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M Sobrinho-Simões

Publications and source records attributed to M Sobrinho-Simões.

At least 19 recordsLinked to original sources
PubMed1999

Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression.

Intestinal metaplasia is a well-established premalignant condition of the stomach that is characterized by mucin carbohydrate modifications defined by histochemical methods. The purpose of the present study was to see whether the expression of mucin core proteins was modified in the different types of intestinal metaplasia and to evaluate the putative usefulness of mucins as "molecular markers" in this setting. We used a panel of monoclonal antibodies with well-defined specificities to MUC1, MUC2, MUC5AC, and MUC6 to characterize the expression pattern of mucins. In contrast to normal gastric mucosa, the complete form or type I intestinal metaplasia (n = 20) displayed little or no expression of MUC1, MUC5AC, or MUC6 in the metaplastic cells and strong expression of the intestinal mucin MUC2 in the goblet cells of all cases. The incomplete forms of intestinal metaplasia, type II (n = 25) and type III (n = 16), expressed MUC1 and MUC5AC in every case, both in goblet and in columnar cells. MUC6 was also expressed in 16 cases of type II intestinal metaplasia and in 11 cases of type III intestinal metaplasia. The intestinal mucin MUC2 was expressed in every case of incomplete intestinal metaplasia, mostly in goblet cells. The mucin expression profile in the different types of intestinal metaplasia allows the identification of two patterns: one defined by decreased levels of expression of "gastric" mucins (MUC1, MUC5AC, and MUC6) and expression of MUC2 intestinal mucin, which corresponds to type I intestinal metaplasia, and the other defined by coexpression of "gastric mucins" (MUC1, MUC5AC, and MUC6) together with the MUC2 mucin, encompassing types II and III intestinal metaplasia. Our results challenge the classical sequential pathway of intestinal metaplasia (from type I to type III via a type II intermediate step).

Antibodies, Monoclonal↗
PubMed1999

E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas.

Inactivation of the E-cadherin gene has been described previously in gastric carcinomas. In the present study, we investigated the alterations of the E-cadherin gene in gastric carcinomas and analyzed the relationship between such alterations and the histotypes of the tumors. We performed PCR/single-strain conformation polymorphism mutation screening and loss of heterozygosity analysis of the E-cadherin gene in a series of 26 gastric carcinomas, including 10 "pure" intestinal, 10 "pure" diffuse, and 6 mixed gastric carcinomas, the latter with intestinal and diffuse components. Fifteen mutations of the E-cadherin gene were identified in 12 cases (46.2%). Mutations included 10 missense mutations, 7 of which occurred in sequences coding for calcium binding motifs, 3 splice site mutations, 1 nonsense mutation, and 1 frameshift deletion. We found mutations of the E-cadherin gene in 7 of 10 "pure" diffuse carcinomas (70.0%) and in 5 of 6 mixed carcinomas (83.3%). No mutations were found in "pure" intestinal carcinomas. In mixed carcinomas, inactivating E-cadherin mutations were exclusively observed in the diffuse component of the tumors. We conclude that E-cadherin inactivation is significantly related with the diffuse histotype in gastric carcinomas, not only in "pure" diffuse carcinomas but also in the diffuse component of mixed tumors. To the best of our knowledge, this is the first report advancing a genetic basis for the phenotypic divergence of mixed gastric carcinomas.

Cadherins↗
PubMed1998

Expression of fully and under-glycosylated forms of MUC1 mucin in gastric carcinoma.

The membrane-bound MUC1 mucin is expressed in normal mucosas and the aberrant expression of its under-glycosylated forms has been reported in carcinomas from different sites. Several studies have provided conflicting evidence regarding the relationship between MUC1 expression and outcome in cancer patients. In this study, we investigated the immunohistochemical expression of MUC1 epitopes, using 2 monoclonal antibodies (MAbs): HMFG1, which reacts with the fully glycosylated MUC1, was studied in 73 gastric carcinomas; and SM3, which recognises an under-glycosylated form of MUC1, was studied in 180 cases. HMFG1 stained the antrum foveolar cells and the body glands of normal gastric mucosa, whereas SM3 reactivity was restricted to the perinuclear region of some foveolar cells. Type I intestinal metaplasia exhibited down-regulation of MUC1 expression using both MAbs. Every gastric carcinoma was stained with HMFG1 and 80% with SM3. High levels of expression of HMFG1 were associated with lymphatic invasion, nodal metastatization, and advanced pTNM staging. The expression of SM3 was associated with the histologic (solid) type of carcinoma, expanding growth pattern, wall penetration, lymphatic invasion and age of the patients. Despite a trend for a poor outcome in patients with tumours (over)expressing MUC1 mucin, the survival of the patients evaluated by univariate and multivariate analysis was not significantly associated with the levels of expression of HMFG1 or with the expression of the SM3 epitope. We conclude that (a) MUC1 expression, namely of the SM3 cancer-associated epitope, is significantly associated with several aspects of gastric cancer development and progression; and (b) MUC1 expression should not be used as a prognostic marker in patients with gastric carcinoma.

Adult↗
PubMed1998

Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms?

Despite the large amount of information accumulated on the role played by ret activation in the oncogenesis of papillary thyroid carcinoma (PTC), the biological and clinical significance of such activation 'in vivo' remains controversial. The aim of this study was to address some of the existing controversies by comparing two groups of unselected PTCs, one with and the other without ret rearrangement, with regard to several clinicopathological and biological features. Thirty-three PTCs were selected at random. ret rearrangement was found in eight cases (24.2 per cent) using Southern blot analysis. The mean age of the patients with tumours displaying ret rearrangement (28 +/- 3.1 years) was significantly lower than that of the patients harbouring cases that did not present rearrangement (45 +/- 2.9 years). The large majority of the tumours with ret rearrangement displayed a papillary or mixed follicular-papillary pattern and very low proliferative activity. ret rearrangement correlated significantly with decreased cytoplasmic expression of E-cadherin. No significant differences were found regarding the gender of the patients, tumour size, multicentricity, extrathyroidal growth, vascular invasion, lymphocytic infiltration, lymph node involvement or the expression of E-cadherin (membrane), c-erb-B2, c-met, Bcl-2, and vimentin. It is proposed that sporadic PTCs harbouring a ret rearrangement occur frequently as slow growing, papillary, or predominantly papillary tumours that do not usually progress towards less differentiated neoplasms representing what might be described as a Bonsai phenotype.

Adolescent↗
PubMed1998

The clinicopathological features of gastric carcinomas with microsatellite instability may be mediated by mutations of different "target genes": a study of the TGFbeta RII, IGFII R, and BAX genes.

Gastric carcinomas with DNA replication errors (RER phenotype) display a particular clinicopathologic profile and carry a putative favorable prognosis. The RER phenotype has been identified as microsatellite instability in noncoding regions, as well as in repeat sequences within exons of several "target genes": TGFbeta RII, IGFII R, and BAX. In an attempt to find out whether the RER status is a significant prognostic factor in gastric carcinoma in a multivariate analysis and whether the clinicopathological features of the RER+ tumors are associated with mutations in the "target genes," we evaluated a series of 152 cases of sporadic gastric carcinoma. Five or six microsatellite loci and/or BAT 26, a poly(A) tract, were analyzed in each case using polymerase chain reaction and electrophoresis. Thirty-five cases (23.0%) were RER+. The RER phenotype was closely associated with a low pTNM stage and carried a significantly better prognosis. The repeat sequences of the target genes were screened for mutations in 28 RER+ and 13 RER-tumors. Mutations in TGFbeta RII occurred in 67.9% of the RER+ tumors and were significantly associated with the glandular histotype. IGFII R and BAX mutations occurred, respectively, in 25.0% and 32.1% of the cases; there was a trend toward an association between mutations in these genes and decreased nodal metastization and wall invasiveness, respectively. We conclude that the RER status is a significant prognostic indicator in gastric carcinoma and that such prognostic influence may be mediated by mutations in TGFbeta RII, IGFII R, and BAX genes.

Aged↗
PubMed1998

Dimeric sialyl-Le(x) expression in gastric carcinoma correlates with venous invasion and poor outcome.

BACKGROUND & AIMS: High expression of sialyl-Le(x) in tumors of different organs correlates with hematogenous metastasis and adverse outcome. Dimeric sialyl-Le(x) expression in gastric carcinoma was evaluated, and its prognostic significance within this setting was determined. METHODS: Dimeric sialyl-Le(x) immunohistochemical expression in 97 gastric carcinomas was analyzed using the FH6 monoclonal antibody. Scoring was based on the percentage of immunoreactive cells: negative, low expression (< or = 25%), and high expression (> 25%). RESULTS: Immunoreactivity was observed in 45 cases (46.4%), encompassing 27 and 18 cases with low and high expression, respectively. Significant relationships were found between dimeric sialyl-Le(x) expression and venous invasion (P = 0.0025) and histological classification (P = 0.05). No correlation was observed with other clinicopathologic features. Patients with tumors showing high expression of dimeric sialyl-Le(x) had a significantly shorter survival time than those with low or no expression (P = 0.03). By multivariate analysis, pathological TNM (pTNM) staging and venous invasion emerged as independent prognostic factors in the whole series. Within the group of patients with tumors in pTNM stages II and III, dimeric sialyl-Le(x) was the only independent prognostic factor. CONCLUSIONS: High expression of dimeric sialyl-Le(x) correlates with venous invasion and poor outcome in gastric carcinoma.

Adult↗
PubMed1998

Synovial sarcoma. Evaluation of prognosis with emphasis on the study of DNA ploidy and proliferation (PCNA and Ki-67) markers.

Controversy still exists regarding the validity of parameters commonly used in the evaluation of prognosis of patients with synovial sarcoma (SS). Forty-nine cases of previously untreated primary SS (23 females and 26 males, ranging in age from 7 to 81, with 31 tumors located in the lower extremity, 8 at the upper extremity and 10 at the trunchus), without regional lymph-node or distant metastases were studied. We investigated the relationship between (flow and image) DNA cytometry, proliferation activity, clinicopathologic parameters, and relapse-free and overall survival of the patients. The prognostic value of gender, age, duration of symptoms, location, compartmentalization, size, adequacy of surgical margins, residual tumor, adjuvant therapy, histologic subtype, extent of necrosis, glandular differentiation, calcification, and extent of hemangiopericytic areas, mitotic rate, amount of mast cells, blood vessel invasion, histologic (UICC and NCI) grades, DNA ploidy, percentage of cells in S and S+G2 phases, PCNA and Ki-67 labeling indices (LI), and TNM (UICC) stage of the tumors, were evaluated by univariate and multivariate (Cox hazard model) analyses. Short duration of symptoms (<12 months), biphasic SS, scarcity of mast cells (<10/10 HPF), high mitotic rate (> or =10/10 HPF), high histologic grade (grade 3), high PCNA-LI (> or =20%), high Ki-67-LI (> or =10%), DNA aneuploidy, and advanced TNM stage (stage III) were features associated with significantly shorter relapse-free and overall 5-year survival rates in the univariate analyses. Scarcity of mast cells, high mitotic rate, or high PCNA-LI were significant predictors of poor survival, in addition to TNM stage in the multivariate analyses. The amount of mast cells was inversely correlated with mitotic rate and PCNA-LI. Scarcity of mast cells, high mitotic rate, or high PCNA-LI are factors associated with poor prognosis, in addition to advanced TNM stage in patients with localized SS.

Adolescent↗
PubMed1998

Metastatic thyroid carcinoma arising from congenital goiter due to mutation in the thyroperoxidase gene.

A very large cervical tumor that extended to the upper mediastinum was seen in a newborn after an uneventful pregnancy. The computed axial tomography scan confirmed the presence of a solid mass with precise limits and scattered foci of calcifications situated in the anterolateral region of the neck. The infant underwent thyroidectomy on the seventh day after birth. Pathological examination revealed a follicular carcinoma of the thyroid and probable dyshormonogenetic hyperplastic goiter. At 5 months of age, whole body scans indicated the presence of lung and bone metastases, which were treated with therapeutic doses of radioiodine. Genomic DNA was obtained from the newborn, her parents, her paternal aunt, and her paternal grandparents. Denaturing gradient gel electrophoresis analysis of PCR fragments corresponding to exon 14 of the thyroid peroxidase (TPO) gene indicated the presence of a mutant TPO allele present in the propositus, her father, and her paternal grandmother. Sequencing of the TPO gene demonstrated a mutation resulting from an insertion of a single extra cytosine in a stretch of seven cytosines at positions 2505-2511. The insertion caused a frame shift and a stop signal in exon 16. This sequence would translate into a structurally modified and probably inactive TPO protein. We conclude that the aggressive thyroid metastatic carcinoma arose from a dyshormonogenetic goiter caused by a defective TPO protein.

Bone Neoplasms↗
PubMed1997

Immunohistochemical study of MUC5AC expression in human gastric carcinomas using a novel monoclonal antibody.

In order to investigate the expression of MUC5AC mucin in normal gastric mucosa and gastric carcinomas, we produced 3 monoclonal antibodies (MAbs) using a MUC5AC synthetic peptide. The immunohistochemical study was performed using one of these MAbs (CLH2) which reacted with the different designs of peptides based on the MUC5AC tandem repeat and with native and deglycosylated mucin extracted from gastric tissues. CLH2 immunoreactivity was restricted to foveolar and mucopeptic neck cells in normal gastric mucosa. No reactivity was observed in type-I intestinal metaplasia. Out of 66 gastric carcinomas, 42 (63.6%) expressed MUC5AC. Most diffuse carcinomas were positive (83.3%), whereas only 59.3% of intestinal and 40.0% of atypical carcinomas expressed MUC5AC (p < 0.05). Gastric carcinomas with mixed pattern showed immunoreactivity in diffuse areas and decreased immunoreactivity in intestinal areas. Every early gastric carcinoma expressed MUC5AC, in contrast to 58.6% of advanced carcinomas (p < 0.05). A trend toward decreased immunoreactivity was observed in deep areas of advanced carcinomas in comparison with the respective superficial areas. Taking together the specific staining of foveolar and mucopeptic neck cells and the absence of immunoreactivity in intestinal metaplasia, we conclude that MUC5AC expression may be used as a marker of gastric differentiation. This assumption is further supported by the finding of MUC5AC immunoreactivity in most diffuse carcinomas, which usually display morphologic and histochemical signs of gastric differentiation. The expression of MUC5AC in early gastric carcinomas, regardless of their histologic type, suggests that all gastric carcinomas retain at least some cells with a gastric phenotype during the first steps of neoplastic development.

Amino Acid Sequence↗
PubMed1997

E-cadherin gene alterations are rare events in thyroid tumors.

Reduced expression of E-cadherin has been associated with loss of differentiation and/or increased invasiveness and metastatic ability in several types of neoplasms. Rare studies on thyroid tumors have shown minimal or absent expression in undifferentiated carcinomas and a variable degree of immunoreactivity/mRNA expression in follicular and papillary carcinomas. We studied immunohistochemically 2 follicular adenomas, 8 follicular carcinomas, 18 papillary carcinomas and 3 poorly differentiated carcinomas to evaluate E-cadherin expression. In 7 papillary carcinomas, lymph node metastases were also studied. The E-cadherin gene was analysed in 27 tumors by PCR/SSCP followed, whenever appropriate, by DNA sequencing. LOH at the E-cadherin locus was assessed in 16 tumors. Reduced and heterogeneous expression of E-cadherin was found in primary and metastatic papillary carcinomas, whereas follicular carcinomas showed moderate to strong homogeneous immunoreactivity, and poorly differentiated carcinomas showed no or very faint immunoreactivity. The only case harbouring a (missense type) mutation of the E-cadherin gene was a papillary carcinoma exhibiting immunoreactivity in the primary tumor as well as in metastasis. LOH was found in a follicular adenoma and in a poorly differentiated carcinoma without evidence of mutation in the remaining allele. Our results show that irreversible alterations (allele loss or mutation) of the E-cadherin gene are infrequent in thyroid tumors. The reduced and heterogeneous expression of E-cadherin in thyroid carcinomas, particularly of the papillary histotype, appears to reflect transcriptional regulation or post-transcriptional modulation rather than structural abnormalities.

Adenocarcinoma, Follicular↗
PubMed1997

Ki67 labelling index in gastric carcinomas. An immunohistochemical study using double staining for the evaluation of the proliferative activity of diffuse-type carcinomas.

The aim of the present study was to clarify the conflicting recorded data on the proliferative features of gastric carcinoma. The Ki67 labelling index (Ki67 LI) was evaluated using MIB-1 in 43 carcinomas (24 diffuse and 19 intestinal). In 18 cases, differential counts were performed in superficial and deep layers. In ten diffuse carcinomas with a prominent desmoplastic response, Ki67 LI was evaluated in sections double-stained with MIB-1 and CAM5.2. Flow cytometry was performed in 26 cases. Ki67 LI of diffuse carcinomas (36.3 +/- 19.0) was not significantly different from that of intestinal carcinomas (28.2 +/- 18.5). Ki67 LI was significantly higher (P = 0.006) in superficial than in deep areas (41.9 +/- 22.7 and 29.7 +/- 19.7, respectively) regardless of histological tumour type. No significant relationship was observed between Ki67 LI and wall invasion, lymph node metastasis, vascular invasion or ploidy. The following conclusions were drawn: double immunostaining techniques are apparently the best way to overcome the underestimation of cell proliferation in diffuse gastric carcinomas with a prominent desmoplastic response; the diffuse and intestinal types of gastric carcinoma have proliferation rates within the same range, even when the comparison is restricted to diploid tumours; and, finally, the major pool of proliferating cells resides in the superficial areas of gastric carcinomas, regardless of the histotype, which should be taken into consideration when overall counts are performed, using either immunohistochemical markers in tissue sections or suspensions of nuclei in flow cytometry.

Adenocarcinoma↗
PubMed1997

Pattern of expression of intermediate cytokeratin filaments in the thyroid gland: an immunohistochemical study of simple and stratified epithelial-type cytokeratins.

The expression of simple and stratified epithelial-type cytokeratin (CK) intermediate filaments was evaluated by immunohistochemistry in a series of 41 papillary carcinomas, 10 follicular carcinomas, 2 poorly differentiated carcinomas and 34 specimens of normal thyroid parenchyma and lymphocytic thyroiditis. The aim of the study was to establish the CK profile of normal thyroid and thyroid carcinomas in order to clarify the putative application of CK immunostaining in diagnostic surgical pathology, and to evaluate whether the process of neoplastic transformation and tumour progression in the thyroid may be associated with any particular change in CK expression. Normal thyroid strongly expressed simple epithelial-type CKs 7 and 18 and, to a lesser degree, CKs 8 and 19, but did not express stratified epithelial-type CKs. The same pattern was found in lymphocytic thyroiditis, though the CK 19 immunoreactivity was stronger in these lesions than in the normal thyroid. Papillary and follicular thyroid carcinomas shared the expression of simple epithelial-type CKs 7, 8, 18 and 19. Immunoreactivity for CK 19 was frequently stronger and more widely distributed within each particular tumour in papillary than in follicular carcinomas, but it could also be detected, at least focally, in every follicular carcinoma. Strong expression of CK 19 highlighted small foci of papillary carcinoma not easily identifiable by conventional histological examination. Stratified epithelial-type CKs 5/6 and 13 were detected in a high percentage of papillary carcinomas, in contrast to their absence in follicular carcinomas and normal thyroid. The CK pattern was similar in primary and metastatic papillary carcinomas. We conclude that papillary carcinoma of the thyroid presents a distinct CK profile that may be used for diagnostic purposes.

Adenocarcinoma, Follicular↗
PubMed1997

[Prognostic factors in differentiated thyroid gland carcinoma].

This review aims at describing the influence of established and not yet sufficiently characterized parameters on the prognosis of thyroid follicle cell carcinomas. The analysis of literature data covers a broad spectrum of pathologic and biologic factors from classical prognostic features like age, gender and tumor stage to mutation, activation or, where applicable, inactivation of tumor suppressor genes, metastasis-related genes and adhesion molecules.

Adenocarcinoma, Follicular↗
PubMed1997

Synovial sarcoma: immunohistochemical expression of P-glycoprotein and glutathione S transferase-pi and clinical drug resistance.

Our purpose was to study the role of the expression of P-glycoprotein (Pgp) and glutathione S transferase-pi (GST-pi) in predicting the response to chemotherapy, relapse-free interval, and survival of patients with synovial sarcoma (SS). Thirty-seven cases of primary SS, without regional lymph node or distant metastases, were studied. There were 17 females and 20 males, ranging in age from 7 to 81 years (median, 31 years) with tumors located in the lower extremity (n = 24) upper extremity (n = 5) and trunchus (n = 8). The cases were retrospectively studied without knowledge of clinical course to compare the immunohistochemical expression of Pgp and GST-pi, flow cytometry parameters (ploidy and % of cells in S+G2 phases), and PCNA and Ki-67 labeling of primary tumors before any therapy, with that observed in local recurrences and metastases after chemotherapy. The relationship of the aforementioned parameters with clinicopathological features (gender, age, and histo-blood group of the patients, size, location, histological subtype. TNM stage, and clinical response to chemotherapy of the tumors) was also evaluated. Results revealed that Pgp and GST-pi were expressed in 29.7% and 40.5% of the cases, respectively. In 48.6% of the tumors there was expression of a least one of the drug resistance markers. The markers were coexpressed in 25.0% of the tumors. The prevalence of Pgp expression was lower, but not significantly, in stage I-II (17.6%) than in stage III (40.0%) tumors, and also in cases without clinical progression (16.7%), than in cases with (36.0%). No such differences were observed for GST-pi expression. Pgp and GST-pi expressions were significantly associated with biphasic SS and were particularly noticeable in solid/glandular areas of biphasic SS. The expression of the drug resistance markers was not significantly associated with gender, age, and histo-blood group of the patients, dimension, location, and proliferative activity of the tumors; it was also not significantly related to relapse-free interval and survival of the patients. The expression of Pgp and GST-pi was not significantly associated either to response to chemotherapy or influenced by chemotherapy. We conclude that Pgp and GST-pi expressions are not good predictors response to of the chemotherapy in patients with localized SS. Other drug resistance mechanisms may be active in SS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗