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To evaluate hyaluronan expression at different stages of tumoral progression in primary breast cancer. Hyaluronan expression was evaluated by histochemical techniques in 42 cases of pure DCIS, in 15 cases of DCIS with a microinvasive component, and in 32 cases of invasive ductal carcinoma of the breast. Staining results were evaluated by calculating the percentage of stained areas by means of a specific software program. Our results show higher values of hyaluronan expression in invasive breast carcinomas [median of percentage of stained areas 41.1 (range 8–69.2)] and in DCIS with a microinvasive component [48.6 (16.8–62.8)] than in pure DCIS [14.5 (1–44.4)] (p

Lymphatic and/or blood vessel tumoral invasion (LBVI) is a common histopathologic finding of gastric carcinomas, which could make it an additional cost efficient marker and help in the detection of patients at risk for recurrence.The subjects of this study were 144 patients with primary gastric adenocarcinoma, who consecutively underwent surgery. LBVI was evaluated by HE staining and complementary with immunohistochemical staining with anti-CD34. Intratumoral levels of EGFR were analyzed with a radioligand technique, whereas c-erbB-2 and tPA were determined by ELISA methods; pS2, cathepsin D and hyaluronic acid by immunoradiometric assays; and VEGFR-1 and -2 by immunohistochemical assays. The mean follow-up period for these patients was 33.1 months.LBVI was present in 46 patients (31.9%). The presence of LBVI correlated significantly with tumor stage, lymph node involvement, surgical resectability, histological type and histological grade, being present in a higher percentage among II-IV tumor stage (P = 0.0001), poorly differentiated (P = 0.01), diffuse type (P = 0.009), R1-R2 (P = 0.002) and lymph node-positive (P = 0.005) tumors. In addition, statistical analysis demonstrated that LBVI was significantly associated with a poorer overall patients' survival in the univariate analysis (P = 0.0001) as well as in the multivariate analysis (P = 0.009). However, our results failed to show any significant relationship between LBVI and any of the intratumoral biological parameters studied.LBVI provides additional useful information that could be applied to identify gastric cancer patients at risk for recurrence, who might be candidates for further adjuvant therapies.

Hyaluronic acid (HA), a high-molecular weight glycosaminoglycan, has been considered to be involved in the growth and progression of malignant tumors in several experimental studies. The objective of this work was to evaluate the cytosolic HA content in breast cancer, its possible relationship with clinicopathological tumor parameters and steroid receptor status, as well as its potential prognostic significance.Cytosolic HA levels were examined by means of immunoradiometric techniques in 850 patients with invasive breast cancer. The mean follow-up period for these patients was 55.1 months.Cytosolic HA levels ranged widely in tumors (4-59767 ng/mg protein; median: 4960). Statistical analysis showed that HA levels were significantly higher in younger patients (p=0.0001), as well as in premenopausal than in postmenopausal patients (p=0.001). HA levels were also significantly higher in ductal or lobular histological type than in other histological types (coloid, medullar or papillar types) (p=0.0001). Likewise, HA correlated significantly and positively with tumoral levels of PgR (r sub S: 0.11; p=0.001) in the all group of patients. In the subgroup of patients with ductal invasive type, HA levels were also significantly higher in well differentiated tumors and in diploid tumors. In addition, in this latter group of patients, HA levels in tumors correlated also positively and significantly with the either estrogen-inducible proteins: PgR (r sub S: 0.11; p=0.001), pS2 (r sub S: 0.117; p=0.008) and tPA (r sub S: 0.314; p=0.0001). On the other hand, significant association between HA intratumoral levels and relapse-free survival and overall survival in the overall group of patients was not found. However, high HA intratumoral levels were significantly associated with longer relapse-free survival in the subgroup of patients with ductal histological type tumors (p=0.01), as well as in those patients without any type of systemic adjuvant treatment (p=0.01).Our results suggest that high intratumoral levels of HA may be associated with tumors of favorable evolution in certain subgroups of patients with breast cancer. Thus, HA may provide additional prognostic information to that given by other biochemical markers currently used in breast cancer.

The Trefoil Factor 1 (TFF1/pS2), a peptide consisting of 60 amino acids, is the most abundant estrogen-induced messenger RNA present in MCF-7 breast cancer cells. The objective of this work was to evaluate the cytosolic TFF1 content in breast carcinomas, its possible relationship with different clinical-pathological parameters, and its potential prognostic significance and predictive value.Cytosolic TFF1 levels were examined by immunoradiometric assay in 1031 patients with invasive breast cancer. The median follow-up period was of 50 months.There was a wide variability of cytosolic TFF1 levels in tumors (0.9-743.2 ng/mg protein). Statistical analysis showed that TFF1 levels were significantly higher in premenopausal patients (p = 0.001), as well as in tumors showing any of the following characteristics: good differentiation (p = 0.0001), ER and PgR positivity (p = 0.0001 and p = 0.001, respectively), diploidy (p = 0.045) and a high S-phase fraction (p = 0.001). In addition, the presence of high intratumoral TFF1 levels (cut-off: 2 ng/mg protein) was independently associated with a shorter overall survival in the group of patients as a whole (p = 0.001) as well as in the subgroup with node-negative breast cancer (p = 0.0004). Likewise, high intratumoral TFF1 levels were associated with a more prolonged overall survival in patients who received adjuvant tamoxifen (p = 0.004).In breast cancer patients, intratumoral TFF1 levels are associated with a better clinical outcome, especially in those with node-negative tumors. In addition, TFF1 levels have a low but significant predictive value in regards to response to adjuvant therapy with tamoxifen.

Purpose: Retrospective analysis to assess the prognostic and predictive value of HER-2/ neu expression in breast tumors, quantified by enzyme immunoassay (ELISA).Methods: Quantification of HER-2/neu was performed on cytosolic extracts from 914 cases of primary invasive breast carcinomas. Relapse-free and overall survival data were available from 889 patients. The prognostic value of HER-2/neu levels was assessed considering them as a continuous, dichotomic or quartile variable.Results: Cytosolic HER-2/neu levels ranged widely in breast carcinomas (median: 746.5 NHU/mg; range: 2.8–80,000 NHU/mg protein). HER-2/neu protein levels were significantly higher in either moderately or poorly differentiated tumors, as well as in those showing a ductal histological type, aneuploidy or a high S-phase fraction. There was a significant and positive association between cytosolic and membranous HER-2/neu levels (n=162, r sub S=0.53; P Q 3), we observed that patients with either low HER-2/ neu levels (≤ Q 1) or high HER-2/neu levels (> Q 3) had shorter both relapse-free survival and overall survival curves than those patients with intermediate HER-2/neu levels. On the other hand, high HER-2/neu levels predicted a poor response to adjuvant chemotherapy but not to adjuvant hormonal therapy with tamoxifen.Conclusions: The results of the present investigation indicate that by quantitatively determining the content of HER-2/neu oncoprotein, groups of high-risk breast cancer patients could be identified, for a more effective clinical management.

This study was conducted to evaluate the prognostic significance of CD44v5 and CD44v6 in resectable colorectal cancer. Membranous CD44v5 and CD44v6 levels were measured by an immunoenzymatic assay in tumors and surrounding mucosal samples obtained from 105 patients with resectable colorectal carcinomas. There were no significant differences of CD44v5 levels between tumors [median: 3.2 (range: 0.9–83.5) ng/mg protein) and surrounding mucosal samples (3 (3–146.2) ng/mg protein]. However, tumor samples showed significantly higher CD44v6 levels [19.5 (2.2–562.9) ng/mg protein] than mucosal samples [5 (5–230) ng/mg protein] (P=0.0001). Patients with higher CD44v5 or CD44v6 content in tumor samples had a considerably shorter relapse-free survival (P

To analyze the expression and prognostic value of matrix metalloproteases and their tissue inhibitors in luminal A and basal-like breast carcinomas, an immunohistochemical study was performed on cancer specimens from 93 randomly selected patients with invasive primary ductal tumors of the breast (46 with and 47 without distant metastasis) and with luminal A (n = 48) (ER+, HER2-) or basal-like (HER2-, ER-, PgR-) (n = 45) lesions. Luminal B cases were too few to analyze. Specimens were also studied using tissue microarrays and specific antibodies against matrix metalloproteases 1, 2, 7, 9, 11, 13, and 14 and tissue inhibitors 1, 2, and 3. There were no significant differences in matrix metalloprotease or tissue inhibitor expression in the 2 phenotypes of tumors. In basal-like carcinomas, high scores for matrix metalloproteases 9 and 11 were significantly associated with a high distant metastasis rate. Likewise, data showed associations between matrix metalloprotease/tissue inhibitor expression by either stromal fibroblasts or mononuclear inflammatory cells and distant relapse-free survival in both tumor phenotypes. In addition, in infiltrating luminal A and basal-like tumors, we identified a prometastatic phenotype of mononuclear inflammatory cells, showing a high matrix metalloprotease/tissue inhibitor molecular profile. Expression of matrix metalloproteases and tissue inhibitors is related to the characteristics of breast tumor cells. As prognostic factors in breast carcinomas of both luminal A and basal-like phenotypes, our results point to the importance of the expression of matrix metalloproteases and tissue inhibitors by the stromal cells.

BackgroundIn the present study we analyze, in patients with breast cancer, the tumor expression of androgen receptors (AR), its relationship with clinicopathological characteristics and with the expression of several matrix metalloproteases (MMPs) and their inhibitors (TIMPs), as well as with prognosis.MethodsAn immunohistochemical study was performed using tissue microarrays and specific antibodies against AR, MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. More than 2,800 determinations on tumor specimens from 111 patients with primary invasive ductal carcinoma of the breast (52 with axillary lymph node metastases and 59 without them) and controls were performed. Staining results were categorized using a score based on the intensity of the staining and a specific software program calculated the percentage of immunostained cells automatically.ResultsA total of 83 cases (74.8%) showed a positive immunostaining for AR, but with a wide variation in the staining score values. There were no significant associations between the total immunostaining scores for AR and any clinicopathological parameters. However, score values for MMP-1, -7 and -13, were significantly higher in AR-positive tumors than in AR-negative tumors. Likewise, when we considered the cellular type expressing each factor, we found that AR-positive tumors had a higher percentage of cases positive for MMP-1, -7, -11, and TIMP-2 in their malignant cells, as well as for MMP-1 in intratumoral fibroblasts. On the other hand, multivariate analysis demonstrated that patients with AR-positive tumors have a significant longer overall survival than those with AR-negative breast carcinomas (p= 0.03).ConclusionOur results confirm that AR are commonly expressed in breast cancer, and are correlated with the expression of some MMPs and TIMP-2. Although we found a specific value of AR expression to be a prognostic indicator in breast cancer, the functional role of AR in these neoplasms is still unclear and further data are needed in order to clarify their biological signification in breast cancer.

Objectives Gene expression analysis has identified several breast cancer subtypes, including luminal, epidermal growth factor receptor-2 positive (HER2+), and basal-like. To determine if our proposed molecular taxonomy correlates with biological and clinical behavior. This is based on four biological markers: estrogen and progesterone receptors (ER and PR, respectively), HER2 and the epidermal growth factor receptor-1 (HER1), all of them being determined by quantitative assays. Study design The biological parameters were examined by enzyme immunoassay, radioligand-binding assay or ELISA, in tumors from 787 patients with invasive breast cancer. Patients were prospectively evaluated over a median follow-up period of 50 months. Subtype definitions were as follows: luminal (ER+), HER2+ (HER2+, ER−, PgR−) and basal-like (HER2−, ER−, PgR−). In addition, we divided basal tumors into two groups based on their HER1 status. Results A 55.8% of tumors were of luminal type, 11.9% basal-like HER1+, 10.7 basal-like HER1−, and the remainder 21.6% HER2+. Both HER2+ and basal-like subtypes were more frequent in younger and premenopausal women, showing a higher percentage of cases of poorly differentiated tumors and higher S-phase fraction, when compared with those of luminal subtype. Multivariate analysis demonstrated that the subtype of tumor was related to both relapse and overall survival, being those of luminal subtype associated with the best prognosis. Conclusions Through the classification of breast tumors in four groups, according to their ER, PgR, HER2 and HER1 status, it is possible to obtain a major division of breast tumors associated with significant differences in biological features and clinical behavior.

To determine whether the expression of collagenase-3 (MMP-13) in biopsies from patients with inflammatory bowel disease is correlated with histological inflammation parameters.Fifty-nine patients with inflammatory bowel disease were included in the study. The control group comprised 20 patients free of inflammatory disease and ten patients with acute diverticulitis. MMP-13 expression was determined by immunohistochemical staining and the specimens were assigned a histological inflammation score.It was found that 62.8% of patients with ulcerative colitis (UC) and 54.1% of patients with Crohn's disease (CD) showed MMP-13-positive immunostaining in biopsies from affected areas. MMP-13-positive staining was more intense in ulcerated colonic mucosa. A positive and significant correlation was found between MMP-13 expression and the histological inflammation scores in mucosal samples from patients with CD (r = 0.74, p0.0001) or UC (r = 0.62, p0.0001). However, no MMP-13-positive immunostaining was found in either the biopsy specimens of the control group or those biopsies taken from patients with UC or CD in microscopically confirmed non-affected areas of the colonic mucosa. Similarly, colonic mucosa samples of the 10 patients with acute diverticulitis did not show immunostaining for MMP-13.Our findings demonstrating the absence of MMP-13 expression in non-inflamed colonic mucosa or in acute diverticulitis, as well as a positive correlation between elevated MMP-13 expression and histological criteria of inflammation in patients with inflammatory bowel diseases (CD and UC) suggest a role of the protease in the pathogenesis of these latter processes.

Objectives To evaluate the clinical significance of the mammographic appearance of tumors in 411 patients with infiltrating ductal carcinoma of the breast. Study design Tumors were classified into five radiographic subgroups: spiculated mass (A-type), diffuse changes with or without suspicious microcalcifications (B-type), microcalcifications with a mass (C-type), circumscribed (D-type), and not visible (E-type). Intratumoral levels of estrogen (ER) and progesterone (PR) receptors, c-erbB-2, EGFR, pS2, cathepsin D and tPA, ploidy and S-phase fraction, were analysed in a significant number of cases. Results A-type A radiographic pattern was detected in 234 patients (57%), B-type in 46 (11%), C-type in 46 (11%), D-type in 68 (17%), and E-type in 17 patients (4%). On the other hand, a total of 155 tumors (37.8%) showed microcalcifications. The percentage of tumors showing A-type pattern was more frequent in postmenopausal women, in well-differentiated tumors, and in those showing higher levels of ER, pS2 of tPA. However, B-type pattern was detected in a high percentage of premenopausal women and in those showing larger tumors, positive nodes, poor differentiation or high S-phase fraction. Cox multivariate analysis showed that B-type pattern and the absence of microcalcifications were factors significantly associated to high risk for relapse. Conclusions Our results suggest that the mammographic appearance of tumor may to provide useful clinical information in addition to classical prognostic factor in infiltrating ductal carcinoma of the breast.

BackgroundMatrix metalloproteases (MMPs), enzymes with the ability to degrade the extracellular matrix, play an important role in tissue invasion by cutaneous malignant melanoma (CMM). One specific MMP, collagenase-3 (MMP-13), is thought to have a key function in the activation of MMP.AimsTo evaluate the expression of MMP-13 in CMM and assess its possible relationship to clinical and pathological parameters.MethodsMMP-13 expression was analyzed in 51 paraffin-embedded tumor samples from patients with invasive CMM, ten samples from in situ melanomas, and in eight samples from benign lesions (three dermal melanocytic nevi, three compound melanocytic nevi and two atypical melanocytic nevi) using immunohistochemical techniques. The median follow-up period in patients with invasive CMM was 50 months.ResultsBenign lesions were consistently negative for MMP-13, whereas three of the ten in situ melanomas (30%) and 23 of the 51 invasive CMMs (45%) showed positive immunostaining for MMP-13. The percentage of MMP-13-positive tumors correlated significantly and positively with the mitotic index (p=0.002) in invasive CMM. However, our results did not show any significant association between tumoral MMP-13 expression and relapse-free survival in patients with invasive CMM.ConclusionsMMP-13 appears to be a factor associated with tumor aggressiveness in CMM. It seems to eliminate an important barrier not only against tumoral invasion but also against proliferation.

Background . Hyaluronan a high-molecular weight glycosaminoglycan, is considered to be involved in the growth and progression of malignant tumours. The objective of this work was to evaluate the cytosolic hyaluronan content in gastric cancer cells, its possible relationship with clinicopathological tumour parameters and its potential prognostic significance. Methods . Cytosolic hyaluronan levels were examined utilizing immunoenzymatic techniques in 129 patients with gastric cancer. The mean follow-up period for these patients was 28 months. Results . Cytosolic hyaluronan levels ranged widely in tumours as well as in adjacent mucosal samples (median (range) 2822 (50–24,523) versus 3650 (507–20,782) ng/mg protein). Statistical analysis showed that tumour hyaluronan levels correlated significantly with patient's sex and the presence of lymphatic invasion. In addition, high tumour hyaluronan levels were significantly associated with shorter overall survival period ( p Conclusions . Our results suggest that high tumoral cytosolic hyaluronan levels are associated with lesions of unfavorable outcome in gastric cancer patients. Thus, hyaluronan may provide additional prognostic information to that given by other biochemical markers currently used in gastric cancer.