Luís Moreira-Dias

A European case series of endoscopic submucosal dissection for gastric superficial lesions

BACKGROUND EMR is an accepted method for resection of superficial lesions in the GI tract. However, because it leads, not unusually, to piecemeal resection, histopathologic interpretation problems and an increased risk of recurrence are noticeable. Endoscopic submucosal dissection (ESD) allows a higher rate of en bloc resection, with low recurrence. Nevertheless, this technique, namely in the upper-GI tract, has rarely been described in Western countries, probably because of the rarity of gastric cancer in most countries. OBJECTIVE To describe the efficacy and safety of ESD for gastric superficial lesions in a European country. DESIGN Consecutive case-series report. SETTING A tertiary specialized center. PATIENTS Nineteen patients with gastric superficial lesions (15-30 mm), with high-grade (n = 15) or low-grade (n = 4) noninvasive epithelial neoplasias, in the antrum (n = 12), incisura angularis (n = 2), body (n = 3), and cardia (n = 2). INTERVENTION ESD with the patient under general anesthesia in the endoscopic room (40-300 minutes) by using an insulated-tip-knife. MAIN OUTCOME MEASUREMENTS Complete (R0) and en bloc resection, and complications. RESULTS ESD was achieved in all cases, with 89% R0 resection and 79% en bloc resection rates observed. Major bleeding was reported in 1 case (5%); there were no cases of perforation. With a median follow-up of 10 months, a single recurrence (5%) was observed. LIMITATIONS A small series at a single center, with a short median follow-up time. CONCLUSION We report the feasibility and effectiveness of gastric ESD in Europe. A further description of a Western series is expected, and guidelines for its dissemination are desirable to define the role of this technique in Western countries.

A follow up model for patients with atrophic chronic gastritis and intestinal metaplasia

Aim: To devise a follow up model for patients with gastric cancer associated lesions, such as atrophic chronic gastritis (ACG) and intestinal metaplasia (IM). Methods: Cohort study of 144 patients, followed for a minimum of one year, in whom at least two upper gastrointestinal endoscopic biopsies in flat gastric mucosa provided a diagnosis of ACG, IM, or low grade dysplasia (LGD). Results: Of those diagnosed with ACG at first endoscopic biopsy (entry biopsy), 12% progressed to LGD in outcome biopsy, as did 8% of those with type I IM, 38% with type II or III IM, and 32% with LGD. Type of IM at entry independently predicted progression to LGD and cancer. Type II and III IM had a higher rate of progression to LGD than type I IM, which showed an indolent behaviour similar to ACG. Patients with type II or III IM were at higher risk for development of dysplasia, and 7% of patients with type III IM at first biopsy progressed to high grade dysplasia (HGD), whereas no cases of ACG or type I/II IM progressed to HGD during the first three years. Conclusion: Patients with ACG or IM could possibly be allocated to different management schedules, based on differences in rate and proportion of progression to LGD or HGD. Less intensive follow up (two/three yearly with “serological evaluation” (pepsinogen)) may suit those with ACG or type I IM. Patients with type III IM may benefit from six to 12 monthly improved endoscopic examination (magnification chromoendoscopy).

External validation of a classification for methylene blue magnification chromoendoscopy in premalignant gastric lesions

BACKGROUND Conventional endoscopy has low sensitivity, specificity, and interobserver agreement for the diagnosis of gastric atrophy, intestinal metaplasia, and dysplasia. Magnification chromoendoscopy (ME) may optimize the evaluation of premalignant gastric lesions. OBJECTIVE AND DESIGN As part of a multicenter trial, we aimed at validating a previously proposed classification for gastric methylene blue ME at a different center. SETTING, PATIENTS, AND INTERVENTIONS: A sample of patients (n = 42) with previously diagnosed chronic atrophic gastritis with or without intestinal metaplasia underwent ME (Pentax EG-3430Z) with 1% methylene blue by 2 endoscopists. MAIN OUTCOME MEASUREMENTS A simplified version of a previously published ME classification (group I, group II [further divided into subgroups IIE and IIF], and group III) was used for macroscopic lesions (n = 203) with Sydney-Houston and Vienna classifications being used for histologic analysis (n = 479 biopsy specimens). RESULTS AND LIMITATIONS Excellent reproducibility (wK = 0.92 [95% CI, 0.88-0.96]) was observed for classification in groups and substantial reproducibility (wK = 0.78 [95% CI, 0.72-0.84]) was found for classification in subgroups. Global validity was 82% (range 78%-86%), showing no false negatives (sensitivity of 100% [1/1 biopsy]) and a very low rate of false positives (specificity 99% [297/299 biopsies]) for dysplasia detection. CONCLUSIONS This classification for methylene blue ME was highly reproducible and valid for the diagnosis of premalignant gastric lesions when used in a center different from that involved in its conception. Despite requiring an unconventional endoscope and a longer procedure, these results could reinforce ME as a valuable technique in the surveillance of patients at risk for gastric cancer.

Functional polymorphisms of Toll-like receptors 2 and 4 alter the risk for colorectal carcinoma in Europeans

BACKGROUND Colon carcinogenesis is associated with increased expression levels of Toll-like receptor 2 and Toll-like receptor 4. AIM To determine in a Caucasian population the role of Toll-like receptor 2 and Toll-like receptor 4 polymorphisms in colorectal cancer development. METHODS Hospital based multicentre case control study involving 193 colorectal cancer patients and 278 healthy individuals. DNA samples were extracted from blood cells and genotyping of TLR2+597T>C, TLR2-4760T>C, TLR4-3745A>G, TLR2Arg753Gln, TLR4Asp299Gly was performed. Functionality of risk polymorphisms was evaluated through production of TNF-α in cell culture and Toll-like receptors levels quantified by real-time RT-PCR. RESULTS TLR2+597CC homozygous had 5-fold decreased risk (odds ratio (OR)=0.21, 95% CI: 0.09-0.50, p<0.001) and TLR4 299Gly homozygous 3-fold increased risk of colorectal cancer (OR=3.30, 95% CI: 1.18-9.28, p=0.015). In stratified analysis, TLR2+597CC genotype protective effect was even higher in overweight individuals (OR=0.17, 95% CI: 0.06-0.53, p<0.001) and in never smokers (OR=0.11, 95% CI: 0.02-0.51, p=0.001). Also, the increased risk effect for TLR4 299Gly homozygous genotype was higher in overweight individuals (OR=8.67, 95% CI: 1.11-87.85, p=0.011). TLR2+597T>C polymorphism conferred 41% less (p=0.03) and TLR4Asp299Gly 65% more TNF-α production (p=0.02) with no differences in Toll-like receptors levels. CONCLUSION Functional Toll-like receptor 2 and Toll-like receptor 4 polymorphisms significantly alter the risk to have colorectal cancer. Obesity and smoking may influence the risk for colorectal cancer in individuals presenting these genetic profiles.

Increased Expression of Toll-like Receptors (TLR) 2, 4 and 5 in Gastric Dysplasia

TLRs are important innate immunity receptors. Even though TLR2, 4 and 5 appear to be important for Helicobacter pylori (HP) recognition, their role in the evolution of gastritis to more advanced lesions is still unknown. To compare the expression of TLR2, 4 and 5 in normal gastric mucosa, HP+ gastritis, intestinal metaplasia, dysplasia and adenocarcinoma. Immunohistochemistry for TLR2, 4 and 5 was performed with anti-TLR2-TLR4-TLR5 antibodies in 117 histological samples of normal gastric mucosa (n = 22), HP+ gastritis (n = 20), intestinal metaplasia (n = 33), dysplasia (mucosectomy specimens, n = 20) and intestinal type adenocarcinoma (surgery specimens,n = 22); quantification of expression was performed independently by two pathologists taking into account the percentage of positive epithelial cells and the degree of expression (zero to three score). A statistically significant trend for progressive increase of TLRs expression from normal mucosa to gastric dysplasia was found (mean expression: normal mucosa 0.1; gastritis 1.0; metaplasia 2.2; dysplasia 2.8, p < 0.01). All dysplasia samples presented more than 90% positive epithelial cells with strong expression (2.8;95%CI2.7–3). There was less TLRs expression in carcinomas (TLR2:1.0; TLR4:2.0 and TLR5:1.2, p < 0.05) when compared with dysplasia, with TLR4 being more expressed than TLR2 and 5 in these lesions (p = 0.03). A score of all markers’ expression of eight leads to a low (4%) false positive rate in patients with precancerous conditions. Progression of gastric lesions associated with gastric carcinogenesis is associated with increased TLRs expression. Gastric dysplasia presents a high level of TLRs expression, suggesting that these receptors may play a role in adenocarcinoma development.

Helicobacter pylori Induces Increased Expression of Toll‐Like Receptors and Decreased Toll‐Interacting Protein in Gastric Mucosa that Persists Throughout Gastric Carcinogenesis

Toll‐like receptors (TLR) are essential for Helicobacter pylori (HP) recognition. Their role in the progression of gastric lesions leading to cancer is not established.

Associated primary tumors in patients with gastric cancer.

Goal To determine the prevalence of associated primary tumors in patients with gastric cancer. Study Retrospective study of 2,668 patients with gastric cancer observed at our department between July 1974 and December 1999. Associated tumors were diagnosed using Warren and Gates criteria, and included tumors that were not considered to be a metastasis, invasion, or recurrence of gastric cancer. Results Of all, 3.4% (n = 78) had primary tumors other than gastric cancer, 27% of which were synchronous (n = 21) and 73%, metachronous (n = 57). The mean follow-up time was 4 years (range, 1–13 years), and the male-to-female ratio was 1:1. The median age at diagnosis of gastric cancer was 67 years (range, 37–84 years), 69 years for patients with synchronous tumors versus 60 years for those with metachronous (p = 0.050). For at least half the patients the median time interval to metachronous cancer was 3 years (range, 1–22 years). Seventy-eight percent (n = 61) had two cancers; most were colonic (19%), uterine and ovarian (16%), and breast tumors (13%). Seventeen percent (n = 13) had three tumors: colon (46%), breast (23%), and skin (23%). Four percent (n = 3) had four tumors. One case with seven tumors was also observed [colon, breast (two tumors), uterus, skin, and stomach (two tumors)]. No statistically significant differences were found between synchronous and metachronous with regard to sex, gastric cancer location, and staging (TNM). Sixty-three percent (n = 49) died while under observation. Conclusions We found associated tumors in 3.4% of patients with gastric cancer. The most frequent associated tumors were breast and colon cancer. Surveillance for these tumors would be appropriate, at least in first years, after diagnosis of gastric cancer.

Long-term follow-up after endoscopic resection of gastric superficial neoplastic lesions in Portugal

BACKGROUND AND STUDY AIMS Although endoscopic resection for the treatment of gastric superficial neoplastic lesions is an established first-line treatment in Eastern countries, its role has yet to be considered in Western guidelines, mostly due to a lack of long-term studies. The aim of this study was to describe long-term outcomes for endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in the treatment of gastric neoplasias in Portugal. PATIENTS AND METHODS This was a single-center, retrospective, cohort study between March 2003 and April 2013. A total of 162 consecutive patients with 195 gastric superficial neoplasias underwent EMR (n = 54) or ESD (n = 141) and were followed up for a median of 3.2 years. RESULTS Resection was feasible in 97 %, with en bloc and R0 resection rates of 85 % (94 % ESD vs. 61 % EMR; P = 0.001) and 81 % (91 % ESD vs. 54 % EMR; P < 0.001), respectively. The recurrence rate was 7 %, and recurrence was associated with Rx/R1 resection irrespective of resection technique (OR 5.8; 95 % confidence interval 3.9 - 8.8). The long-term curative resection rate was 86 % after one procedure and 91 % after two procedures. Adverse events were observed in 13 % of cases: 8 % bleeding and 2 % of perforations (EMR = ESD). Surgery was performed in 7 %: 6 % after noncurative endoscopic resection and 1 % due to complications. Metachronous lesion detection rate was 1 % - 1.5 % per patient year. Cancer-specific survival rate was 100 % at follow-up. CONCLUSIONS For the first time in a Western country, results are reported to be similar to those in Eastern countries. Endoscopic resection, particularly ESD, is a highly effective treatment for gastric superficial lesions, without compromising cancer survival. Endoscopic resection should also be considered as first-line treatment for gastric neoplasias in Western countries.

Increased hepatic expression of TLR2 and TLR4 in the hepatic inflammation-fibrosis-carcinoma sequence:

We evaluated expression of TLR2, TLR4 and proinflammatory genes [NF-κB, TNF-α, cyclooxygenase-2 (COX-2)] in liver samples of patients in different stages of liver disease. Fifteen patients with unexplained transaminases elevation (reference group), 22 with viral chronic hepatitis (hepatitis group), 14 with virus-induced severe fibrosis/cirrhosis (cirrhosis group) and 10 with hepatocarcinoma (hepatocarcinoma group) were consecutively included in the study. Quantification of TLR2, TLR4, NF-κB, TNF-α and COX-2 mRNA was done by real-time RT-PCR and TLR2 and TLR4 protein expression was evaluated by immunohistochemistry. Compared with reference, TLR2 and TLR4 mRNA was increased in hepatitis (TLR2: 2.66 ± 0.69; TLR4: 3.11 ± 0.79; P < 0.05) and cirrhosis (TLR2: 2.14 ± 0.5; TLR4: 1.74 ± 0.27; P < 0.05) and decreased in hepatocarcinoma (TLR2: 0.48 ± 0.15; TLR4: 0.54 ± 0.10; P < 0.05). This associated with increased TNF-α and COX-2 mRNA in hepatitis (TNF-α: 3.24 ± 0.79; COX-2: 2.47 ± 0.36; P < 0.05) and cirrhosis (TNF-α: 1.73 ± 0.28; COX-2: 1.8 ± 0.35, P < 0.05), whereas NF-κB mRNA was increased in hepatitis (2.42 ± 0.31; P < 0.05) and unchanged in cirrhosis (1.34 ± 0.17; P = 0.3). Hepatocarcinoma presented increased COX-2 mRNA (1.63 ± 0.15; P < 0.05) and maintained (at decreased levels) mRNA of NF-κB (0.52 ± 0.12) and TNF-α (0.52 ± 0.12; P < 0.05, all genes). Immunohistochemistry confirmed increased expression of TLR2 and TLR4 in hepatitis and cirrhosis and maintained expression in hepatocarcinoma. Upregulation of TLR2, TLR4 and their proinflammatory mediators is associated with virus-induced hepatic IFC sequence.

Feasibility and cost-effectiveness of using magnification chromoendoscopy and pepsinogen serum levels for the follow-up of patients with atrophic chronic gastritis and intestinal metaplasia

Background:  The follow‐up of patients with atrophic chronic gastritis or intestinal metaplasia may lead to early diagnosis of gastric cancer. However, to‐date no cost‐effective model has been proposed. Improved endoscopic examination using magnification chromoendoscopy together with non‐invasive functional assessment with pepsinogen serum levels are accurate in the diagnosis of intestinal metaplasia (extension) and minute dysplastic lesions. The aim of this study was to assess the feasibility and cost‐effectiveness of a follow‐up model for patients with atrophic chronic gastritis and intestinal metaplasia based on gastric mucosal status using magnification chromoendoscopy and pepsinogen.