Construction and testing of a risk prediction classifier for cardia carcinoma.

OBJECTIVES: This research aimed to construct a prediction model for stages II and III cardia carcinoma (CC), and provide an effective preoperative evaluation tool for clinicians. METHODS: CC mRNA expression matrix was obtained from Gene Expression Omnibus and The Cancer Genome Atlas databases. Non-negative matrix factorization was used to cluster data to obtain subgroup information, and weighted gene co-expression network analysis was used to uncover key modules linked to different subgroups. Gene-set enrichment analysis analyzed biological pathways of different subgroups. The related pathways of multiple modules were scrutinized with Kyoto Encyclopedia of Genes and Genomes. Key modules were manually annotated to screen CC-related genes. Subsequently, quantitative real-time polymerase chain reaction assessed CC-related gene expression in fresh tissues and paraffin samples, and Pearson correlation analysis was performed. A classification model was constructed and the predictive ability was evaluated by the receiver operating characteristic curve. RESULTS: CC patients had four subgroups that were associated with brown, turquoise, red, and black modules, respectively. The CC-related modules were mainly associated with abnormal cell metabolism and inflammatory immune pathways. Then, 76 CC-elated genes were identified. Pearson correlation analysis presented that THBS4, COL14A1, DPYSL3, FGF7, and SVIL levels were relatively stable in fresh and paraffin tissues. The area under the curve of 5-gene combined prediction for staging was 0.8571, indicating good prediction ability. CONCLUSIONS: The staging classifier for CC based on THBS4, COL14A1, DPYSL3, FGF7, and SVIL has a good predictive effect, which may provide effective guidance for whether CC patients need emergency surgery.

Effect of Radical Surgery for Advanced Adenocarcinoma of Esophagogastric Junction on Perioperative Cellular Cell Immunity.

Background: To investigate the perioperative peripheral blood levels of CD4+CD25+ regulatory T cells, programed cell death 1 (PD-1), and lymphocyte activation gene 3 (LAG-3) in patients with advanced Siewert type II adenocarcinoma of esophagogastric junction (AEG). Methods: Patients (n = 102) with advanced Siewert type II AEG underwent open total gastrectomy/proximal gastrectomy with a transhiatal resection of the distal esophagus and lymphadenectomy of the lower mediastinum and the abdominal D2 compartment. Flow cytometry was used to detect CD4+CD25+ T cells, PD-1 and LAG-3 expression on both CD4+ and CD8+ T cells in the peripheral blood of the Siewert type II AEG patients prior to surgery and on postoperative day (POD) 1, 3, 7, and 9. Results: The proportion of CD4+CD25+ T cells rapidly decreased on POD 1, then gradually increased and peaked at POD 7. The proportion of CD4+PD-1+ T cells significantly increased after surgery, reaching a maximum on POD 1, and remained significantly elevated on POD 3 compared to the preoperative day. The proportion of CD8+ PD-1+ and CD4+LAG-3+ T cells gradually increased after surgery and reached a peak at POD 7. The change in proportion of CD8+LAG-3+ T cells in the peripheral venous blood lymphocytes after surgery was not statistically significant. Conclusion: The change in the CD4+PD-1+ T lymphocyte ratio may likely reflect the cellular immunity status of the perioperative period.

Corrigendum: Modularized Perturbation of Alternative Splicing Across Human Cancers.

[This corrects the article DOI: 10.3389/fgene.2019.00246.].

Modularized Perturbation of Alternative Splicing Across Human Cancers.

Splicing perturbation in cancers contribute to different aspects of cancer cell progression. However, the complete functional impact of cancer-associated splicing have not been fully characterized. Comprehensive large-scale studies are essential to unravel the dominant patterns of cancer-associated splicing. Here we analyzed the genome-wide splicing data in 16 cancer types with normal samples, identified differential splicing events in each cancer type. Then we took a network-based and modularized approach to reconstruct cancer-associated splicing networks, determine the module structures, and evaluate their prognosis relevance. This approach in total identified 51 splicing modules, among which 10/51 modules are related to patient survival, 8/51 are related to progression-free interval, and 5/51 are significant in both. Most of the 51 modules show significant enrichment of important biological functions, such as stem cell proliferation, cell cycle, cell growth, DNA repair, receptor or kinase signaling, and VEGF vessel development. Module-based clustering grouped cancer types according to their tissue-of-origins, consistent with previous pan-cancer studies based on integrative clustering. Interestingly, 13/51 modules are highly common across different cancer types, suggesting the existence of pan-cancer splicing perturbations. Together, modularized perturbation of splicing represents an functionally important and common mechanism across cancer types.

Identification of Sensitivity Predictors of Neoadjuvant Chemotherapy for the Treatment of Adenocarcinoma of Gastroesophageal Junction.

The identification of reliable predictors of chemotherapy sensitivity and early screening of adenocarcinoma of gastroesophageal junction (AGEJ) patients who are resistant to chemotherapy has become an important area of clinical and translational research. We aimed to investigate the predictive value of seven cancer-associated cellular proteins for neoadjuvant chemotherapy in AGEJ patients. Clinical data of 93 patients who received neoadjuvant chemotherapy for locally advanced AGEJ between June 2010 and December 2014 were reviewed. All patients were administered the combination regimen of S-1 and oxaliplatin (SOX). Expression of P-glycoprotein (P-gp), glutathione S-transferase-π (GST-π), topoisomerase II (topo II), multidrug resistance gene-associated protein (MRP), lung resistance-related protein (LRP), Ki-67, and p53 was determined by immunohistochemistry (IHC) in AGEJ tissues before neoadjuvant chemotherapy. Chemotherapeutic efficacy was evaluated according to RECIST 1.0 standards and histopathological results, and the relationship between the expression of the cellular proteins and chemotherapy efficacy was analyzed. The SOX regimen was associated with an overall response rate of 46.2%. The frequency of expression of the seven cancer-associated factors in the AGEJ tissues was as follows: P-gp, 64.5%; GST-π, 39.8%; topo II, 72.0%; MRP, 33.3%; LRP, 68.8%; Ki-67, 62.4%; and p53, 40.9%. Expression of Ki-67 (p = 0.003) and p53 (p = 0.009) was significantly correlated with chemotherapy sensitivity. Elevated Ki-67 expression and decreased p53 expression predict for SOX insensitivity in AGEJ, and the cellular expression of these respective proteins may provide a useful reference for designing individualized chemotherapy regimens for AGEJ patients in the future.

[Predictive value of P53, Ki-67, HER2 protein detection in neoadjuvant chemotherapy for adenocarcinoma of gastroesophageal junction].

OBJECTIVE: To investigate the predictive value of P53, Ki-67, HER2 protein detection in neoadjuvant chemotherapy for adenocarcinoma of gastroesophageal junction (AGEJ). METHODS: Preoperative biopsy specimens and clinical data of 72 patients of locally advanced Siewert II AGEJ between June 2010 and December 2013 were reviewed. All the patients received SOX scheme neoadjuvant chemotherapy, and were divided into effective group (complete response plus partial response) and ineffective group (stable disease plus progressive disease). Expressions of above 3 proteins were detected by immunohistochemistry in all the patients before neoadjuvant chemotherapy. The relationship between various proteins and efficacy of chemotherapy was analyzed by univariate and logistic multivariate regression analyses. RESULTS: All the 72 patients successfully completed 2 cycles of SOX neoadjuvant chemotherapy, among them, 5 cases (6.9%) with complete response, 30 cases (41.7%) with partial response, 31 cases (43.1%) with stable disease, 6 cases (8.3%) with progressive disease, including 35 cases in effective group and 37 cases in ineffective group. Compared with ineffective group, the positive expression rate of P53 was significantly reduced (25.0% vs. 45.9%, P=0.020), and that of Ki-67 significantly increased (77.1% vs. 43.2%, P=0.003), however, there was no significant difference in the expression rate of HER2 between the two groups (P>0.05). Multivariate analysis showed that Ki-67 was the independent predictive factor for the efficacy of neoadjuvant chemotherapy (P=0.015). Spearman rank correlation showed that Ki-67 expression was positively correlated with HER2 expression (r=0.259, P=0.028), but P53 expression was not correlated with Ki-67 or HER2 (r=0.140, 0.042, P=0.240, 0.725, respectively). CONCLUSIONS: SOX neoadjuvant chemotherapy is safe and effective for AGEJ, especially for patients with depressed expression of P53 and elevated expression of Ki-67, which both may be used as reference for the prediction of chemotherapy efficacy. There is no correlation between P53 and Ki67 proteins, so combined detection may improve the predictive value.

Analysis of a cytoskeleton-associated kinase PEAK1 and E-cadherin in gastric cancer.

The expression of pseudopodium-enriched atypical kinase 1(PEAK1) has been studied in human cancers. However, their roles in gastric cancer are still unknown. In this study, gastric cancer tissue microarrays were constructed with 159 gastric cancer tissue samples, 150 non-neoplastic gastric epithelium specimens and 152 lymph node samples. Immunohistochemical staining for PEAK1 and E-cadherin was performed. Our study found negative expression of PEAK1 in 113 of 159 (71.1%) gastric cancers, in 46 of 150 (30.7%) non-neoplastic gastric epithelium tissues and in 69 of 94 (73.4%) metastatic lymph nodes. Negative expression of PEAK1 and E-cadherin associated with tumor grading, depth of invasion, lymph node metastases, pTNM stage and macroscopic type. Patients with either positive PEAK1 or E-cadherin expression had a significantly higher survival than those with negative expression. When combined, PEAK1(-)/E-cadherin(-) had a significantly poor prognosis than the rest of the patients. The expression of PEAK1 protein was positively correlated with E-cadherin in cancer tissues. Cox regression analyses showed that PEAK1, E-cadherin and PEAK1(-)/E-cadherin(-) were independent predictors of overall survival. In conclusion, our findings suggest that loss of PEAK1 may play an important role in carcinogenesis and development of gastric cancer through activating epithelial to mesenchymal transition.

[Clinical characteristics of lymph node metastasis in Siewert type II adenocarcinoma of the gastroesophageal junction].

OBJECTIVE: To explore the pattern of lymph node metastasis (LNM) in advanced Siewert type II adenocarcinoma of the gastroesophageal junction (AGEJ) in order to properly guide lymphadenectomy. METHODS: From January 2009 to Jun 2011, a total of 86 patients with advanced Siewert type II AGEJ underwent radical esophagogastrectomy by thoracic-abdominal incision and two-field lymphadenectomy. The clinical characteristics, pathologic features, LNM, and influence factor of thoracic metastasis were retrospectively analyzed. RESULTS: LNM was observed in 65 of the 86 cases (75.6%). Simple abdominal lymph node metastasis was observed in 49 of the 86 cases (57.0%), simple thoracic lymph node metastasis was 2.3%, and thoracic-abdominal metastasis was 16.3%, with a significant difference between the abdominal and thoracic metastatic patterns. LNM frequency was found in the lymph node groups No. 3, No. 1, No. 7, No. 110, No. 2 and No. 9 (from the highest to the lowest). The incidences of those lymph node metastases were 46.5%, 41.9%, 17.4%, 14.0%, 10.5%, and 5.8%, respectively. Vascular tumor embolus was the only independent factor for thoracic lymph node metastasis. CONCLUSIONS: Abdominal lymph node metastases of advanced Siewert type II AGEJ mainly occur around the proximal stomach and the coeliac trunk. The metastatic rate of distal stomach and splenic perihilar lymph nodes is low, but metastatic rate of the group No.110 lymph nodes is high. The thoracic lymph node metastasis is only correlated with vascular tumor embolus.

Left thoracoabdominal approach in surgical treatment of adenocarcinoma of the esophagogastric junction in the Northern Henan Province of China.

BACKGROUND: The left thoracoabdominal (LTA) approach is the conventional way to treat adenocarcinoma of the esophagogastric junction (EGJ). The study was to review the outcome of the LTA approach with adenocarcinoma of the EGJ in a single institution in China. METHODS: 135 consecutive adenocarcinomas of EGJ patients who underwent surgical treatment were retrospectively analyzed; data gathered included basic information on the tumor, surgical approach, postoperative complications and survival rate. RESULTS: LTA esophagogastrectomy was performed in all patients. No patients received allogeneic blood transfusion during the operation. Among the resective procedures, proximal gastrectomy was performed in 122 cases. The mean operation time was 150 min (90-240). R(0) resection was obtained in 120 patients (88.9%). Two patients developed respiratory failure 2 days after surgery. Contrast swallow revealed a leak at the anastomosis in 2 patients. One early anastomotic stricture was observed radiologically, and pneumonia was observed in 3 patients. The number of patients with spontaneous pneumothorax and wound infections were 3 and 5, respectively. The percentage was zero in-hospital deaths. The overall survival rates at 1 year and 2 years were 89.2 and 69%, respectively. The median survival was 27.1 months. CONCLUSION: LTA esophagogastrectomy has a major role in the management of adenocarcinoma of the EGJ, at least in the northern Henan Province of China.