c-Fos/ c-Jun transcription factors in non-small cell lung carcinoma.

During lung carcinoma development, progression and metastasis, a variety of gross (chromosome) and specific (gene) genomic alterations are detected in dysplastic, neoplastic, and progressively malignant transformed epithelia as early or late genetic events. Oncogenes' overactivation combined with suppressor genes silence are crucial genetic events in malignant and pre-malignant epithelia. Especially, deregulation of crucial signalling transduction pathways that interact with strong transcription factors - such as c-Fos and c-Jun - leads to an aberrant expression of other critical genes responsible for cell homeostasis. Upregulation of c-Fos and c-Jun leading to other oncogenes overactivation seems to be correlated with aggressive biological behaviour in non-small cell lung carcinomas (NSCLCs). In the current special molecular article we explored the role of c-Fos/c-Jun complex deregulation in NSCLC based on their interactions with other genes that demonstrate modified expression profiles.

Mechanisms of C-myc oncogenic activity in head and neck squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) demonstrates increased rates due to pathogenetic factors including tobacco, chronic alcohol consumption and also viral-mediated deregulation. During carcinogenetic process, laryngeal epithelia accumulate gross chromosome and specific gene aberrations. Oncogenes' overactivation is a crucial genetic event in malignant and pre-malignant neoplastic epithelia. Among oncogenes, C-myc (gene locus: 8q24.12-q24.13) acts as a strong transcription factor, implicated in the control of cell differentiation and apoptosis. Upregulation of the gene - due to increased copy numbers (amplification) - seems to be correlated with aggressive biological behaviour in LSCCs. In the current special molecular article we explored the role of C-myc deregulation in LSCC.

DNA mismatch repair deficiency in lung and oral cavity carcinomas: the role of histogenetic origin.

DNA mismatch repair system (DNA MMR) is a crucial genetic mechanism for DNA homeostasis in prokaryotic and eukaryotic cells. During DNA replication and also recombination, point intra-nucleotide errors including base deletion, insertion, and mis-incorporation happen. These raised abnormalities in the newly synthesized DNA strand could affect negatively the stability of the molecule and the function of the corresponding genes. DNA MMR proteins prevent these errors by recognizing and repairing them, securing directly the normal anatomy of the DNA double strand and indirectly the expression of the genes. Specific genomic alterations - mutations, loss of heterozygosity (LOH), or promoter hypermethylation - regarding the MMR genes (human homologues) hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2 modify negatively their expression leading to loss of their function in repairing the corresponding base to base errors. The result known as microsatellite instability (MSI) was initially recognized in colonic carcinoma, especially in its inherited aspect - the Lynch syndrome -, the most common form of hereditary colon carcinoma. Since then, acquired deficiencies in specific DNA MMR genes have been detected in a broad spectrum of malignancies including different anatomic regions and histologies such as stomach, prostate, esophageal, endometrial, lung and head & neck. In the current special review we explored the role of DNA MMR deficiency in lung and oral cavity carcinomas in order to identify similarities and differences regarding the corresponding genes alterations.

EGFR gene deregulation mechanisms in lung adenocarcinoma: A molecular review.

For the last two decades, evolution in molecular biology has expanded our knowledge in decoding a broad spectrum of genomic imbalances that progressively lead normal cells to a neoplastic state and finally to complete malignant transformation. Concerning oncogenes and signaling transduction pathways mediated by them, identification of specific gene alterations remains a critical process for handling patients by applying targeted therapeutic regimens. The epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in regulating cell proliferation, differentiation and apoptosis in normal cells. EGFR mutations and amplification represent the gene's main deregulation mechanisms in cancers of different histo-genetic origin. Furthermore, intra-cancer molecular heterogeneity due to clonal rise and expansion mainly explains the variable resistance to novel anti-EGFR monoclonal antibody (mAb), and also tyrosine kinase inhibitors (TKIs). According to recently published 2015 WHO new classification, lung cancer is the leading cause of death related to cancer and its incidence is still on the increase worldwide. The majority of patients suffering from lung cancer are diagnosed with epithelial tumors (adenocarcinoma predominantly and squamous cell carcinoma represent ∼85% of all pathologically defined lung cancer cases). In those patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify patients' sensitivity (i.e. exon 21 L858R, exon 19 LREA deletion) or resistance (ie exon 20 T790M and/or insertion) to TKI mediated targeted therapeutic strategies. Additionally, the role of specific micro-RNAs that affect EGFR regulation is under investigation. In the current review, we focused on EGFR gene/protein structural and functional aspects and the corresponding alterations that occur mainly in lung adenocarcinoma to critically modify its molecular landscape.

E-cadherin/α-catenin deregulated co-expression in thyroid carcinoma based on tissue microarray digital image analysis.

PURPOSE: Deregulation of cell-to-cell adhesion molecules is a common and also critical genetic event in epithelial malignancies leading to an increasing metastatic potential. Among them, e-cadherin and catenins--especially α and ß--, act as oncogenes during the carcinogenetic process affecting specific signaling transduction pathways (i.e. Wnt/ b-catenin). Concerning thyroid carcinoma, decreased or loss of expression in these proteins seems to affect the biological behavior of the neoplasm increasing its aggressiveness. The aim of this study was to investigate the deregulation of e-cadherin/α-catenin complex in thyroid carcinomas. METHODS: Thirty-five paraffin-embedded tissue samples including thyroid carcinomas (N=20) and also 15 cases of benign follicular nodules were cored at 1 mm diameter and transferred to a microarray block. Immunohistochemistry (IHC) was performed using anti-e-cadherin/α-catenin antibodies. Digital image analysis was also implemented for measuring the corresponding protein expression levels. RESULTS: E-cadherin/α-catenin protein expression demonstrated a significant progressive decrease regarding benign and malignant lesions (p=0.001). Simultaneous e-cadherin/α-catenin reduced or loss of expression was observed in 10/20 (50%) cancer cases correlated to advanced stage (especially nodal metastasis) of the examined tumours (p=0.02). Concerning the histological type, combined loss of e-cadherin/α-catenin expression was predominantly associated with follicular and anaplastic histology (p=0.001). Interestingly, α-catenin protein expression pattern was significantly correlated with the grade of differentiation of the examined malignancies (p=0.01). CONCLUSIONS: Progressive loss of e-cadherin mainly and also α-catenin expression is associated with an aggressive phenotype (low differentiation, increased metastatic activity/advanced stage) in thyroid carcinomas. Based on their aberrant protein expression, novel agents have been developed for restoring their normal function.

Molecular assays in detecting EGFR gene aberrations: an updated HER2-dependent algorithm for interpreting gene signals; a short technical report.

Purpose: Among oncogenes that have already been identified and cloned, Epidermal Growth Factor Receptor (EGFR) remains one of the most significant. Understanding its deregulation mechanisms improves critically patients' selection for personalized therapies based on modern molecular biology and oncology guidelines. Anti-EGFR targeted therapeutic strategies have been developed based on specific genetic profiles and applied in subgroups of patients suffering by solid cancers of different histogenetic origin. Detection of specific EGFR somatic mutations leads to tyrosine kinase inhibitors (TKIs) application in subsets of them. Concerning EGFR gene numerical imbalances, identification of pure gene amplification is critical for targeting the molecule via monoclonal antibodies (mAbs). In the current technical paper we demonstrate the main molecular methods applied in EGFR analyses focused also on new data in interpreting numerical imbalances based on ASCO/ACAP guidelines for HER2 in situ hybridization (ISH) clarifications.

Impact of the functional neck dissection in maxillofacial surgical oncology: its role in robotic-based surgery era.

Head and neck cancers demonstrate an increased prevalence worldwide. The main therapeutic approaches are still surgery and radiotherapy, although in selective cases novel targeted therapeutic strategies based on monoclonal antibodies (ie anti-EGFR) are also applied. Concerning maxillofacial surgical oncology, a variety of methods has been developed. Among them the functional neck dissection technique seems to be a reliable and significant surgical approach, especially in removing identified cervical metastatic lymph node(s). In this technical paper, we focused on the method, its modifications adding our experience and also the challenges that arise in the modern robotic-based era regarding head and neck surgery.

A large neglected pleomorphic adenoma of the lung: Report of a rare case.

Primary pleomorphic adenomas of the lung are very rare tumors that have peculiar clinical and oncologic features. We report here on the diagnostic and therapeutic approach for a patient with a large neglected pulmonary pleomorphic adenoma that presented initially as pneumonia.

Screening practice and misplaced priorities.

PURPOSE: To estimate cancer screening coverage among a large sample of Greek individuals. METHODS: 7012 adults from 30 Hellenic areas were surveyed. Tests included: faecal occult blood test, sigmoidoscopy,chest X-ray, urine test, testicular examination,trans-rectal ultrasound, full blood count, skin examination,digital rectal examination, PSA, Pap test, mammography,clinical breast examination (CBE), self breast examination and breast ultrasound. RESULTS: Eighty-eight percent of males and 93% of females declared being interested in cancer screening; 37.8% of men and 37.9% of women had had a medical consultation for screening purpose in the previous 2 years. Less than 2%reported having received screening for colorectal cancer or skin malignancies. Screening for cervical cancer, mammography and CBE was reported by 39.6%, 22.8% and 27.9% of females respectively. Twenty percent of males reported screening for prostate cancer. CONCLUSION: The actual opportunistic screening approach presents important deficiencies with displaced priorities in test performance and a low proportion of individuals undergoing recommended tests.

Simultaneous EGFR and VEGF alterations in non-small cell lung carcinoma based on tissue microarrays.

BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression is observed in significant proportions of non-small cell lung carcinomas (NSCLC). Furthermore, overactivation of vascular endothelial growth factor (VEGF) leads to increased angiogenesis implicated as an important factor in vascularization of those tumors. PATIENTS AND METHODS: Using tissue microarray technology, forty-paraffin (n = 40) embedded, histologically confirmed primary NSCLCs were cored and re-embedded into a recipient block. Immunohistochemistry was performed for the determination of EGFR and VEGF protein levels which were evaluated by the performance of computerized image analysis. EGFR gene amplification was studied by chromogenic in situ hybridization based on the use of EGFR gene and chromosome 7 centromeric probes. RESULTS: EGFR overexpression was observed in 23/40 (57.5%) cases and was correlated to the stage of the tumors (p = 0.001), whereas VEGF was overexpressed in 35/40 (87.5%) cases and was correlated to the stage of the tumors (p = 0.005) and to the smoking history of the patients (p = 0.016). Statistical significance was assessed comparing the protein levels of EGFR and VEGF (p = 0.043, k = 0.846). EGFR gene amplification was identified in 2/40 (5%) cases demonstrating no association to its overall protein levels (p = 0.241), whereas chromosome 7 aneuploidy was detected in 7/40 (17.5%) cases correlating to smoking history of the patients (p = 0.013). CONCLUSIONS: A significant subset of NSCLC is characterized by EGFR and VEGF simultaneous overexpression and maybe this is the eligible target group for the application of combined anti-EGFR/VEGF targeted therapies at the basis of genetic deregulation (especially gene amplification for EGFR).

Predictors of common bile duct lithiasis in laparoscopic era.

AIM: To analyze retrospectively the records of 294 consecutive patients operated upon for gallbladder stones, to determine the predictive factors of synchronous common bile duct (CBD) stones and validate prospectively the generated model. METHODS: The prognostic estimation of a biochemical test and ultrasonography alone to differentiate between the absence and presence of choledocholithiasis was assessed using receiver operating characteristics curve analysis. Multivariate analysis was employed using discriminant analysis for establishment of a best model. Prospective validation of the model was made. RESULTS: Discriminant forward stepwise analysis disclosed that high values (> or = 2 x normal) of SGOT, ALP, conjugated bilirubin and CBD diameter on ultrasound > or = 10 mm were all prognostic factors of CBD lithiasis in univariate and multivariate analysis, P< 0.01. History was not included in the model. Prospective validation of the model was performed by multivariate analysis using Visual General Stepwise Regression. Positive predictive value, when considering all these predictors, was 93.3%, while the negative predictive value was 88.8%. Sensitivity of the model was 96.5% and specificity 80%. CONCLUSION: The above model can be objectively applied to predict the presence of CBD stones.