Teresa Starzyńska

Prognostic significance of p53 overexpression in gastric and colorectal carcinoma.

p53 expression was examined in 55 gastric and 107 colorectal carcinomas with an immunoperoxidase technique, using the polyclonal antibody CM1 on routinely fixed, paraffin embedded tissue. p53 protein was detected in 47% gastric and in 46% colorectal carcinomas and found to correlate with stage of disease and unfavourable clinical outcome (P less than 0.001). Thus, the proportion of positively reacting neoplasms increased as the stage progressed, tumours which had invaded regional lymph-nodes overexpressed p53 more frequently than localised carcinomas and an elevated level of p53 was associated with early relapse and death. In colorectal carcinoma p53 positivity was also linked with site and macroscopic configuration of the primary tumour and was most frequently expressed in carcinomas from the rectum and in ulcerative tumours. p53 overexpression was irrespective of tumour grade. Uniform negative reactivity with anti-p53 antibody was seen in normal epithelium adjacent to carcinoma, intestinal metaplasia, atrophic gastritis and in colonic adenomas. There was a good correlation between immunohistochemical staining on paraffin and frozen sections. These studies suggest that in gastric and colorectal carcinoma, immunohistochemical detection of p53 protein in routinely fixed tissue can be used along with other established parameters to assess prognostic outcome, especially to identify patients with poor short-term prognosis.

Effect of CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer patients

ObjectiveEradication of Helicobacter pylori is an important treatment strategy in peptic ulcer patients. Current regimens of eradication consist of proton pump inhibitor (PPI) and two antibiotics. The principal enzyme involved in PPIs metabolism is CYP2C19, which exhibits an interindividual variability of activity, mainly due to genetic polymorphism. Two alleles (CYP2C19*2 and CYP2C19*3), responsible for slow PPIs metabolism, were previously associated with higher efficacy of eradication. Recently, a novel CYP2C19 gene variant (CYP2C19*17), associated with faster metabolism of CYP2C19 substrates, was described. In the present study, a potential association between CYP2C19*17 allele and lower H. pylori eradication efficacy was tested in a group of peptic ulcer patients.MethodsA total of 125 peptic ulcer patients, positive for H. pylori infection, were treated with triple therapy (pantoprazole+amoxicillin+metronidazole). Subsequently, the patients were divided into two groups (group 1 – success, and group 2 – failure of eradication after therapy) and genotyped for the presence of CYP2C19 variant alleles (*2, *3, and *17).ResultsFrequency of CYP2C19 alleles in two groups of patients were: 56.4 versus 65 (p=0.060) for *1, 15.4 versus 5.3 (p=0.015) for *2, and 28.2 versus 25.5 (p=0.663) for *17 allele, respectively. CYP2C19*3 was not detected in the evaluated population. No significant differences in frequency nor distribution of *17 allele were found between two groups of patients. CYP2C19*2 allele was associated with successful H. pylori eradication (p<0.02), *2 allele carriers were found to be over 4-times more prone to the treatment compared to *1/*1 homozygotes (OR=4.2, p=0.015).ConclusionOur results suggest that, contrary to CYP2C19*2, CYP2C19*17 allele has no impact on efficacy of H. pylori eradication in peptic ulcer patients treated with pantoprazole.

Endoscopic submucosal dissection for treatment of gastric subepithelial tumors (with video).

BACKGROUND Endoscopic submucosal dissection (ESD) is a well-accepted method for removing superficial mucosal tumors; however, there is limited data on the use of this method for removing subepithelial tumors. OBJECTIVE To investigate the efficacy, safety, and outcome of ESD for gastric subepithelial tumors and determine factors related to treatment success. DESIGN Retrospective analysis of a prospectively maintained database. SETTING Single tertiary academic center. PATIENTS AND INTERVENTIONS From April 2007 to November 2010, 37 patients with gastric subepithelial tumors were treated with ESD. MAIN OUTCOME MEASUREMENTS Macroscopically and microscopically complete en block resection rate (R0), complication rate, and endosonographic features predictive of R0 resection. RESULTS The median tumor diameter was 25.0 mm, (range 10-60 mm, IQR 17-37). The overall rate of R0 resections was 81.1% (30/37, 95%CI: 61.8-90.2%), including 100% (15/15, 95%CI: 78.2-100.0%) of tumors from the submucosa and 68.2% (15/22, 95%CI: 45.1-86.1%) of tumors from the muscularis propria. Seventeen patients had a final diagnosis of gastrointestinal stromal tumor. The severe complication (perforation) rate was 5.4% (2/37, 95%CI: 0.0-9.5%). One patient required surgery; the other was treated conservatively. No recurrence was observed in patients with R0 resections at a median follow up of 21.0 months (IQR 11-35). Successful R0 resections were predicted by the observation of no, or only narrow, tumor connections with the underlying muscle layer during EUS (OR=35.0, 95%CI: 3.7-334.4, p=0.001). LIMITATIONS Single-center, retrospective analysis, short follow-up. CONCLUSIONS ESD is an effective and relatively safe method for removing gastric subepithelial tumors. Endoscopic ultrasonography findings can predict complete tumor resections.

5T4 oncofetal antigen expression in ovarian carcinoma.

5T4 oncofetal antigen is defined by a monoclonal antibody raised against human placental trophoblast, and recognizes a 72 kD glycoprotein expressed in many different carcinomas but detected only at low levels in some normal epithelia. Analysis of the patterns of expression of 5T4 oncofetal antigen in colorectal carcinomas has indicated a significant association between the presence of the antigen in tumor cells and metastatic spread. The 5T4 antigen expression of 72 epithelial ovarian carcinomas has been investigated by immunohistochemistry; 71% of the carcinomas demonstrated positive 5T4 immunoreactivity in adenocarcinoma cells and/or associated stromal tissue. In order to assess any relationship to prognosis, the 5T4 phenotypes were analyzed with respect to various clinicopathologic features of the tumors and the clinical outcome of the patients assessed by survival and disease-free interval. There was a significant correlation between 5T4 expression and more advanced stage of disease (FIGO stages III and IV) (P < 0.001) and with poorly differentiated tumors (P = 0.036) compared to well or moderately differentiated tumors. Patients with tumors expressing 5T4 were less likely to respond well to adjuvant therapy (P = 0.030) and had a significantly worse outlook in terms of survival (P = 0.033) and disease-free interval (P = 0.033). This significance was not demonstrated as acting independently of FIGO stage and tumor differentiation.

The expression of 5T4 antigen in colorectal and gastric carcinoma.

The expression of 5T4, an oncotrophoblast cell surface antigen was examined in 72 colorectal and 27 gastric carcinomas, with immunoperoxidase technique, on frozen sections. Highly significant association was found between 5T4 expression in the malignant cells and metastatic spread. The results suggest that the appearance of 5T4 molecules in cancer cells reflects a change which may contribute to the development of metastatic potential.

Various types of stem cells, including a population of very small embryonic-like stem cells, are mobilized into peripheral blood in patients with Crohn's disease†

Background: Developmentally early cells, including hematopoietic stem progenitor cells (HSPCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic‐like stem cells (VSELs), are mobilized into peripheral blood (PB) in response to tissue/organ injury. We sought to determine whether these cells are mobilized into PB in patients with Crohns disease (CD). Methods: Twenty‐five patients with active CD, 20 patients in clinical remission, and 25 age‐matched controls were recruited and PB samples harvested. The circulating CD133+/Lin−/CD45+ and CD34+/Lin−/CD45+ cells enriched for HSPCs, CD105+/STRO‐1+/CD45− cells enriched for MSCs, CD34+/KDR+/CD31+/CD45−cells enriched for EPCs, and small CXCR4+CD34+CD133+ subsets of Lin−CD45− cells that correspond to the population of VSELs were counted by fluorescence‐activated cell sorting (FACS) and evaluated by direct immunofluorescence staining for pluripotency embryonic markers and by reverse‐transcription polymerase chain reaction (RT‐PCR) for expression of messenger (m)RNAs for a panel of genes expressed in intestine epithelial stem cells. The serum concentration of factors involved in stem cell trafficking, such as stromal derived factor‐1 (SDF‐1), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) were measured by enzyme‐linked immunosorbent assay (ELISA). Results: Our data indicate that cells expressing markers for MSCs, EPCs, and small Oct‐4+Nanog+SSEA‐4+CXCR4+lin−CD45− VSELs are mobilized into PB in CD. The mobilized cells also expressed at the mRNA level genes playing a role in development and regeneration of gastrointestinal epithelium. All these changes were accompanied by increased serum concentrations of VEGF and HGF. Conclusions: CD triggers the mobilization of MSCs, EPCs, and VSELs, while the significance and precise role of these mobilized cells in repair of damaged intestine requires further study. (Inflamm Bowel Dis 2012;)

Expression of hepatocyte growth factor, transforming growth factor alpha, apoptosis related proteins Bax and Bcl-2, and gastrin in human gastric cancer

Gastric cancer is one of the most frequent neoplasms and a leading cause of the death world‐wide. In recent years, epidemiological and animal studies demonstrated a link between gastric cancer and chronic infection with H. pylori. The exact mechanism responsible for the development of gastric cancer in H. pylori‐infected patients still remains unclear. There is evidence that the up‐regulation of certain growth factors could play an important role in the promotion of the gastric carcinogenesis.

5T4 oncofetal antigen in gastric carcinoma and its clinical significance.

Objective To evaluate the role of 5T4 antigen in gastric cancer progression and prognosis. Design A prospective study of 5T4 antigen expression in primary, secondary and recurrent gastric carcinoma, the relationship to selected prognostic parameters and the course of disease. Patients Eighty six patients operated on for gastric cancer. Tissue One hundred and twenty two gastric tumours were studied, including 86 primary carcinomas, 32 coexisting lymph node métastases and four recurrent carcinomas. Methods Immunohistochemistry using 5T4 monoclonal antibody on frozen sections. Results The 5T4 antigen was detected in 41% of primary gastric tumours including early gastric cancer. A strong relationship was found between 5T4 positivity and tumour histology. Thus, 52% of gastric carcinomas of intestinal type expressed 5T4 antigen compared with 28% of the diffuse type (P= 0.028). Among 16 sets of primary gastric carcinomas and regional lymph node métastases, coordinate 5T4 expression was seen in 14 cases; the other two showed acquisition of positivity on metastatic tumour cells (carcinomas of diffuse type). 5T4 antigen was detected more frequently in carcinomas with p53 accumulation compared with those with undetectable p53 levels (P=0.015). The presence of 5T4 in cancer cells was correlated with poor short-term prognosis (24% vs 49% of 2 year survival for 5T4 positive and negative tumours respectively, P= 0.024). The effect on survival was evident in the p53 negative group, with patients 5T4 positive showing worse survival (28% vs 60% in 2 years). Conclusions Our results suggest that the assessment of 5T4 expression in gastric carcinoma can be helpful in identifying patients with poor short-term prognosis.

The clinical significance of p53 accumulation in gastric carcinoma

Alterations in the expression of p53 tumor suppressor protein is a frequent event in human cancer but the practical implications of this phenomenon are yet to be fully exploited. The objective of this study was to determine the value of p53 accumulation as a marker of tumor progression and prognosis of gastric carcinoma patients and to evaluate whether this parameter can be properly assessed prior to surgery.

Helicobacter pylori and CagA status, serum gastrin, interleukin-8 and gastric acid secretion in gastric cancer.

Background: Despite numerous epidemiological studies, the association between Helicobacter pylori infection and gastric cancer (GC) remains unexplained. This study was designed to determine the seropositivity of H. pylori and cytotoxin-associated gene A (CagA), serum gastrin and interleukin-8 (IL-8) levels as well as basal intragastric pH and maximal histamine-induced gastric acid outputs (MAO) in a large series of GC patients and controls. Methods: 337 GC patients (118 men and 219 women; median age 59.4; range 21-87) and 337 controls randomized for sex and age entered the study. Serum IgG antibodies to H. pylori and CagA and serum levels of IL-8 were measured by enzyme-linked immunosorbent assay, while serum-amidated gastrin was determined by specific radioimmunoassay and correlated with gastric luminal pH. Results: The numbers of GC patients and controls involved in the study in various age groups, ranging from 20 to >70 years, were similar, but overall H. pylori IgG seropositivity in GC patients was significantly higher (90.8%) than in controls (79.2%). The overall CagA seropositivity in GC patients was about double (58.2%) that in controls (25.2%). Serum gastrin levels over the calculated cut-off value (38.88 pM/L) were found in several-fold larger number in GC patients (48%) than in controls (8.3%) and, similarly, serum IL-8 values over the cut-off point (1.77 pg/mL) occurred in almost all (99.7%) GC patients but in only a few controls (0.3%). Basal intragastric pH above the cut-off point (pH = 4.50) was observed in about 58.2% of GC patients compared to 15.1% in controls, and strong correlation between the serum gastrin and gastric pH was found in GC but weak in controls. The cut-off value for MAO was 12.3 mml/h; MAO below this cut-off value occurred in 89.9% of GC patients and in only 4.7% of controls. A summary odds ratio (SOR) in GC for H. pylori IgG was 2.59 (95% Cl; 1.61-4.22) for CagA - 4.12 (95% Cl; 2.93-5.8), for serum gastrin - 10.25 (95%; 6.47-16.47) and for MAO - 15.2 (95% Cl; 9.45-39.82). Multivariable analysis of serum gastrin, IgG and CagA, and luminal pH and MAO values revealed that only gastrin and CagA have significant influence on GC formation (OR >1 in logistic regression). Conclusions: 1. CG patients show significantly higher H. pylori IgG and CagA seropositivity than dyspeptic age- and gender-matched controls, confirming that gastric infection with CagA expressing H. pylori greatly increases the risk of GC. 2. Serum gastrin levels in GC but not in controls are correlated with the rise in intragastric pH, indicating that excessive gastrin release in GC is affected by lower intragastric pH. 3. Serum gastrin level and CagA seropositivity are significantly increased in the majority of GC patients, and are the only variables in multivariable analysis to have a predominant influence on GC formation, which suggests that both these parameters may be implicated in H. pylori -related gastric carcinogenesis. 4. H. pylori -infected GC patients produce significantly more IL-8 than do non-GC controls, probably reflecting CagA-positive H. pylori -associated gastritis.