Genomic and genetic alterations influence the progression of gastric cancer

Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma.

Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome

AIM:To describe our patients affected with ectopic biliary tree gastrinoma and review the literature on this topic.METHODS:Between January 1992 and June 2012,28 patients affected by duodenopancreatic endocrine tumors in multiple endocrine neoplasia type 1(MEN1)syndrome underwent surgery at our institution.This retrospective review article analyzes our experience regarding seventeen of these patients subjected to duodenopancreatic surgery for Zollinger-Ellison syndrome(ZES).Surgical treatment consisted of duodenopancreatectomy(DP)or total pancreatectomy(TP).Regional lymphadenectomy was always performed.Any hepatic tumoral lesions found were removed during surgery.In MEN1 patients,removal of duodenal lesions can sometimes lead to persistence or recurrence of hypergastrinemia.One possible explanation for this unfavorable outcome could be unrecognized ectopic localization of gastrin-secreting tumors.This study described three cases among the seventeen patients who were found to have an ectopic gastrinoma located in the biliary tree.RESULTS:Seventeen MEN1 patients affected with ZES were analyzed.The mean age was 40 years.Fifteen patients underwent DP and two TP.On histopathological examination,duodeno pancreatic endocrine tumors were found in all 17 patients.Eighty-one gastrinomas were detected in the first three portions of the duodenum.Only one gastrinoma was found in the pancreas.The mean number of gastrinomas per patient was 5(range 1-16).Malignancy was established in 12 patients(70.5%)after lymph node,liver and omental metastases were found.Three patients exhibited biliary tree gastrinomas as well as duodenal gastrinoma(s).In two cases,the ectopic gastrinoma was removed at the same time as pancreatic surgery,while in the third case,the biliary tree gastrinoma was resected one year after DP because of recurrence of ZES.CONCLUSION:These findings suggest the importance of checking for the presence of ectopic gastrinomas in the biliary tree in MEN1 patients undergoing ZES surgery.

Is lymphatic status related to regression of inflammation in Crohn's disease?

AIM:To investigate the status of the lymphatic vessels in the small bowel affected by Crohn's disease(CD) at the moment of surgery.METHODS:During the period January 2011-June 2011,25 consecutive patients affected by CD were operated on in our Institution.During surgery,Patent Blue Ⅴ was injected subserosally and the way it spread along the subserosa of the intestinal wall,through the mesenterial layers towards the main lymphatic collectors and eventually to the lymph nodes was observed and recorded.Since some patients had been undergone strictureplasty at previous surgery,we also examined the status of intestinal lymph vessels after previous strictureplasties.The same procedure was performed in a control group of 5 patients affected by colorectal cancer.Length of lesions,caliber,maximal thickness of the diseased intestinal wall,thickness of the wall at injection site and thickness of the mesentery were evaluated at surgery.RESULTS:We observed three features after the injection of Patent Blue Ⅴ in the intestinal loops:(1) Macroscopically healthy terminal ileum of patients with CD or colon cancer showed thin lymphatic vessels linearly directed toward the mesentery;(2) In mild lesions in which the intestinal wall did not reach 8 mm of thickness,we observed short,wide and tortuous lymphatic vessels directed longitudinally along the intestinal axis toward disease-free areas and then transversally toward the mesentery;and(3) Injection in the severely affected lesions,that had a thickness of the intestinal wall over 10 mm,did not show any feature of lymphatic vessels at least on the subserosal surface.There was a correlation between the thickness of the parietal wall and the severity of the lymphatic alterations.Normal lymphatic vessels were observed at previous strictureplasties in the presence of complete regression of the inflammation.CONCLUSION:Injection of Patent Blue Ⅴ in the intestinal wall could help distinguish healthy tracts of the small bowel from those macroscopically borderline.

Small diameter H-graft porta-caval shunt performed at different stages of liver disease

BACKGROUND: Partial porto-systemic shunts have been popularized because of reported low rate of mortality and morbidity (especially encephalopathy, liver failure and oc- clusion). To further investigate these assumptions, we ret- rospectively reviewed the results of partial porta-caval shunts performed at different stages of liver disease. METHODS: Twenty-nine cirrhotic patients underwent a partial porta-caval shunt with a ringed polytetrafluoroethy- lene interposition prosthesis of 8-mm ( 20 patients) or 10- mm (9 patients) in diameter. Pre- and post-shunt porta- caval pressure was measured in all patients. Twelve patients (41.4%) belonged to Child A, 11 Child B (37.9%), and 6 Child C (20.7%). Eleven patients (37.9%) suffered from hepatic encephalopathy preoperatively. Twelve patients (41%) were operated on in emergency/urgency. RESULTS: Porta-caval pressure gradient, reduced signifi- cantly using either 8- or 10-mm prosthesis. The overall ear- ly mortality and morbidity were 13. 8% and 48% respec- tively. The early mortality and morbidity were different be- tween patients of Child A and B when compared to those of Child C (0 vs 66.6% and 34.8% vs 66.6% respectively). No patient re-bled early from varices. The overall late mor- tality and morbidity were 40% and 64% respectively. Shunt thrombosis and stenosis took place in 16% and 8% of the two groups of patients respectively; variceal re-bleeding oc- curred in 4 patients (16%). Encephalopathy occurred post- operatively in 5 patients (20%), acute in 3 patients (12%), and chronic in 2 (8%). The actuarial survival rate at 3 and 5 years was 92% and 75% for patients of Child A, 70% and 60% for patients of Child B, and 0% for patients of Child C. CONCLUSIONS: Our results indicate that partial porta-ca- val shunt with a small diameter interposition H-graft is an effective procedure for the treatment of variceal bleeding, as well as for the prevention of re-bleeding in patients of Child A and those of Child B, as an elective or emergency/ urgency procedure, with a low rate of complications and encephalopathy. This technique could be used safely in pa- tients with good liver function but they should be moni- tored closely because of the risk of shunt occlusion.

Multiplex gene expression profile in inflamed mucosa of patients with Crohn’s disease ileal localization: A pilot study

BACKGROUND Crohn’s disease (CD) is a complex disorder resulting from the interaction of genetic,environmental,and microbial factors.The pathogenic process may potentially affect any segment of the gastrointestinal tract,but a selective location in the terminal ileum was reported in 50% of patients.AIM To characterize clinical sub-phenotypes (colonic and/or ileal) within the same disease,in order to identify new therapeutic targets.METHODS 14 consecutive patients undergoing surgery for ileal CD were recruited for this study.Peripheral blood samples from each patient were collected and the main polymorphisms of the gene Card15/Nod2 (R702W,G908R,and 1007fs) were analyzed in each sample.In addition,tissue samples were taken from both the tract affected by CD and from the apparently healthy and disease-free margins (internal controls).We used a multiplex gene assay in specimens obtained from patients with ileal localization of CD to evaluate the simultaneous expression of 24 genes involved in the pathogenesis of the disease.We also processed surgery gut samples with routine light microscopy (LM) and transmission electron microscopy (TEM) techniques to evaluate their structural and ultrastructural features.RESULTS We found a significant increase of Th17 (IL17A and IL17F,IL 23R and CCR6) and Th1 (IFN-γ) gene expression in inflamed mucosa compared to non-inflamed sites of 14 CD patients.DEFB4 and HAMP,two genes coding for antimicrobial peptides,were also strongly activated in inflamed ileal mucosa,suggesting the overwhelming stimulation of epithelial cells by commensal microbiota.IFN-γ and CCR6 were more expressed in inflamed mucosa of CD patients with ileal localization compared with patients with colonic localization suggesting a more aggressive inflammation process in this site.Morphological analysis of the epithelial lining of Lieberkün crypts disclosed enhanced release activity from goblet mucocytes,whereas the lamina propria contained numerous cells pertaining to various lines.CONCLUSION We observed that the expression of ileal genes related to Th1 and Th17 activity is strongly activated as well as the expression of genes involved in microbiota regulation.

Epithelial turnover in duodenal familial adenomatous polyposis: A possible role for estrogen receptors?

AIM: To investigate estrogen receptors expression in duodenal familial adenomatous polyposis(FAP) and any relationship with epithelial proliferation/apoptosis markers.METHODS: Twenty-two patients affected by FAP undergoing duodenal resection for malignancies were recruited. Controls were 15 healthy subjects undergoing endoscopy for dyspeptic symptoms. ER-α, ER-α, Ki-67, TUNEL and caspase 3 expression(labeling index: percentage of positive cells) were evaluated by immunohistochemistry or immunofluorescence and examined by light or confocal microscopy. Samples were assigned to four groups: normal tissue, low(LGD)and high-grade dysplasia(HGD), adenocarcinoma(AC). One-way analysis of variance, corrected by Bonferroni's test, and Pearson's correlation test were applied for statistical analysis.RESULTS: ER-beta showed a progressive decline: normal tissue(23.5 ± 4.9), LGD(21.1 ± 4.8), HGD(9.3 ± 3.5), AC(7.1 ± 3.1). The normal tissue of FAP subjects expressed ER-beta like the controls(23.9 ± 6.2). Conversely, ER-α showed a progressive increase from normal tissue(24.8 ± 5.6) to AC(52.0 ± 8.2); the expression in normal tissue was similar to controls(22.5 ± 5.3). Ki67 demonstrated a statistically significant progressive increase at each disease stage up to AC. TUNEL did not reveal differences between controls and normal tissue of FAP subjects, but progressive decreases were observed in LGD, through HGD to AC. Pearson's correlation test showed a direct relationship between ER-b and TUNEL LI(r = 0.8088, P < 0.0001). Conversely, ER-α was inversely correlated with TUNEL LI(r =- 0.7257, P < 0.0001). The co-expression of ER-b and caspase 3 declined progressively from normal to neoplastic tissue.CONCLUSION: This study confirmed that ER-b is strongly decreased in duodenal FAP carcinomas, declining in a multiple step fashion, thereby suggesting a putative anti-carcinogenic effect. ER-α showed the opposite trend. ER-b/caspase 3 co-expression suggests this hormone's possible involvement in apoptosis. Hormonal influences in FAP duodenal tumorigenesis, and modulation of these as a possible chemoprevention strategy, may be a promising approach.