Marcelo Binato

P53 and Ki-67 overexpression in gastroesophageal reflux disease – Barrett's esophagus and adenocarcinoma sequence

Gastroesophageal reflux disease (GERD) is a major risk factor for the development of esophageal adenocarcinoma (ACE). Many molecular alterations occur in esophageal carcinogenesis, yet the exact mechanism of ACE development remains unknown. This study aims to determine p53 protein and Ki-67 expression in esophageal mucosa of patients with GERD and study the correlation between these markers and the progression from normal squamous epithelium to esophagitis, columnar epithelium with or without intestinal metaplasia and ACE. We analyzed p53 protein and Ki-67 expression in biopsies of 200 patients with GERD and 35 patients with ACE. Those biopsies were classified into five groups: (i) G1 normal squamous epithelium (58); (ii) G2 esophagitis (80); (iii) G3 columnar epitheliums without intestinal metaplasia (30); (iv) G4, columnar epitheliums with intestinal metaplasia (32); and (v) G5 ACEs (35). p53 protein overexpression was found in 7% (4) of G1, 37.5% (30) of G2, 30% (9) of G3, 62.5% (20) of G4, and 71.4% (25) of G5 (p < 0.001). Ki-67 index increased according to the severity of histopathological diagnoses. Ki67 index was 21.3 +/- 19.5% in G1, 38.8 +/- 24.9% in G2, 37.7 +/- 26.3% in G3, 52.8 +/- 24.6% in G4, and 57.1 +/- 25.1% in G5 (P < 0.001). Linear correlation between p53/Ki67 expression and the multistep progression from squamous epithelium to ACE was observed (P < 0.001 and P < 0.05). Our results indicate that overexpression of p53 and increased Ki-67 could be associated with the development and progression to ACE in patients with GERD.

Immunohistochemical overexpression of the p53 protein and Ki-67 (MIB-1) antigen in patients with GERD and chronic esophagitis.

Background and Study AimsPatients with gastroesophageal reflux disease and Barrett esophagus have an increased risk of developing adenocarcinoma of the esophagus. It is uncertain whether molecular or proliferative alterations are present in the early stages of disease. MethodsOne hundred thirty-eight patients with gastroesophageal reflux disease symptoms were subjected to upper gastrointestinal endoscopy with biopsies of the esophageal mucosa. p53 protein expression and the Ki-67 proliferation index were determined by immunohistochemical studies. Patients were divided into 4 groups according to histopathologic diagnosis: G1, normal epithelium (n=58); G2, mild esophagitis (n=42); G3, moderate esophagitis (n=23), and G4, severe esophagitis (n=15). Resultsp53 overexpression was detected in 7% of G1, 21.4% of G2, 52.2% of G3, and 60% of G4 patients. There were significant differences between G1 and G3 or G4 (P<0.001) and between G2 and G4 (P<0.05). The Ki-67 index was 21.3±19.5% in G1, 30.8±23.4% in G2, 47.1±23.2% in G3, and 48.3±25.7% in G4. Significant differences in the Ki-67 index were found between groups: G1×G3 (P<0.001), G1×G4 (P<0.001), G2xG3 (P=0.026), and G2xG4 (P=0.046). p53 and Ki-67 overexpression were correlated with the severity of esophagitis (P<0.001). Conclusionsp53 overexpression and the Ki-67 (MIB-1) index were correlated with histologic findings of inflammation in the esophageal mucosa, particularly in the moderate and severe forms of chronic esophagitis.

Tratamento cirúrgico do divertículo de Zenker

RACIONAL: O tratamento cirurgico do diverticulo de Zenker inclui na maioria dos casos a cricomiotomia do musculo cricofaringeo, a qual pode ser associada a diverticulopexia ou diverticulectomia. A escolha destas opcoes cirurgicas ainda e controversa. OBJETIVO: Avaliar os resultados de dois tratamentos cirurgicos (diverticulopexia ou diverticulectomia, ambos associados a cricomiotomia) em uma serie de casos. METODOS: Estudo retrospectivo em periodo de 10 anos de 26 pacientes submetidos ao tratamento cirurgico do diverticulo de Zenker. Para analise estatistica, os pacientes foram divididos em dois grupos: Grupo 1 - diverticulectomia (n=17) e Grupo 2 - diverticulopexia (n=9). Em todos realizou-se miotomia. Foram avaliadas as variaveis: tempo cirurgico, de internacao e de inicio da alimentacao via oral, complicacoes gerais, ocorrencia de fistulas, recidiva dos sintomas e mortalidade. Consideraram-se diferencas significativas quando P<0.05. RESULTADOS: A idade media dos pacientes foi de 64 anos. Sintomas pre-operatorios principais: disfagia (91%) e regurgitacao (46%). Todos foram investigados com estudo radiografico contrastado de faringe-esofago-estomago e 58% dos casos com endoscopia digestiva alta. Nao houve diferenca significativa entre os Grupos 1 e 2 em relacao ao tempo operatorio (96 x 99 min), tempo de internacao (5,5 x 5 dias), inicio da alimentacao via oral (7,5 x 4 dias), ocorrencia de fistulas esofago-cutâneas (35 x 22%), recidiva da disfagia (6 x 11%), complicacoes pos-operatorias em geral (41 x 33%) e tempo de seguimento (7,5 x 9 meses). A mortalidade foi nula. CONCLUSAO: O tratamento cirurgico do diverticulo de Zenker e metodo terapeutico relativamente seguro, com morbidade aceitavel e seus resultados independem da opcao por resseccao ou pexia do diverticulo.

Mo1879 EGFR in Gastroesophageal Reflux Disease, Barrett's, Esophagus, and Esophageal Adenocarcinoma

Adipose tissue has been shown to produce a number of inflammatory cytokines and may play a role in the development and progression of several inflammatory diseases. Accumulation of intra-abdominal fat correlates more strongly with inflammatory disease states than does total body fat, suggesting depot-specific differences in the inflammatory potential of adipose tissue. In inflammatory bowel disease specifically, recent clinical studies suggest that patients with increased intra-abdominal fat may suffer a more aggressive clinical course. Objective: The purpose of the present study was to evaluate the significance of inflammatory cytokine production by various adipose tissue depots during acute experimental colitis. Methods: Colitis was induced in C57BL mice by addition of 2% dextran sulfate sodium (DSS) to drinking water for 5 days. Mice were sacrificed at Day 3, 7, 14, and 21 following initiation of DSS treatment. Control mice were sacrificed prior to initiation of treatment. Plasma cytokine levels at time of sacrifice were analyzed by multiplex assays. Colonic tissue damage was evaluated histologically by H&E staining. Tissue levels of cytokine mRNAwere compared between the colon, 3 adipose tissue depots (mesenteric, epididymal, and subcutaneous), kidney, and liver by qRT-PCR. Results: Histologic evidence of colitis and significantly increased plasma IL-6 levels were evident by Day 7 and peaked at Day 14. Changes in cytokine expression within the colon occurred earlier, with significant increases in TNF-a, IL-1b, and IL-6 mRNA all evident by Day 3 (P=0.016). Of the cytokines analyzed, IL-6 in the colon exhibited the most profound increase with colitis, with levels at Day 7 increased 230-fold from baseline (P=0.002). Analysis of adipose tissues from this time point revealed that while IL-6 mRNA expression in mesenteric and epididymal adipose tissue was significantly increased compared to controls, 8.6-fold (P=0.016) and 3.8-fold (P=0.004) respectively, no increase in subcutaneous adipose tissue IL-6 mRNA was observed. Multi-tissue analysis at this time point revealed that mesenteric and epididymal adipose tissue expressed significantly more IL-6 mRNA than the kidney or the liver, whose levels of IL-6 did not increase significantly from baseline. Conclusions: This study demonstrates that intra-abdominal adipose tissue is a major source of IL-6 during acute experimental colitis. The time course analysis suggests that intra-abdominal fat may have a significant impact on plasma IL-6 levels. Unlike the mesentery, the epididymal fat pad is not contiguous with the inflamed bowel and does not contain the venous or lymphatic drainage of the affected bowel. This suggests a tissue-specific response by the intra-abdominal adipose tissue, rather than merely a local lymphoid reaction to tissue damage in the colon.