEs included anemia, decrease in white blood cell count, nausea/vomiting, and hypoproteinemia. Sintilimab-based regimens achieved good disease control and tolerance for treating advanced EC in the real world. Combined radiotherapy can improve the efficacy and deserves further study.

Efficacy and Safety of Apatinib plus Neoadjuvant Chemotherapy for Locally Advanced Esophageal Squamous Cancer: A Phase II Trial.

Evidence for neoadjuvant chemotherapy combined with targeted therapy for locally advanced esophageal squamous cancer (ESCC) is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of apatinib combined with taxol and cisplatin (ATP) for locally advanced ESCC. All patients were cT3-4aN0-3 M0 (IIIb-IVa) stage, which were confirmed by histopathology. Apatinib was taken orally (425 mg/d) for two cycles, followed by one cycle of rest. Taxol was administered at 135 mg/m2 intravenously on day 1, and cisplatin was administered at 20 mg/m2 intravenously on day 1 to day 3. Radical ESCC resection was performed 4 weeks after ATP. The primary endpoint was pathological response rate (pCR). Secondary endpoints were pathologic response rate (MPR), disease-free survival (DFS), overall survival (OS), R0 resection rate, and safety profile. This trial was registered. We evaluated 41 patients for screening from Oct 2018 to July 2020, of whom 39 were enrolled in the study, with a median age of 65 years (range 49-75 years), and 29 (74.4%) were male. Among the 39 patients, 1 was considered unresectable by the multidisciplinary team due to tumor progression, and 38 patients underwent surgery eventually. The median follow-up was 22 months (range 5-29 months), and the follow-up rate was 100%. The 1-year and 2-year OS was 95% and 95%, and the 1-year and 2-year DFS was 85% and 82%, respectively. Thirty-eight (97.3%) successfully underwent R0 resection. Of the 38 evaluable patients, 9 (23.6%) were pCR, and 15 (39.5%) were MPR. The most common ATP-related AEs were nausea (76.9%), leucopenia (53.8%), neutropenia (51.2%) and vomit (51.2%), anemia (41.0%), and hypertension (25.6%). The most frequent grade 3-4 events included leucopenia (15.3%), neutropenia (15.3%), nausea (12.8%), vomit (12.8%), and hypertension (10.2%). No treatment-related death occurred. Neoadjuvant apatinib combined with taxol and cisplatin for locally advanced ESCC showed favorable activity and manageable safety.

Development and Validation of a Nomogram for Predicting Overall Survival to Concurrent Chemoradiotherapy in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma.

This study aims to develop and validate a effective prognostic nomogram for locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients undergoing concurrent chemoradiotherapy (CCRT). Retrospective analysis of 503 patients with LA-ESCC given CCRT in our hospital from 2009 to 2016 was conducted. Two-thirds of the patients were randomly assigned to the training set (n = 335), and one-third were assigned to the validation set (n = 168). In order to generate the nomogram, multivariate cox regression analysis was undertaken in the training set for uncovering significant prognostic variables for overall survival. The C-index and calibration plot were used to verify nomogram discrimination and calibration, respectively. Five independent prognostic variables were found and incorporated into a nomogram: age, N stage, location, tumor response, and MLR (monocyte/lymphocyte ratio). The C-indexes of the training set and the validation set were 0.730 and 0.745, respectively. The discrimination and calibration of this nomogram showed good predictive power in both sets. Conclusively, the proposed nomogram may be served as an effective tool for prognostic evaluation of LA-ESCC patients receiving CCRT.

Identification of crucial long non-coding RNAs and mRNAs along with related regulatory networks through microarray analysis in esophageal carcinoma.

Esophageal carcinoma (EC) is a tremendous threat to human health and life worldwide. Long non-coding RNAs (lncRNAs) have been identified as crucial players in carcinomas including EC. An in-depth understanding on regulatory networks of lncRNAs contributes to the better management of EC. In this text, 2052 lncRNAs and 3240 mRNAs were found to be differentially expressed in 5 EC tumor tissues versus adjacent normal tissues by microarray analysis. Moreover, 297 carcinoma-related genes were screened out according to pathway and disease annotation analyses. In addition, 410 potential lncRNA-mRNA cis-regulation pairs and 395 lncRNA-mRNA trans-regulation pairs were screened out. Among these genes, 14 trans-regulated and 19 cis-regulated genes were found to be related with carcinomas. Additionally, 42 possible lncRNA-mRNA trans-regulation pairs and 26 cis-regulation pairs were found to be related with carcinomas. Also, 4 differentially expressed transcription factors in EC and lncRNAs possibly regulated by these transcription factors were screened out. Moreover, plenty of common upregulated or downregulated lncRNAs and mRNAs in EC were identified by comparative analysis for our microarray outcomes and previous high-throughput data. Furthermore, we demonstrated that ENST00000437781.1 knockdown inhibited cell proliferation and facilitated cell apoptosis by downregulating SIX homeobox 4 (SIX4) and ENST00000524987.1 knockdown had no influence on anoctamin 1 calcium activated chloride channel (ANO1) expression in EC cells. In conclusion, we identified some crucial lncRNAs and genes along with potential regulatory networks of lncRNAs/genes, deepening our understanding on pathogenesis of EC.

Mirror siRNAs loading for dual delivery of doxorubicin and autophagy regulation siRNA for multidrug reversing chemotherapy.

The multidrug resistance (MDR) which widely observed in multiple cancer types is responsible for the poor chemotherapy benefits of doxorubicin (Dox). Here in our study, Dox was firstly loaded into a scramble siRNA and then condensed by polyethyleneimine (PEI) 25k together with anti-autophagy siRNA, the obtained PEI/Si-D containing mirror RNAs was further coated with hyaluronic acid (HA) to shield the surface charge of PEI and offer tumor-homing property that finally developed a platform for effective cancer chemotherapy (HP/Si-D). Our results revealed that the obtained HP/Si-D was showed high stability and biocompatibility with promising transfection profile. As a result, the anti-autophagy siRNA downregulated autophagy level of target cells, which further decreased ATP supply to enhance drug retention and cell cycle arrest. These results contributed significantly to reverse the MDR of A549/Dox (Dox resistance A549 cell line) cells with promising in vitro and in vivo results, which suggested the potential of effective MDR cancer therapy using synergistic anti-autophagy and chemotherapy.

NR2F1-induced NR2F1-AS1 promotes esophageal squamous cell carcinoma progression via activating Hedgehog signaling pathway.

Emerging evidence has uncovered the extremely important roles of long noncoding RNAs (lncRNAs) in the progression of malignant tumors which includes numerous processes of gene regulation. LncRNA NR2F1-AS1 has been confirmed to have close correlation with the tumorigenesis of diverse cancers. However, the underlying regulatory function of it on esophageal squamous cell carcinoma (ESCC) progression is poorly known and thus needs more elucidations. In this study, a markedly elevated expression of NR2F1-AS1 was discovered in ESCC cells. Functional assays demonstrated that NR2F1-AS1 deficiency repressed ESCC progression. Molecular mechanism tests verified that knockdown of NR2F1-AS1 could lower the expression of GLI2 (a key protein molecule of Hedgehog signaling pathway) in ESCC. Additionally, NR2F1-AS1 was confirmed to facilitate ESCC progression via activation of Hedgehog signaling pathway. NR2F1-AS1 activated Hedgehog signaling pathway by regulating GLI2 to upregulate NR2F1 expression in ESCC. Besides, NR2F1 was testified to activate NR2F1-AS1 transcription in ESCC. Final rescue assays further demonstrated that NR2F1 upregulation could reverse the NR2F1-AS1 knockdown-mediated function on ESCC progression. Briefly, NR2F1-induced NR2F1-AS1 promotes ESCC progression through activation of Hedgehog signaling pathway.