Germline mutation in e-cadherin gene (CDH1) is found in approximately 25% to 30% of individuals fulfilling the clinical criteria for hereditary diffuse gastric cancer (HDGC). Prophylactic gastrectomy is the mainstay of the management of cases with pathogenetic CDH1 mutation. However, some individuals refuse gastrectomy and prefer to delay it for medical or psychosocial reasons. For these patients as well as for those in which a pathogenetic mutation is not found, endoscopic surveillance is recommended. The suggested endoscopic protocol involves targeted as well as 30 random biopsies, which is tedious and time-consuming . In order to save time, two specimens can be taken during a single passage of the biopsy forceps ("double-bite" technique). The aim of this study was to determine the adequacy and utility of the "double-bite" technique in patients undergoing surveillance for HDGC as compared to the standard "single-bite technique".

Previous studies have validated endoscopy, as an efficient tool for initial screening and in selected cases surveillance of families fulfilling the clinical criteria for hereditary diffuse gastric cancer (HDGC). The aim is to detect microscopic foci of in situ or intramucosal signet ring cell carcinoma (SRCC), which are characteristic of early HDGC. Currently, the recommended endoscopic protocol involves targeted biopsies of any suspicious lesion as well as a minimum of 30 mapping random biopsies specimens taken from all anatomic areas of the gastric mucosa, also known as Cambridge endoscopy protocol. However this is a time-consuming and tedious process, which significantly prolongs the duration of the procedure and might reduce patient tolerance. In order to save time two specimens can be taken during a single passage of the forceps ("double-bite" technique).

In order to evaluate the adequacy and utility of the "double-bite" technique, patients undergoing surveillance for HDGC, are randomized to the single-bite vs double-bite arm. Endoscopies are performed according to a standardized protocol. Briefly, a white-light high-resolution endoscope with 85 magnification and a maximal resolution of 7.9 mm (GIF-FQ260Z; Olympus, Tokyo, Japan) is used to examine all anatomic segments of the insufflated stomach. Any abnormalities on white-light endoscopy are recorded and assessed further by narrow-band imaging magnification with or without autofluorescence imaging. Targeted biopsy specimens are taken from identified lesions, and 5 random biopsy specimens are taken in each of the siz gastric anatomical areas (prepylorus, antrum, transitional zone, body, fundus, and cardia). The double-bite technique involves taking an initial biopsy, repositioning the forceps, and taking another biopsy from the same area with the initial specimen still on the forceps. The single bite technique involves removing the forceps with its specimen after each individual biopsy. Time is recorded between the first and last random biopsy. Comfort score is reported after the procedure, according to the modified Gloucester scale. The investigators use Boston Single-Use Radial Jaw™ 4 biopsy forceps with a spike. Biopsy specimens are stained with hematoxylin and eosin and periodic acid-Schiff diastase and are assessed for size and presence of SRCC foci by an upper specialist GI pathologist, who have significant experience in SRCC identification. Any lesions are checked by a second pathologist within the Cambridge Pathology team before reporting. Both pathologists are blinded to study arm.

Inclusion criteria:

• Patients in the Familial Gastric Cancer Registry held in Cambridge fulfilling clinical criteria for HDGC.
• Patients willing to undergo at least one upper GI endoscopy with random biopsies according to Cambridge biopsy protocol.

Exclusion criteria:

• Patients who decline evaluation with endoscopy either as a screening or surveillance tool
• Patients on clopidogrel, and/or warfarin for high risk condition and unable to withhold temporarily the medication.