Anti-tumor activity of all-trans retinoic acid in gastric-cancer: gene-networks and molecular mechanisms.

BACKGROUND: Gastric-cancer is a heterogeneous type of neoplastic disease and it lacks appropriate therapeutic options. There is an urgent need for the development of innovative pharmacological strategies, particularly in consideration of the potential stratified/personalized treatment of this tumor. All-Trans Retinoic-acid (ATRA) is one of the active metabolites of vitamin-A. This natural compound is the first example of clinically approved cyto-differentiating agent, being used in the treatment of acute promyelocytic leukemia. ATRA may have significant therapeutic potential also in the context of solid tumors, including gastric-cancer. The present study provides pre-clinical evidence supporting the use of ATRA in the treatment of gastric-cancer using high-throughput approaches. METHODS: We evaluated the anti-proliferative action of ATRA in 27 gastric-cancer cell-lines and tissue-slice cultures from 13 gastric-cancer patients. We performed RNA-sequencing studies in 13 cell-lines exposed to ATRA. We used these and the gastric-cancer RNA-sequencing data of the TCGA/CCLE datasets to conduct multiple computational analyses. RESULTS: Profiling of our large panel of gastric-cancer cell-lines for their quantitative response to the anti-proliferative effects of ATRA indicate that approximately half of the cell-lines are characterized by sensitivity to the retinoid. The constitutive transcriptomic profiles of these cell-lines permitted the construction of a model consisting of 42 genes, whose expression correlates with ATRA-sensitivity.  The model predicts that 45% of the TCGA gastric-cancers are sensitive to ATRA. RNA-sequencing studies performed in retinoid-treated gastric-cancer cell-lines provide insights into the gene-networks underlying ATRA anti-tumor activity. In addition, our data demonstrate that ATRA exerts significant immune-modulatory effects, which seem to be largely controlled by IRF1 up-regulation. Finally, we provide evidence of a feed-back loop between IRF1 and DHRS3, another gene which is up-regulated by ATRA. CONCLUSIONS: ATRA is endowed with significant therapeutic potential in the stratified/personalized treatment gastric-cancer. Our data represent the fundaments for the design of clinical trials focusing on the use of ATRA in the personalized treatment of this heterogeneous tumor. Our gene-expression model will permit the development of a predictive tool for the selection of ATRA-sensitive gastric-cancer patients. The immune-regulatory responses activated by ATRA suggest that the retinoid and immune-checkpoint inhibitors constitute rational combinations for the management of gastric-cancer.

Minimally invasive esophagectomy: thoracoscopic esophageal mobilization for esophageal cancer with the patient in prone position.

BACKGROUND: Surgical resection is the mainstay treatment for resectable esophageal cancer. Minimally invasive esophagectomy is performed with increasing frequency and proves to be a safe and effective surgical alternative to the open technique. Minimally invasive esophagectomy using thoracoscopic esophageal mobilization with the patient in prone position seems to offer some advantages with regard to surgeon ergonomics and clinical outcome. METHODS: Between July 2005 and September 2010, 46 patients (35 men and 11 women) underwent minimally invasive esophagectomy in the prone position at the authors' institution. Three patients had previously undergone a thoracic intervention (one patient had previously undergone left pneumonectomy because of lung cancer). The preoperative indication was squamous cell carcinoma for 35 patients and adenocarcinoma for 11 patients. In one case, the histology of the biopsy samples showed a squamous cell carcinoma with neuroendocrine differentiation. Neoadjuvant treatment was administered to 15 patients. RESULTS: All 46 patients underwent esophagectomy using minimally invasive thoracic mobilization of the esophagus with the patient in prone position. The abdominal stage of intervention was performed by laparoscopy for 37 patients and by laparotomy for 9 patients. No thoracotomic conversion was performed. In all cases, a cervical end-to-side anastomosis was performed using a circular stapler. The mean operative time was 263 min. The median intensive care unit stay was 2 days, and the median postoperative hospital stay was 15 days. The mean number of procured lymph nodes was 13. The perioperative morbidity rate was 37%, and the perioperative mortality rate was 4.4%. CONCLUSIONS: Minimally invasive esophagectomy is safe and technically feasible. It entails a lower mortality rate and a shorter hospital stay than those reported in most open series. Thoracoscopy with the patient in prone position offers results comparable with those obtained using other minimally invasive techniques regarding the number of procured lymph nodes. This technique shows considerable advantages such as improved surgeon ergonomics, increased operative field exposure, and satisfactory respiratory results.

Analysis of survival after pancreatic resection for oncological pathologies.

Surgical treatment of pancreatic cancer is to date the only modality that offers a chance of long-term survival. Potentially curative surgery is an option for only about 15% of patients with pancreatic adenocarcinoma. The aim of this study was to determine the survival and to assess the association of clinical, pathological, and treatment features with survival of patients who underwent resection of pancreatic cancer at the Department of Surgery of Udine University Hospital. From November 1989 to December 2005, 137 consecutive patients, who underwent surgical procedures for pancreatic cancer, were followed in our department. We performed 76 pancreatico-duodenectomy, 26 distal pancreatectomies and 35 total pancreatectomies. The surgical reconstruction after pancreatico-duodenectomy was as follows: 11 closures of the main duct with manual nonabsorbable stitches, 24 closures of the main duct with a linear stapler, 17 occlusions of the main duct with neoprene glue and 24 duct-to-mucosa anastomoses. Mean survival time was 27.7 +/- 26.93 months (mean +/- SD) and mean disease-free survival time was 25.4 +/- 23.06 months (mean +/- SD). 1, 3, 5, 7 and 9-year survival rates were 63.9, 33.7, 21.17, 12.7 and 10.2%, respectively. Significant differences in survival were recorded by the Log-rank test for age > 70 (p = 0.001), surgical procedures (p = 0.00046) and presence of metastases (p = 0.0055) The treatment of pancreatic cancer is undertaken with two different aims. The first is radical surgery for patients with early-stage disease, mainly stage I and partly stage II. In all other cases, the aim of treatment is the palliation of the several distressing symptoms related to this cancer. The standard treatment option for resectable tumours is radical pancreatic resection according to the Whipple procedure or total pancreatectomy.