Background/Aim:Significant transcription factors - including c-Fos (gene locus: 14q24.3) and c-Jun (gene locus: 1p32-p31) - regulate cell homeostasis preventing abnormal signal transduction to nucleus. Their over-activation seems to be associated with an aggressive phenotype in non-small cell lung carcinomas (NSCLCs). In the current study, our aim was to co-analyze c-FOS/c-JUN protein expression in a series of NSCLCs correlating them to the corresponding clinico-pathological features. Materials and Methods:A set of fifty (n=50) paraffin embedded NSCLC tissue sections were selected comprising of adenocarcinomas (n=25) and squamous cell carcinomas (n=25), respectively. Immunocytochemistry (IHC) for the c-FOS/c-JUN markers was implemented. Digital image analysis (DIA) was also performed for evaluating objectively the corresponding immunostaining intensity levels of the examined proteins. Results:All the examined tissue samples expressed the markers in different protein levels. High staining intensity levels were detected in 34/50 (68%) and 24/50 (48%), respectively. C-FOS over expression was statistically significant correlated to stage (p=0.033), whereas C-JUN over expression was associated with NSCLC histotype (p=0.05) and with maximum tumor diameter (p=0.046). Conclusion:C-FOS/C-JUN co- over activation is observed frequently in NSCLC, playing potentially a central role in the aggressiveness of the malignancy's phenotype (advanced stage, increased metastatic potential). Development and implementation of novel agents that target these transcription factors is a promising approach for applying targeted therapeutic strategies in NSCC patients based on specific genetic signatures and protein profiles.

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.

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.

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.

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 T790 M 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.

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.

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.

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 β--, 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.

Ganglioneuroma (GN) and ganglioneuroblastoma (GNB) are a subset of peripheral neurogenic tumors. They are grouped according to their neuroblastic grade of differentiation, type, malignant potential and schwannian stroma development [1]. They are mostly seen in mediastinum, followed by retroperitoneum, adrenals, neck, and pelvis [2,3]. GN is a rare, benign and slow growing tumor. It is usually seen in children. While the prognosis of GN is favorable, GNB has a poor prognosis. Therefore, careful distinction must be made between the two [1-3]. The goal of primary treatment of GN and GNB is complete surgical excision [2,4,5]. It is curative and recurrences haven’t been reported after removal [1]. But, in a small number of cases, lymph node metastasis adjacent to tumor, metastasis to distant organs and unresectable cases were reported. In such situations, in order to control tumor growth and induce regression, radiotherapy or, especially in children, chemotherapy is recommended. In GN treatment there is no room for preoperative/postoperative chemotherapy or radiotherapy, but in GNB treatment, although without full consensus, chemotherapy or radiotherapy is recommended after surgery [2,4,5]. In conclusion, because of their rarity, it is difficult to analyze treatment options for these tumors. They were first described in 1965. After this period, a large number of cases have been published regarding GN and GNB. Treatment plans were created based on follow-up of these patients. Surgical excision is the primary treatment but in inoperable, unresectable and metastatic cases, radiotherapy should be considered for symptom palliation associated with metastatic masses.