Predictive value of prognostic nutritional index in complications after thoracoscopy-assisted esophagectomy / 中国胸心血管外科临床杂志

@#Objective    To investigate the predictive value of prognostic nutritional index (PNI) in complications after thoracoscopy-assisted radical resection of esophageal cancer. Methods    We collected the clinical data of patients who underwent thoracoscopy-assisted esophagectomy in the First Affiliated Hospital of Xinjiang Medical University from January 2015 to June 2020. The predictive value of PNI for postoperative complications was evaluated by establishing receiver operating characteristic (ROC) curve and the optimal cut-off point was determined. The patients were divided into a high PNI group and a low PNI group according to the cut-off point. The differences of baseline data and perioperative complications-related indicators between the two groups were compared and analyzed. Univariate and multivariate analyses were used to investigate the influence of PNI and other related indexes on postoperative complications. Results    A total of 116 patients were enrolled in this study, including 75 males and 41 females, aged 65 (58-69) years. The area under ROC curve was 0.647, and the optimal cut-off point was 51.9. According to the cut-off point, there were 45 patients in the high PNI group and 71 patients in the low PNI group. The overall complication rate (χ2=10.437, P=0.001) and the incidence of postoperative pulmonary infection (χ2=10.811, P=0.001) were statistically different between the two groups. The results of univariate analysis showed that the duration of ventilator use (Z=–3.136, P=0.002), serum albumin value (t=2.961, P=0.004), and PNI value (χ2=10.437, P=0.001) were the possible risk factors for postoperative complications after thoracoscopy-assisted esophagectomy. The results of multivariate analysis suggested that the duration of ventilator use (OR=1.015, P=0.002) and the history of drinking (OR=5.231, P=0.013) were independent risk factors for postoperative complications, and high PNI was the protective factor for postoperative complications (OR=0.243, P=0.047). Conclusion    PNI index has a certain value in predicting postoperative complications, which can quantify the preoperative nutritional and immune status of patients. Drinking history and duration of ventilator use are independent risk factors for postoperative complications of thoracoscopy-assisted esophagectomy, and high PNI is a protective factor for postoperative complications.

A novel transfer-learning based physician-level general and subtype classifier for non-small cell lung cancer.

Confirming histological patterns of lung carcinoma is important for determining the prognosis and the next steps of treatment for a patient. Confirming the histologic patterns (subtype) of lung adenocarcinoma is important for determining the prognosis and treatment options for a patient. The task is challenging, and often requires the input of experienced pathologists, who by themselves lack interobserver concordance. A computer-aided diagnosis holds the potential to accelerate the time to diagnosis. As many adenocarcinoma tissue samples contain multiple histologic patterns, accurate computer-aided diagnosis requires annotations manually labeled by pathologists. We propose a method that merges weak supervised learning and Integrated Learning using Transfer Learning using two datasets: The Cancer Genome Atlas (TCGA), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) to reduce the need for manual annotation by a pathologist while maintaining accuracy. Whole-slide images (WSI) are first determined to be either adenocarcinoma or squamous cell carcinoma, then further identify the subtypes by generating weak classifiers for each subtype, then using integrated learning to create a strong classifier. Our model was evaluated with independent datasets from the CPTAC dataset and a dataset from a private hospital. It can achieve AUC values of 0.86, 0.91, 0.82, 0.77, 0.96, 0.98 in Acinar, LPA, Micropapillary, Papillary, Solid, and Normal, respectively.

The diagnostic significance of blood-derived circRNAs in NSCLC: Systematic review and meta-analysis.

Background: Using blood-derived circular RNAs (circRNAs) may be an efficient tool for noninvasive fluid biopsy in diagnosing non-small cell lung cancer (NSCLC). However, no relevant systemic meta-analysis has been conducted so far to support the diagnostic value of using blood-derived circRNAs in NSCLC clinically. The aim of this study is to clarify the issue through a meta-analysis. Methods: A systematic search strategy was used to search relevant literature in the databases of PubMed, Web of Science, and Cochrane Library from 2017 to 2022. The relationship between the diagnostic accuracy of circRNAs and NSCLC was analyzed. For the purpose of evaluating the quality of the literature, Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used. Statistical analyses were assessed using Stata software (version 17.0) and META-DISC (version 1.4). Results: The meta-analysis included 1,093 patients with NSCLC and 959 controls. Results are as follows: pooled sensitivity, 0.78 (95% CI = 0.71-0.83, I2 = 71.86); pooled specificity, 0.76 (95% CI = 0.70-0.82, I2 = 70.12); pooled positive likelihood ratio (PLR), 3.3 (95% CI = 2.6-4.2, I2 = 37.56); pooled negative likelihood ratio (NLR), 0.29 (95% CI = 0.23-0.37, I2 = 64.67); diagnostic odds ratio (DOR), 11.42 (95% CI = 7.88-16.56, I2 = 99.05); area under the receiver operating characteristic curve (AUC), 0.84 (95% CI = 0.80-0.87). Based on the subgroup analysis, it appears that the heterogeneity is primarily caused by the NSCLC subgroup. Conclusion: circRNAs are highly useful diagnostic biomarkers for NSCLC in China. Further prospective studies on the diagnostic value of circRNAs should be conducted in multiple countries. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022323804.

Alpha Protein Kinase 2 Promotes Esophageal Cancer via Integrin Alpha 11.

Background: As a common disease around the world, esophageal cancer (EC) primarily includes two subclasses: esophageal adenocarcinoma and esophageal squamous cell carcinoma. Mortality has been rising over the years; hence, exploring the mechanism of EC development has become critical. Among the alpha protein kinases, alpha protein kinase 2 (ALPK2) presumably has a connection with EC, but it has never been revealed before. Methods: In this study, IHC analysis was used for ALPK2 expression quantification in ES tissues. TE-1 and Eca-109, which are both human EC cell lines, were used for in vitro analysis of cell proliferation, migration, apoptosis, and colony formation. Results: ALPK2 was found to have an abundant expression within EC tissues (P < 0.001), as well as in the two selected human EC cell lines (P < 0.05). The data showed that ALPK2 depletion suppressed EC cell proliferation, migration, and colony formation, meanwhile stimulating apoptosis (P < 0.001). The in vivo experiments also displayed inhibitory effects caused by ALPK2 depletion on EC tumorigenesis (P < 0.001). It was further validated that ALPK2 depletion made the phosphorylation of Akt and mTOR, as well as CDK6 and PIK3CA levels downregulated (P < 0.001). Mechanistically, we identified integrin alpha 11 (ITGA11) as a downstream gene of ALPK2 regulating EC. More importantly, we found that ITGA11 elevation promoted cell proliferation and migration and rescued the suppression effects caused by ALPK2 depletion (P < 0.001). Conclusions: ALPK2 promotes esophageal cancer via integrin its downstream gene alpha 11; ALPK2 can potentially act as a target for the treatment of EC.

Highly Expressing SCARA5 Promotes Proliferation and Migration of Esophageal Squamous Cell Carcinoma.

Background: Thrombospondin type 1 domain-containing 7A (THSD7A) was reported to play a procancer role in esophageal squamous cell carcinoma (ESCC). The aim of the study was to screen the downstream functional genes of THSD7A and explore their functions in ESCC, based on the reported research into THSD7A function and on gene microarrays. Methods: We adopted quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Celigo high-content screening (HCS) technology to screen the downstream genes of THSD7A. The expression level of target genes was examined by PCR, western blot, and immunohistochemistry (IHC). The effects of these target genes on ESCC malignant biological behavior were performed in vivo and in vitro. The Kaplan-Meier (K-M) survival analysis and Cox regression were used to analyze the prognostic significance of target genes in ESCC patients. Experiments in the literature on liver cancer (LC) were repeated to verify the functions of these genes in different tumors. We further explored the cancer-promoting mechanism of target genes in ESCC by sequencing of the genes' exons. Results: Scavenger receptor class A member 5 (SCARA5) was proved to be the downstream driving gene of THSD7A. SCARA5 promoted cell proliferation and migration but inhibited apoptosis in ESCC. IHC results confirmed that SCARA5 expression in ESCC exceeded that in normal tissues. The K-M survival analysis indicated that SCARA5 expression quantity was not related to prognosis, but tumor volume and T classification were both the independent prognostic factors. Repetition of experiments in LC in the literature confirmed that SCARA5 had exactly opposite functions in EC and LC. Conclusion: SCARA5 was related to the development and occurrence of ESCC. Our findings suggested that it was a potentially diagnostic individualized therapeutic target for ESCC in the future and that its application could possibly be combined with that of upstream THSD7A gene.

Application of standard operation procedure of thoracentesis in clinical skills training for undergraduates / 中华医学教育探索杂志

Objective:To investigate the application value of standard operation procedure (SOP) of thoracentesis in clinical skills training for undergraduates.Methods:In this study, 63 undergraduates were randomized into two groups, with 29 students in experimental group receiving SOP training, and 34 students in control group trained by traditional teaching methods. The performance of the two groups at different stages of thoracentesis were compared after the training. SPSS 19.0 was used to analyze the assessment data.Results:The experimental group was significantly superior to the control group in the stages of "puncture operation" and "post-puncture operation" [(33.76±2.46) points vs. (31.91±3.60) points, P=0.02; (7.93±1.53) points vs. (6.79±1.84) points, P=0.01], as well as the total scores [(82.59±4.14) points vs. (79.26±4.94) points, P=0.01]. Conclusion:It's suggested that application of SOP may improve the effectiveness of thoracentesis training, and organized teaching methods are essential for clinical skills training.

Amplification and clinicopathological significance of HER-2 in Kazakh esophageal squamous cell carcinoma.

Amplification and overexpression of the human epidermal growth factor receptor-2 (HER-2) gene accelerates cell division and proliferation, and promotes tumor growth and metastasis in various malignant tumors. However, there are few reports on its influence and mechanism in esophageal cancer. The aim of the present study was to investigate the gene amplification and clinicopathological significance of HER-2 in Kazakh esophageal squamous cell carcinoma (ESCC). HER-2 gene amplification was detected in 70 esophageal cancer tissues using fluorescence in situ hybridization. The association between the HER-2 gene amplification and the clinicopathological characteristics of patients with esophageal cancer was also analyzed. The amplification rate of the HER-2 gene in patients with esophageal cancer was 54.2% (38/70). The results also revealed a positive association between the amplification rate of the HER-2 gene in esophageal squamous cell carcinomas and the level of tissue differentiation, increasing gradually and significantly among the highly, moderately and poorly differentiated tissues (P<0.05). The amplification rate of the HER-2 gene in patients with lymph node metastasis was higher than those without (P<0.05). There was no significant association between the amplification rate of the HER-2 gene and any of the clinic pathological parameters, such as sex, age, depth of invasion and 3-year survival, among patients (P>0.05). In conclusion, the amplification rate of the HER-2 gene in patients with Kazakh ESCC was high. There was an association with various prognostic factors, including cancer differentiation and lymph node metastasis. HER-2 gene expression levels may be considered as an indicator of poor prognosis in patients with ESCC in the clinical setting, and this may provide a basis of treatment for individualized targeted therapies.

Association between TP53 gene deletion and protein expression in esophageal squamous cell carcinoma and its prognostic significance.

The aim of the present study was to investigate the association between tumor protein 53 (TP53) gene deletion and protein expression and clinical features in esophageal squamous cell carcinoma (ESCC), and to evaluate the predictive value of these two characteristics in the prognosis of ESCC. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were performed to detect the expression of p53 protein and gene deletion in ESCC tissue samples from different ethnic groups in Xinjiang, in order to analyze their association with clinicopathological characteristics and patient prognosis, as well as the sensitivity and specificity of the two methods. In addition, the results were further validated by tissue microarray from a different region. The positive rate of p53 protein expression was 54.5% (201/369) in the multi-ethnic group, and was significantly different between sex (P=0.026) and between tumor differentiation groups (P=0.032). FISH demonstrated that the TP53 gene deletion rate was 31.8% (68/214), which was significantly different between different tumor differentiation (P=0.002), lymph node metastasis (P=0.005) and vascular invasion (P<0.001) groups. The survival rate of patients with TP53 gene deletion was significantly lower than those without TP53 gene deletion (P<0.05). The positive rate of p53 protein expression in the tissue microarray was 58.1% (68/117), which was significantly different between the depth of invasion groups (P=0.011). The TP53 gene deletion rate was 47.9% (56/117), which significantly differed according to lymph node metastasis (P=0.003) and TNM stage (P=0.01). In addition, the total concordance rates of the two methods were 60.3 and 64.1%, respectively. There were also significant differences in the positive rate of TP53 gene deletion and protein expression in different stages of ESCC (P<0.05), which increased gradually with the progression of ESCC. The deletion of the TP53 gene in esophageal cancer was associated with poor prognosis and may be an important biomarker for evaluating the prognosis of patients with ESCC. The combination of FISH and IHC methods could significantly improve the detection rate of TP53 gene abnormalities and the accuracy of prognostic assessment of ESCC.

The long non-coding RNA MIAT/miR-139-5p/MMP2 axis regulates cell migration and invasion in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is a complex disease which is influenced by multiple factors. Recent studies demonstrated that long non-coding RNA (lncRNA) MIAT was involved in tumor metastasis. However, the underlying mechanism of MIAT in NSCLC remains largely unknown. In this study, MIAT, miR-139-5p and MMP2 expression were measured by quantitative reverse transcriptase PCR (QRT-PCR) or Western blotting, respectively, and we found the expression of MIAT and MMP2 were elevated, while miR-139-5p was decreased in NSCLC tissues and cell lines. Transwell assay showed MIAT and MMP2 functioned as an oncogene to induce cell migration and invasion in NSCLC, but miR-139-5p served as a tumor suppressor in NSCLC to inhibit cell migration and invasion. Besides that, in vivo experiments also indicated MIAT deletion inhibited tumor growth. The relationship between miR-139-5p and MIAT or MMP2 was then confirmed by Luciferase reporter assay, and the results showed that MIAT directly interacted with miR-139-5p and miR-139- 5p targetedly suppressed MMP2 in NSCLC cells. Furthermore, expression analysis showed that MIAT indirectly regulated MMP2 by sponging miR-139-5p. Finally, rescue assay suggested that miR-139-5p restoration reversed MIAT-overexpression-induced promotion on the migration and invasion of NSCLC cells. In conclusion, our results demonstrated that lncRNA MIAT modulated the migration and invasion of NSCLC by regulating miR-139-5p and MMP2.

High MLL2 expression predicts poor prognosis and promotes tumor progression by inducing EMT in esophageal squamous cell carcinoma.

BACKGROUND: MLL2 has been identified as one of the most frequently mutated genes in a variety of cancers including esophageal squamous cell carcinoma (ESCC). However, its clinical significance and prognostic value in ESCC has not been elucidated. In the present study, we aimed to investigate the expression and role of MLL2 in ESCC. METHODS: Immunohistochemistry (IHC) and qRT-PCR were used to examine the expression profile of MLL2. Kaplan-Meier survival analysis and univariate and multivariate Cox analyses were used to investigate the clinical and prognostic significance of MLL2 expression in Kazakh ESCC patients. Furthermore, to evaluate the biological function of MLL2 in ESCC, we applied the latest gene editing technique CRISPR/Cas9 to knockout MLL2 in ESCC cell line Eca109. MTT, colony formation, flow cytometry, scratch wound-healing and transwell migration assays were performed to investigate the effect of MLL2 on ESCC cell proliferation and migration. The correlation between MLL2 and epithelial-mesenchymal transition (EMT) was investigated by Western blot assay in vitro and IHC in ESCC tissue, respectively. RESULTS: Both mRNA and protein expression levels of MLL2 were significantly overexpressed in ESCC patients. High expression of MLL2 was significantly correlated with TNM stage (P = 0.037), tumor differentiation (P = 0.032) and tumor size (P = 0.035). Kaplan-Meier survival analysis showed that patients with low MLL2 expression had a better overall survival than those with high MLL2 expression. Multivariate Cox analysis revealed that lymph node metastasis and tumor differentiation were independent prognostic factors. Knockout of MLL2 in Eca109 inhibited cell proliferation and migration ability, induced cell cycle arrest at G1 stage, but it had no significant effect on apoptosis. In addition, knockout of MLL2 could inhibit EMT by up-regulation of E-Cadherin and Smad7 as well as down-regulation of Vimentin and p-Smad2/3 in ESCC cells. In cancer tissues, the expression of E-Cadherin was negatively correlated with MLL2 expression while Vimentin expression was positively correlated with MLL2 expression. CONCLUSION: Our results indicate that overexpression of MLL2 predicts poor clinical outcomes and facilitates ESCC tumor progression, and it may exert oncogenic role via activation of EMT. MLL2 may be used as a novel prognostic factor and therapeutic target for ESCC patients.

Expression, prognosis and functional role of Thsd7a in esophageal squamous cell carcinoma of Kazakh patients, Xinjiang.

Thsd7a (Thrombospondin type 1 domain containing 7a) is a critical transmembrane protein. Studies have indicated that Thsd7a was associated with cytoskeletal organization, cell migration and filopodia formation. However, the involvement of Thsd7a remains elusive in human Esophageal Squamous Cell Carcinoma (ESCC). Consequently, immunohistochemistry and reverse transcription-polymerase chain reaction were utilized to study the correlation between the expression of Thsd7a and clinical-pathological characteristics. The influence of Thsd7a on apoptosis, cell proliferating activity, cell cycle, migratory and invasive capacity was determined in Eca 109 and EC 9706 cell lines in vitro. And the influence on proliferating activity was testified using naked mice model in vivo. In addition, the potential molecular mechanism was tested by microarray. It was discovered that there is a certain correlation between Thsd7a and the Kazakh ESCC. By knocking out Thsd7a, the invasion, migration and proliferation could be decreased. And it could also arrest the cell cycle at G1 phase and increase the apoptosis rate. It was further verified that Thsd7a had obvious effect on proliferation in naked mice with xenograft of Eca109 cells. Finally, it was uncovered by microarray analysis that a variety of tumor genes and pathways related to Thsd7a. Together, it was demonstrated that Thsd7a might have a certain degree of carcinogenesis in ESCC.

Association of the plasma riboflavin levels and riboflavin transporter (C20orf54) gene statuses in Kazak esophageal squamous cell carcinoma patients.

To evaluate the association of the plasma riboflavin level in Kazak esophageal cancer patients and their riboflavin transporter (C20orf54) gene statuses. Plasma riboflavin levels were detected by high performance liquid chromatography in Kazak patients with esophageal squamous cell carcinoma (ESCC) and healthy controls. C20orf54 mRNA and protein expression were analyzed by real-time fluorogenic quantitative polymerase chain reaction and immunohistochemistry in samples from 61 ESCC patients consisting of both tumor and normal tissue, respectively. C20orf54 mRNA expression was decreased in ESCC (0.279 ± 0.102) than in normal counterpart tissue (0.479 ± 0.287; P = 0.049) significantly. Tumors exhibited low C20orf54 protein expression (42.6, 26.2, 18.0 and 13.1% for no C20orf54 staining, weak staining, medium staining and strong staining, respectively), which was significantly lower than that in the normal mucous membrane (13.1, 26.2, 41.0 and 19.7% for no C20orf54 staining, weak staining, medium staining and strong staining, respectively). Defective expression of C20orf54 in tumor cells was significantly associated with poor differentiation. However, other parameters such as depth of invasion and lymph node metastasis had no significant relationship with C20orf54 expression. The average blood concentration of riboflavin was 2.6468 ± 1.3474 ng/ml in ESCC patients lower than control group (4.2960 ± 3.2293 ng/ml, P = 0.015). A positive correlation of plasma riboflavin levels with defective expression of C20orf54 protein was found in ESCC patients (F = 8.626; P = 0.038). Defective expression of C20orf54 is associated with the development of Kazak esophageal squamous cell carcinoma and this may represent a mechanism underlying the decreased plasma riboflavin levels in ESCC.

Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma.

AIM: To investigate the expression of Toll-like receptor (TLR) 3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma (ESCC). METHODS: Reverse transcription-polymerase chain reaction and immunohistochemistry were used to analyze the expression of TLR3, TLR4, TLR7 and TLR9 mRNA and protein in samples from 87 esophageal cancer patients consisting of both tumor and normal tissue. RESULTS: A significant increase in TLR3, TLR4, TLR7 and TLR9 mRNA levels was detected in ESCC samples. Tumors exhibited high TLR protein expression, (70.1%, 72.4%, 66.7% and 78.2% for TLR3, TLR4, TLR7 and TLR9, respectively, P < 0.05). Nevertheless, a significant percentage of tumors also exhibited TLR4 expression in mononuclear inflammatory cells (48.3%) and TLR9 expression in fibroblast-like cells (60.9%). Tumors with high TLR3 expression in tumor cells or high TLR4 expression in mononuclear inflammatory cells were significantly associated with a higher probability of lymph node metastasis and increased depth of invasion. However, tumors with high TLR9 expression in fibroblast-like cells were associated with low probabilities of invasion and metastasis. There was no significant variation between the expression of TLR3, TLR4, TLR7 and TLR9 among different ethnic groups. CONCLUSION: TLR3, TLR4, TLR7 and TLR9 expression appears important to the biological pathogenesis of ESCC. TLRs may represent therapeutic targets for ESCC.

[Application of serum proteomic patterns for the detection of esophageal carcinoma in Kazakh in Xinjiang].

OBJECTIVE: To detect the serum protein profiles of Kazakh's esophageal carcinoma (EC) patients in Xinjiang by SELDI-TOF-MS (surface enhanced laser desorption & ionization time-of-flight mass spectrometry) and build up a diagnostic model of Kazakh's EC in Xinjiang. METHODS: The serum samples from 41 Kazakh's EC patients and 20 Kazakh's healthy controls were collected and analyzed on weak cation exchange and hydrophobic surface protein chip by SELDI-TOF-MS technology. The differentially expressed markers of esophageal carcinoma were detected. RESULTS: The values of M/Zs were significantly different between Kazakh's EC patients and controls (P < 0.05). Among these, 6 proteins peaks were up-regulated (5495.2265, 15 964.6951, 16 152.0872, 4488.4818, 8164.7652, 4979.4223) and 4 down-regulated (6900.3285, 13 790.9241, 8790.8130, 8714.7915) in the Kazakh's EC group. According to cross validation, the model of Kazakh's EC made up of 7 proteins (M/Z 6900.3285, 13 790.9241, 8790.8130, 15 964.6951, 16 152.0872, 4488.4818, 4979.4223) was established. The sensitivity and specificity of this model were 100% (41/41) and 100% (20/20) respectively. CONCLUSION: The model with 7 proteins markers has a higher sensitivity and specificity for Kazakh's EC patients in Xinjiang. It may provide a new serum diagnostic tool for Kazakh's EC patients in Xinjiang.