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Biomedical subjects

M I Filipe

Publications and source records attributed to M I Filipe.

At least 19 recordsLinked to original sources
PubMed1992

p53 expression and prognosis in gastric carcinoma.

Abnormalities of the p53 gene have been identified in many malignancies, with reports of aberration in over half of colorectal, lung, breast and hepatocellular carcinoma cases. The normal gene acts as a recessive oncogene, while mutations change the apparent function to that of a dominant oncogene. In this investigation a 3-layered immunoperoxidase technique was applied to routinely fixed and paraffin-embedded tissue sections from 125 gastric carcinomas, using a polyclonal anti-p53 antibody (CM-I). We found that 57% of these carcinomas expressed high levels of p53 protein (positive nuclear staining). Survival analysis revealed a strong association between p53 status of the tumour and patient survival time after diagnosis (p = 0.02, Mantel-Cox Test); odds ratio of death, 2.09 (95% confidence interval 1.02 to 4.25). The 5-year survival of patients with p53-expressing tumours was 24%, compared with 56% for those non-p53-expressing tumours (the median survival times were 13 and 102 months, respectively).

Biomarkers, Tumor↗
PubMed1992

Measurement of cell proliferation in gastric carcinoma: comparative analysis of Ki-67 and proliferative cell nuclear antigen (PCNA).

Immunostaining to identify nuclear antigens expressed throughout the cell cycle provides a convenient way of assessing proliferating kinetics in tumours. We studied proliferation activity of gastric carcinomas by Ki-67 and PCNA immunostaining and the two methods were compared. The mode of tissue preparation differed, fresh frozen for Ki-67 and formalin-fixed paraffin-embedded for PCNA. Immunostaining with avidin-biotin was used in both. The labelling index (LI) and a semi-quantitative grading of cell proliferation were assessed in both markers. Significant correlation was shown between LI and grading with either Ki-67 and PCNA. However, no correlation was found between PCNA and Ki-67. This lack of relationship between the two markers may be attributed to a number of factors. 1. The most likely is the marked inter- and intra-tumour heterogeneity of gastric carcinomas reflected in high standard deviation values. 2. Preparation of tissue and small size sampling with Ki-67. 3. Long life of PCNA leading to detection of cells that have recently left the cell cycle. 4. One may be observing deregulated expression of DNA as seen in certain tumours. PCNA offers the advantage of being applicable to archival material.

Analysis of Variance↗
PubMed1992

Growth regulatory peptides in gastric mucosa.

1. Epidermal growth factor and the related peptide transforming growth factor alpha have been implicated in the stimulation of gastric mucosal proliferation. We assessed the immunohistochemical distribution of these peptides and their receptor, epidermal growth factor receptor, in mucosa from the antrum and body of the stomach from 28 patients. Twenty-three of the 56 biopsies were histologically normal (12 antrum and 11 body), whereas the other 33 showed varying degrees of inflammation. 2. Epidermal growth factor, transforming growth factor alpha and epidermal growth factor receptor had maximal density of distribution on the apical surfaces of the superficial epithelial cells, but were also expressed to a lesser extent on neck and body cells of the glandular tissue (P less than 0.05). We also demonstrated that epidermal growth factor expression was greater in the epithelial cells of inflamed mucosa than in those of normal mucosa (P less than 0.05). 3. We assessed mucosal proliferation by the Ki-67 labelling index. Ki-67-positive cells were found predominantly in the neck area of the glands and were more frequent in glandular antral tissue than in body glandular tissue (P less than 0.05). Expression of epidermal growth factor receptor in the neck and isthmus cells had a significant correlation with the Ki-67 labelling index (P less than 0.05). 4. We conclude that epidermal growth factor and epidermal growth factor receptor may be important in the adaptation of gastric mucosa to inflammation.

Epidermal Growth Factor↗
PubMed1992

Cell proliferation study on gastric carcinoma and non-involved gastric mucosa using a bromodeoxyuridine (BrdU) labelling technique.

Previous reports using [3H]thymidine have shown altered patterns of cell proliferation in gastric carcinogenesis. In this study we applied in vitro bromodeoxyuridine (BrdU) uptake and immunohistochemistry to tissue from carcinoma, its adjacent mucosa and distant mucosa (n = 16) cases and 10 normal control cases. The labelling index (LI) was calculated for the upper, neck/isthmus and lower gland compartments and in 10 random fields/carcinoma. The LI was greater in the carcinoma than in either the adjacent or far mucosa or the controls (p < 0.001). No difference was observed between the non-carcinoma areas. However, the LI varied significantly between the gland compartments within each area (p < 0.001). In the normal control cases, the location of the proliferating cells was limited to the neck/isthmus region and perhaps the most significant observation was the change of location and expansion of the proliferative zone towards the surface in the normal mucosa adjacent to carcinoma compared with distant mucosa and controls (p < 0.001). These altered patterns of cell proliferation may be an important aspect of the precancerous potential of field changes in gastric carcinoma patients and could help patient follow-up and serve as a marker in monitoring intervention studies.

Bromodeoxyuridine↗
PubMed1992

Transforming growth factor alpha expression in normal gastric mucosa, intestinal metaplasia, dysplasia and gastric carcinoma--an immunohistochemical study.

Using a monoclonal antibody (GF10) and a standard immunohistochemical technique, immuno-expression of transforming growth factor alpha (TGF-alpha) was found consistently within the differentiated compartment of normal adult human gastric mucosa. In 70% of mucosal samples exhibiting intestinal metaplasia there was more or less uniform TGF-alpha immunoreactivity throughout the intestinalized mucosa. Similarly, 60% of cases of dysplasia and 60% of gastric carcinomas showed strong immunoreactivity in most of the cells. However, whereas 93% of intestinal-type cancers showed strong immunoreactivity only 30% of the diffuse type were stained and then only weakly. Transforming growth factor alpha expression is thus a fairly regular feature of several types of differentiated gastric epithelia (normal, metaplastic, dysplastic and intestinal-type carcinoma), while its relative absence may be a factor in the histogenesis of the diffuse type of gastric carcinoma.

Gastric Mucosa↗
PubMed1992

Ultrastructural study of inflammatory bowel disease.

Ultrastructural changes that occurred in chronic active ulcerative colitis and Crohn's disease were investigated and compared to normal as well as to higher grades of dysplasia in adenomas and carcinomas. A greater number of immature absorptive cells, undifferentiated and intermediate cells were seen as compared to normal. One case of Crohn's and two cases of chronic ulcerative colitis including one with coexisting carcinoma showed increased number of vesicles and electron-dense bodies (EDB) in the absorptive cells and increased heterogeneity of mucin droplets in goblet cells and presence of atypical secretory cells (ASC). Higher grades of dysplasia characterised by large numbers of atypical secretory cells were not seen in the present series and provide no relationship between the atypical ultrastructural features and increased risk of malignancy. However, the number of cases investigated is too small and a large series is required to clarify the significance of observations such as increased number of electron-dense bodies and vesicles in the apical cytoplasm and presence of atypical secretory cells.

Adenoma↗
PubMed1991

c-erbB-2 proto-oncogene expression and its relationship to survival in gastric carcinoma: an immunohistochemical study on archival material.

The c-erbB-2 proto-oncogene encodes a growth factor receptor which is over-expressed in a variety of human adenocarcinomas. Recent reports suggest that it may be of value in arriving at prognosis in breast and ovarian cancer. In this study, c-erbB-2 expression was investigated in 93 routinely processed cases of gastric carcinoma, using an immunohistochemical technique. c-erbB-2 membrane immunoreactivity was observed in 11% (10/93) of tumours, all of which were of the well differentiated intestinal type (p less than 0.01). Overall, patients with tumours expressing this proto-oncogene had a significantly improved prognosis (p less than 0.05). Within the group of intestinal-type tumours, those that were c-erbB-2-positive formed a distinct sub-population which had a better prognosis (p less than 0.02), suggesting possible differences in aetiology.

Biomarkers, Tumor↗
PubMed1991

Is DNA ploidy and proliferative activity of prognostic value in advanced gastric carcinoma?

We analyzed the DNA content of 116 gastric carcinomas and lymph node metastasis in 53 of these using flow cytometry on archival material. DNA index and proliferative activity (% S-phase) values were obtained in 111 and 76 tumors, respectively, and survival rates were obtained for 108. Tumor classification was based on histologic type, grade, and growth pattern and stage. All were advanced gastric carcinomas. Fifty four tumors (47%) were aneuploid. In single variable analysis, survival was related to stage (muscularis propria versus serosa P = .002) and lymph node metastasis (P = .04). Infiltrative tumor growth had a slightly worse prognosis (P = .06). In multifactorial analysis, tumor stage was the only independent prognostic factor. Neither DNA ploidy nor % S-phase values had any effect on survival, although, patients with tumors with higher DNA indexes (greater than 1.7) showed a tendency toward worse survival rates. We failed to prove the prognostic value of DNA ploidy in gastric carcinoma. Before its effect is ruled out, some factors have to be considered: (1) all tumors were in advanced stage and the true effect of ploidy on survival may have been diluted, (2) quality of fixation--near diploid aneuploid populations may have been overlooked, and (3) intratumoral DNA ploidy heterogeneity can cause sample discrepancy (20% in our series).

Adenocarcinoma↗
PubMed1991

Hyperganglionosis mimicking Hirschsprung's disease.

Three patients with hyperganglionosis are reported in whom an initial diagnosis of Hirschsprung's disease was suspected. In one patient there was a classic presentation with constipation, in another Hirschsprung's disease coexisted, and in the third the initial inadequate suction rectal biopsy specimen was suggestive of Hirschsprung's disease on acetylcholinesterase staining. Evidence of hypertrophy and hyperplasia of the intermuscular and submucosal plexuses on a full thickness bowel biopsy specimen was used to confirm the diagnosis of hyperganglionosis, suggested by the characteristic demonstration of moderate increase in the number of acetylcholinesterase stained nerve fibres in the lamina propria mucosae on rectal biopsy. Surgical management was guided by clinical signs. Two patients had colonic resections; the third had temporary stomal diversion. Hyperganglionosis is rarer than Hirschsprung's disease but is known to mimic it. We suggest full thickness bowel specimens are needed to confirm the diagnosis and that inadequate rectal suction biopsies must be interpreted with caution.

Constipation↗
PubMed1991

Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up.

Because early gastric cancer is associated with a much better prognosis than advanced disease, its diagnosis is important. Over a 12 year period (1976-87), a progressive increase in the incidence of early gastric cancer was observed. Twenty four of the 718 (3.3%) consecutive gastric resections for gastric cancer in this period were in patients with early gastric cancer. Six of the 24 were diagnosed in the first six year period (1976-81) and 18 in the second six year period (1982-87) (p less than 0.01). This increase was observed during the prospective phase of the study, when all patients diagnosed on initial biopsy specimen as showing type III intestinal metaplasia underwent follow up endoscopy and biopsy at six to 12 month intervals. Eleven of the 18 with early gastric cancer detected in this period were diagnosed as a direct result of this follow up. We conclude that early gastric cancer can be diagnosed with increasing frequency if patients with type III intestinal metaplasia are closely followed endoscopically.

Follow-Up Studies↗
PubMed1991

Gastric carcinogenesis in the rat induced by duodenogastric reflux without carcinogens: morphology, mucin histochemistry, polyamine metabolism, and labelling index.

Chronic duodenogastric reflux induces gastric adenocarcinomas in the rat without the use of carcinogens. Altogether, 186 male Wistar rats were randomised to undergo either a simple gastrojejunostomy or a gastrotomy and sacrificed at eight weekly intervals for 56 weeks. No control animals developed dysplasia or carcinoma. All rats subjected to a gastrojejunostomy showed hyperplasia of the proliferative neck zone, with increased sulphomucin production adjacent to the scar. Low grade dysplasia was found at 16 weeks, and carcinoma was first seen at 32 weeks. Most carcinomas were well differentiated mucin secreting adenocarcinomas of the expanding type, which secreted a mixture of sialomucins and sulphomucins. Duodenogastric reflux was associated with a 100% increase in labelling index (assessed autoradiographically with tritiated thymidine) in the gastric mucosa when compared with corresponding tissue adjacent to a gastrotomy scar. This increase was significant at eight weeks and persisted for 56 weeks after surgery. This study supports the theory that, in this model, hyperplasia precedes the development of carcinoma.

Animals↗
PubMed1991

Prognostic value of proliferating cell nuclear antigen in gastric carcinoma.

A new monoclonal antibody to proliferating cell nuclear antigen (PCNA), PC10, which can be used on routinely processed tissue, was applied to 93 cases of gastric carcinoma. Significant intra-tumoural variation in staining occurred. In addition to a PCNA index (percentage of positive cells per 1000 tumour cells), a semiquantitative PCNA grading system was devised, based on estimates of less than or more than 50% of positive tumour cells in whole sections. Neither PCNA index nor PCNA grade showed any correlation with established histological variables, tumour stage, or the presence of lymph node metastases. No significant correlation was observed between PCNA index and S + G2M phase fraction measured by flow cytometric analysis. To analyse survival tumours with PCNA indices above and below the median level (41%) were compared. Those with a higher index tended to have a worse prognosis, but when PCNA grade was considered, it was found to have definite independent prognostic value, tumours of low grade surviving better than those of high grade. The ability of semiquantitative PCNA grading to allow for intra-tumoural variation suggests it may have advantages over absolute counting, which is prone to sampling error when tumour heterogeneity is a major factor. The prognostic value of PC10 staining in gastric carcinoma is therefore promising.

Adult↗
PubMed1990

Morphometric definition and grading of gastric intestinal metaplasia.

Type I and type III intestinal metaplasia in gastric mucosa have been examined using morphometric methods. Tissue (volume per cent gland, lumen, epithelium, goblet cell vacuoles) and nuclear parameters (area, with related standard deviation, and form factors) were used as indicators of gland crowding, nuclear-cytoplasmic ratio, nuclear atypia, and pleomorphism. In type III intestinal metaplasia, there is significantly (i) greater nuclear pleomorphism, (ii) a higher nuclear-cytoplasmic ratio, and (iii) smaller and less numerous goblet cell vacuoles in both the upper and the lower parts of the crypts. These two parameters have significantly higher values in the lower than in the upper part of individual crypts. No cell population with large pleomorphic nuclei characterized type III metaplasia, though there was more variation in nuclear size.

Adult↗
PubMed1990

Problems and advantages of acetylcholinesterase histochemistry of rectal suction biopsies in the diagnosis of Hirschsprung's disease.

One hundred fifty-seven children, aged 2 days to 15 years, had rectal biopsies for suspected Hirschsprung's disease from 1980 to 1987. Sixty had adequate suction rectal biopsies stained for acetylcholinesterase (ACE); 41 of these were reported as normal and eight showed atypical innervation in children who progressed satisfactorily without surgery. Two showed hyperganglionosis and nine were from children with Hirschsprung's disease. Four of the latter nine biopsies (44%) gave false-negative results in infants aged 9, 10, 13 days, and 6 weeks. The last had total colonic aganglionosis. There were two false-positive results, one in a normal child with atypical innervation and the other in a child with hyperganglionosis. Thus, six of 60 (10%) of ACE-stained suction rectal biopsies gave misleading results.

Acetylcholinesterase↗
PubMed1990

Nucleolar organizer regions in gastric carcinoma and its precursor stages.

A silver technique for nucleolar organizer regions (AgNOR) was applied to sections from 156 gastric biopsies and gastrectomy specimens. These included normal controls, normal gastric mucosa from carcinoma-bearing stomachs, intestinal metaplasia types I and III, dysplasia and carcinoma. AgNOR counts gradually increased from normal, through intestinal metaplasia, to carcinoma. This finding supports the chronic atrophic gastritis-intestinal metaplasia-dysplasia-carcinoma sequence concept for gastric carcinogenesis. Normal gastric mucosa was different from all lesions, including normal mucosa from carcinoma-bearing stomachs. Significantly higher AgNOR counts were observed in tumours compared to all other lesions except dysplasia. Dysplasia differed from intestinal metaplasia type I but not from type III. Eighty-five per cent of metaplasia cases overlapped with carcinoma and 19% with normal controls. The spread of AgNOR values in intestinal metaplasia reinforces the concept that this lesion is a heterogeneous entity reflecting a dynamic and continuous process. The AgNOR technique may contribute to the assessment of the stage of evolution of 'borderline' lesions.

Biopsy↗
PubMed1990

Variants of intestinal metaplasia in the evolution of chronic atrophic gastritis and gastric ulcer. A follow up study.

A follow up study with biopsy was initiated in 1982 to define the relations between variants of intestinal metaplasia and the evolution of chronic atrophic gastritis and gastric ulcer. All patients (58 with chronic atrophic gastritis and 66 with gastric ulcer) had intestinal metaplasia at the start of the study. In the six year period to 1988 a total of 241 biopsies were performed on the patients with chronic atrophic gastritis and 243 on the patients with gastric ulcer. Initially, 81% of the patients with chronic atrophic gastritis presented with type I intestinal metaplasia and 14% with type III intestinal metaplasia. During follow up type I was predominant, often associated with grades 2 and 3 active disease (81%) and 45% of these patients reverted to a non-intestinal metaplasia status by the third year of follow up. In contrast, type III metaplasia was more common in the absence of appreciable inflammation (78% of biopsy specimens), being persistent in five of seven patients in the third year of follow up, and was found to be associated with dysplasia in three of these patients. Similarly, the initial biopsy specimen showed type I metaplasia in most patients with gastric ulcer (82%) and type III in only 4%. Type I metaplasia was also predominant in these patients (80%), particularly in active disease (68%), gradually regressing with healing. In contrast, type III was associated with delayed ulcer healing and reactivation (75%; six of eight patients). We conclude that (a) type I is a short term reactive process which regresses with healing; (b) type III is related to prolonged injury and chronicity and may regress or progress to dysplasia; (c) persistent and more immature forms of metaplasia may carry an increased risk of malignancy.

Adult↗