Expression of TLR3, 4, 7 and 9 in cutaneous malignant melanoma: relationship with clinicopathological characteristics and prognosis.

Toll-like receptors (TLRs) have achieved an extraordinary amount of interest in cancer research due to their role in tumor progression. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4, 7 and 9 in cutaneous malignant melanoma (CMM). The expression levels of TLR3, 4, 7 and 9 were analyzed in tumors from 30 patients with CMM. The analysis was performed by immunohistochemistry, and the results were correlated with various clinicopathological findings and with relapse-free survival. Our results indicate that there was a wide variability in the immunostaining score values for each receptor. Positive staining for TLRs was generally found in tumor cells, especially for TLR4 and TLR9. Nevertheless, a significant percentage of tumors also showed TLR4 expression in mononuclear inflammatory cells (62.1 %) and in fibroblast-like cells (34.5 %). Our results showed no significant association between score values for each TLR and clinicopathological characteristics of patients. However, our results demonstrated that high TLR4 expression was significantly associated with a shortened relapse-free survival (p = 0.001). Therefore, TLR4 expression may be a new prognostic factor of unfavorable evolution in cutaneous malignant melanoma.

Expression of metalloproteases and their inhibitors by tumor and stromal cells in ductal carcinoma in situ of the breast and their relationship with microinvasive events.

AIMS: This study aimed to investigate the expression of matrix metalloproteases (MMPs) and their inhibitors (TIMPs) in ductal carcinoma in situ (DCIS). METHODS: We used inmunohistochemistry to compare the expression of MMPs and TIMPs in tumor or stromal cells for 50 pure DCIS and 12 DCIS with microinvasive foci. RESULTS: Score values for collagenase-1 (MMP-1), membrane type 1 MMP (MMP-14), and TIMP-1, were significantly higher in pure DCIS than in DCIS with microinvasive foci, whereas stromalysin-3 (MMP-11) expression was significantly higher in DCIS with microinvasive foci. Both fibroblasts and mononuclear inflammatory cells (MICs) surrounding pure DCIS showed more frequently expression of MMP-1, MMP-14, and TIMP-3, whereas MMP-11 expression was more frequent in MICs of microinvasive tumors. MICs of microinvasive foci more frequently showed the expression of gelatinase A (MMP-2), MMP-11, collagenase-3 (MMP-13), and TIMP-1, than MICs surrounding pure DCIS; whereas peri-ductal MICs and fibroblasts from pure DCIS expressed TIMP-3 more commonly than these cells at microinvasive foci. CONCLUSIONS: There are significant differences in the expression of MMPs and TIMPs, so in tumor cells and stromal cells, between pure DCIS and DCIS with microinvasive foci. Therefore, these staining patterns might display potential applications as biological markers, such as in evaluating microinvasion in resection specimens of breast tumors.

Study of matrix metalloproteinases and their inhibitors in prostate cancer.

BACKGROUND: Extracellular matrix metalloproteases (MMPs) have raised an extraordinary interest in cancer research because of their potential role in basal membrane and extracellular matrix degradation, consequently facilitating tumour invasion and metastases development. METHODS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs 1, 2, 7, 9, 11, 13, 14, and their tissue inhibitors, TIMPs 1, 2 and 3. More than 2600 determinations on cancer specimens from 133 patients with clinically localised prostate carcinoma, 20 patients with prostatic intraepithelial neoplasia and 50 patients with benign prostate hyperplasia and controls, were performed. RESULTS: When compared with benign pathologies, prostate carcinomas had higher expression of all MMPs and TIMPs. Dendogram shows a first-order division of tumours into two distinct MMPs/TIMPs molecular profiles, one of them with high MMPs/TIMs expression profile (n=70; 52.6%). Tumours with high expression of MMP-11 or -13, or cluster thereof, were significantly associated with higher probability of biochemical recurrence. CONCLUSION: The expression of MMPs and TIMPs seems to have an important role in the molecular biology of prostate carcinomas, and their expression by tumours may be of clinical interest to used as indicators of tumour aggressiveness.

Expression of metalloproteases and their inhibitors in different histological types of breast cancer.

PURPOSE: Metalloproteases (MMPs) and their tissue inhibitors of metalloproteases (TIMPs) are involved in several key aspects of tumoral growth, invasion and metastasis. The purpose of this study was to characterize on how the different histological types of breast cancer differ in the expression of several components of this enzymatic system. METHODS: An immunohistochemical study was performed in 50 ductal, 23 lobular, 14 mucinous, 7 tubular, 4 papillary and 5 medullary invasive carcinomas, using tissue arrays and specific antibodies against 7 MMPs and 3 tisullar TIMPs. Staining results were categorized by means of a specific software program (score values). RESULTS: Carcinomas of the ductal type showed higher score values for MMPs and TIMPs than the other histological types; whereas mucinous carcinomas had lower scores values for expressions of the majority of these proteins. Stromal fibroblasts were more frequently positive for MMP-1, -7 and -13 and TIMP-1 and -3, when present in carcinomas of the ductal type than in other histological types of breast carcinomas. Stromal mononuclear inflammatory cells were more frequently positive for MMP-1 and TIMP-3, but more often negative for MMP-7, -9 and -11, when located in carcinomas of the ductal type than in other histological types of breast carcinomas. CONCLUSIONS: We found variations in MMP/TIMP expressions among the different histological subtypes of breast carcinomas suggesting differences in their tumor pathophysiology.

The Pit-1/Pou1f1 transcription factor regulates and correlates with prolactin expression in human breast cell lines and tumors.

The transcription factor Pit-1/Pou1f1 regulates GH and prolactin (PRL) secretion in the pituitary gland. Pit-1 expression and GH regulation by Pit-1 have also been demonstrated in mammary gland. However, no data are available on the role of Pit-1 on breast PRL. To evaluate this role, several human breast cancer cell lines were transfected with either the Pit-1 expression vector or a Pit-1 small interference RNA construct, followed by PRL mRNA and protein evaluation. In addition, transient transfection of MCF-7 cells by a reporter construct containing the proximal PRL promoter, and ChIP assays were performed. Our data indicate that Pit-1 regulates mammary PRL at transcriptional level by binding to the proximal PRL promoter. We also found that Pit-1 raises cyclin D1 expression before increasing PRL levels, suggesting a PRL-independent effect of Pit-1 on cell proliferation. By using immunohistochemistry, we found a significant correlation between Pit-1 and PRL expression in 94 human breast invasive ductal carcinomas. Considering the possible role of PRL in breast cancer disorders, the function of Pit-1 in breast should be the focus of further research.

Liver expression of matrix metalloproteases and their inhibitors in hepatocellular carcinoma.

BACKGROUND: Several studies have suggested the significance of some metalloproteases in the malignant behaviour of hepatocellular carcinoma. AIMS: To evaluate the liver expression of MMPs and their tissular inhibitors in patients with HCC. METHODS: An immunohistochemical study using tissue microarrays on samples obtained from 30 HCC patients, with antibodies against MMPs (1, 2, 7, 9, 11, 13 and 14) and TIMPs (1, 2 and 3) was performed. Results were correlated with various clinico-pathological findings and with overall survival. RESULTS: MMP-1 is mainly expressed by stromal cells, and MMP-13, TIMP-1 and TIMP-2 by inflammatory cells. A positive correlation between MMP-1 expression and larger size tumours (p<0.01) was found. Increased TIMP-2 expression was associated with higher preoperative serum levels of alpha-fetoprotein (p<0.01). Unsupervised hierarchical clustering for total score values designated two groups, one of them characterised by high MMPs and TIMPs expressions, including 21 cases (70%) for tumour cell clustering, 5 cases for fibroblasts (16.6%) and 6 cases for inflammatory cells (20%). All patients showing elevated MMPs and TIMPs expression in stromal cells presented a poor prognosis (p<0.05). CONCLUSIONS: High liver MMPs and TIMPs expressions in peritumour stromal cells are related to a poorer prognosis in HCC.

Comparative analysis and clinical value of the expression of metalloproteases and their inhibitors by intratumor stromal fibroblasts and those at the invasive front of breast carcinomas.

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. More than 5,000 determinations on cancer specimens from 124 patients with invasive breast cancer were performed at the center of the tumor and the invasive front. Immunostaining for MMPs/TIMPs by fibroblasts was evaluated. To identify specific groups of tumors with distinct expression profiles, the data obtained from both fibroblast populations were analyzed by unsupervised hierarchical cluster analysis. Intratumor stromal fibroblasts more frequently showed expression of MMP-2, -7, and -14, and TIMP-3, but less frequently of MMP-9 than fibroblasts at the invasive front. Multivariate analysis showed that a high profile of MMPs and TIMPs staining in both fibroblast populations was the most potent predictor factor of distant metastases, whereas a low staining profile in fibroblasts was associated with a low risk of metastases.

Study of matrix metalloproteinases and their tissue inhibitors in ductal in situ carcinomas of the breast.

AIMS: To analyse the expression of metalloproteinases (MMPs) and their inhibitors (TIMPs) in ductal carcinoma in situ of the breast (DCIS). METHODS AND RESULTS: An immunohistochemical study was performed in 56 patients with pure DCIS, in 39 with DCIS adjacent to invasive carcinoma (IDC) and 63 patients with T1 IDC, using tissue microarrays and specific antibodies against MMPs and TIMPs. Immunohistochemical results were categorized using a specific software program. The data were analysed by unsupervised hierarchical cluster analysis by each cellular type. IDC showed a higher expression rate of MMP-7 and TIMP-1 than pure DCIS, as well as a higher expression rate of MMP-9 and TIMP-3 than the DCIS component of mixed cases, whereas pure DCIS showed a higher rate of expression of MMP-9 and -11 and TIMP-3 than in the DCIS component of mixed cases. Pure DCIS with a periductal inflammatory infiltrate showed significantly higher MMP-2, -14 and TIMP-1. Dendograms identified two cluster groups with distinct MMP/TIMP expression profiles in neoplastic cells and fibroblastic or mononuclear inflammatory cells surrounding the neoplastic ducts of pure DCIS. CONCLUSIONS: The results indicate the distinct variability in MMP/TIMP expression by DCIS, which may be of potential biological and clinical interest in breast cancer.

Characterization of breast cancer subtypes by quantitative assessment of biological parameters: relationship with clinicopathological characteristics, biological features and prognosis.

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.

Overexpression of matrix metalloproteinases and their inhibitors in mononuclear inflammatory cells in breast cancer correlates with metastasis-relapse.

An immunohistochemical study was performed using tissue microarrays and specific antibodies against matrix metalloproteinase (MMP)-1, -2, -7, -9, -11, -13 and -14, tissular inhibitors of metalloproteinase (TIMP)-1, -2 and -3. More than 2600 determinations on cancer specimens from 131 patients with primary ductal invasive tumours of the breast were performed. To identify specific groups of tumours with distinct expression profiles the data were analysed by unsupervised hierarchical cluster analysis by each cellular type. We did not find well-defined cluster of cases for tumour cells or fibroblastic cells. However, for mononuclear inflammatory cells the dendogram shows a first-order division of the tumours into two distinct MMP/TIMP molecular profiles, designated group 1 (n=89) and group 2 (n=42). Matrix metalloproteinase-7, -9, -11, -13 and -14, and TIMP-1 and -2, were identified as showing significant high expression in group 2 compared with group 1. Multivariate analysis demonstrated that clustering for mononuclear inflammatory cells was the most potent independent factor associated with distant relapse-free survival (group 2: 5.6 (3.5-9.6), P<0.001). We identify a phenotype of mononuclear inflammatory cells infiltrating tumours, which is associated with the development of distant metastasis. Therefore, this finding suggests that these host inflammatory cells could be a possible target for inhibition of metastasis.

Expression of androgen receptor and two androgen-induced proteins (apolipoprotein D and pepsinogen C) in ductal carcinoma in situ of the breast.

AIMS: To evaluate the expression of androgen receptors (AR) and two androgen-induced proteins [apolipoprotein D (ApoD) and pepsinogen C (PepC)] in ductal carcinoma in situ (DCIS) of the breast. METHODS AND RESULTS: AR, ApoD and PepC expression was examined in 28 cases of pure DCIS and in 31 cases of DCIS adjacent to invasive carcinoma of the breast using immunohistochemical methods and then correlated with the architectural subtype, the degree of differentiation and the ostrogen receptor (ER)/progesterone receptor (PgR)/HER-2 status. We found no significant differences between pure DCIS and DCIS adjacent to invasive breast cancer regarding the percentage of positive cases for ApoD (64.3% versus 54.8%), PepC (42.9% versus 48.4%), ER (64.3% versus 58.1%), PgR (60.7% versus 58.1%) and HER-2 (39.3% versus 67.7%). However, there was a significantly higher percentage of AR+ DCIS among those adjacent to invasive carcinomas of the breast than among pure DCIS lesions (93.5% versus 60.9%) (P = 0.009). AR expression did not correlate with architectural subtype, degree of differentiation, or ER/PgR/HER-2/ApoD/PepC status, in cases of pure DCIS, nor in DCIS adjacent to invasive carcinoma of the breast. CONCLUSIONS: AR expression may represent an independent predictive factor in DCIS of the breast.

Liver expression of steroid hormones and Apolipoprotein D receptors in hepatocellular carcinoma.

AIM: To evaluate the tissular expression of Androgen (A), Estrogen (E) and Progesterone (Pg) receptors, and Apolipoprotein D (ApoD), in liver tumors from resected hepatocellular carcinoma (HCC) cases in order to assess their possible relationship to prognosis. METHODS: We performed an immunohistochemical study using tissue microarrays (containing more than 260 cancer specimens, from 31 HCC patients and controls) to determine the presence of specific antibodies against AR, ER, PgR and ApoD, correlating their findings with several clinico-pathological and biological variables. The staining results were categorized using a semi-quantitative score based on their intensity, and the percentage of immunostained cells was measured. RESULTS: A total of 21 liver tumors (67.7%) were positive for AR; 16 (51.6%) for ER; 26 (83.9%) for PgR and 12 (38.7%) stained for ApoD. We have found a wide variability in the immunostaining score values for each protein, with a median (range) of 11.5 (11.5-229.5) for AR; 11.1 (8.5-65) for ER; 14.2 (4-61) for PgR; and 37.7 (13.8-81.1) for ApoD. A history of heavy ethanol consumption, correlated positively with AR and PgR and negatively with ER status. HCV chronic infection also correlated positively with AR and PgR status. However, the presence of ApoD immunostaining did not correlate with any of these variables. Tumors with a positive immuno-staining for PgR showed a better prognosis. CONCLUSION: Our results indicate a moderate clinical value of the steroid receptor status in HCC, emphasizing the need to perform further studies in order to evaluate the possible role of new hormonal-based therapies.

Study of matrix metalloproteinases and their inhibitors in breast cancer.

An immunohistochemical study was performed using tissue microarrays and specific antibodies against matrix metalloproteinases (MMPs) 1, 2, 7, 9, 11, 13, 14, and their tisullar inhibitors (TIMPs) 1, 2, and 3. More than 2600 determinations on cancer specimens from 131 patients with primary ductal invasive tumours of the breast (65 with and 66 without distant metastasis) and controls were performed. Staining results were categorised using a score based on the intensity of the staining and a specific software program calculated the percentage of immunostained cells automatically. We observed a broad variation of the total immunostaining scores and the cell type expressing each protein. There were multiple and significant associations between the expression of the different MMPs and TIMPs evaluated and some parameters indicative of tumour aggressiveness, such as large tumour size, advanced tumour grade, high Nottinham prognostic index, negative oestrogen receptor status, peritumoural inflammation, desmoplastic reaction, and infiltrating tumoural edge. Likewise, the detection of elevated immunohistochemical scores for MMP-9, 11, TIMP-1, and TIMP-2, was significantly associated with a higher rate of distant metastases. The expression of MMP-9 or TIMP-2 by tumour cells, MMP-1, 7, 9, 11, 13, or TIMP-3 by fibroblastic cells, and MMP-7, 9, 11, 13, 14, TIMP-1, or TIMP-2 by mononuclear inflammatory cells, was also significantly associated with a higher rate of distant metastases.

Expression and clinical signification of cytosolic hyaluronan levels in invasive breast cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Cytosolic levels of TFF1/pS2 in breast cancer: Their relationship with clinical-pathological parameters and their prognostic significance.

BACKGROUND: 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. METHODS: Cytosolic TFF1 levels were examined by immunoradiometric assay in 1031 patients with invasive breast cancer. The median follow-up period was of 50 months. RESULTS: 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). CONCLUSIONS: 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.

Expression and prognostic value of EGFR in invasive breast cancer.

Epidermal growth factor receptor (EGFR) is a membrane receptor expressed in a variety of solid human cancers and directly related with poor prognosis. The objective of this work was to evaluate the EGFR content in breast carcinomas, its possible relationship with different clinical-pathological parameters, and its potential prognostic significance and predictive value. EGFR levels were examined by radioligand binding assays in 846 patients with invasive breast cancer. The median follow-up period was 50 months. There was a wide variability of EGFR levels among the studied tumors (0.01-403 fmol/mg protein). Statistical analysis showed that EGFR levels were significantly higher in younger patients (p=0.0001). EGFR were also notably higher in ER-negative or PgR-negative tumors than in ER-positive (p=0.0001) or PgR-positive tumors (p=0.001). In addition, the presence of high intratumoral EGFR levels (cut-off: 6 fmol/mg protein) was associated with both shorter relapse-free survival (p=0.04) and overall survival (p=0.01) in the group of patients as a whole, as well as with overall survival in the subgroup of patients without any type of systemic adjuvant treatment (p=0.02). However, EGFR levels did not achieve significance as independent prognostic factor in the multivariate analysis. There is a wide variability of intratumoral EGFR levels in breast carcinomas, and these protein levels correlated positively with a poor prognosis in the t univariate analysis. However, further studies are necessary in order to assess the possible clinical value of EGFR in combination with other essential components of the EGFR family network.

Collagenase-3 (MMP-13) expression in cutaneous malignant melanoma.

BACKGROUND: Matrix 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. AIMS: To evaluate the expression of MMP-13 in CMM and assess its possible relationship to clinical and pathological parameters. METHODS: MMP-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. RESULTS: Benign 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. CONCLUSIONS: MMP-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.

Expression and clinical significance of pepsinogen C in uveal melanomas.

PURPOSE: we investigated by immunohistochemistry the pepsinogen C (pepC) expression in uveal melanomas and analyzed the possible relationship to clinicopathological parameters and prognostic significance. METHODS: We studied 22 patients who had undergone enucleation of the eyeball or local tumor resection for uveal melanoma. The specimens were immunostained for pepC on formalin-fixed, paraffin-embedded sections. Sex, age, tumor location, histological type, local invasion, postoperative treatment and metastasis were evaluated. RESULTS: Eleven tumors (50%) were positive for pepsinogen C. The percentage of pepC-positive tumors was significantly higher in uveal melanomas with scleral invasion than in those without scleral invasion (p < 0.01). PepC expression was significantly associated with a shortened overall survival (p < 0.05). CONCLUSIONS: Our results show that pepsinogen C may be expressed by uveal melanoma and suggest that this protein could be considered as a new, unfavorable prognostic factor in these tumors.

Expression and clinical significance of pepsinogen C in uveal melanomas.

PURPOSE: we investigated by immunohistochemistry the pepsinogen C (pepC) expression in uveal melanomas and analyzed the possible relationship to clinicopathological parameters and prognostic significance. METHODS: We studied 22 patients who had undergone enucleation of the eyeball or local tumor resection for uveal melanoma. The specimens were immunostained for pepC on formalin-fixed, paraffin-embedded sections. Sex, age, tumor location, histological type, local invasion, postoperative treatment and metastasis were evaluated. RESULTS: Eleven tumors (50%) were positive for pepsinogen C. The percentage of pepC-positive tumors was significantly higher in uveal melanomas with scleral invasion than in those without scleral invasion (p<0.01). PepC expression was significantly associated with a shortened overall survival (p<0.05). CONCLUSIONS: Our results show that pepsinogen C may be expressed by uveal melanoma and suggest that this protein could be considered as a new, unfavorable prognostic factor in these tumors. (Int J Biol Markers 2004; 19: 240-4).

Membranous levels of c-erbB-2 oncoprotein in gastric cancer: their relationship with clinicopathological parameters and their prognostic significance.

BACKGROUND: The protein encoded by the c-erbB-2 gene is a membrane receptor expressed in a variety of solid human cancers and directly related to poor prognosis. The objective of this work was to evaluate the clinical value of the quantification of membranous oncoprotein levels in gastric cancer. MATERIALS AND METHODS: Membranous c-erbB-2 levels were examined by means of a sandwich immunoenzymatic assay in 82 patients with gastric cancer. The median follow-up period for these patients was 16 months. In addition, c-erbB-2 expression was analyzed by immunohistochemistry in 57 gastric carcinomas. RESULTS: Membranous c-erbB-2 levels ranged widely in the studied tumors (44-112,000 NHU/mg protein). Median c-erbB2 content was significantly higher in intestinal-type tumors than in diffuse-type tumors (p = 0.01). In addition, high levels of c-erbB-2 were significantly associated with shorter relapse-free survival and overall survival in patients with resectable gastric carcinomas (p = 0.01 and p = 0.04, respectively). However, the correlation between immunohistochemistry and ELISA determinations did not reach statistical significance. CONCLUSION: Our results suggest a potential prognostic value of membranous c-erbB-2 quantification by immunoenzymatic assay in gastric cancer. However, its possible role in the selection of patients with a view to the possible introduction of Herceptin as a novel drug against gastric cancer is at present uncertain.