Clinical significance of farnesoid X receptor expression in thyroid neoplasia.

AIM: To evaluate the clinical significance of farnesoid X receptor (FXR) in thyroid neoplasia. PATIENTS & METHODS: FXR expression was assessed immunohistochemically on 88 thyroid neoplastic tissues (benign = 44, malignant = 44). RESULTS: Enhanced FXR was more frequently observed in papillary carcinomas compared with hyperplastic nodules (p = 0.0489). In malignant lesions, elevated FXR was associated with capsular (p = 0.0004) and vascular invasion (p = 0.0056) and increased follicular cells' proliferative rate (p < 0.0001). Elevated FXR expression was also associated with larger tumor size (p = 0.0086), presence of lymph node metastases (p = 0.0239) and lymphatic invasion (p = 0.0086) and increased recurrence rate risk (p = 0.0239). CONCLUSION: FXR may be associated with tumor aggressiveness that affects patients' survival in thyroid neoplasia.

Evaluation of cannabinoid CB1 and CB2 receptors expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients' survival.

Cannabinoid receptors (CB1R and CB2R) constitute essential members of the endocannabinoid system (ECS) which participates in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects. The present study aimed to assess the clinical significance of CB1R and CB2R protein expression in mobile tongue squamous cell carcinoma (SCC). CB1R and CB2R expression was assessed immunohistochemically on 28 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics and overall and disease-free patients' survival. CB1R, CB2R, and concomitant CB1R/CB2R expression was significantly increased in older compared to younger mobile tongue SCC patients (p = 0.0243, p = 0.0079, and p = 0.0366, respectively). Enhanced CB2R and concomitant CB1R/CB2R expression was significantly more frequently observed in female compared to male mobile tongue SCC patients (p = 0.0025 and p = 0.0016, respectively). Elevated CB2R expression was significantly more frequently observed in mobile tongue SCC patients presenting well-defined tumor shape compared to those with diffuse (p = 0.0430). Mobile tongue SCC patients presenting enhanced CB1R, CB2R, or concomitant CB1R/CB2R expression showed significantly longer overall (log-rank test, p = 0.004, p = 0.011, p = 0.018, respectively) and disease-free (log-rank test, p = 0.003, p = 0.007, p = 0.027, respectively) survival times compared to those with low expression. In multivariate analysis, CB1R was identified as an independent prognostic factor for disease-free patients' survival (Cox-regression analysis, p = 0.032). The present study provides evidence that CB1R and CB2R may play a role in the pathophysiological aspects of the mobile tongue SCC and even each molecule may constitute a potential target for the development of novel anti-cancer drugs for this type of malignancy.

Hu-antigen receptor (HuR) and cyclooxygenase-2 (COX-2) expression in human non-small-cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival.

Hu-antigen R (HuR) is considered to play a central role in tumor formation, growth, and metastasis by binding to messenger RNAs (mRNAs) encoding proteins such as cyclooxygenase-2 (COX-2) and inducing their expression via mRNA stabilization and/or altered translation. The present study aimed to evaluate the clinical significance of HuR and COX-2 protein expression in non-small-cell lung carcinoma (NSCLC). HuR and COX-2 expression was assessed immunohistochemically on tissue microarrays of 81 surgically resected NSCLC and was analyzed in relation with clinicopathological characteristics and patients' survival. Enhanced total HuR expression was significantly associated with tumor histological type and presence of lymph node metastases, as well as with increased tumor proliferative capacity and poor patients' outcome (p = 0.039, p = 0.017, p = 0.033, and p = 0.022, respectively). Enhanced COX-2 expression was significantly associated with the presence of lymphovascular invasion and increased tumor proliferative capacity (p = 0.031 and p = 0.023, respectively). Concomitant elevated HuR/COX-2 expression levels were significantly associated with tumor histological type and increased proliferative capacity (p = 0.002 and p = 0.045, respectively). Enhanced total HuR expression, as well as its cytoplasmic localization, was significantly associated with increased COX-2 expression (p = 0.015 and p = 0.001, respectively). The present study supported evidence that HuR may participate in malignant transformation of NSCLC, reinforcing its usefulness as potential therapeutic target in this type of neoplasia.

Clinical significance of histone deacetylase (HDAC)-1, HDAC-2, HDAC-4, and HDAC-6 expression in human malignant and benign thyroid lesions.

Histone deacetylases (HDACs) have been associated with human malignant tumor development and progression, and HDAC inhibitors are currently being explored as anticancer agents in clinical trials. The present study aimed to evaluate the clinical significance of HDAC-1, HDAC-2, HDAC-4, and HDAC-6 proteins' expression in human malignant and benign thyroid lesions. HDAC-1, HDAC-2, HDAC-4, and HDAC-6 proteins' expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 74 patients with benign and malignant thyroid lesions. Enhanced HDAC-2 and HDAC-6 expression was significantly more frequently observed in malignant, compared to benign, thyroid lesions (p = 0.0042 and p = 0.0069, respectively). Enhanced HDAC-2, HDAC-4, and HDAC-6 expression was significantly more frequently observed in cases with papillary carcinoma compared to hyperplastic nodules (p = 0.0065, p = 0.0394, and p = 0.0061, respectively). In malignant thyroid lesions, HDAC-1, HDAC-4, and HDAC-6 expression was significantly associated with tumor size (p = 0.0169, p = 0.0056, and p = 0.0234, respectively); HDAC-2 expression with lymphatic and vascular invasion (p = 0.0299 and p = 0.0391, respectively); and HDAC-4 expression with capsular invasion (p = 0.0464). The cellular pattern of HDAC-1 and HDAC-2 distribution (nuclear vs. nuclear and cytoplasmic) presented a distinct discrimination between malignant and benign thyroid lesions (p = 0.0030 and p = 0.0028, respectively) as well as between papillary carcinoma and hyperplastic nodules (p = 0.0036 and p = 0.0028, respectively). HDAC-1, HDAC-2, HDAC-4, and HDAC-6 may be associated with the malignant thyroid transformation and could be considered as useful biomarkers and possible therapeutic targets in this neoplasia.

Extracellular signal-regulated kinase (ERK) expression and activation in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival.

Extracellular signal-regulated kinase (ERK) has been considered as a critical regulator of diverse cellular processes such as proliferation, survival and motility, being implicated in the malignant transformation in several tissue types. The present study aimed to evaluate the clinical significance of total ERK1 (t-ERK1) and phosphorylated ERK1/2 (p-ERK1/2) protein expression in mobile tongue squamous cell carcinoma (SCC). t-ERK1 and p-ERK1/2 protein expression in tumour cells and infiltrating the tumour microenvironment lymphoid cells was assessed immunohistochemically on 47 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics, overall and disease-free patients' survival. Enhanced nuclear t-ERK1 and p-ERK1/2 expression in tumour cells was associated with the absence of perineural invasion (p = 0.043) and shorter overall patients' survival (log-rank test, p = 0.028), respectively. Enhanced t-ERK1 expression in infiltrating lymphoid cells was significantly associated with female gender, absence of vascular and perineural invasion, lymph node metastases and early depth of invasion (p = 0.008, p = 0.019, p = 0.011, p = 0.036 and p = 0.001, respectively), as well as with longer disease-free survival times (log-rank test, p = 0.038). Enhanced p-ERK1/2 expression in infiltrating lymphoid cells was significantly associated with the presence of vascular invasion and lymph node metastases (p = 0.019 and p = 0.004, respectively) and shorter overall patients' survival (log-rank test, p = 0.013). In multivariate analysis, p-ERK1/2 expression in tumour cells and infiltrating lymphoid cells was identified as independent prognostic factors of overall survival (Cox regression analysis, p = 0.045 and p = 0.032, respectively). The present study supported evidence that ERK signalling pathway may exert a potential role in the pathophysiological aspects of the mobile tongue SCC, presenting also potential utility as a biomarker for patients' survival and reinforcing the development of novel anti-cancer therapies targeting ERK signalling cascade in this type of human malignancy.

Ephrin (Eph) receptor A1, A4, A5 and A7 expression in human non-small cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival.

BACKGROUND: Ephrin (Eph) receptors are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate the clinical significance of EphA1, A4, A5 and A7 protein expression in non-small cell lung carcinoma (NSCLC). METHODS: EphA1, A4, A5 and A7 protein expression was assessed immunohistochemically in tissue microarrays of 88 surgically resected NSCLC and was analyzed in relation with clinicopathological characteristics and patients' survival. RESULTS: Elevated EphA4 expression was significantly associated with low histopathological stage and presence of inflammation (p = 0.047 and p = 0.026, respectively). Elevated EphA7 expression was significantly associated with older patients' age, presence of fibrosis and smaller tumor size (p = 0.036, p = 0.029 and p = 0.018, respectively). EphA1, A5 and A7 expression were positively associated with tumor proliferative capacity (p = 0.047, p = 0.002 and p = 0.046, respectively). Elevated EphA4, A5 and A7 expression were identified as predictors of favourable patients' survival at both univariate (Log-rank test, 0 = 0.019, p = 0.006 and p = 0.012, respectively) and multivariate levels (Cox-regression analysis, p = 0.029, p = 0.068 and p = 0.044, respectively). CONCLUSIONS: The present study supported evidence that Ephs may be involved in lung cancer progression, reinforcing their utility as clinical biomarkers for patients' management and prognosis, as also as potential targets for future therapeutic interventions.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) expression in human benign and malignant thyroid lesions.

BACKGROUND: The receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that contributes to tumor progression by enabling cancer cells to evade immune surveillance. The present study aimed to evaluate the clinical significance of RCAS1 expression in human benign and malignant thyroid lesions. MATERIAL/METHODS: RCAS1 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 121 patients with benign and malignant lesions and was associated with type of thyroid histopathology and tumor stage parameters such as tumor size, lymph node metastases, capsular, lymphatic and vascular invasion. RESULTS: RCAS1 positivity, overexpression and staining intensity provided a distinct discrimination between benign and malignant thyroid cases (p=0.0006, p=0.0001 and p=0.0001, respectively), as well as between hyperplastic nodule and papillary carcinoma cases (p=0.0229, p=0.0001 and p=0.0001, respectively). RCAS1 positivity, overexpression and staining intensity also provided distinct discrimination between cases with Hashimoto thyroiditis and those with hyperplastic nodule (p=0.0221, p=0.0001 and p=0.0019, respectively). In the subgroup of malignant thyroid lesions, RCAS1 overexpression was significantly associated with large tumor size (p=0.0246), the presence of lymph node metastases (p=0.0351) and capsular invasion (p=0.0397). CONCLUSIONS: RCAS1 protein may participate in thyroid neoplastic transformation and could be considered as a useful biomarker to improve diagnostic scrutiny.

EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer.

Ongoing research continues to elucidate the complex role of ephrin receptors (EPHs) and their ligands (ephrins) in breast cancer pathogenesis, with their varying expression patterns implied to have an important impact on patients' outcome. The current study aims to investigate the clinical significance of EPHA2, EPHA4, and EPHA7 expression in triple-negative breast cancer (TNBC) cases. EPHA2, EPHA4, and EPHA7 protein expression was assessed immunohistochemically on formalin-fixed and paraffin-embedded (FFPE) TNBC tissue sections from 52 TNBC patients and correlated with key clinicopathologic parameters and patients' survival data (overall survival (OS); disease-free survival (DFS)). EPHA2, EPHA4, and EPHA7 expression was further examined in TNBC cell lines. EPHA2 overexpression was observed in 26 (50%) of the TNBC cases, who exhibited a shorter OS and DFS than their low-expression counterparts, with EPHA2 representing an independent prognostic factor for OS and DFS (p = 0.0041 and p = 0.0232, respectively). EPHA4 overexpression was associated with lymph node metastasis in TNBC patients (p = 0.0546). Alterations in EPHA2, EPHA4, and EPHA7 expression levels were also noted in the examined TNBC cell lines. Our study stresses that EPHA2 expression constitutes a potential prognostic factor for TNBC patients. Given the limited treatment options and poorer outcome that accompany the TNBC subtype, EPHA2 could also pose as a target for novel, more personalized, and effective therapeutic approaches for those patients.

Histone deacetylase-1 and -2 expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival.

BACKGROUND: Histone deacetylases (HDACs) have been associated with tumor development and progression in several types of human malignancy and HDAC inhibitors are currently being explored as anti-cancer agents in clinical trials. The aim of the present study was to evaluate the clinical significance of HDAC-1 and -2 protein expression in mobile tongue squamous cell carcinoma (SCC). METHODS: HDAC-1 and -2 protein expression was assessed immunohistochemically on 49 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics, overall and disease-free patients' survival. RESULTS: HDAC-1 overexpression was significantly associated with younger patients' age (P = 0.0381) and male gender (P = 0.0345), poor histopathological grade of differentiation (P = 0.0236) and the presence of lymph node metastases (P = 0.0104). Intense HDAC-1 staining intensity was significantly associated with male gender (P = 0.0127), increased stromal infiltration reaction (P = 0.0125) and well-defined shape of tumor invasion (P = 0.0396). HDAC-2 overexpression did not show significant correlations with any clinicopathological parameters, whereas intense HDAC-2 staining intensity was significantly associated with the presence of muscular invasion (P = 0.0466) and advanced depth of invasion (P = 0.0251). Mobile tongue SCC patients with HDAC-1 overexpression presented shorter overall and disease-free survival compared to those with no evidence of HDAC-1 overexpression (log-rank test, P = 0.0651 and 0.0247, respectively). CONCLUSIONS: The present study supported evidence that HDACs may participate in the formation and progression of mobile tongue SCC, reinforcing their possible use as biomarkers as also the therapeutic utility of HDAC inhibitors in mobile tongue SCC chemoprevention and treatment.

Eph-A2 and Eph-A4 expression in human benign and malignant thyroid lesions: an immunohistochemical study.

BACKGROUND: Ephrin receptors (Ephs) are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, metastasis and angiogenesis. The aim of the present study was to evaluate the clinical significance of Eph-A2 and Eph-A4 expression in human benign and malignant thyroid lesions. MATERIAL/METHODS: Eph-A2 and Eph-A4 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 131 patients with benign and malignant lesions. RESULTS: Eph-A2 was significantly overexpressed in malignant compared to benign thyroid lesions (p<0.001). Papillary carcinoma cases presented significantly increased Eph-A2 expression compared to those with hyperplasia nodules (p<0.001). Eph-A4 expression was not differentiated between cases with malignant or benign thyroid lesions. Papillary carcinoma cases presented significantly increased Eph-A4 expression compared to those with hyperplasia nodules (p=0.006). In the subgroup of malignant thyroid lesions, Eph-A2 and Eph-A4 expression was not associated with TNM stage, capsular, lymphatic or vascular invasion. CONCLUSIONS: The present data suggest that Eph-A2, but not Eph-A4, overexpression may be associated with the malignant transformation of thyroid neoplasia. Further studies conducted on cohorts including a higher proportion of patients with advanced nodal and metastatic disease are recommended to draw definite conclusions on the clinical significance of Eph proteins in thyroid neoplasia.

Expression of DNA repair proteins MSH2, MLH1 and MGMT in human benign and malignant thyroid lesions: an immunohistochemical study.

BACKGROUND: DNA repair is a major defense mechanism, which contributes to the maintenance of genetic sequence, and minimizes cell death, mutation rates, replication errors, DNA damage persistence and genomic instability. Alterations in the expression levels of proteins participating in DNA repair mechanisms have been associated with several aspects of cancer biology. The present study aimed to evaluate the clinical significance of DNA repair proteins MSH2, MLH1 and MGMT in benign and malignant thyroid lesions. MATERIAL/METHODS: MSH2, MLH1 and MGMT protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 90 patients with benign and malignant lesions. RESULTS: The expression levels of MLH1 was significantly upregulated in cases with malignant compared to those with benign thyroid lesions (p = 0.038). The expression levels of MGMT was significantly downregulated in malignant compared to benign thyroid lesions (p = 0.001). Similar associations for both MLH1 and MGMT between cases with papillary carcinoma and hyperplastic nodules were also noted (p = 0.014 and p = 0.026, respectively). In the subgroup of malignant thyroid lesions, MSH2 downregulation was significantly associated with larger tumor size (p = 0.031), while MLH1 upregulation was significantly associated with the presence of lymphatic and vascular invasion (p = 0.006 and p = 0.002, respectively). CONCLUSIONS: Alterations in the mismatch repair proteins MSH2 and MLH1 and the direct repair protein MGMT may result from tumor development and/or progression. Further studies are recommended to draw definite conclusions on the clinical significance of DNA repair proteins in thyroid neoplasia.

Ephrin Receptors (Ephs) Expression in Thymic Epithelial Tumors: Prognostic Implications and Future Therapeutic Approaches.

Ephrin receptors (Ephs) are receptor tyrosine kinases (RTKs) implicated in tissue development and homeostasis, and they are aberrantly expressed in tumors. Here, immunohistochemical Eph type-A and -B expression in thymic epithelial tumors (TETs) was assessed and correlated with clinicopathological parameters. Tissue microarrays from 98 TETs were stained for EphA1, -A2, -A4 -A6, -B1, -B2, -B4 and -B6. The relationship between neoplastic and lymphoid cell immunoreactivity score (H-score), histopathological parameters (Pearson's test) and survival of 35 patients (Mantel-Cox model) was explored. Epithelial-rich subtypes showed higher EphA6 cytoplasmic H-score (B2/B3, carcinoma) (p < 0.001) and stronger EphA4 H-score (B3, carcinoma) (p = 0.011). The immature T-cells, especially in subtypes AB/B1, had higher EphB6 H-score than carcinoma-associated mature lymphocytes (p < 0.001); carcinomas had higher lymphocytic EphB1 H-score (p = 0.026). Higher lymphocytic and lower epithelial EphB6 H-score correlated with Masaoka stage ≤II (p = 0.043, p = 0.010, respectively). All cases showed variable epithelial and lymphocytic EphA2 expression, but clinicopathological associations were not reached. Our study confirmed that Eph type-A and -B expression in TETs is associated with established prognostic parameters, i.e., tumor subtype and Masaoka stage, although correlation with patient survival was not reached. Such findings suggest involvement of these RTKs in thymic neoplasia, as well as their potential utility as treatment targets.

MTOR/4EBP1 signaling and MMR status in colorectal cancer: New correlations and arising perspectives.

This is the first study aiming to investigate mTOR signaling and its relation to mismatch repair status (MMR status) in colorectal cancer (CRC). MMR status and the phosphorylated proteins, pmTOR and p4EBP1, have been immunohistochemically analyzed in 108 formalin-fixed, paraffin-embedded CRC specimens. The correlations between them and with clinicopathological data, MAPK pathway (KRAS, NRAS, BRAF) as well as their impact on patients' overall survival have been statistically analyzed. Our results indicated that positive pmTOR expression was significantly associated with KRAS mutations (p = 0.004). From multivariate survival analysis, only p4EBP1 expression emerged as independent adverse prognostic factor for overall survival (HR, 3.322; 95%CI, 1.110-9.945; p = 0.032). Furthermore, MMR deficient carcinomas tend to express low p4EBP1 protein levels (p = 0.002). A survival analysis stratified by MMR status and p4EBP1 expression, showed that MMR proficient tumours with high p4EBP1 expression had the worst overall survival compared with the other examined subgroups (p = 0.019). In conclusion, MAPK and PI3k/Akt pathways seem to be simultaneously overactivated in CRC. P4EBP1 could be used as a prognostic biomarker. By further analyzing the significant association between MMR status and p4EBP1 expression, we suggest that MMR deficient tumours could represent a subpopulation most likely to derive treatment benefit from mTOR inhibition.

High Pregnane X Receptor (PXR) Expression Is Correlated with Poor Prognosis in Invasive Breast Carcinoma.

Pregnane X Receptor (PXR) is involved in human cancer, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The clinical significance of PXR expression in invasive breast carcinoma was evaluated in the present study. PXR protein expression was assessed immunohistochemically on formalin fixed paraffin-embedded breast invasive carcinoma tissue sections, obtained from 148 patients, and was correlated with clinicopathological parameters, molecular phenotypes, tumor cells' proliferative capacity, and overall disease-free patients' survival. Additionally, the expression of PXR was examined on human breast carcinoma cell lines of different histological grade, hormonal status, and metastatic potential. PXR positivity was noted in 79 (53.4%) and high PXR expression in 48 (32.4%), out of 148 breast carcinoma cases. High PXR expression was positively associated with nuclear grade (p = 0.0112) and histological grade of differentiation (p = 0.0305), as well as with tumor cells' proliferative capacity (p = 0.0051), and negatively with luminal A subtype (p = 0.0295). Associations between high PXR expression, estrogen, and progesterone receptor negative status were also recorded (p = 0.0314 and p = 0.0208, respectively). High PXR expression was associated with shorter overall patients' survival times (log-rank test, p = 0.0009). In multivariate analysis, high PXR expression was identified as an independent prognostic factor of overall patients' survival (Cox-regression analysis, p = 0.0082). PXR expression alterations were also noted in breast cancer cell lines of different hormonal status. The present data supported evidence that PXR was related to a more aggressive invasive breast carcinoma phenotype, being a strong and independent poor prognosticator.

Synchronous chromophobe and papillary renal cell carcinoma. First report and review of the pathogenesis theories.

The coexistence of different subtypes of renal cell carcinoma (RCC) within a single kidney is an extremely unusual entity. Presented herein is the case of a 57-year-old man with two RCC of chromophobe and papillary histology. Very few reports in the literature describe double or triple synchronous renal neoplasms. To our knowledge this is the first report of this RCC subtype combination, which might trigger further investigation on the RCC pathogenesis theories.

Ovarian metastasis of renal cell carcinoma: Clinical and pathological presentation of a case.

A 82-year-old woman was referred to our hospital with complaints of weight loss, loss of appetite, abdominal pain and a palpable pelvic mass. Abdominal imaging revealed a tumour at the upper pole of the right kidney with a maximum diameter of 8 cm and a second tumour in the pelvis, mostly solid, with a maximum diameter of 16 cm, that seemed to originate from the left ovary. As she was initially considered to have two distinct tumours, through a single transabdominal incision, she simultaneously underwent right radical nephrectomy and also bilateral salpingo-oophorectomy for the tumour that originated from the left ovary. Histopathological examination showed that the tumour in the right kidney was a clear-cell renal cell carcinoma (RCC) (stage pT3a, Fuhrman grade 2). The ovarian tumour proved to be an ovarian fibroma that included a circumscribed focus with a diameter of 0.7 cm which was a metastasis from the kidney tumour. Immunohistochemistry contributed significantly to the diagnosis, as the focus showed strong and diffuse expression of CD10 and RCC antigen, which are reliable markers of RCC. With less than 30 reported cases in the literature, it is very important to differentiate ovarian metastasis of RCC from primary ovarian tumour due to different treatment alternatives and prognosis.

Apoptosis and hepatitis C virus infection in renal transplant recipients.

Hepatocellular injury in renal transplant recipients with hepatitis C virus (HCV) infection remains unclear. The suppressed immune response, in combination with increased viremia levels, provides a unique setting for the study of a potential HCV-induced apoptotic process. Liver biopsy specimens from 59 HCV-infected renal transplant recipients were examined histologically. DNA fragmentation was detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labeling assay, and the CD8 T-cell count was assessed immunohistochemically.A low apoptotic index (0-2.5) was observed in 31 cases, a moderate index (2.6-5) in 16, and a high index (>5) in 12. Apoptotic cell death correlated significantly with viremia because it was demonstrated by higher HCV-RNA levels in cases with a high number of apoptotic cells (odds ratio, 2.96; 95% confidence interval, 1.0-8.5; P = .04). No correlation was found between the apoptotic index and hepatitis necroinflammatory activity, CD8 cell count, fibrosis stage, immunosuppressive therapy, or genotype. In HCV-infected renal transplant recipients, apoptotic cell death seems to be associated with high viral load, thus providing indications of viral interference in the pathogenetic process.

Effect of the different phosphorylated Smad2 protein localizations on the invasive breast carcinoma phenotype.

Smad2 participates in the TGF-beta signaling pathway, where it cooperates with transcription factors to regulate expression of defined genes. The purpose of this study was to investigate the expression pattern of phosphorylated Smad2 (pSmad2) in association with clinicopathological parameters and biological markers of proliferation and invasion. Immunohistochemistry was applied on paraffin-embedded sections from 164 patients with invasive breast carcinomas to detect the expression of the proteins pSmad2, ER, PR, Ki67, topoisomerase IIa, ERK2, catenin-p120, MMP-14 and TIMP-2. pSmad2 protein was detected in the nuclei of the malignant cells (68.1%) and in the tumor fibroblasts (55.2%). Nuclear pSmad2 was inversely correlated with histological grade and LN (p=0.047 and p=0.05) as well as with Ki67 and topoIIa (p=0.003 and p=0.021, respectively). There was also an inverse relation between nuclear pSmad2 and normal immunoexpression of the adhesion molecule catenin-p120 (p=0.028). Both nuclear and stromal pSmad2 were positively correlated with ERK2 of tumor fibroblasts (p=0.008 and p=0.0001, respectively), while stromal pSmad2 was furthermore related to stromal MMP-14 and tumor TIMP-2 (p=0.006 and p=0.022, respectively). Patients with high expression of cancerous pSmad2 tended to have a better prognosis, although statistic significance was never reached. pSmad2 was found to play a dual role, according to its distribution. Nuclear localization was thus found to be related to a less aggressive tumor phenotype, whereas stromal location was associated with an invasive phenotype.

Extra copies of chromosomes 16 and X in invasive breast carcinomas are related to aggressive phenotype and poor prognosis.

BACKGROUND: Breast cancer is a genetically complex disease, which involves the accumulation of various structural and numerical chromosomal aberrations. AIM: To assess the numerical status of chromosomes 16 and X by interphase cytogenetics, in 114 women with primary invasive breast carcinomas, in relation to clinicopathological parameters, patients' overall survival and indices of cell growth (c-erbB-2, topoisomerase IIalpha (topoIIalpha)) and cell survival (caspase-3, bcl-2). EXPERIMENTAL DESIGN: Chromogenic in situ hybridisation with pericentromeric probes was performed for molecular analysis, while oestrogen and progesterone receptors, cerbB-2, topoIIalpha, caspase-3 and bcl-2 expression was immunohistochemically detected (ABC/HRP). The results were statistically assessed by univariate and multivariate analyses. RESULTS: Polysomy of chromosomes 16 and X was detected as the predominant aberration (73.7% and 57.9%, respectively). Gain of chromosome 16 copies was associated with high nuclear grade (p = 0.009), increased tumour size (p = 0.041), advanced stage (p = 0.002), the expression of topoIIalpha (p = 0.005) and worse overall survival by multivariate analysis (p = 0.032). Chromosome X polysomy was increased in ductal carcinomas of high histological grade (p = 0.008), in high nuclear grade tumours (p = 0.001), and was associated with the expression of topoIIalpha (p = 0.005), loss of caspase-3 (p = 0.036) and impaired prognosis of ductal carcinomas (p = 0.041). CONCLUSIONS: Polysomy of chromosomes 16 and X was reported as the predominant alteration in phenotypically aggressive breast tumours, characterised by poor differentiation, increased growth potential and impaired prognosis, whereas gain of chromosome X in particular is probably implicated in cell survival.