PARP-1 expression as a prognostic factor in Desmoid-type fibromatosis

Desmoid-type fibromatoses (or desmoid tumors) are entities of intermediate biological potential and are locally invasive. Radical surgery, as state of the art therapy, is frequently limited by incomplete resections. Hormone modifying therapies are promising but further research is required. Poly Adenosine Diphosphate Ribose Polymerase-1 (PARP-1), a DNA repairing enzyme, might be a pathogenetic factor and could become a potential target for therapy as shown by the successful treatment of selected carcinomas and sarcomas by PARP-inhibition. In this study, we investigated the expression of estrogen receptors (ER) α (1) and β (2), progesterone receptor (PR), androgen receptor (AR), as well as PARP-1 via immunohistochemistry and quantitative RT-PCR in 69 tissue samples of desmoid tumors. Immunohistochemistry was quantified using the Immunoreactivity Score (IRS). Overall expression patterns were correlated with clinical-pathologic parameters to determine their value as a prognostic factor. Among the investigated hormone receptors only ERβ showed partial cytoplasmic reactivity. PARP-1 revealed variable nuclear positivity with IRS ranging from 0 to 6. Univariate survival analysis showed that higher expression of estrogen receptor 1 was associated with shorter disease-free survival (p = 0.005). Uni- (p = 0.03) and multivariate (p = 0.003) analyses of mRNA data revealed that higher PARP-1 expression correlated with earlier recurrence. According to this study PARP-1 expression is associated with poorer prognosis, that is faster recurrence, highlighting the possibility of PARP-1-targeting agents as a therapeutic option. Hormone receptors were of minor prognostic relevance in this study.     

The role of sex as a prognostic factor in lung cancer

The aim of this study was to demonstrate the prognostic role of the gender. Lung cancer was diagnosed in 785 female and 4619 male registered in Pulmonary Outpatients Departments in 1995. Women were younger than man when all histologic types of lung cancer were analysed (59.7 vs 61.9 years of age p. < 0.001), particularly those with adenocarcinoma(56.9 vs 60.2 years of age, p. < 0.012) and small cell lung cancer (57.4 vs 59.6 years of age, p. < 0.001). Although squamous lung cancer was the most prevalent among men (43.7%) and women (24.7%), about two times higher percentage of men had this neoplasm. Adenocarcinoma (18% vs 6.6%, p. < 0.001) and small cell lung cancer (28.5% vs 15.5% p. < 0.001) were prevalent in significantly higher percentage among female than male. Women were treated more aggressively by surgery (17.1% vs 14.1%, p. = 0.04) but similar percentage of men and women received radiotherapy, chemotherapy and multimodality treatment. Women more frequently survived one year (43% vs 35.7%, p. < 0.04). Significant and independent negative prognostic factors were: gender (RR-1.17 for men), age older than 50 age (RR-1.2), bed performance status (RR-3.28), disseminated disease (RR-2.78) small cell histological type of cancer (RR-1.21) and nonsurgical therapy (RR-3.29).     

BRCA1 expression in canine mammary dysplasias and tumours: relationship with prognostic variables

BRCA1 is a nuclear phosphoprotein that participates in the regulation of the cell cycle. The role of the BRCA1 gene in canine mammary tissue and mammary tumours has not been studied. The present study examined immunohistochemically the expression and intracellular distribution of BRCA1 protein in two normal, seven dysplastic and 44 neoplastic canine mammary glands and its relationship with clinical and pathological variables and other prognostic parameters. Strong nuclear immunolabelling of BRCA1 protein was observed in the epithelial cells of the normal mammary glands and mammary dysplasias. The majority of benign tumours, and more especially of malignant tumours, showed a significant reduction in the nuclear expression of BRCA1 protein and an increase in cytoplasmic expression. Loss of BRCA1 expression was associated with high proliferation marker Ki-67 and ER-alpha negative tumours. The reduction and aberrant distribution of BRCA1 in canine mammary tumours were significantly associated with malignant characteristics. The results may indicate that BRCA1 has a role in the malignant behaviour of these tumours.     

P-cadherin expression in canine mammary tissues

P-cadherin is a classical cadherin expressed by myoepithelial cells in mammary tissue. Its expression in human breast cancer has been associated with aggressive tumour behaviour. To analyse the possible role of P-cadherin in canine mammary carcinogenesis, its expression was examined immunohistochemically in 82 samples of normal (n=2), hyperplastic (n=11) and neoplastic (n=69) canine mammary tissues. In normal and hyperplastic canine mammary glands, P-cadherin was restricted to myoepithelial cells, usually at sites of cell-to-cell contact. In tumour tissues, however, P-cadherin expression was observed in both epithelial and myoepithelial cells, with a cytoplasmic pattern of cellular distribution. Aberrant epithelial P-cadherin immunolabelling was found in 19/44 (43%) benign tumours and in 16/25 (64%) malignant tumours (P<0.001). In malignant tumours, a significant correlation between P-cadherin expression intensity and histological type was observed (P<0.05).     

CD147 expression as a significant prognostic factor in differentiated thyroid carcinoma

CD147 is 1 of the molecules involved in regulating the expression of matrix metalloproteinases (MMPs). The goal of this study was to analyze the expression of CD147 in differentiated thyroid carcinoma (DTC) tissues as well as its association with the clinicopathologic features of DTC patients and its prognostic significance. During our research, CD147 expression in 156 patients who underwent operation for DTC [100 with papillary thyroid carcinoma (PTC) and 56 with follicular thyroid carcinoma (FTC)] were examined by immunostaining on paraffin-embedded tumor specimens. Then, the association of CD147 expression with clinicopathologic characteristics and patients' prognosis was analyzed. As a result, CD147 was expressed in cancerous lesions but not in normal tissues. Overall, 55 of 156 (35.26%) cases showed low CD147-positive expression, 52 of 156 (33.33%) showed intermediate CD147-positive expression, and 49 of 156 (31.41%) showed high CD147-positive expression. Positive CD147 staining was associated significantly with various clinicopathologic features, such as extrathyroidal invasion (P = 0.02), lymph node metastasis (P = 0.01), and depth of tumor invasion (P < 0.01). Patients with low CD147 expression showed better survival rates than those with intermediate and high expression (90.91% for low expression, 82.69% for intermediate expression, and 65.31% in high expression, respectively; P < 0.05 for analyses). Using Cox regression analysis of the 156 patients, high expression of CD147, extrathyroidal invasion, lymph node metastasis, and the pathologic grading of tumor invasion seemed to be independent prognostic indicators (P < 0.01, P = 0.02, P < 0.01, and P < 0.01, respectively). Therefore, we conclude that the expression of CD147 may be useful to predict the prognosis of DTC patients.     

Vimentin immunohistochemical expression as a prognostic factor in gastric cancer: A meta-analysis

Objective

The prognostic value of vimentin expression in Gastric Cancer (GC) has been assessed for years while the results are still in dispute. Thus, we performed a meta-analysis to determine the effect of vimentin immunohistochemical (IHC) expression on the prognosis of GC.

Significance of p53 expression as a prognostic factor in oesophageal squamous cell carcinoma

The tumour suppressor gene product p53 is believed to play an important role in the progression of human malignant tumours through mutation and over-expression. Using a microwave oven heating method, we have detected over-expression of p53 in buffered-formalin fixed, paraffin-embedded sections of oesophageal carcinomas immunohistochemically and examined the relationship between the p53 over-expression and postoperative survival. Employing a monoclonal antibody (pAb1801), nuclear p53 was detected in 56 of 105 (53%) tumour specimens. Homogeneous, heterogeneous, and focal immunostaining patterns were noted. No immunostaining was found in adjacent benign tissues. The results in buffered-formalin fixed sections were similar to those in the frozen sections. The cumulative survival rate of patients with p53 expression was significantly lower than that of the patients without expression (P<0.05), even though there were no significant differences between the clinicopathological features of the two groups. The results indicate that the nuclear accumulation of p53 might be an independent prognostic factor in patients with oesophageal squamous cell carcinomas.     

Immunohistochemical expression of galectin-3 in canine mammary tumours

Galectin-3, an endogenous beta-galactoside-binding protein, plays a significant role in cell growth, cell activation, and cell to extracellular matrix interactions. To define the role of galectin-3 in canine mammary tumours, its expression was determined in mammary samples by immunohistochemical methods. In adjacent normal mammary glands, distant from the neoplasm, mammary epithelial cells showed little or no expression of galectin-3. In the majority of adenomas, the neoplastic cells showed moderate to strong galectin-3 immunoreactivity, but in the majority of adenocarcinomas such immunoreactivity was weak. These results suggest that the progression of canine mammary tumours is associated with low galectin-3 expression.     

Hyaluronan expression as a significant prognostic factor in patients with malignant peripheral nerve sheath tumors

Hyaluronan (HA) regulates malignant tumor growth, invasion, and metastasis. However, few studies have focused on the roles of HA in tumorigenicity in malignant peripheral nerve sheath tumors (MPNST). In this study, we sought to clarify the prognostic value of HA in patients with MPNST. Specimens obtained from 15 patients with neurofibroma and 30 with MPNST were subjected to HA staining and scored as three grades. Protein expressions of HA synthase 1–3 were examined in the 22 MPNST tissue samples available. Statistically higher HA positivity was observed in MPNST as compared with neurofibroma (P = 0.020). The univariate analysis revealed that increased HA expression, age, neurofibromatosis type 1 (NF1) status, large tumor size, and histological grade were significantly associated with reduced overall survival of patients with MPNST; while increased HA expression, NF1 status, tumor size, and histological grade were correlated with disease-free survival. However, HA synthase 1–3 expression related to neither overall survival nor disease-free survival of these patients. In multivariate analysis, large tumor size (P = 0.022) was an independent prognostic factor for overall survival, and HA expression (P = 0.028) and tumor size (P = 0.002) were independent prognostic factors for disease-free survival. Statistically higher levels of HA in the human MPNST cells were observed compared with neurofibroma cells in vitro. Our results demonstrate that HA expression can be a useful marker in differentiating MPNST from neurofibroma, and in identifying patients with a poor prognosis. Hyaluronan-targeting therapy for patients with MPNST may have potential as a therapeutic tool.     

Desmoglein 3 as a prognostic factor in lung cancer

Desmoglein 3 is a desmosomal protein of the cadherin family. Our cDNA expression profile demonstrated that desmoglein 3 was highly expressed in squamous cell carcinoma of the lung but not detected in pulmonary adenocarcinoma or normal lung. To investigate the clinical significance of desmoglein 3 in lung cancer, we surveyed its expression in primary non-small-cell lung cancers and neuroendocrine tumors. We used immunohistochemical analysis to examine the expression of desmoglein 3 by using tissue microarrays containing samples from 300 surgical non-small-cell lung cancer and 183 lung neuroendocrine tumor. Staining status was determined based on the sum of the distribution score (0, 1, or 2) and the intensity score (0, 1, 2, or 3) of the staining signal. Follow-up was available for 346 cases (median follow-up of 2.8 years). We determined the survival statistical significance of desmoglein 3 by using the log-rank test, and we plotted Kaplan-Meier curves. Negative immunohistochemical staining with desmoglein 3 was associated with shorter survival for all lung cancer patients regardless of the histologic subtype (5-year survival of 20.9% versus 49.5%, P < .001) in our series. In patients with atypical carcinoid tumors, lacking desmoglein 3 expression showed a 5-year survival of 0% compared with 36.8% for desmoglein 3-positive cases (P < .001). Desmoglein 3 status indicated a poor prognosis in lung cancers and portends a more aggressive behavior for atypical carcinoid tumors.     

Metallothionein expression in canine and feline mammary and melanotic tumours

Moderate to strong immunohistochemical metallothionein (MT) positivity (MT expression) is associated with a poor prognosis in some human tumours. The aim of this study was to determine MT expression in mammary tumours and cutaneous melanomas in dogs and cats. Canine (67) and feline (47) mammary tumours, and cutaneous melanomas (canine 40, feline 26) were immunolabelled with MT monoclonal antibody E9. The overall incidence of MT expression of these tumours was similar to that observed in various human neoplasms. However, a striking interspecies difference was detected. In dogs, MT expression occurred in 100% of benign and 57% of malignant mammary tumours. In cats, however, 30% of malignant mammary tumours expressed MT but benign mammary tumours and cases of fibroadenomatous hyperplasia did not. Moderate to strong MT immunoreactivity was detected in 30% of benign and 25% of malignant cutaneous melanomas in dogs, and in 6% of malignant melanomas in cats. The findings in feline mammary tumours resembled findings reported in human breast cancer, but the cause of tumour-associated MT expression is unknown. Studies are in progress to determine whether the MT state (apo [metal-free] or holo [metal-bound]) accounts for the paradoxical association of MT expression with individual types of tumours and the animal species in which they arise.     

Stratifin expression is a novel prognostic factor in human gliomas

Stratifin (14-3-3σ or SFN) is a member of the 14-3-3 family of proteins which play critical roles in different cellular signaling processes. Stratifin as a potential tumor suppressor gene plays an important role in carcinogenesis and metastasis. The aim of this study was to investigate the expression of Stratifin in human gliomas and to analyze its expression profile with respect to tumor development.The expression pattern of Stratifin was analyzed by immunohistochemistry and/or Western blotting in tumor samples from 186 patients with different grades of gliomas. Prognostic significance was assessed using Kaplan-Meier survival estimates and Cox regression analyses.The expression pattern of Stratifin was correlated with the pathological and clinical characteristics of the patients with gliomas. Western blot analysis indicated that the average optical densitometry (OD) ratio of Stratifin in high-grade gliomas (World Health Organization [WHO] grade III/IV) was lower than in low-grade tumors (WHO grade I/II, p = 0.026). In addition, statistical analysis showed that patients expressing a high level of Stratifin have favorable overall survival rates relative to those expressing a low level of this protein. Cox multi-factor analysis showed that Stratifin (p = 0.02) was an independent prognosis factor for human gliomas.Our results provide convincing evidence that the expression of Stratifin is down-regulated in human gliomas. Its expression level is correlated with the clinicopathological parameters and prognosis in patients with gliomas. Pending validation targeting, Stratifin might also be a novel opportunity to improve the therapy of this tumor.     

Cytogenetic studies in a canine mammary tumor

In a 9-year-old female dog (Basset Artesian Normand) with a mammary adenocarcinoma, cytogenetic evaluation of tumor cells showed a chromosome number of 76 in most metaphases (95%). The following abnormalities were found: symmetric metacentric chromosomes 1 and 6, centric fusion 3/38, a marker X-chromosome (Xmar) and a biarmed small marker chromosome (mar). In the remaining metaphases (5%) there were additional biarmed marker chromosomes present.     

Survivin as a prognostic factor for osteosarcoma patients

PURPOSE: Survivin is one of the apoptosis inhibitor genes and is rarely expressed in adult -tissues. However, survivin expression has been detected in various human cancers and -correlations have been recognized between the level of expression of this gene in tumors and prognosis. In this study, we investigated the correlations between survivin mRNA expres-sion in osteosarcoma tissues and clinicopathological parameters.METHODS: There were 22 osteosarcoma patients in our hospital with paraffin-embedded -tissues which could be extracted from biopsy specimens. We used the RT-PCR method after extracting total RNA and conducted a densitometric analysis to determine the ratio of survivin relative to h-GAPDH as an internal marker.RESULTS: Expression of survivin mRNA was detected in all osteosarcoma samples. Patients with metastasis had high survivin mRNA levels in initial biopsy specimens (p<0.01). Moreover, there was a statistically significant difference in survivin mRNA expression between -patients with and without metastasis (p<0.01).CONCLUSION: We concluded that high levels of survivin mRNA expression suggest poor prognosis for osteosarcoma patients.     

Prolactin potentiates transforming growth factor alpha induction of mammary neoplasia in transgenic mice

Prolactin influences mammary development and carcinogenesis through endocrine and autocrine/paracrine mechanisms. In virgin female mice, pro-lactin overexpression under control of a mammary selective nonhormonally responsive promoter, neu-related lipocalin, results in estrogen receptor alpha (ERalpha)-positive and ERalpha-negative adenocarcinomas. However, disease in vivo occurs in the context of dysregulation of multiple pathways. In this study, we investigated the ability of prolactin to modulate carcinogenesis when co-expressed with the potent oncogene transforming growth factor alpha (TGFalpha) in bitransgenic mice. Prolactin and TGFalpha cooperated to reduce dramatically the latency of mammary macrocyst development, the principal lesion type induced by TGFalpha. In combination, prolactin and TGFalpha also increased the incidence and reduced the latency of other preneoplastic lesions and increased cellular turnover in structurally normal alveoli and ducts compared with single transgenic females. Bitransgenic glands contained higher levels of phosphorylated ERK1/2 compared with single TGFalpha transgenic glands, suggesting that this kinase may be a point of signaling crosstalk. Furthermore, transgenic prolactin also reversed the decrease in ERalpha induced by neu-related lipocalin-TGFalpha. Our findings demonstrate that locally produced prolactin can strikingly potentiate the carcinogenic actions of another oncogene and modify ovarian hormone responsiveness, suggesting that prolactin signaling may be a potential therapeutic target.     

Beta-catenin expression as a prognostic indicator in cervical adenocarcinoma

The purpose of this study was to assess the prognostic influence of beta-catenin expression by immunohistochemistry in patients with cervical adenocarcinomas. The study group comprised of 51 patients who underwent total hysterectomy for cervical cancer. The median follow-up was 39 months (range 1-138 months). beta-catenin was expressed strongly on the membranes of normal cervical epithelial and glandular cells. Uniform membranous beta-catenin staining localized to intercellular borders was observed in 35% of tumors, whereas 65% of tumors demonstrated an abnormal pattern of reduced or aberrant beta-catenin expression (i.e., cytoplasmic and/or nuclear staining patterns). Abnormal beta-catenin immunoreactivity was associated statistically with advanced pathologic stage (p=0.018). The 10-year disease-free survival was 51.0% in patients with preserved expression of beta-catenin. On the other hand, a poorer prognosis was noted in the group with abnormal expression of beta-catenin with a 10-year disease-free survival of 43.4%. By multivariate analysis, low pathologic stage (stages I and II, p=0.001) and preservation of beta-catenin expression (p=0.012) were independently favorable prognostic factors. Our results indicate that changes in beta-catenin expression occur during the progression of cervical adenocarcinoma to an invasive phenotype. These results suggest that beta-catenin is an important intercellular adhesion molecule. Assessment of beta-catenin immunoreactivity may be a useful prognostic tool in cervical adenocarcinoma complementary to established prognostic factors. Furthermore, we developed a strategy for choosing biomarkers representing the steps in malignant progression in an effort to identify patients with occult metastases who will need adjuvant therapy and spare women from unnecessary interventions.