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.

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.

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.

A unique tripartite collision tumor of the esophagus: A case report.

RATIONALE: We report a unique case of a tripartite esophageal collision tumor consisting of three separate histologic types. PATIENTS CONCERNS: Therapeutic dilemmas on the proper treatment of those rare neoplasms remain unanswered considering both proper surgical therapy and adjuvant therapy. DIAGNOSE: In this paper, we report a unique case of a patient with a tripartite esophageal collision tumor consisting of a small cell carcinoma, an adenocarcinoma of medium differentiation and a signet ring cell carcinoma. Diagnosis is difficult as clinical presentation of the patient was undistinguishable from other, commoner tumor types. INTERVENTIONS: The patient's diagnostic and therapeutic course along with available data on the collisions tumor's biological behavior and treatment are briefly discussed. OUTCOMES: Esophagectomy is the best treatment options for these patients. Unique nature of this tumor demands aggresive oncologic treatment. LESSONS: Collision tumors are rare neoplasms consisting of distinct cell populations developing in juxtaposition to one another without any areas of intermingling. Various cell types can be found. However, collision neoplasms of the esophagus combining adenomatous and neuroendocrine components are exceedingly rare, with only 5 cases described to date in the literature. Given their rarity, limited information is available on their tumorigenesis, biological behavior and clinical course. In general, these tumors are aggressive neoplasms and significantly affect patient treatment and prognosis.

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.

Expression and Clinical Significance of Concomitant FAK/SRC and p-Paxillin in Mobile Tongue Squamous Cell Carcinoma.

BACKGROUND/AIM: The focal adhesion kinase (FAK)/SRC phosphorylation cascade and its downstream target paxillin have been implicated in malignant transformation, tumor growth and progression, together with metastasis. The present study aimed to evaluate the clinical significance of concomitant FAK/SRC and p-paxillin expression in mobile tongue squamous cell carcinoma (SCC). MATERIALS AND METHODS: FAK, SRC and phospho-paxillin expression in 48 mobile tongue SCC tissue samples was assessed immunohistochemically and analyzed with respect to clinicopathological characteristics and patient survival. RESULTS: Concomitant high FAK/SRC expression was significantly associated with high grade of tumor differentiation (p=0.048) and longer disease-free patient survival (log-rank test, p=0.019). High p-paxillin expression was significantly associated with greater depth of invasion (p=0.002), lymph node metastasis (p=0.048) and poorer disease-free patient survival (log-rank test, p=0.021; Cox-regression analysis, p=0.031). CONCLUSION: The present study provides evidence that FAK/SRC and paxillin play a role in the pathophysiological aspects of mobile tongue SCC and could constitute therapeutic targets.

Clinical Significance of EphB4 and EphB6 Expression in Human Malignant and Benign Thyroid Lesions.

Ephrin receptors (Ephs) are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, angiogenesis and metastasis. The present study aimed to evaluate the clinical significance of EphB4 and EphB6 protein expression in human malignant and benign thyroid lesions. EphB4 and EphB6 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 127 patients with benign (n = 71) and malignant (n = 56) thyroid lesions. Enhanced EphB4 and EphB6 expression was more frequently observed in malignant compared to benign thyroid lesions (p = 0.0508 and p = 0.0006, respectively). EphB4 and EphB6 expression also provided a distinct discrimination between papillary carcinoma and hyperplastic nodules (p = 0.0302 and p = 0.0013, respectively). In malignant thyroid lesions, enhanced EphB4 expression was significantly associated with larger tumor size (p = 0.0366). Enhanced EphB6 expression was significantly associated with larger tumor size (p = 0.0366), the presence of lymph node metastases (p = 0.0023), the presence of capsular (p = 0.0038), lymphatic (p = 0.0053) and vascular invasion (p = 0.0018) and increased risk of recurrence rate (p = 0.0038). The present study supported evidence that EphB4 and mainly EphB6 may participate in the malignant thyroid transformation, reinforcing their utility as useful biomarkers and possible therapeutic targets in this type of neoplasia.

Clinical Significance of Hu-Antigen Receptor (HuR) and Cyclooxygenase-2 (COX-2) Expression in Human Malignant and Benign Thyroid Lesions.

Hu-antigen R (HuR) is considered to play a crucial role in tumor formation and growth by binding to 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 proteins' expression in human benign and malignant thyroid lesions. HuR and COX-2 proteins' expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 98 patients with benign (n = 48) and malignant (n = 50) lesions and was statistically analyzed with clinicopathological parameters, follicular cells' proliferative capacity and recurrence risk rate. Enhanced HuR and COX-2 expression was significantly more frequently observed in malignant compared to benign thyroid lesions (p = 0.0073 and p = 0.0016, respectively), as well as in papillary carcinomas compared to hyperplastic nodules (p = 0.0039 and p = 0.0009, respectively). Positive associations of both HuR and COX-2 expression with follicular cells' proliferation rate were also noted (p = 0.0087 and p = 0.0127, respectively). In malignant thyroid lesions, elevated COX-2 expression was significantly associated with female patients' gender (p = 0.0381) and the presence of lymph node metastases (p = 0.0296). The present data support evidence that both HuR and COX-2 may be involved in the malignant state of thyroid neoplasia and may be utilized in the diagnosis of malignant thyroid tumors.

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.

Clinical Significance of Cannabinoid Receptors CB1 and CB2 Expression in Human Malignant and Benign Thyroid Lesions.

The endocannabinoid system is comprised of cannabinoid receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and proteins responsible for their metabolism participate in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects. The present study aimed to evaluate the clinical significance of CB1 and CB2 expression in human benign and malignant thyroid lesions. CB1 and CB2 proteins' expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 87 patients with benign (n = 43) and malignant (n = 44) lesions and was statistically analyzed with clinicopathological parameters, follicular cells' proliferative capacity, and risk of recurrence rate estimated according to the American Thyroid Association (ATA) staging system. Enhanced CB1 and CB2 expression was significantly more frequently observed in malignant compared to benign thyroid lesions (p = 0.0010 and p = 0.0005, resp.). Enhanced CB1 and CB2 expression was also significantly more frequently observed in papillary carcinomas compared to hyperplastic nodules (p = 0.0097 and p = 0.0110, resp.). In malignant thyroid lesions, elevated CB2 expression was significantly associated with the presence of lymph node metastases (p = 0.0301). Enhanced CB2 expression was also more frequently observed in malignant thyroid cases with presence of capsular (p = 0.1165), lymphatic (p = 0.1989), and vascular invasion (p = 0.0555), as well as in those with increased risk of recurrence rate (p = 0.1165), at a nonsignificant level though, whereas CB1 expression was not associated with any of the clinicopathological parameters examined. Our data suggest that CB receptors may be involved in malignant thyroid transformation and especially CB2 receptor could serve as useful biomarker and potential therapeutic target in thyroid neoplasia.

Pregnane X Receptor Expression in Human Pancreatic Adenocarcinoma: Associations With Clinicopathologic Parameters, Tumor Proliferative Capacity, Patients' Survival, and Retinoid X Receptor Expression.

OBJECTIVES: Pregnane X receptor (PXR) has been involved in human malignancy, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The present study aimed to assess the clinical significance of PXR in pancreatic adenocarcinoma. METHODS: Pregnane X receptor and its heterodimers' PXR/retinoid X receptor α (RXR-α), RXR-ß, and RXR-γ expression were assessed immunohistochemically on tumoral samples from 55 pancreatic adenocarcinoma patients and were associated with clinicopathologic parameters, tumor proliferative capacity, and patients' survival. RESULTS: Enhanced PXR expression was noted in 24 (43.6%) of 55 pancreatic adenocarcinoma cases. Pancreatic adenocarcinoma patients presenting increased histological grade of tumor differentiation showed a significant increased incidence of elevated PXR expression (P = 0.023). Enhanced PXR/RXR-ß expression was significantly associated with smaller tumor size and earlier clinical stage (P = 0.005 and P = 0.003, respectively). Elevated PXR/RXR-γ expression was significantly associated with smaller tumor size and earlier clinical stage (P = 0.012 and P = 0.014, respectively) and borderline with the absence of lymph node metastases (P = 0.056). In addition, pancreatic adenocarcinoma patients presenting enhanced PXR/RXR-γ expression showed marginally longer survival times compared with those with decreased expression (log-rank test, P = 0.053). CONCLUSIONS: This study supported evidence that PXR and its copartners' overexpression may be associated with favorable clinicopathologic parameters and better outcome in pancreatic adenocarcinoma.

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.

Expression of lymphatic markers and lymphatic growth factors in psoriasis before and after anti-TNF treatment

BACKGROUND: Angiogenesis is an early stage of psoriatic lesion development, but less is known about lymphagiogenesis and its role in the development of psoriasis. OBJECTIVE: To examine the expression of specific lymphatic markers and lymphatic growth factors in untreated psoriatic skin, in the unaffected skin of patients and skin of healthy volunteers, as well as their alteration after treatment with an anti-TNF agent. METHODS: Immunohistochemistry for the lymphatic markers D2-40 and LYVE-1, in addition to the VEGF-C and VEGF-D growth factors, was performed in the skin biopsies of psoriatic lesions and adjacent non-psoriatic skin of 19 patients before and after treatment with etanercept, as well as in the skin biopsies of 10 healthy volunteers. RESULTS: The expressions of D2-40, VEGF-C and VEGF-D on lymphatic vessels underwent statistically significant increases in untreated psoriatic skin compared with non-lesional skin, in contrast to LYVE-1, which did not involve significant increase in expression in psoriatic skin. VEGF-C expression on lymphatic vessels diminished after treatment with etanercept. Moreover VEGF-C and VEGF-D staining on fibroblasts presented with higher expression in lesional skin than in non-lesional adjacent skin. CONCLUSION: Remodeling of lymphatic vessels possibly occurs during psoriatic lesion development, parallel to blood vessel formation. The exact role of this alteration is not yet clear and more studies are necessary to confirm these results. .

Expression of lymphatic markers and lymphatic growth factors in psoriasis before and after anti-TNF treatment.

BACKGROUND: Angiogenesis is an early stage of psoriatic lesion development, but less is known about lymphagiogenesis and its role in the development of psoriasis. OBJECTIVE: To examine the expression of specific lymphatic markers and lymphatic growth factors in untreated psoriatic skin, in the unaffected skin of patients and skin of healthy volunteers, as well as their alteration after treatment with an anti-TNF agent. METHODS: Immunohistochemistry for the lymphatic markers D2-40 and LYVE-1, in addition to the VEGF-C and VEGF-D growth factors, was performed in the skin biopsies of psoriatic lesions and adjacent non-psoriatic skin of 19 patients before and after treatment with etanercept, as well as in the skin biopsies of 10 healthy volunteers. RESULTS: The expressions of D2-40, VEGF-C and VEGF-D on lymphatic vessels underwent statistically significant increases in untreated psoriatic skin compared with non-lesional skin, in contrast to LYVE-1, which did not involve significant increase in expression in psoriatic skin. VEGF-C expression on lymphatic vessels diminished after treatment with etanercept. Moreover VEGF-C and VEGF-D staining on fibroblasts presented with higher expression in lesional skin than in non-lesional adjacent skin. CONCLUSION: Remodeling of lymphatic vessels possibly occurs during psoriatic lesion development, parallel to blood vessel formation. The exact role of this alteration is not yet clear and more studies are necessary to confirm these results.

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.

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.