Clinical Research Directory

How Epigenetic Changes in hMLH1 Connect Lab Research With Diagnosis in Gastric Cancer

DNA methylation is one of the key mechanisms that are thought to underlie the association between aging and cancer. Several methylation-based measures of biological aging have been developed and have demonstrated an association with mortality and, in some cases, with cancer incidence. Accordingly, CpG promoter hypermethylation is a well-known mechanism of gene inactivation in carcinogenesis. Gastric cancer has been classified in different molecular phenotypes based on genetic and epigenetic characteristics. One of these subtypes is characterized by a high grade of microsatellite instability (MSI-H). In gastric cancer, the MSI-H status is mostly caused by methylation of the hMLH1 gene promoter (between 71% and 78%), that is also considered the representative of a gastric-specific CpG island methylation pattern (CIMP). Gastric cancer with hMLH1 hypermethylation is frequently expressed in the MSI-H phenotype but also reported in the MSI-L type. Hypermethylation has been associated with advanced age, dietary habits, smoking and alcohol consumption. Moreover, other studies on GI cancer (colorectal, rectal and gastric) have associated hMLH1 hypermethylation with decreased levels of folate, vitamin C and niacin. Last, increased oxidative stress has been proposed as one of the possible initiators of cancer development and progression through epigenetic mechanism as hypermethylation. From a clinical standpoint, MSI-H gastric cancers have been associated with increased resistance to standard chemotherapy and increased immunogenicity, representing a hypothetic ideal target to immunotherapy, that has documented clinical efficacy for this subtype. However, some authors have suggested that MSI-H GCs without hMLH1 hypermethylation and GCs with hMLH1 hypermethylation could be different in terms of clinicopathologic characteristics and biological behavior. In addition, the specific role of hMLH1 hypermethylation in resistance to standard chemotherapy is unknown, as well as its potential adjunctive role in the chemoresistance of hypermethylated - but MSI-L - tumors. Identifying risk factors for hMLH1 hypermethylated GC could have relevant implications in terms of disease prevention and even reversal of the hypermethylation mechanisms through natural as well as synthetic compounds. It could also identify a predictive tool to better stratify patients for expected sensitivity to specific chemotherapy (or biological therapy) regimens. Therefore, this preliminary study aims to determine if the development of hMLH1-methylated GC is associated with specific clinicopathologic characteristics and environmental habits. It also aims to report on the biological behavior of these tumors, as well as on their chemosensitivity to platin-based chemotherapy regimens.

Effectiveness of ERAS on Postoperative Recovery After Minimally Invasive Gastrectomy

This prospective, randomized, open-label, multicenter study is designed to evaluate the impact of an enhanced recovery after surgery (ERAS) protocol on the rate of meeting discharge criteria in patients undergoing minimally-invasive gastrectomy for gastric cancer. We hypothesize that implementation of our ERAS protocol will significantly increase the proportion of patients who meet standardized discharge criteria following minimally-invasive gastrectomy.

Total Neoadjuvant FLOT Chemotherapy in Locally Advanced Gastric and Gastroesophageal Junction Cancer

The main goal of this study is to investigate the proportion of participants with locally advanced gastric and gastroesophageal adenocarcinoma without previous treatment during the last 5 years who can tolerate all planned cycles of chemotherapy and radical surgical treatment who will be prospectively randomized into two groups to undergo one of two chemotherapy regimens, followed by surgery: 1. 8 cycles of Total Neoadjuvant ChemoTherapy (TNT) with 5-Fluorouracil (5-FU), Leucovorin, Oxaliplatin, and Docetaxel (FLOT) followed by surgery. 2. 4 cycles of Neoadjuvant FLOT chemotherapy scheme preoperatively and 4 adjuvant FLOT cycles postoperatively.

Investigation of Impact of Indocyanine Green on Volume of Lymphadenectomy in Resectable Gastric Cancer

The study aims to evaluate the safety and benefits of using indocyanine green in lymph node dissection for gastric cancer surgery. The primary endpoint is the average number of lymph nodes removed. Secondary study points are the average number of ICG-positive lymph nodes; the average number of metastatic ICG-positive lymph nodes; the number of postoperative complications and complications associated with the administration of ICG. Patients who meet the inclusion criteria for this study will be enrolled in the study after reviewing and signing an informed consent form. All patients will be included in one group and will receive surgical treatment in the amount of total or subtotal gastrectomy with lymphadenectomy D1, D1+, D2 or D2+. ICG is injected by the patient by endoscopic submucosal injection into 4 points around the tumor 24-12 hours before the start of the surgical intervention. Assessment of the number of fluorescent lymph nodes will be performed intraoperatively with their subsequent removal and mapping. The incidence of postoperative complications will be assessed by Clavien-Dindo.

Evaluation of Intra-operative Photographs for the Assessment of a Proper Lymphadenectomy in Minimally-invasive Gastrectomies for Gastric Cancer (PhotoNodes)

Even after the wide introduction of chemo/radiotherapy in the treatment algorithm, adequate surgery remains the cornerstone of gastric cancer treatment with curative intent. A proper D2 lymphadenectomy is associated with improved cancer specific survival as confirmed in Western countries by fifteen-year follow-up results of Dutch and Italian randomized trials. In clinical practice, the total number of harvested lymph nodes is often considered as a surrogate marker for adequate D2 lymphadenectomy; nonetheless, the number of retrieved nodes does not necessarily correlate with residual nodes, which intuitively could represent a more reliable marker of surgical adequacy. The availability of an efficient tool for evaluating the absence of residual nodes in the operative field at the end of node dissection could better correlate with survival outcomes. The goal of this multicentric observational prospective study is to test the reliability of a new score (PhotoNodes Score) created to rate the quality of the lymphadenectomy performed during minimally invasive gastrectomy for gastric cancer. The score is assigned by assessing the absence of residual nodes at the end of node dissection on a set of laparoscopic/robotic high quality intraoperative images collected from each patient undergoing a minimally invasive gastrectomy with D2 node dissection. Ideally, this tool could be a new indicator of the quality of D2 dissection and could assume a prognostic role in the treatment of gastric cancer.