Efficacy analysis of Cheng's GIRAFFE reconstruction after proximal gastrectomy for adenocarcinoma of esophagogastric junction.

Objective: Reconstruction of the digestive tract for adenocarcinoma of esophagogastric junction (AEG) is in dispute. This study evaluated Cheng's gastric tube interposition esophagogastrostomy with reconstruction of His angle and fundus (Cheng's GIRAFFE anastomosis) in laparoscopic/open proximal gastrectomy for Siewert type II AEG, which was performed at Zhejiang Cancer Hospital and the First Affiliated Hospital of Zhejiang Chinese Medical University. Here, we discuss the preliminary results of gastric emptying and anti-reflux. Methods: From a retrospective database, 74 patients with advanced Siewert type II AEG underwent curative proximal gastrectomy with GIRAFFE anastomosis, and their gastric emptying and anti-reflux outcomes were evaluated by the Reflux Disease Questionnaire (RDQ) score, nuclide gastric emptying, 24-h impedance-pH monitoring and gastroscopy. Results: Seventy-four patients successfully completed proximal partial gastrectomy with Cheng's GIRAFFE esophagogastric anastomosis. RDQ score six months after the operation was 2.2±2.5. Results of nuclide gastric emptying examinations showed that the gastric half-emptying time was 67.0±21.5 min, the 1-h residual rate was (52.2±7.7)%, the 2-h residual rate was (36.4±5.1)%, and the 3-h residual rate was (28.8±3.6)%; 24-h impedance-pH monitoring revealed that the mean DeMeester score was 5.8±2.9. Reflux esophagitis was observed by gastroscopy in 7 patients six months after surgery. Conclusions: Cheng's GIRAFFE anastomosis is safe and feasible for Siewert type II AEG.

GPR30 Activation Promotes the Progression of Gastric Cancer and Plays a Significant Role in the Anti-GC Effect of Huaier.

Gastric cancer (GC) is one of the most common types of cancer. The n-butanol extract of Huaier (NEH) is the alcohol-soluble part extracted by the systematic solvent method, which is effective against gastric cancer (GC). However, the mechanism of action of NEH remains unclear. In this study, we aim to evaluate the clinical relevance of GPR30 expression in GC patients and the role of the GPR30/PI3K/AKT signalling pathway in the anti-GC effect of NEH. The expression of GPR30 was examined using immunohistochemistry. Cell counting kit 8 (CCK-8) assay, wound healing, and transwell experiments were used to investigate the viability, migration, and invasion of gastric cancer cells. Western blotting was used to detect the expression of GPR30 and its downstream signalling molecules of the PI3K/AKT signalling pathway. Gastric cancer patient-derived xenografts (PDX) mouse model was used to evaluate the antitumor effect of NEH in vivo. In addition, the graded doses and the maximum tolerated dose of NEH were administered intraperitoneally into the mice for acute toxicity test. We demonstrate that GPR30 expression in GC tissues was significantly higher than that in corresponding adjacent noncancerous tissues and the expression of GPR30 was correlated with a poor prognosis in GC patients. Moreover, GPR30 expression was involved in the migration and invasion of GC cells in vitro. Additionally, we found that NEH can suppress the growth of GC in patient-derived xenograft tumors in vivo. Furthermore, NEH inhibited the proliferation, migration, and invasion in GC cells in a concentration-dependent manner through inhibiting the GPR30-mediated PI3K/AKT signalling pathway in vitro. Acute toxicity test showed that NEH caused no toxic reaction or death and the maximum tolerated dose of NEH in mice was greater than 1600 mg/kg. Our results demonstrate that the high expression of GPR30 is an independent factor of poor prognosis in patients with GC and NEH could be a new agent for the treatment of gastric cancer.

Genome-Wide Identification of Autophagy Prognostic Signature in Pancreatic Cancer.

BACKGROUND: Autophagy plays a vital role in cancer development. However, there is currently no comprehensive study regarding the effects of autophagy-related genes (ARGs) on pancreatic cancer prognosis. Thus, this study aimed to establish an autophagy-related signature for predicting the prognosis of patients with pancreatic cancer. METHODS: We identified and validated differentially-expressed ARGs using data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression project (GTEx) and Expression Omnibus (GEO) database. We performed Cox proportional hazards regression analysis on the differentially-expressed ARGs to develop an autophagy-related signature. We tested the expression of these genes through western blotting and verified their prognostic values through gene expression profiling and interactive analyses (GEPIA). RESULTS: We identified a total of 21 differentially-expressed ARGs and screened 4 OS-related ARGs (TP63, RAB24, APOL1, and PTK6). Both the training and validation sets showed that the autophagy-related signature was more accurate than the Tumor Node Metastasis (TNM) staging system. Moreover, the western blotting result showed that the expression of TP63, APOL1, and PTK6 was high, whereas that of RAB24 was low in cancer tissues. CONCLUSION: This 4-ARG signature might potentially help in providing personalized therapy to patients with cancer.

Efficacy of Conversion Surgery Following Apatinib Plus Paclitaxel/S1 for Advanced Gastric Cancer With Unresectable Factors: A Multicenter, Single-Arm, Phase II Trial.

Objective: Conversion therapy (surgical resection after chemotherapy) is a promising option for unresectable gastric cancer (GC) patients. Addition of anti-angiogenesis drug improves response to chemotherapy. Hence, this study explored the feasibility and efficacy of preoperative paclitaxel (PTX)/S1 chemotherapy combined with apatinib for unresectable GC. Methods: Thirty-one eligible patients with a single unresectable factor were enrolled in this multi-center, single-arm trial. Apatinib (500 mg qd) was administered continuously, while PTX (130 mg/m2) on day 1 and S1 (80 mg/m2) on day 1-14 were given every 3 weeks. The treatment was given for three cycles preoperatively, but the last cycle did not include apatinib. The primary objective measurements included R0 resection rate, objective response rate (ORR) and morbidity of preoperative treatment. Results: Among the 31 patients, 30 patients were evaluable for tumor response, the ORR to preoperative treatment was 73.3%. Eighteen of 30 patients underwent surgery, and R0 resection was achieved in 17 patients. The patients who underwent the conversion surgery had a superior OS compared with those who did not (3 years OS: 52.9 vs 8.3%, p = 0.001). The surgery was operated after apatinib had stopped for a median duration of 4 weeks. Neither anastomotic leakage nor wound healing complications was observed. No increased bleeding event was observed compared with historical data. During preoperative treatment, grade 3 or 4 toxicities were experienced by 58.1% of the patients. Conclusion: Chemotherapy in combination with apatinib demonstrated higher rates of conversion and R0 resection and a superior survival benefit in initial unresectable GC. It is safe and reasonable to suspend apatinib for 4 weeks before the gastrectomy.

Adjuvant albumin-bound paclitaxel combined with S-1 vs. oxaliplatin combined with capecitabine after D2 gastrectomy in patients with stage III gastric adenocarcinoma: a phase III multicenter, open-label, randomized controlled clinical trial protocol.

BACKGROUND: Surgery is the only treatment option for operable gastric cancer. The CLASSIC and ACTS-GC studies showed that the 5-year overall survival (OS) of patients with stage III gastric cancer undergoing D2 gastrectomy is still very low. Whether adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) combined chemotherapy is more effective than the XELOX standard adjuvant chemotherapy in patients with stage III gastric cancer has not been confirmed. METHODS: This is a multicenter, open-label, phase III clinical study. In this trial, 616 patients with locally advanced stage III gastric cancer that underwent curative D2 radical surgery and achieved R0 are planned to be included. Patients will be randomized 1:1 to nab-paclitaxel combined with S-1 (AS) vs. oxaliplatin combined with capecitabine (XELOX). XELOX group: Patients assigned to the XELOX group received eight 3-week cycles of oral capecitabine (1000 mg/m2) twice daily on days 1-14 of each cycle plus intravenous oxaliplatin 130 mg/m2 on day 1 of each cycle. AS group: AS group received eight 3-week cycles of oral S-1 (80-120 mg) (< 1.25 m2, 40 mg; 1.25 to < 1.5 m2, 50 mg; and > 1.5 m2, 60 mg) twice daily on days 1-14 plus intravenous nab-paclitaxel 120 mg/m2 on days 1 and 8 of each cycle. The primary endpoint was the 3-year disease-free survival (3-year-DFS) defined as the time from randomisation to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. The secondary endpoints were the overall survival, (defined as the time from the date of randomisation to date of death from any cause) and safety (any adverse event). DISCUSSION: Compared with previous studies, this study includes nab-paclitaxel based on S-1 adjuvant chemotherapy, which is expected to achieve better efficacy and lower toxicity than the standard treatment. This study is the first clinical study to evaluate the safety and efficacy of nab-paclitaxel combined with S-1 in patients with stage III gastric cancer after D2 radical resection. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov, registration number: NCT04135781 , on October 20th, 2019.

Apatinib enhances chemosensitivity of gastric cancer to paclitaxel and 5-fluorouracil.

Background and aim: Paclitaxel (PTX) plus 5-fluorouracil (5-Fu) has become the standard chemotherapy for advanced gastric cancer (GC). Apatinib, a small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, improves outcomes in GC patients as a third-line treatment. However, its impact on the chemosensitivity of GC remains to be determined. Hence, we aimed to assess the efficacy and safety of apatinib combined with chemotherapy in vivo and in vitro. Methods: The MGC803 cell viability was determined by Cell Counting Kit-8 assay, and the interactions between apatinib and conventional cytotoxic agents revealed by combination index values were calculated using Calcusyn 2.0 software. We also used a zebrafish embryo xenograft model to validate the synergistic interactions. Furthermore, 4 patients with late-stage GC were enrolled to explore the efficacy and safety of PTX/Tegafur Gimeracil Oteracil Potassium (S1) (PS) chemotherapy plus apatinib in conversion surgery. Results: Apatinib showed synergistic interactions with both PTX and 5-Fu in vivo. The zebrafish embryo xenograft model also demonstrated that apatinib significantly enhanced the antitumor activity of PTX and 5-Fu. Apatinib plus PS chemotherapy was well tolerated before surgery. Objective response to preoperative SPA treatment was achieved in all 4 patients. No postoperative bleeding events or wound-healing complications were observed. No postperative morbidity occurred and no morbidity was encountered. Pathological examination showed that all patients had grade Ib pathological response. Conclusion: The experimental data suggested that apatinib improves the efficacy of PTX and 5-Fu both in vitro and in vivo. Clinical evidence showed that a combination of PS chemotherapy with apatinib may be an efficient and acceptable safety treatment for late-stage GC, especially in conversion surgery.

Novel abdominal approach for dissection of advanced type II/III adenocarcinoma of the esophagogastric junction: a new surgical option.

OBJECTIVE: The optimal surgical approach for Siewert type II adenocarcinoma of the esophagogastric junction (AEG) is controversial. In this study, we evaluated the outcomes of total gastrectomy for Siewert type II/III AEG via the left thoracic surgical approach that is used at our center. METHODS: We identified 41 patients with advanced AEG in our retrospective database and analyzed their 3-year survival rate, upper surgical margin, postoperative complications, and index of estimated benefit from lymph node dissection. RESULTS: The 3-year overall survival rate of the whole group was 63%, but no difference was observed between Siewert type II and III AEGs. Esophageal exposure and lymphadenectomy were sufficient. Eight patients developed postoperative complications, but none of the patients developed anastomotic leakage. Dissection of lymph node station Nos. 19 and 110 may be necessary for patients with Siewert type II AEG. Multivariate analysis revealed that the cT category was the only independent risk factor. CONCLUSIONS: Total gastrectomy via an approach from the abdominal cavity into the thoracic cavity may be an optimal surgical technique for advanced Siewert type II AEG.

Aqueous Huaier Extract Suppresses Gastric Cancer Metastasis and Epithelial to Mesenchymal Transition by Targeting Twist.

Trametes robiniophila Murr. (Huaier) is a widely used anti-cancer agent in China. Strong evidence for the anti-proliferative activity of Huaier has been reported; however, its anti-metastatic potential against gastric cancer (GC) as well as its underlying mechanism of action are unknown. Here, we show that treatment with an aqueous Huaier extract over a range of concentrations significantly suppressed both the invasiveness and migratory ability of GC cells. Huaier could also partly reverse the epithelial-mesenchymal transition (EMT), as characterized by increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. In addition, Huaier-treated cells expressed lower levels of Twist compared to untreated controls, and overexpression of Twist via transfection could partially abolish the anti-metastatic activity of Huaier. Furthermore, elevated Twist expression was correlated with an advanced TNM stage, a high rate of lymph node metastasis, and reduced disease-free survival in GC patients. These findings reveal a novel anti-metastatic mechanism for Huaier, which inhibits the EMT by targeting Twist, suggesting its potential application against a GC relapse.

Curcumin combined with cis-platinum promote the apoptosis of human colorectal cancer HT29 cells and mechanism.

Colorectal carcinoma is one of the common malignant carcinoma that severely harms the public health. Curcumin (Cur) exhibits anti-tumor, antioxidant, anti-inflammatory and antiviral effects, which result in the promotion of the apoptosis of cancer cells. The present study aimed to investigate the effect of cis-platinum (DDP) combined with Cur on the apoptosis of colorectal carcinoma cells, and to elucidate its underlying mechanism of action. The cell viability of human colorectal cancer HT29 cells was detected by MTT after DDP treatment. The effect of DDP/Cur co-treatment on cell proliferation and apoptosis were investigated using CCK-8 assay and flow cytometry assay. HT29 cells growth was significantly inhibited after DDP treatment and DDP combined with Cur treatment for 24 h. In our results, DDP in combination with Cur significantly promoted the apoptosis of HT29 colorectal carcinoma cell in a dose dependent manner. Bcl-2-associated X protein (Bax) expression was promoted and B-cell lymphoma-2 (Bcl-2) expression was suppressed, In addition, Notch1, Notch1 intracellular domain (NICD1) and hairy and enhancer of split 1 (Hes-1) were decreased dramatically in HT29 cells treated with Cur combined with DDP. The effect of Cur combined with DDP treatment was better than the effect of DDP treatment. It showed that DDP combined with Cur promote the apoptosis of HT29 cells via regulating the expression of related apoptotic genes and inhibiting the activation of Notch1 signaling pathway.

[Clinical study of continual jejunal interposition after subtotal gastrectomy].

OBJECTIVE: To explore the clinical effect of continual jejunal interposition in digestive tract reconstruction after subtotal gastrectomy. METHODS: Thirty-four patients with distal gastric cancer were divided randomly into two groups. In group A, the digestive continuity was reconstructed by continual jejunal interposition in 16 patients after subtotal gastrectomy. In group B, the digestive tract of other 18 cases were reconstructed by Billroth II procedure. The postoperative comp1ications, nutritional status, food intake and gastroscopic results were compared. RESULTS: There were no complications such as anastomotic leakage or obstruction in the two groups. The Visick scoring of group A was better than that of group B, and the difference was significant one year after operation (mu= 1.98, P< 0.05). All patients retrieved 85% of preoperative food intake per meal in group A, while only l4 patients got such results in group B. The weight loss was significantly higher in group B than that in group A(t = - 2.181, P= 0.037) after operation. The serum albumin level after operation in group A was significantly higher than that in group B (t=2.125, P=0.041), the level one year after operation in group A was also significantly higher than that before operation (t= - 2.175, P= 0.011). Gastroscopy one year after operation revealed fluent stoma,no bile reflux,and no congestion and edema in stomal mucosa and interposed jejunum in group A, while bile retention in 11 cases (61.1%), stomal inflammation in 13 cases (72.2%), and stomal ulcer in 2 cases (11.1%) in group B. CONCLUSION: Continual jejunal interposition after subtotal gastrectomy can recover physiological continuity of digestive tract and improve the quality of 1ife without reflux gastritis.

[Residual stomach, duodenum, and continual jejunal interposition after subtotal gastrectomy].

OBJECTIVE: To investigate the clinical effect of residual stomach, duodenum, and continual jejunal interposition on the patients of gastric cancer after subtotal gastrectomy. METHODS: Fifty-four patients with gastric cancer after subtotal gastrectomy were randomly divided into 2 groups: Group A (n = 26, receiving digestive tract reconstruction by manual end-to-side anastomosis of residual stomach and jejunum, end-to-side anastomosis of residual duodenum and jejunum, and side-to-side anastomosis of jejunum and jejunum, then the jejunum proximal to the stomach-jejunum anastomosis and the jejunum distal to the duodenum-jejunum anastomosis were ligated so as to form an integral continual jejunal interposition; and Group B (n = 28, receiving Bilroth digestive tract reconstruction. The operation time, body weight, prognosis nutrition index (PNI), and Visick score 3 and 6 months after the operation were observed. RESULTS: All patients recovered quickly and no complicating anastomosis leakage and obstruction was found. It took 53 +/- 9 minutes to finish the reconstruction in Group A, significantly shorter than that in Group B (57 +/- 6 minutes, t = -2.145, P = 0.037). The body weight and PNI of both groups decreased significantly 3 months after the operation in comparison with those before the operation (both P < 0.05). The body weight and PNI of Group A returned to the levels before operation. Although the body weight and PNI of Group B recovered to some extent 6 months after operation, they remained significantly lower than those before operation both P < 0.05). The Visick score 6 months after operation of Group A was superior to that of Group B (t = 2.1 P < 0.05). CONCLUSION: Residual stomach, duodenum, and continual jejunal interposition after subtotal gastrectomy helps overcome the difficulty in the procedure of digestive tract reconstruction and restore the physiological passage through duodenum, thus avoiding reflux and improving patients' quality of life.