Relationship between Metalloprotease-7 and -14 and Tissue Inhibitor of Metalloprotease 1 Expression by Mucosal Stromal Cells and Colorectal Cancer Development in Inflammatory Bowel Disease.

Colorectal carcinoma (CRC) associated with inflammatory bowel disease (IBD) is an example of an inflammation-related cancer. Matrix metalloproteases (MMP) are known to be associated with both processes. The aim of the study was to compare the expression of MMP-7, MMP-14 and tissue inhibitor of metalloproteases-1 (TIMP-1) in sporadic CRC- and IBD-associated CRC, and to compare the expression in inflamed and non-inflamed colonic tissue samples from IBD patients without or with associated CRC. An immunohistochemical study of MMP-7, -14 and TIMP-1 was performed on sporadic CRC (n = 86), IBD-associated CRC (n = 23) and colorectal mucosa of non-tumor samples from IBD patients without (n = 47) and with (n = 23) associated CRC. These factors were more frequently expressed by cancer-associated fibroblasts (CAF) from IBD-associated CRC than by CAF from CRC not associated with IBD. Regarding the inflamed tissue of IBD patients, Crohn's disease (CD) patients with CRC development showed a higher expression of MMP-14 by fibroblasts and by mononuclear inflammatory cells (MICs) than CD patients without CRC development. In non-inflamed tissue samples, MMP-7 associated with fibroblasts and MICs, and TIMP-1 associated with MICs, were more frequently expressed in CD patients with CRC development than in CD patients without CRC development. Our data suggest that these factor expressions by stromal cells may be biological markers of CRC development risk in IBD patients.

Joint Tumor Bud-MMP/TIMP Count at the Invasive Front Improves the Prognostic Evaluation of Invasive Breast Carcinoma.

BACKGROUND: Tumor budding is a histological phenomenon consisting of the formation of small clusters of one to five undifferentiated malignant cells detached from the main tumor mass which are observed in the tumor stroma. In the present study, we investigated the prognostic significance of tumor budding in breast cancer and its relationship with the expressions of matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs). METHODS: The number of buds was counted in whole-tissue sections from 153 patients with invasive ductal carcinomas who underwent a long follow-up period. In addition, an immunohistochemical study of MMP-9, -11, and -14 TIMP-1 and -2 expression by cell types at the invasive tumor front was carried out. RESULTS: There was a wide variability in the number of buds among tumors, ranging from 0 to 28 (median = 5). Tumor budding count ≥ 4 was the optimal cut-off to predict both relapse-free and overall survival. High-grade tumor budding was associated with MMP/TIMP expression by cancer-associated fibroblasts. In addition, we found that the combination of tumor budding grade with MMP/TIMP expression by stromal cells, and especially with MMP-11 expression by mononuclear inflammatory cells, significantly improved the prognostic evaluation. CONCLUSION: High-grade tumor budding is associated with a more aggressive tumor phenotype, which, combined with MMP/TIMP expression by stromal cells at the invasive front of the tumor, identifies patients with poor prognosis.

MMP11 expression in intratumoral inflammatory cells in breast cancer.

AIMS: It is known that matrix metalloproteinase (MMP)-11 has a role in tumour development and progression, and also that immune cells can influence cancer cells to increase their proliferative and invasive properties. The aim of the present study was to propose the evaluation of MMP11 expression by intratumoral mononuclear inflammatory cells (MICs) as a useful biological marker for breast cancer prognosis. METHODS AND RESULTS: This study comprised 246 women with invasive breast carcinoma, and a long follow-up period. Patients were stratified with regard to nodal status and to the development of metastatic disease. The median follow-up period in patients without metastasis was 146 months and in patients with metastatic disease 31 months. MMP11 was determined by immunohistochemistry. For relapse-free survival (RFS) and overall survival (OS) analysis we used the Cox's univariate method. Cox's regression model was used to examine the interactions between different prognostic factors in a multivariate analysis. CONCLUSIONS: Our results showed that MMP11 expression by stromal cells was significantly associated with prognosis. MMP11 expression by cancer-associated fibroblasts (CAFs) was associated with both shortened RFS and OS, but MMP11 expression by MICs showed a stronger association with both shortened RFS and OS, therefore being the most potent and independent factor to predict RFS and OS.

Toll-Like Receptor 4 and Matrix Metalloproteases 11 and 13 as Predictors of Tumor Recurrence and Survival in Stage II Colorectal Cancer.

Current clinical-pathologic stratification factors do not allow clear identification of high-risk stage II colorectal cancer (CRC) patients. Therefore, the identification of additional prognostic markers is desirable. Toll-like receptor (TLR)-4 is activated during tumorigenesis and matrix metalloproteases (MMPs) are involved in invasion and metastasis. We aimed to evaluate the expression and clinical relevance of TLR4, MMP11 and MMP13 for patients with stage II CRC. Immunohistochemistry was used to study the expression of TLR4, MMP11 and MMP13 in 96 patients with stage II CRC. We measured the global expression and the expression by different cell types (tumor cells, cancer-associated fibroblasts (CAFs) and mononuclear inflammatory cells (MICs)). The potential relationship between expressions of factors and different prognostic variables were evaluated. Our results show significant relationships between either TLR4 expression by tumor cells and MMP11 expression by CAFs and high risk of tumor recurrence. In addition, the concurrence of age ≥ 75 years and the non-expression of MMP11 by CAFs identify a subgroup of patients with a good prognosis. Our results show that TLR4 expression by tumor cells and MMP11 expression by CAFs may to improve the identification of patients with stage II CRC with a high-risk of relapse.

Prognostic Influence of Tumor Stroma on Breast Cancer Subtypes.

INTRODUCTION: The objective of the present work was to evaluate the impact of the phenotype of both intratumoral mononuclear inflammatory cells (MICs) and cancer-associated fibroblast (CAFs), assessed as to their expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) on prognosis in different breast cancer subtypes. MATERIALS AND METHODS: A total of 247 tumors of patients with primary ductal invasive breast cancer were categorized into 1 of 4 major subtypes, using the 3 standard immunohistochemical markers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor/Neu 2 [HER2] receptor status). An immunohistochemical study was performed using tissue arrays and specific antibodies against MMP-9, MMP-11, and MMP-14, and TIMP-1 and TIMP-2. RESULTS: MMP-11 expression by MICs was significantly and strongly associated with prognosis in all breast cancer subtypes. There were other significant associations with poor prognosis in luminal A tumors: expressions of MMP-9, MMP-11, and TIMP-2 by CAFs, in luminal B tumors: MMP-14 expression by MICs and TIMP-2 expression by MICs, in HER-2-positive tumors: expression of MMP-9 by MICs, and in triple negative breast cancers: expression of TIMP-1 by MICs. CONCLUSION: Characterization of both tumor stromal CAFs and MICs, with regard to the expression of MMPs and TIMPs, improve the prognostic evaluation of all breast cancer subtypes.

Matrix metalloproteases expression in different histological types of colorectal polyps

Introduction: Colorectal carcinoma (CC) may begin as benign polyps, which may be classified in different histological types with a different risk to develop cancer. Matrix metalloproteases (MMPs) are able to degrade all components in the extracellular matrix and are important tissue-remodeling enzymes and key elements in tumor invasion and metastasis. The aim of this study was to investigate the expression and clinical relevance of MMPs in different histological types of colorectal polyps. Methods: The expression levels of MMP-1, 2, 7, 9, 11, 13 and 14 were analyzed by real-time PCR, Western-blot and immunohistochemistry in 50 patients with different histological types of colorectal polyps, 28 of which developed CC. Results: The results indicate that hyperplastic polyps had the lowest levels of MMP-1 and MMP-7, tubular polyps showed higher levels of both MMP-7 and MMP-14, and tubulovillous adenoma showed higher levels of MMP-1, MMP-7 and MMP-14. Conclusion: MMP expression was decreased in hyperplastic, tubular and tubulovillous adenoma polyps from patients who developed CC. Our findings suggest that MMP expression may be a pathological marker of colorectal polyps and for cancer susceptibility, which may improve strategies for CC prevention based on screening colonoscopy (AU)

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Matrix metalloproteases expression in different histological types of colorectal polyps.

INTRODUCTION: Colorectal carcinoma (CC) may begin as benign polyps, which may be classified in different histological types with a different risk to develop cancer. Matrix metalloproteases (MMPs) are able to degrade all components in the extracellular matrix and are important tissue-remodeling enzymes and key elements in tumor invasion and metastasis. The aim of this study was to investigate the expression and clinical relevance of MMPs in different histological types of colorectal polyps. METHODS: The expression levels of MMP-1, 2, 7, 9, 11, 13 and 14 were analyzed by real-time PCR, Western-blot and immunohistochemistry in 50 patients with different histological types of colorectal polyps, 28 of which developed CC. RESULTS: The results indicate that hyperplastic polyps had the lowest levels of MMP-1 and MMP-7, tubular polyps showed higher levels of both MMP-7 and MMP-14, and tubulovillous adenoma showed higher levels of MMP-1, MMP-7 and MMP-14. CONCLUSION: MMP expression was decreased in hyperplastic, tubular and tubulovillous adenoma polyps from patients who developed CC. Our findings suggest that MMP expression may be a pathological marker of colorectal polyps and for cancer susceptibility, which may improve strategies for CC prevention based on screening colonoscopy.

Toll-like receptor-4 expression by stromal fibroblasts is associated with poor prognosis in colorectal cancer.

Because of the important role in inflammation and tissue regeneration, toll-like receptors (TLR) are likely candidates to mediate effects of the innate immune system on tumorigenesis. The aim of this study was to investigate the expression and clinical relevance of TLR in colorectal cancer (CRC). The expressions of TLR3, TLR4, TLR7, and TLR9 were analyzed in 104 patients with resectable CRC by immunohistochemistry. The evaluation of the expression consisted on measuring the overall level of TLR expression and by each cell type. The results showed a direct association between the histologic grade of tumor and TLR9 expression by tumor cells. TLR4 expression by tumor cells was significantly associated with a lower rate of tumor recurrence, whereas the expression by fibroblasts was significant and independently associated with a high rate of tumor recurrence and with a shortened overall survival in patients; particularly in tumors from left colon and rectum. Therefore, TLR4 expression by fibroblasts could be a useful prognostic marker in CRC.

Low microvascular density at the tumor center is related to the expression of metalloproteases and their inhibitors and with the occurrence of distant metastasis in breast carcinomas.

BACKGROUND: The aims of this study were to evaluate the microvascular density (MVD) at the center of breast carcinomas, its relationship with the expression of metalloproteases (MMPs) and their inhibitors (TIMPs), and its connection with the distant metastasis rate. METHODS: An immunohistochemical study of four MMPs and two TIMPs was performed on cancer specimens from 97 women with a histological confirmed diagnosis of early invasive breast cancer. RESULTS: Expressions of MMP-9 by cancerous cells, or MMP-11 and TIMP-2 by stromal cells, were all negative and significantly associated with MVD, whereas MMP-7 score values were positive and also significantly associated with MVD. However, positive expression of MMP-1 by mononuclear inflammatory cells was significantly associated with MVD. Multivariate analysis demonstrated a significant and inverse relationship between MVD and the occurrence of distant metastasis. CONCLUSIONS: Our data point out the clinical importance of low MVD at the tumor center as an independent prognostic factor of distant metastasis development in breast cancer.

Duodenal expression of Toll-like receptors and interleukins are increased in both children and adult celiac patients.

BACKGROUND: Toll-like receptors (TLRs) have achieved an extraordinary amount of interest in inflammatory diseases due to their role in the inflammatory activation. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive the inflammatory response and activate the adaptive immune system. AIMS: The aim of this study was to investigate and compare the expression and clinical relevance of TLRs and interleukins in pediatric and adult celiac disease (CD), defined as intolerance to dietary proteins found in wheat, barley, and rye. METHODS: The expression levels of TLR3, TLR4, and TLR7, interleukins, and different transcription factors were analyzed on duodenal biopsies from ten children and 31 adults with CD, and 21 duodenal controls biopsies without CD (ten children and 11 adults). The analyses were performed by immunohistochemistry and real-time PCR. RESULTS: There were no significant differences in the studied parameters between adults and children. TLR4 expression level was increased twofold in CD specimens compared to controls. CD patients with high levels of TLR4 also showed high levels of interleukins (IL1, IL6, IL8, and IL17) as well as transcription factors (IRAK4, MyD88, and NF-κB). CONCLUSIONS: TLR4 expression is associated with CD independently of age at diagnosis. Pediatric patients and adult patients have a similar inflammatory profile, making it possible to treat both with the same immunological therapy in the future.

Effect of the expression of matrix metalloproteases and their tissue inhibitors on survival of patients with resectable colorectal cancer.

BACKGROUND: Matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) are of crucial importance in the degradation of the stromal connective tissue and basement membrane components. Study of the behavior of these components might help to predict the aggressiveness of tumors. AIMS: To evaluate the expression and clinical relevance of MMPs and TIMPs for patients with resectable colorectal carcinoma. METHODS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs-1, 2, 7, 9, 11, 13, and 14, and TIMPs-1, 2 and 3. Determinations were performed in cancer specimens from 104 patients with resectable colorectal cancer. The minimum period of follow-up was 12.5 years for patients without recurrence. To identify specific groups of tumors with distinct expression profiles, the data were analyzed by unsupervised hierarchical cluster analysis. RESULTS: Expression of MMP-11 by fibroblasts and MMP-13 by tumor cells were associated with poor prognosis. The dendrogram revealed first-order division of tumors into two distinct MMP/TIMP molecular profiles, designated group 1 (n = 50) and group 2 (n = 54). Group 2 was characterized by significantly higher expression of MMP-1, 11, and 13, and TIMP-3. CONCLUSION: Our results emphasize the prognostic value of MMP-11 and 13 expression in colorectal cancer.

Clinical significance of myosin in colorectal cancer.

Myosin has raised an interest in cancer research because of its role in tumor progression. The aim of this study was to investigate the expression and clinical relevance of myosin in colorectal cancer (CC). Myosin was detected in CC tumors with recurrence using matrix-assisted laser desorption/ionization time-of-flight analysis. An immunohistochemical study was performed using tissue arrays and specific antibodies against myosin heavy chain. Determinations on cancer specimens from 91 patients with resectable CCs were performed. The minimum follow-up period was of 12.5 years for these patients without tumor recurrence. Western blot and real-time polymerase chain reaction analysis were also performed. Samples of carcinomas with recurrence showed an increased expression of myosin. Tumors with high myosin expression by tumor cell were significantly associated with higher probability of metastasis. Our results suggest that myosin expression in CCs is associated with tumor progression and metastasis development. Therefore, myosin tumor expression may contribute to an improved prognostic evaluation in patients with CC.

Study of the expression of toll-like receptors in different histological types of colorectal polyps and their relationship with colorectal cancer.

PURPOSE: Dysregulation of toll-like receptors (TLR) signaling can result in chronic inflammatory and over-exuberant repair responses. The aim of this study was to investigate the expression and clinical relevance of TLR in colorectal polyps. METHODS: The expression levels of six TLR were analyzed in 70 patients with different histological types of colorectal polyps, 38 of which developed colorectal carcinoma (CC). These analyses were performed by real-time polymerase chain reaction, western blot, and immunohistochemistry. RESULTS: TLR9 expression was higher in hyperplastic or adenomatous polyps compared to other polyp types. Hyperplastic polyps also showed increased TLR7 levels compared to the other polyp types. TLR7 expression was lower in both hyperplastic and tubulovillous adenoma polyps from patients who developed CC. TLR9 expression was decreased in hyperplastic and villous polyps from patients who developed CC. CONCLUSIONS: Our findings suggest a possible protective role of TLR expression against malignant transformation in the colorectal mucosa. TLR may represent a pathological marker of CC risk in colorectal polyps. The role of these factors in the pathology of colorectal polyps deserves further investigation.

Comparative analysis of the expression of metalloproteases and their inhibitors in resected crohn's disease and complicated diverticular disease.

BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), are expressed in the gastrointestinal tract by different cellular types. Nevertheless, the imbalance between MMPs and TIMPs plays an important role in the physiopathology of diverse intestinal inflammatory processes. METHODS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. Immunohistochemical staining of intestinal samples from surgical interventions from 30 patients with complicated Crohn's disease (CD) and 25 patients with diverticulitis were performed at the inflamed mucosa and in adjacent noninflamed mucosa. A reverse-transcription polymerase chain reaction (RT-PCR) analysis was performed to confirm the results obtained by immunohistochemistry. In addition, western blot experiments were carried out. RESULTS: CD inflamed mucosa showed higher global expression of MMP-2, MMP-9, and MMP-13 than diverticulitis inflamed mucosa. However, inflamed and noninflamed diverticulitis mucosal samples showed higher global expression of MMP-1, TIMP-1, and 3 than the CD samples. Epithelial cells of inflamed mucosa showed higher expression of MMP-2, 9, and 13 in CD than diverticulitis. However, the latter showed higher expression of TIMP-1. Similar differences for fibroblast-like cells and mononuclear inflammatory cells were found. CD samples presented an increased expression of MMPs and a decreased expression of TIMPs compared to diverticulitis. CONCLUSIONS: These results indicate a differential pattern of expression of MMPs and TIMPs in CD and diverticulitis and the necessity to study the potential role of MMP inhibitors as new protective agents in both diseases.

Comparative analysis and clinical value of the expression of metalloproteases and their inhibitors by intratumour stromal mononuclear inflammatory cells and those at the invasive front of breast carcinomas.

AIMS: Matrix metalloproteases (MMPs) and their inhibitors (TIMPs) play an essential role in the degradation of stromal connective tissue and basement membrane components. The aim of this study was to determine whether the dynamic analysis of these components can help to predict tumour aggressiveness. METHODS AND RESULTS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs -1, -2, -7, -9, -11, -13 and -14 and TIMPs -1, -2 and -3. More than 5000 determinations on cancer specimens from 124 patients with invasive breast cancer were performed on the tumour centre core as well as on the invasive front. Immunostaining for MMPs/TIMPs on mononuclear inflammatory cells (MICs) was evaluated. To identify specific groups of tumours with distinct expression profiles, data obtained from both MICs populations were analysed by unsupervised hierarchical cluster analysis. When compared with MICs at the invasive front, intratumour MICs more frequently showed expression of MMP-7 and -1 and TIMP-3, but less frequently expression of MMP-9 and -11 and TIMP-2. CONCLUSIONS: Our data led us to consider the need of further studies in order to identify subsets of MICs and other protein elements of the microenvironment as attractive targets for new therapeutic strategies against cancer.

Immunohistochemical study of matrix metalloproteinases and their inhibitors in pure and mixed invasive and in situ ductal carcinomas of the breast.

We assessed differences in the patterns of expression of matrix metalloproteases and their inhibitors (tissue inhibitors of metalloproteases) in ductal carcinoma in situ alone and admixed with invasive ductal carcinomas (n = 40), as well as in pure invasive ductal carcinomas (n = 40), immunohistochemically and using tissue arrays. The invasive ductal carcinoma components showed higher expression of matrix metalloprotease-9 and -13 than did the admixed ductal carcinoma in situ, whereas stromal fibroblasts of the invasive components showed higher expression of matrix metalloprotease-2, -7, -9, -13, and -14 and tissue inhibitor of metalloprotease-1 and -3 than did fibroblasts around the neoplastic ducts of the admixed ductal carcinoma in situ. Expression of matrix metalloprotease-14 and tissue inhibitor of metalloprotease-3 was significantly higher in the mononuclear inflammatory cells of the invasive components. By contrast, matrix metalloprotease-1 expression was significantly higher in stromal cells of the ductal carcinoma in situ admixed with invasive ductal carcinoma. The pure invasive ductal carcinomas had significantly higher expression of matrix metalloprotease-1, -9, -11, and -14 and tissue inhibitor of metalloprotease-1 and -3 than the invasive ductal carcinomas admixed with ductal carcinoma in situ. Our findings indicate a significant association of matrix metalloprotease expression by the periductal stromal cells of the ductal carcinoma in situ component of mixed tumors and the occurrence of distant metastasis. Our data suggest that the molecular matrix metalloprotease/tissue inhibitor of metalloprotease profile can contribute to better characterization of early breast carcinomas.

Relationship between morphological features and kinetic patterns of enhancement of the dynamic breast magnetic resonance imaging and clinico-pathological and biological factors in invasive breast cancer.

BACKGROUND: To investigate the relationship between the magnetic resonance imaging (MRI) features of breast cancer and its clinicopathological and biological factors. METHODS: Dynamic MRI parameters of 68 invasive breast carcinomas were investigated. We also analyzed microvessel density (MVD), estrogen and progesterone receptor status, and expression of p53, HER2, ki67, VEGFR-1 and 2. RESULTS: Homogeneous enhancement was significantly associated with smaller tumor size (T1: < 2 cm) (p = 0.015). Tumors with irregular or spiculated margins had a significantly higher MVD than tumors with smooth margins (p = 0.038). Tumors showing a maximum enhancement peak at two minutes, or longer, after injecting the contrast, had a significantly higher MVD count than those which reached this point sooner (p = 0.012). The percentage of tumors with vascular invasion or high mitotic index was significantly higher among those showing a low percentage (150%) of enhancement rate (p = 0.016 and p = 0.03, respectively). However, there was a significant and positive association between the mitotic index and the peak of maximum intensity (p = 0.036). Peritumor inflammation was significantly associated with washout curve type III (p = 0.042). CONCLUSIONS: Variations in the early phase of dynamic MRI seem to be associated with parameters indicatives of tumor aggressiveness in breast cancer.

Expression and prognostic significance of metalloproteases and their inhibitors in luminal A and basal-like phenotypes of breast carcinoma.

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.

Prognostic value of pre-operative serum CA 15.3 levels in breast cancer.

BACKGROUND: CA15.3 (also known as MUCI) is the most widely used marker in breast cancer. The aim of the present work was the evaluation of the prognostic value of preoperative serum CA15.3 levels in patients with primary breast cancer. PATIENTS AND METHODS: This study included 818 women with a histologically verified diagnosis of invasive breast cancer. The serum values of CA15.3 were investigated at the time of primary diagnosis by means of an immunoradiometric assay based on the "sandwich" principle. The median follow-up period of patients free of recurrence was 38 months. RESULTS: Pre-operative CA15.3 serum levels ranged from 6 to 452 U/ml. Elevated CA15.3 levels (>30 U/ml) were found in 15.2% of patients. Statistical analysis showed that pre-operative CA15.3 serum levels were significantly higher in patients with large size tumors (T3 or T4) (p = 0.0001), as well as in those with node-positive tumors (p = 0.0001). In the univariate analysis, high CA15.3 levels were significantly associated with a lower probability of both relapse-free and overall survival in the overall group of patients (p = 0.0001 and p = 0.004, respectively) and in the subgroup with node-positive breast cancer (p = 0.001 and p = 0.03, respectively). In addition, multivariate analysis demonstrated that pre-operative levels of the antigen were significantly and independently associated with relapse-free survival in the overall group of patients, as well as in the subgroup of patients with node-positive breast cancer (p = 0.02 and p = 0.01, respectively). CONCLUSION: These results show that high pre-operative CA15.3 levels correlate with large size tumors and the presence of lymph node metastases and suggest that this antigen could be used as an additional prognostic marker.

Collagenase-3 (MMP-13) expression by inflamed mucosa in inflammatory bowel disease.

OBJECTIVE: To determine whether the expression of collagenase-3 (MMP-13) in biopsies from patients with inflammatory bowel disease is correlated with histological inflammation parameters. MATERIAL AND METHODS: 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. RESULTS: 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, p < 0.0001) or UC (r = 0.62, p < 0.0001). 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. CONCLUSIONS: 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.