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Biomedical subjects

G M Paganelli

Publications and source records attributed to G M Paganelli.

At least 19 recordsLinked to original sources
PubMed1999

Pattern of epithelial cell proliferation in colorectal mucosa of patients with large bowel adenoma or cancer: an ECP case-control study. European cancer prevention.

Proliferative abnormalities of the normal colorectal mucosa have been proposed as a possible marker of enhanced susceptibility to colorectal cancer. A case-control study was conducted to compare the cell kinetics of normal colon mucosa through the different steps of the adenoma-carcinoma sequence. The number and position of labelled epithelial nuclei after in vitro incubation of tritiated thymidine were compared in patients with large bowel cancer (n = 39), large adenoma >1 cm (n = 47), small adenoma (n = 30) and in controls (n = 135). The distribution of tertiles between cases and controls was analysed using odds ratio (OR), comparing the second tertile (OR2) and the third tertile (OR3) to the first one. There was no significant difference in the overall cell proliferation rate when comparing cancer, large adenoma and small adenoma groups to the control group. The ratio number of labelled cells in the upper 40% of the crypt/total number of labelled cells (4h index) was found to be significantly higher only when the cancer group was compared to the control group: OR2 = 5.87 (1.33-25.90), OR3 = 9.48 (2.07-43.38), P for trend = 0.002. The upward shift of the proliferative compartment in the normal mucosa of patients with large bowel cancer suggests that this abnormality is related to cancer risk.

Adenoma↗
PubMed1999

European trials on dietary supplementation for cancer prevention.

European institutions aimed at cancer research and control are spending sizable resources to develop preclinical and clinical chemoprevention trials. Pilot studies showed positive effect on colorectal cell proliferation from supplementation with calcium; vitamins A, C, and E; omega-3 fatty acids; and folic acid. A significant reduction in adenoma recurrence after polypectomy was found in patients randomly assigned to take vitamin A, C, and E supplementation or, to a lesser extent, lactulose. Although first reports showed a disquieting higher incidence of lung cancer in male smokers who took beta-carotene supplementation, the European Organization of Research and Treatment of Cancer (EORTC) planned a chemoprevention study on the prevention of second primary tumors in patients with curatively treated head and neck or lung cancer (EUROSCAN). Retinol palmitate or N-acetylcysteine or both are given for two years. The European Cancer Prevention Organization (ECP) is carrying out a clinical trial in patients with previous adenomas of the large bowel, to test the efficacy of calcium or fiber supplementation on adenoma recurrence. ECP in collaboration with EURONUT has also started a multinational intervention study of the effect of H. pylori eradication and/or dietary supplementation with vitamin C on intestinal metaplasia.

Colonic Neoplasms↗
PubMed1997

Cell proliferation of the duodenal mucosa in patients affected by familial adenomatous polyposis.

BACKGROUND & AIMS: Patients affected by familial adenomatous polyposis (FAP) are at increased risk of developing duodenal adenomas. In this study, cell proliferation of duodenal mucosa was analyzed to detect kinetic abnormalities related to cancer risk. METHODS: Duodenal biopsy specimens were collected in three groups of patients: group A, 9 hospital controls; group B, 14 patients with FAP without duodenal adenomas; and group C, 6 patients with FAP and duodenal adenomas. Proliferative cell nuclear antigen was assessed through immunohistochemistry. The main labeling parameters were (1) overall labeling index (LI) and (2) LI in the upper 40% of the crypts. RESULTS: Overall LI in groups B and C was higher than in group A (both P < 0.01). LI in group C was also significantly higher than in group B (P < 0.01). Similarly, the upper 40% LI was higher in groups B and C than in group A (both P < 0.01). This value was higher in group C than in group B (P < 0.05). CONCLUSIONS: These data suggest the presence of cell kinetics abnormalities in FAP and the existence of two subgroups of patients with FAP at different risks of duodenal neoplasia. These abnormalities could be used as an intermediate biomarker for chemoprevention studies of duodenal cancer in FAP.

Adenomatous Polyposis Coli↗
PubMed1997

Rectal cell proliferation and colon cancer risk in patients with hypergastrinaemia.

BACKGROUND: The influence of gastrin on the colonic mucosa is still uncertain. Some authors have suggested a stimulating effect on the growth of normal and malignant colonic epithelium, while others have shown no association between gastrin and neoplastic development. AIMS: To evaluate the effect of gastrin on colorectal cell proliferation, patients with chronic endogenous hypergastrinaemia underwent proctoscopy. Biopsy specimens were taken in order to study rectal cell kinetics. PATIENTS AND CONTROLS: Ten patients with chronic autoimmune gastritis (CAG), six patients with Zollinger-Ellison syndrome (ZES), and 16 hospital controls took part in this study. Patients with CAG and ZES had basal serum gastrin concentrations significantly higher than controls (p < 0.001). METHODS: Immunohistochemistry was performed on 3 microns sections of rectal biopsy specimens incubated with 5'-bromodeoxyuridine. RESULTS: The percentage of proliferating cells in the entire crypts (overall labelling index) was similar in all the groups. However, the labelling frequency in the upper two fifths of the glands (phi h value) was significantly higher in patients with CAG or ZES compared with controls (p < 0.01 in both patient groups versus controls). CONCLUSIONS: Endogenous hypergastrinaemia is associated with rectal cell proliferation defects, similar to those observed in conditions at high risk for colon cancer. The effect of the increased serum concentrations of gastrin on the colorectal mucosa after treatment with drugs inhibiting gastric acid secretion should be investigated.

Adult↗
PubMed1997

Folic acid supplementation and cell kinetics of rectal mucosa in patients with ulcerative colitis.

It has been suggested that colon cancer risk in ulcerative colitis (UC) is correlated to a reduced bioavailability of folate. We studied the effects of folate supplementation on the pattern of rectal cell proliferation in patients affected by long-standing UC. In the rectal mucosa of these patients, an expansion of proliferating cells to the crypt surface is found frequently. This abnormality is considered an intermediate biomarker in chemoprevention trials. Twenty-four patients (13 males; age, 26-70 years; UC duration, 7-34 years) with UC in remission for 1 month at least were assigned randomly to one of the following treatments: (a) folinic acid (15 mg/day) or (b) placebo. Cell proliferation was analyzed through immunohistochemistry on sections of rectal biopsies incubated for 1 hour in a culture medium containing bromodeoxyuridine. Fragments were taken at admission to the study and after 3 months of treatment. As compared to the baseline values, after 3 months of therapy in patients treated with folinic acid, a significant reduction of the frequency of occurrence of labeled cells in the upper 40% of the crypts (phi h value) was observed (0.1836 +/- 0.0278 versus 0.1023 +/- 0.0255; P < 0.01). On the contrary, no significant proliferative changes were observed in the placebo group. These results suggest that folate supplementation contributes to regulating rectal cell proliferation in patients with long-standing UC. These findings may be significant for chemoprevention of colon cancer in these patients.

Adult↗
PubMed1995

Colorectal cancer in patients with ulcerative colitis. A prospective cohort study in Italy.

BACKGROUND: The aim of this study was to assess the development of dysplasia or cancer in patients with ulcerative colitis and to determine the effectiveness of colonoscopy and biopsy follow-up in colon cancer surveillance. METHODS: From 1980 to 1986, 65 patients who had ulcerative colitis for 7 years or more participated in a surveillance program of colonoscopy and biopsy. This cohort was followed until December 1992. Forty-nine patients (75.4%) had extensive colitis and 16 (24.6%) left-sided colitis. The mean disease duration was 17.2 years. Three hundred four colonoscopies were performed. During each endoscopy, random biopsies were performed. RESULTS: Seven patients had definite dysplasia of the colorectal mucosa. Four of them had high grade lesions and underwent surgery. In all of these patients, colon cancer (3 Dukes' Stage A, 1 Dukes' Stage B) was found. No cancer was found in the other patients. Pedunculated adenomas were excised from 6 other patients during colonoscopy. When dysplasia was diagnosed, these patients were older than those who were dysplasia free, whereas the age at onset of colitis was significantly higher in the former (P < 0.01). Fifteen patients discontinued follow-up. Two of them developed colon cancer diagnosed at an advanced stage. CONCLUSIONS: Dysplasia, especially of high grade, is a marker of colon cancer risk in patients with longstanding ulcerative colitis. Intensive colonoscopy and biopsy surveillance can lead to the diagnosis of colon cancer at a potentially curable stage. In this series, older age appeared to be an additional risk factor. A careful selection of patients with ulcerative colitis seems mandatory to minimize the cost and optimize the benefit of colon cancer surveillance programs.

Adult↗
PubMed1994

Methodological problems in the use of rectal cell proliferation as a biomarker of colorectal cancer risk.

Clinical and experimental studies have shown that the carcinogenic process of colorectal mucosa is linked to the development of proliferative abnormalities which precede the occurrence of morphological abnormalities such as epithelial dysplasia. In humans, proliferative defects have been demonstrated in the normal rectal mucosa of population groups at risk for colon cancer. Several techniques are available to study cell kinetics in the gastrointestinal mucosa. Each explores different aspects of cell proliferation. We have attempted to evaluate the correlation between various techniques in the normal rectal mucosa of high-risk patients. We found a good correlation between bromodeoxyuridine (BrdU) labeling index and the mucosal activity of the enzyme ornithine decarboxylase, and between tritiated thymidine and the percentage of cells in the S phase of the proliferative cycle as determined by flow cytometry. However, these correlations concern only labeling indices, which can be influenced by physiological events, such as active inflammation or increased cell loss. It may not be the most reliable proliferative marker of cancer risk. Moreover, methods using cells isolated from homogenized tissue do not allow us to evaluate the pool of cells which are examined nor the distribution of proliferating cells within the tissue. For example, an inflamed mucosal specimen is highly infiltrated with inflammatory cells which can interfere with the measurement of epithelial cell proliferation. Nevertheless, the labeling index may be normal even in patients at high risk. For these reasons, we think that the most reliable methods are those using tissue culture, such as tritiated thymidine or BrdU uptake and proliferating cell nuclear antigen (PCNA) immunostaining.

Adenoma↗
PubMed1994

Flow cytometry and in vitro tritiated thymidine labeling in normal rectal mucosa of patients at high risk of colorectal cancer.

OBJECTIVES: To compare two different methods to evaluate rectal epithelial cell proliferation as a biomarker of risk of developing colon cancer. METHODS: Samples of normal rectal mucosa from 26 patients at increased risk for colorectal cancer (22 patients with adenoma, three with adenocarcinoma of the large bowel, and one with longstanding ulcerative colitis) were examined by means of in vitro labeling with tritiated thymidine and flow cytometry. RESULTS: We found a significant correlation between thymidine-labeling index and the percentage of cells in S-phase, measured by flow cytometry both in formalin-fixed, paraffin-embedded specimens and in frozen specimens (respectively, r = 0.7647, p < 0.001, and r = 0.4503, p < 0.01). However, using flow cytometry, the percentage of cells in S-phase was significantly higher than the thymidine-labeling index in both fixed-embedded and frozen specimens (p < 0.01). Proliferative parameters were not higher in patients with colon carcinoma, and were not related to the degree of dysplasia, the number of adenomas, or familial occurrence of colorectal cancer. Two specimens taken from normal rectal mucosa of two patients with adenomas showed aneuploidy. No aneuploidy was found in normal rectal specimens of patients with adenocarcinoma. CONCLUSIONS: These results show that the calculation of cells in S-phase with in vitro tritiated thymidine labeling or by flow cytometry produces different results. However, the significant correlation between corresponding parameters obtained with these techniques support the use of either method as "intermediate biomarkers" of colorectal cancer risk and prognosis.

Adenocarcinoma↗
PubMed1993

Abnormal rectal cell proliferation and p52/p35 protein expression in patients with ulcerative colitis.

We evaluated the presence of cell proliferation and antigenic abnormalities in rectal biopsies from 37 patients affected by ulcerative colitis and 15 controls. The study was carried out by thymidine labeling and immunochemistry, using antibodies against specific cytoskeletal-associated proteins (p52, p35, alpha-actinin). Among ulcerative colitis patients, 24 had an immunofluorescence pattern similar to that of controls, while 13 showed an abnormal distribution of one or more proteins (p52 alone or p52 and either p35 or alpha-actinin) within the rectal crypts. Patients showed a shift of the proliferative compartment towards the top of the rectal crypts compared with controls. This finding was more evident in patients with p52 or p35 abnormalities. Proliferative and antigenic defects were not related either to age or the duration of colitis. These phenotypic changes might be a biomarker of increased risk of colon cancer in ulcerative colitis.

Adult↗
PubMed1993

Serum pepsinogen I and II concentrations and IgG antibody to Helicobacter pylori in dyspeptic patients.

AIMS: To investigate the association between histologically confirmed gastritis, carriage of Helicobacter pylori and pepsinogen (PG) I and PG II concentrations. METHODS: Prospective study of 81 dyspeptic patients undergoing upper gastrointestinal endoscopy was made. The extent of gastric mucosal inflammation and the presence of H pylori was determined, and serology to evaluate PG I and II concentrations and IgG titres to H pylori was carried out. RESULTS: The presence of H pylori was strongly correlated with high IgG antibody titres to H pylori and gastritis. Patients who were H pylori positive had significantly higher PG I and PG II concentrations and a significantly lower PG I:PG II ratio than patients who were negative for H pylori. In 13 patients with duodenal ulcer and H pylori positive gastritis serum PG I concentrations were significantly higher than in H pylori positive patients without duodenal ulcer. Significant correlations were found between the age of patients and serum PG II, the PG I:PG II ratio, IgG antibodies to H pylori, the severity of body gastritis and H pylori infection, and between the degree of gastritis in the body of the stomach and the PG II concentration. CONCLUSIONS: Serum PG I and II concentrations, together with a fall in the PG I:PG II ratio, could be used as predictors of H pylori infection as well as serum IgG antibody response to H pylori.

Adolescent↗
PubMed1992

Effect of vitamin A, C, and E supplementation on rectal cell proliferation in patients with colorectal adenomas.

Studies suggest that cell proliferation abnormalities of the colorectal mucosa are associated with risk of neoplasia, and most cancers of the large bowel are thought to arise from adenomas. The results of other studies suggest that vitamins A, C, and E have chemopreventive efficacy against colon cancer in animal models. This study evaluates the effect of dietary vitamin supplementation on cell kinetics in uninvolved rectal mucosa in patients with colorectal adenomas. Twenty patients with colorectal adenomas were given vitamins A, C, and E for 6 months after complete polypectomy, and 21 patients with adenomas received placebo. In each patient, six biopsy specimens were taken from normal-appearing rectal mucosa before treatment and after 3 and 6 months of treatment and were incubated with tritiated thymidine ([3H]thymidine), and the [3H]thymidine-labeled cells were counted by use of autoradiography. Two parameters of cell proliferation were evaluated: 1) the ratio of the number of labeled cells to the total number of cells (thymidine labeling index) and 2) the ratio of the number of labeled cells in the upper 40% of the crypt to the total number of labeled cells in the crypt (phi h). The latter index reflects abnormal expansion of the proliferative compartment and is thought to be an intermediate biomarker of cancer risk. In patients receiving vitamins, phi h decreased progressively from baseline values, with increasing statistical significance (P less than .05 after 3 months, P less than .01 after 6 months). There was a statistically significant decrease in the thymidine labeling index in the 40% of the crypt near the mucosal surface, but the variation in the overall labeling index was not statistically significant. In the placebo group, we observed no statistically significant change in cell kinetics. These findings suggest that vitamin A, C, and E supplementation is effective in reducing abnormalities in cell kinetics that may indicate a precancerous condition. Before larger trials on chemoprevention of colorectal adenoma recurrence are conducted, additional studies are needed (a) to validate that cell kinetics is an intermediate biomarker, (b) to determine active agents, optimal dosage, and the relative efficacy of agents given alone and in combination, and (c) to test toxicity.

Adenoma↗
PubMed1992

Cell proliferation biomarkers in the gastrointestinal tract.

Measurements of epithelial cell proliferation in the mucosa of the gastrointestinal tract pointed out the existence of cell kinetic abnormalities which can be involved in the first steps of carcinogenesis. In particular, an increase in the cell proliferation rate and an abnormal distribution of proliferating cells were found both in animals exposed to carcinogens and in human subjects at high risk of gastrointestinal cancer. In some diseases which predispose to cancer (i.e., chronic atropic gastritis, hereditary gastrointestinal cancer, sporadic colorectal neoplasia, chronic ulcerative colitis) we observed an expansion of the proliferative compartment even when the mucosa was not affected by morphological abnormalities. This proliferative feature seems to be associated with the presence of defects in cell differentiation. The abnormality is well detected by the histological examination of the proliferative pattern using microautoradiography after incorporation of tritiated thymidine, or using immunohistochemistry after bromodeoxyuridine uptake. The literature, and our own results, indicate that the search for abnormalities of epithelial cell proliferation can be useful in studying the earliest mechanisms leading to gastrointestinal cancer, in detecting subjects at high cancer risk, and for pilot chemoprevention studies using these abnormalities as intermediate biomarkers of gastrointestinal cancer risk.

Animals↗
PubMed1992

Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia.

Helicobacter pylori infection, histological features of the gastric mucosa, and gastric motor and secretory functions were evaluated in 45 consecutive patients with chronic idiopathic dyspepsia. H. pylori infection was found in 60% of dyspeptic patients, compared with 33% of 15 healthy controls (P = 0.1). No difference was detected in basal or stimulated gastric acid secretion between dyspeptic patients and healthy controls. Gastric emptying was significantly (P less than 0.01) delayed in dyspeptic patients compared with healthy controls when standardized for age and sex. Delayed gastric emptying was associated with a low frequency of H. pylori infection, female gender, and young age. Epigastric pain or burning and postprandial fullness were, respectively, more severe in patients with H. pylori infection (P less than 0.02) and in those with delayed gastric emptying (P less than 0.01). These findings support the existence of separate subsets of patients with chronic idiopathic dyspepsia. Despite the presence of overlaps, there appear to be partially different functional derangements and clinical features in different subgroups of dyspeptic patients.

Adult↗
PubMed1992

Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis.

Short-chain fatty acid irrigation has been shown to ameliorate inflammation in diversion colitis. In this study the effect of butyrate enemas was tested in 10 patients with distal ulcerative colitis who had been unresponsive to or intolerant of standard therapy for 8 weeks. They were treated for 2 weeks with sodium butyrate (100 mmol/L) and 2 weeks with placebo in random order (single-blind trial). Before and after treatment, clinical symptoms were noted and the degree of inflammation was graded endoscopically and histologically. Rectal proliferation was assessed by autoradiography. After butyrate irrigation, stool frequency (n/day) decreased from 4.7 +/- 0.5 to 2.1 +/- 0.4 (P less than 0.01) and discharge of blood ceased in 9 of 10 patients. The endoscopic score fell from 6.5 +/- 0.4 to 3.8 +/- 0.8 (P less than 0.01). The histological degree of inflammation decreased from 2.4 +/- 0.3 to 1.5 +/- 0.3 (P less than 0.02). Overall crypt proliferation was unchanged, but the upper crypt-labeling index fell from 0.086 +/- 0.019 to 0.032 +/- 0.003 (P less than 0.03). On placebo, all of these parameters were unchanged. These data support the view that butyrate deficiency may play a role in the pathogenesis of distal ulcerative colitis and that butyrate irrigation ameliorates this condition.

Adult↗