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Background/Aim: Meningiomas represent the main intracranial primary central nervous system (CNS) tumour in adults worldwide. Oncogenes’ over-activation combined with suppressor genes’ silencing affect negatively the biological behavior of these neoplasms. This study aimed to explore the impact of p53 suppressor gene expression in meningiomas’ clinic-pathological features based on a combination of sophisticated techniques. Materials and Methods: Fifty (n=50) meningiomas were included in the study, comprising a broad spectrum of histopathological sub-types. An immunohistochemistry assay was applied on tissue microarray cores followed by digital image analysis. Results: p53 protein over-expression (high staining intensity levels) was observed in 27/50 (54%) cases, whereas the rest (23/50-/46%) demonstrated moderate to low levels of the protein. p53 over-expression was statistically significantly correlated to the mitotic index of the examined cases (p-value=0.001). Interestingly, the atypical/anaplastic group of histotypes demonstrated the strongest p53 expression rates compared to the others (p-value=0.001). Conclusion: p53 over-expression is observed in a broad spectrum of meningiomas. High expression levels lead to an aggressive biological behavior of the malignancy (combined with increased mitotic rates), especially in atypical and anaplastic sub-types that also have a high recurrence rate.

Background: Oral squamous cell carcinoma (OSCC) is characterized by a broad spectrum of genomic imbalances, including gross chromosomal (polysomy/ aneuploidy) ones as well as specific gene alterations. Aberrant expression of anaplastic lymphoma kinase (ALK) seems to be a useful molecular marker for discriminating patients based on genetic signatures in a variety of solid malignancies, such as lung carcinoma. Our aim was to analyze ALK protein expression patterns in a series of OSCCs. Materials and Methods: Fifty (n=50) OSCC tissue sections were analyzed by implementing an ALK-based immunohistochemistry protocol. Digital image analysis was performed for measuring the corresponding protein expression levels. Results: ALK overexpression was observed in 14/50 (28%) OSCC tissue sections, whereas the rest 36/50 (72%) demonstrated low expression levels. ALK expression was negatively associated with grade (p=0.027) and stage (p=0.0028) of the examined cases. Conclusion: Abnormal ALK expression in subsets of patients with OSCC seems to be related to an aggressive phenotype (advanced stage/progressive dedifferentiation). ALK protein overexpression may be used as a significant marker for applying targeted therapeutic regimens.

Thyroid carcinoma represents a leading malignancy among those derived from human endocrine systems. It comprises a variety of different histological subtypes, including mainly papillary carcinoma, follicular carcinoma, anaplastic carcinoma, and medullar carcinoma. A broad spectrum of genetic imbalances, comprising gross chromosomal (polysomy/aneuploidy) and specific gene (mutations, amplifications, deletions) alterations, has been reported. Interestingly, the role of isolated, specific gene polymorphisms, especially of the single nucleotide polymorphism (SNP) type, in thyroid carcinoma is under investigation. SNPs are the most common genetic variations in the genome. The current molecular review focuses on the impact of specific SNPs on the biological behavior of papillary thyroid carcinoma in their carriers.

Head and neck carcinoma (HNC) comprises a variety of pathological entities. Among them, squamous cell carcinoma (SCC) is histo-pathologically prominent. Specific malignancies, such as nasopharyngeal carcinoma (NPC) arise also from the same anatomical region. In all of them, genomic instability (GI) is implicated not only in the early stages of epithelial malignant transformation, but also in the aggressiveness of the corresponding phenotypes. Among the molecules that are frequently deregulated in solid malignancies including HNCs, topoisomerases (Topo) are of increased significance due to their involvement in DNA topological, structural, and functional stability. The main members are Topo I (20q11), Topo II alpha (17q21) and Topo IIb (3p24). In the current article, we describe the mechanisms of Topo I and Topo IIa deregulation leading to GI in a variety of HNCs. Furthermore, novel data regarding the corresponding targeted therapeutic strategies are presented.

Background: Fos Proto-Oncogene (c-Fos) represents a well analyzed gene involved in solid malignancies’ development and progression. The corresponding protein forms heterodimer with c-jun, a strong transcription factor. C-Fos/c-Jun complex influences critically the intracellular signal transduction to the nucleus. Our aim was to detect and evaluate c-Fos protein expression patterns in oral squamous cell carcinomas (OSCC) tissues. Materials and Methods: Fifty (n=50) formalin-fixed, paraffin-embedded primary OSCCs tissue sections were used. Immunohistochemistry and digital image analysis were implemented for identifying and evaluating c-Fos protein expression levels, respectively. Results: C-Fos protein over expression (moderate to high imunostaining intensity values) was observed in 28/50 (56%) tissue cores, whereas low expression rates were detected in the rest of the examined cases (22/50- 44%). C-Fos overall expression was strongly associated with the stage and grade of the examined tumors (p=0.014, p=0.003, respectively) and also with Human papillomavirus (HPV) persistent infection (p=0.004). c-Fos up regulation is frequently observed in OSCCs. Conclusion: C-Fos high expression levels are correlated with an aggressive phenotype (advanced stage/lymph node metastasis) in patients with OSCC, especially in HPV positive cases, especially High Risk subtypes. Due to its elevated oncogenic activity, c-Fos should be a target for novel therapeutic strategies in OSCC combined or not with other oncogenes involving in signaling transduction pathways.

Caspases (cysteine-aspartic proteases) represent a family of enzymes that critically influence cell homeostasis by being involved in inflammation and apoptosis mechanisms. Meningiomas demonstrate the most common intracranial primary central nervous system tumors in adults worldwide.Our purpose was to explore the role of caspase 8 expression in meningiomas' pathological features.A total of 50 meningioma cases were included in the study, comprising a broad spectrum of histopathological sub-types. An immunohistochemistry assay was applied on tissue microarray cores followed by digital image analysis.Overexpression of caspase 8 protein was observed in 21/50 (42%) cases, whereas the rest of them (29/50, 58%) demonstrated moderate to low levels of the molecule. Caspase 8 overall expression was statistically significantly correlated to grade of the examined tumors and to mitotic index (p=0.001,p=0.002, respectively).Caspase 8 aberrant expression is observed in meningiomas associated with their differentiation grade and mitotic activity. Targeted therapeutic strategies focused on enhancing caspase 8 expression and also inducing the overall apoptotic activity should be a very promising approach in rationally handling sub-groups of meningioma patients.

Background/aim Oral squamous cell carcinoma (OSCC) is an aggressive malignancy due to its increased ability for local metastases and distant lymph node metastases. Extensive cytogenetic analyses have detected chromosome instability (CI) patterns in OSCC including gross chromosome numerical alterations, such as polysomy and sporadically monosomy that negatively affect the biological behaviour of the malignancy. Our aim was to investigate the frequency and impact of chromosome 17 (Chr 17) numerical imbalances in OSCC. Materials and methods Fifty (n=50) formalin-fixed, paraffin-embedded primary OSCCs tissue sections were used. Chromogenic in situ hybridization (CISH) was implemented for detecting Chr 17 centromeric numerical imbalances. Concerning the screening process in CISH slides, a novel real-time reference and calibration grid platform was implemented. Results Chr 17 multiple copies were observed in 12/50 (24%) of the examined cases. Polysomy was observed in 10/50 (20%) tissue sections, monosomy in 2/50 (4%), whereas the rest of them demonstrated a normal, diploid pattern (38/50-76%). Chr 17 numerical differences were associated with the grade of differentiation of the examined tumors (p=0.001). Conclusion Chr 17 numerical imbalances (polysomy predominantly and monosomy) are observed in sub-groups of OSCCs correlating with a progressive dedifferentiation of malignant tissues. The proposed grid-based platform on CISH slides provides a novel, fast and accurate screening-mapping mechanism for detecting chromosome numerical aberrations.

BACKGROUND/AIM Topoisomerase II alpha (TopoIIa) is a critical gene associated with response to chemo-therapeutic agents, such as anthracyclines, especially in breast adenocarcinoma. The aim of this study was to investigate the role of aberrant TopoIIa protein expression in laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS Fifty (n=50) LSCC cases were enrolled in the study. Immunohistochemistry and a digital image analysis assay were implemented. RESULTS TopoIIa protein overexpression was observed in 32/50 (64%) cases, whereas low expression rates were detected in 18/50 (36%). TopoIIa overall expression presented strong association with the grade of the examined malignant tissues and borderline association with stage. TopoIIa overexpression correlated also with Human papillomavirus (HPV) positivity. CONCLUSION TopoIIa overexpression was observed in significant subsets of LSCCs, and correlated predominantly with the grade of differentiation. HPV persistent infection seems to be associated with increased TopoIIa protein expression. TopoIIa expression analysis appears to be critical in identifying sub-groups of patients eligible for specific chemotherapy.

Background: Deregulation of critical proteins involved in cell cycle stability, such as cyclins, is a frequent genetic event in the development and progression of solid malignancies. Concerning laryngeal squamous cell carcinoma (LSCC), cyclin D1 oncogenic transformation leads to an aberrant protein expression and seems to affect the biological behaviour of the neoplasm. The aim of this study was to determine the correlation of cyclin D1 numerical imbalances with the corresponding protein expression levels in LSCCs. Material and Method: Using tissue microarray (TMA) technology, fifty (n=50) histologically confirmed primary LSSCs were cored at a diameter of 1.5 mm. Immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) analyses were applied. Concerning the screening process in CISH slides, a novel real-time reference and calibration grid platform was implemented. Results: Protein overexpression was observed in 22/50 (44%) cases; whereas, gene amplification was seen in 13/50 (26%) cases (p=0.02). Combined protein/ gene deregulation was associated with the stage of malignancy (p= 0.0014, p=0.001), whereas overall protein expression was strongly correlated with the grade of tumour (p= 0.001). Conclusion: Cyclin D1 gene amplification led to aberrant protein expression in LSCCs and it was also correlated with an aggressive biological behaviour. To best of our knowledge, this study was the first described grid based CISH analysis under conventional bright field microscopy for detecting gene numerical imbalances while providing a novel and accurate description for screening-mapping process in the entire slide area.

Topoisomerases represent a super-family of nucleic enzymes involved in the DNA replication, transcription, recombination, and also chromosome topological formation. Topoisomerase II alpha (Topo IIa-gene location 17q21) is a critical gene associated with response to chemotherapeutic agents such as anthracyclines especially in breast adenocarcinoma. Our aim was to investigate the role of aberrant Topo IIa protein expression in oral squamous cell carcinoma (OSCC).Fifty formalin-fixed, paraffin-embedded primary OSCCs tissue sections were used. Immunohistochemistry was performed using an anti- Topo IIa antibody. Digital image analysis was implemented for evaluating objectively the protein expression levels on the corresponding stained nuclei.Topo IIa protein overexpression (moderate to high immunostaining intensity values) was observed in 29/50 (58%) tissue cores, whereas low expression rates were detected in the remaining cases (21/50;42%). Topo IIa overall expression was strongly associated with the differentiation grade of the examined tumors (p=0.037) and also with human papillomavirus (HPV) positivity (p=0.029). No other statistical correlations were identified.Topo IIa overexpression is observed in significant subsets of OSCCs correlated with the grade of differentiation. Additionally, HPV persistent infection is associated with increased Topo IIa protein expression levels. Topo IIa expression analysis should be critical for identifying patients eligible for applying specific chemotherapeutic strategies based on anti-Topo IIa agents.

To describe a new technique of surgical treatment of the lip commissure or buccal mucosa carcinomas, where we use local flaps (skin, buccal mucosa) of the sliding type.According to the current technique, the ectomy ranges horizontally and in a cuneiform shape towards the side of the buccal cavity, and in the whole thickness of the layer (skin - mucosa), where the neoplastic focus is enclosed.The difference in our technique consists of the following: To the vertical bi-cuneiform part of the wound a horizontal cuneiform part (with the top showing upwards) is added, with extent and width analogous to those of the cancerous injury (tri-cuneiform ectomy). The width of the gap across its horizontal part is larger on the side of the mucosa (continuous line), compared to the one along the side of the skin (punctuated line), since the mucosa, as a more versatile tissue, can be sutured easily, in contrast to the buccal skin, which is of greater thickness and shows lack of versatility, so that it can be pulled on with difficulty in order to be sutured. The planning of the injury, according to our described technique, facilitates the broad ectomy of the intraoral injuries in the area of the lip commissure and the buccal mucosa, with immediate suture of the flaps (buccal and skin gap), and the occlusion of the wound by primary intention.Using this specific technique, in the cases of extended injuries infiltrating the skin or the subcutaneous tissue, the harming use of transposition (sliding or free) flaps is avoided.

Nasopharyngeal carcinoma (NPC) represents a specific, aggressive pathological entity included in the Head and Neck Carcinoma (HNC) family of malignancies. NPC is derived from the nasopharyngeal epithelia expressing a high invasive and metastatic potential affecting negatively patients' prognosis due to poor survival rates. Concerning pathogenetic factors implicated in its rise and progression, Epstein-Barr virus (EBV) latent but persistent infection is considered the main one. Novel therapeutic strategies are based on targeting specific molecules such as epidermal growth factor receptor (EGFR) by applying anti-EGFR monoclonal antibodies (mABs) that block their natural ligands interrupting also aberrant signal transduction to nucleus. Anti-EGFR therapies combined or not with radiotherapy seem to be a very promising tool in handling the corresponding patients with NPC that demonstrate specific genetic signatures. In the current article, we focused on presenting EGFR expression in NPC combined with novel anti-EGFR agents.

Background Deregulation of apoptosis is critical regarding the development and progression of malignancies, including laryngeal squamous cell carcinoma (LSCC). B-Cell lymphoma 2 (BCL2) (gene locus:18q21.33), located on the outer mitochondrial membrane, acts mainly as an anti-apoptotic factor suppressing and blocking apoptotic signal transduction. Materials and methods Fifty (n=50) primary LSCC tissue sections were used. Immunohistochemistry and digital image analysis were implemented for evaluating BCL2 protein expression levels. Results High BCL2 protein expression levels were observed in 21/50 (42%) LSCC tissue sections, whereas the remaining cases (n=29) demonstrated a low expression. Overall, BCL2 expression was associated with grade (p=0.046) and anatomical region of the examined malignancies (transglottic, p=0.047). Interestingly, high BCL2 expression levels were strongly associated with radiotherapy-based only regimens (p=0.01) in corresponding patients. Conclusion BCL2 overexpression was found to be correlated with an aggressive phenotype (advanced grade of differentiation) in LSCC, also demonstrating a potential selective anatomic localization (transglotic region). Additionally, BCL2 overexpression appears to be a negative regulator for successful radiotherapy implementation by reducing the apoptotic process in patients.

Background/aim Epidermal growth factor receptor (EGFR) acts as an oncogene in malignancies. Our aim was to examine the role of combined EGFR/ anaplastic lymphoma kinase (ALK) expression as molecular markers in laryngeal squamous cell carcinoma (LSCC) patients. Materials and methods Fifty (n=50) tissue sections derived from twenty-five (n=25) primary LSCCs were analyzed by immunohistochemistry (IHC). Results EGFR overexpression was observed in 17/25 (68%) cases. Concerning ALK, 23/25 (92%) demonstrated low expression. EGFR expression was associated with grade (p=0.049), whereas ALK expression was correlated with stage (p=0.048). ALK overexpression was detected at advanced-stage EGFR-positive cases. A biphasic EGFR protein expression pattern was observed in five (n=5) LSCC cases, whereas ALK expression was stable in all cases. Conclusion EGFR overexpression is frequently observed in LSCC combined with low ALK expression. LSCC patients with EGFR/ALK protein overexpression should be eligible for targeted therapeutic strategies.

Background/Aim: Oncogene up-regulation combined with suppressor gene down-regulation is a crucial genetic combination that promotes cell neoplastic phenotype and progressively malignant transformation in solid malignancies, including laryngeal squamous cell carcinoma (LSCC). Among oncogenes, the Kirsten ras oncogene homolog (K-Ras) is involved in LSCC onset and progression. Patients and Methods: Sixty (n=60) primary LSCC tissue sections were analyzed by immunohistochemistry (IHC). Digital image analysis (DIA) was also implemented for measuring K-Ras protein expression levels. Results: High K-Ras protein expression levels were observed in 20/60 (33.3%) LSCC tissue sections, whereas the rest of the cases (n=40; 66.7%) demonstrated low expression. Overall K-Ras expression was borderline significantly associated to the grade of the examined malignancies (p=0.048), whereas no other strong statistical correlations were identified. A progressive K-Ras overexpression was observed in all grades of the examined cases. Conclusion: K-Ras over expression is correlated to a progressive dedifferentiation in LSCC.

Among biomarkers that should be useful for a molecular discrimination of patients regarding treatment strategies and prognosis in solid malignancies, novel micro-RNAs (miRs) are under investigation. Quite recently, miRs are considered very promising and significant genetic markers for categorizing patients by their molecular characteristics, as well as extending their complicated genetic signatures. miRs are short, non-coding RNAs consisting of 20-25 nucleotides located at intra- or inter-gene regions. Functional miRs mediate a positive regulation of posttranscriptional gene silencing. Their deregulation in cancer cells due to genetic (e.g., mutations, translocations), epigenetic (e.g., DNA hyper-methylation of tumor suppressor genes, extensive genomic DNA hypo-methylation, aberrant histone modification patterns) and transcriptional alterations lead to a loss of miRs-mediated repression of target mRNA. Interestingly, a biphasic role of miRs in cancers of different histogenetic origin has been confirmed. In some of them, their upregulation is correlated with an increased oncogenic activity, whereas in others, the same miR type acts as a suppressor agent. Thyroid carcinoma comprises different histological subtypes, such as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), anaplastic thyroid cancer (ATC), and medullary thyroid carcinoma. In the current molecular review, we explored the role of a specific fraction of miRs in PTC subtype by categorizing them according to their up- or down-regulation status.

Background/aim Oral squamous cell carcinoma (OSCC) demonstrates aggressive biological behavior in subgroups of patients with specific molecular characteristics. Concerning metastatic potential, disruption of cell to cell adhesion is a critical event in epithelial malignancies including OSCC. Our aim was to investigate the role of E-Cadherin expression in OSCC patients as a valuable protein marker. Materials and methods Fifty (n=50) tissue sections derived from primary OSCCs were analyzed by implementing an immunohistochemistry (IHC) assay based on a proper anti-E-cadherin antibody. Digital image analysis was also implemented for an objective evaluation of the corresponding protein expression levels. Results E-cadherin altered expression (low to negative) was observed in 34/50 (68%) cases, whereas the rest (16/50-32%) demonstrated normal (high to moderate) expression. E-Cadherin abnormal expressionwas associated with the stage of the examined malignancies (p=0.023), whereas no significant correlations with grade, gender, smoking status or human papilloma virus (HPV) history were observed. Conclusion E-Cadherin down regulation is frequently observed in OSCC and is correlated to a progressively aggressive phenotype of the malignancy in the corresponding patients (advanced stage), but it seems that the impact of HPV persistent infection on these patients is not a critical parameter.

Laryngeal squamous cell carcinoma (LSCC) demonstrates increasing rates worldwide due to viral-related (High Risk Human Papilloma Virus-HR HPV) persistent infection, cigarette and alcohol consumptions. Gross chromosomal alterations and specific gene aberrations-such as amplifications, deletions, point mutations-combined or not with epigenetic changes are responsible for the progressive transformation of normal squamous epithelia to their malignant phenotype. Among oncogenes that are implicated in the development and progression of LSCC, mouse double minute 2 homolog / murine double minute 2 (mdm2) seems to be an interesting marker for the biological behavior of the malignancy. Mdm2 is a proto-oncogene (gene locus: 12q14.3), encodes for a nuclear-localized E3 ubiquitin ligase, and acts as a major negative regulator in p53-mdm2 auto-regulatory pathway. Mdm2 directly binds to p53 and represses its transcriptional activity and promotes p53 proteasomal degradation. Aberrant mdm2 overexpression is a frequent observation in breast carcinomas, whereas there are limited data regarding LSCC. In the current molecular review we explored the role and specific aspects of mdm2 gene in LSCC.

During laryngeal carcinogenesis, a variety of genomic imbalances are involved in hyperplastic and dysplastic laryngeal epithelia as early or progressive genetic events, respectively. Oncogenes' overactivation is a crucial genetic event in malignant and pre-malignant neoplastic epithelia. Especially, deregulation of crucial pathways including transcription factors - such as c-Fos and c-Jun - leads to an aberrant expression of other crucial genes responsible for cell homeostasis. Upregulation of c-Fos and c-Jun proto-oncogenes -due to increased copy numbers (amplification) or intra-genic point mutations- seems to be correlated with aggressive biological behaviour in laryngeal squamous cell carcinomas (LSCCs). In the current special molecular article we explored the role of c-Fos/c-Jun complex deregulation in LSCC.

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy due to its increased ability for local metastases and distant lymph node metastases. Extensive cytogenetic analyses have detected chromosome instability (CI) patterns in OSCC including gross chromosome numerical alterations, such as polysomy and sporadically monosomy that negatively affect the biological behaviour of the malignancy. Our aim was to investigate the frequency and impact of chromosome 17 (Chr 17) numerical imbalances in OSCC.Fifty (n=50) formalin-fixed, paraffin-embedded primary OSCCs tissue sections were used. Chromogenic in situ hybridization (CISH) was implemented for detecting Chr 17 centromeric numerical imbalances. Concerning the screening process in CISH slides, a novel real-time reference and calibration grid platform was implemented.Chr 17 multiple copies were observed in 12/50 (24%) of the examined cases. Polysomy was observed in 10/50 (20%) tissue sections, monosomy in 2/50 (4%), whereas the rest of them demonstrated a normal, diploid pattern (38/50-76%). Chr 17 numerical differences were associated with the grade of differentiation of the examined tumors (p=0.001).Chr 17 numerical imbalances (polysomy predominantly and monosomy) are observed in sub-groups of OSCCs correlating with a progressive dedifferentiation of malignant tissues. The proposed grid-based platform on CISH slides provides a novel, fast and accurate screening-mapping mechanism for detecting chromosome numerical aberrations.

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.

Background/aim p16 (gene locus: 9p21) tumor suppressor gene is considered an important biomarker for the progression and prognosis in a variety of malignancies and pre-cancerous lesions, including high-risk (HR-) human papilloma virus (HPV)-mediated squamous intraepithelial lesions (SILs), based on cytological and the corresponding cervical intraepithelial neoplasia (CIN) histopathological categorization. p16 acts as a cyclin-dependent kinase-4 inhibitor negatively regulating the cell cycle. In persistent HPV infection, E7 oncogenic protein binds retinoblastoma protein leading to its proteolytic transformation, also triggering E2F dissociation, which increases DNA transcription and progression to S phase. This mechanism promotes aberrant p16 over-expression. Our aim was to comparatively analyze p16 protein expression patterns in laryngeal squamous cell carcinomas (LSCC) and also in SILs. Materials and methods Fifty (n=50) primary LSCCs tissues all non-HPV-dependent, and a set of 50 liquid-based SILs, were analyzed by immunohistochemistry and immunocytochemistry, respectively. Concerning the screening process in cytological slides, a novel real-time reference and calibration grid platform was implemented and employed. Results Decreased protein expression was observed in 34/50 (68%) tissues regarding LSCCs. Overall p16 expression was associated to smoking status of the patients (p=0.001), and also with the p-stage of the examined malignancies (p=0.033). A strong statistical significance was assessed correlating LSIL/HSIL cases with a progressive p16 over expression (p=0.001), also reflecting a higher CIN diagnosis (p=0.001). Conclusion p16 down-regulation is a frequent genetic event in LSCCs, which is associated with advanced disease. In contrast to this, p16 over-expression triggered by a specific molecular mechanism shows a strong relationship with a progressively aggressive phenotype due to upgraded SIL/CIN cervical categorization. The first described application of the grid platform demonstrated a considerable improvement in the immunocytochemistry slide screening process enhancing the diagnostic reliability.

Infections in immunocompromised-neoplastic patients represent a severe complication. Among bacteria, Enterococcus species constitute a common causative pathogen of urinary tract infections (UTIs), especially among hospitalized patients with or without urinary tract carcinoma, related commonly to urinary tract abnormalities, urinary catheters or prolonged antibiotic treatment. Although enterococci have been considered more commonly as colonization bacteria in the intestine than virulent agents, they are frequently implicated in UTIs. The high incidence of enterococcal UTIs is associated with several risk factors including age, female gender, previous UTI, diabetes, pregnancy, immunosuppression due to cancer development and progression, renal transplantation and spinal cord injury. Clinical manifestations are usually absent or mild in enterococcal UTIs, which may also become an important source for both bacteremia and endocarditis. Over the last years, the prevalence of multidrug resistant enterococci, particularly vancomycin-resistant E. faecium and E. faecalis has significantly risen worldwide, associated with increased morbidity, limited treatment options and increased health-care costs. In this review, the current knowledge on enterococcal UTIs epidemiology and influence in the corresponding immunocompromised patients is highlighted.

Even though different imaging modalities are available in sole or in combination for the optimal detection of bone metastases, whole-body bone scintigraphy (BS) in a single session seems to be advantageous. We present an 80-year-old male with unilateral left hypoglossal nerve palsy (HNP) and no other focal deficits on neurological examination. Initial brain computed tomography (CT) scan revealed no pathological findings, while the subsequent cranial CT and magnetic resonance imaging (MRI) scans uncovered only mild nonspecific sclerotic lesions in left occipital condyle. All laboratory examinations were within normal limits, except for an elevated alkaline phosphatase (170 U/L) and a markedly increased prostate-specific antigen (609 ng/mL). The patient underwent whole-body BS with technetium-99m that revealed increased radiotracer deposition compatible with metastases in multiple foci, including the left occipital condyle. Prostate biopsy confirmed the diagnosis of prostate adenocarcinoma. Our case suggests that a complete and thorough workup for hidden malignancies should be performed in all patients with HNP, even in the absence of a finding in brain neuroimaging. Bone scintigraphy is an essential investigation that should be considered in uncertain cases of HNP, and especially in those with negative CT and MRI scans.

Background P53 is a key regulator of genomic stability and function, acting as a tumor suppressor protein. Our aim was to correlate P53 expression with murine double minute 2 (MDM2), a proto-oncogene that interacts with P53 and forms an auto-regulatory pathway, in laryngeal squamous cell carcinoma (LSCC). Materials and methods A total of 50 LSCC cases were included in the study. Immunohistochemistry was applied by using antibodies to P53 and MDM2 in the corresponding tissue sections. Protein expression levels for both molecules were measured by implementing a digital image analysis assay (immunostaining intensity levels, densitometric evaluation). Results Overexpression of P53 protein was observed in 16/50 (32%) LSCC cases, while 22/50 (44%) cases strongly expressed MDM2 protein. Interestingly, in 13/50 (26%) cases, combined overexpression of P53/MDM2 was detected. Overall P53 was strongly positively correlated with MDM2 expression (p=0.001). Both P53 and MDM2 overexpression were significantly correlated with advanced stage of LSCC (p=0.032 and p=0.001, respectively). Additionally, MDM2 was found to be associated with poorer survival of patients (p=0.046). Conclusion Aberrant co-expression of P53 and MDM2 is associated with advanced stage in LSCC. Furthermore, MDM2 overexpression is a frequent and critical genetic event in LSCC and seems to negatively affect survival.

Immunoglobulin G4-related disease (IgG4RD) is a systemic fibro-inflammatory disease of unknown aetiology, which is characterized by tumefactive lymphoplasmatocytic infiltrative lesions, with a predominance of IgG4 positive plasma cells, fibrosis and obliterative phlebitis. Adult-onset asthma and periocular xanthogranuloma (AAPOX) is a rare disease of unknown aetiology characterized by violaceous or yellow cutaneous papules and nodules usually accompanied with adult-onset asthma. We report a case of IgG4RD associated with AAPOX. We also conducted a literature search with keywords including IgG4RD and AAPOX. A 36-year-old woman presented with bilateral exophthalmos and periorbital oedema. Keratoconjunctivitis sicca, painless left parotid gland and submandibular left lymph node enlargement were also noted. Two and half years ago biopsy of yellow plaques of her right lower eyelid confirmed periorbital xanthogranuloma. She underwent parotid gland biopsy which showed IgG4RD. She was treated with steroids and two cycles of rituximab with complete remission. The literature review revealed 8 articles describing 14 cases with IgG4RD and AAPOX, 9 men and 5 women (ratio M:F = 1.8:1) were affected. The age at diagnosis was greater in men compared to women. In the majority of patients, ophthalmic presentation included bilateral upper and lower eyelid swelling while systemic features were asthma, lacrimal and parotid involvement, lymphadenopathy, sclerosing pancreatitis and sclerosing cholangitis. Prednisone and rituximab were effective treatments. It has to be clarified whether the association between IgG4RD and AAPOX represents shared pathophysiology, a common underlying cause or coincidence. Rituximab added to steroids resulted in complete remission of the two entities.

Aspergillosis, which is saprophytic in nature, is known to cause massive destruction of paranasal sinuses in immunocompromised hosts, but in immunocompetent individuals invasive aspergillosis is rare. Diagnosis is posed from history, physical examination including anterior and posterior rhinoscopy, endoscopy of the nose and paranasal sinuses, radiological findings (CT and/or MRI), fungus cultures and histopathological examination. Non-specific presenting symptoms provide time for infection to extent from sinuses to vital surroundings such as bony, vascular and central nervous system structures, thereby increasing morbidity and mortality. Mass lesions involving the sinuses are initially misdiagnosed as tumors, inflammatory pseudotumors or pituitary adenomas. Therefore, diagnosis should be always confirmed by histopathology. Aspergillus sinusitis is a potentially fatal complication of immunosupression or of chemotherapy-induced leucopenia. Concerning patients with hematologic malignancies, it seems that its incidence is progressively increased. A combination of early diagnosis and application of specific antifungals provides the perfect management and prognosis in the corresponding patients. In the current special review, we present new data regarding the infection in patients with hematologic malignancies.

Aberrant cell proliferation is a major cause in the development and progression of carcinogenic process. Epithelia characterized by increased mitotic rates accumulate easily gross numerical and structural chromosomes (polysomy/aneuploidy) and specific gene (deletions, amplifications, point mutations, translocations) deregulations that lead to their progressive neoplastic and finally malignant transformation. Molecules that are critical for evaluating the proliferation status of the corresponding tissues include mainly ki-67 (cytogenetic band: 10q26.2), and also Topoisomerase IIa/Topo IIa (cytogenetic band: 17q21.2). Both of them demonstrate different expression patterns in every cell cycle phase and their estimated expression as Nuclear Labeling Index (NLI) is a very useful tool for assessing the aggressiveness of the examined pre- and malignant tissues. In fact, ki-67 expression increases as a cell progresses through the cell cycle, with highest expression being seen in G2/M phase cell, whereas Topo IIa is expressed in proliferating cells in the late S phase with a peak in G2-M phases. Concerning colon adenocarcinoma, high expression levels of them seem to correlate with advanced disease and also with modified response rates to specific chemotherapeutic agents, such as doxorubicin, an inhibitor of Topo IIa. In the current molecular review we explored the role of these proliferative markers in colon adenocarcinoma and their influence in the tumor biological behavior.

Oral squamous cell carcinoma (OSCC) demonstrates an increasing rate due to high risk Human Papilloma Virus (HR-HPV) persistent infection, and also to chronic cigarette and alcohol consumption. Gross chromosomal alterations (polysomy, aneuploidy, intra-chromosome rearrangements) and specific gene aberrations such as amplifications, deletions, point mutations combined or not with epigenetic ones (promoter methylations and miRNA deregulations) are responsible for the progressive transformation of normal squamous cell epithelia to the corresponding malignant. Chromosomal instability (CI) -based on structural or numerical abnormalities- leads to specific abnormal karyotypes combined or not with functional suppressor gene inactivation and oncogene overactivation in solid malignancies, including OSCC. Extensive cytogenetic analyses have shown that gross alterations (gains/losses) in chromosomes 3, 4, 7, 8, 9, 11, 14, 17, 18, 19 and also 20 form different CI patterns in OSCC, which in conjunction with an aggressive phenotype (presence of lymph nodal metastasis) negatively affect the prognosis in the corresponding patients. In the majority of OSCC cases, loss of chromosomal bands are almost equally detected compared with gains regarding the chromosomes referred above. In the current special molecular paper we explored the role of CI in the progression and biological behavior of OSCCs.

Head and neck squamous cell carcinoma (HNSCC) includes a variety of SCCs derived from the anatomic regions of the oral and nasal cavity and also of the pharynx and larynx. Oral cavity SCC (OCSCC) demonstrates an increasing rate due to viral -related (High Risk Human Papilloma Virus-HR HPV) persistent infection, cigarette smoking and alcohol consumption. Gross chromosomal alterations (polysomy, aneuploidy) and specific gene aberrations such as amplifications, deletions, point mutations combined or not with epigenetic ones (promoter methylations and miRNA deregulations) are responsible for the progressive transformation of normal squamous epithelia to the corresponding malignant. In the majority of OCSCC cases, critical genes, such as p53 are found to be inactivated, leading to an overactivated cell cycle correlated to carcinogenetic process. P53 (gene location: 17p13.1) is a suppressor gene acting as a key regulator of the cell's genomic stability, function and homeostasis. P53 aberrant overexpression is frequently observed in OCSCC tissues as a result of point mutation or deletion. In the current special article we explored the role of the p53 gene deregulation - especially focused on its mutation status - in OCSCCs.

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.

Oral squamous cell carcinoma (OSCC) is considered an aggressive malignancy, mainly due to its increased propensity to provide local and distant lymph node metastases. Gross chromosome instability (CI; polysomy/aneuploidy/monosomy), combined or not with specific gene alterations, is implicated in the development and progression of solid malignancies, including OSCC. In order to further study the relationship between these genetic alterations and the aggressive biological behavior of OSCCs, we investigated the frequency and impact of chromosome 9 numerical imbalances in these tumors. Fifty (n = 50) formalin-fixed, paraffin-embedded primary OSCC tissue sections were used. Chromogenic in situ hybridization (CISH) was implemented for detecting chromosome 9 (CEN—centromere enumeration) numerical alterations. Concerning the screening process in CISH slides, a novel, real-time reference and calibration grid platform was implemented. Chromosome 9 polysomy was observed in 8/50 (16%) tissue sections, whereas the rest of them demonstrated a normal, diploid pattern (42/50; 84%). Chromosome 9 polysomy was associated with the grade of differentiation of the examined tumors (p = 0.036). Chromosome 9 numerical imbalances (polysomy) were observed in sub-groups of OSCCs correlating with a progressive dedifferentiation of the malignant tissues. Concerning the implementation of the proposed grid-based platform as described above on CISH slides, it provides a novel, fast, and accurate screening mapping mechanism for detecting chromosome numerical imbalances.

Definitive radiotherapy is a treatment option for patients with inoperable meningiomas. The purpose of this study was to evaluate the results of stereotactic radiotherapy as first-line treatment for intracranial meningiomas that were diagnosed radiologically.Between January 2010 and June 2016, 56 patients with intracranial meningioma treated with Cyberknife- based Stereotactic Radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (hFSRT) were included. The median prescribed radiation dose was 16 Gy (range 13-18) for SRS and 25 Gy (range 18-33) for hFSRT. hFSRT doses were delivered in 3 to 5 fractions.Median follow-up was 58 months (range 6-97). Overall survival (OS) for the whole group was 89.2%; for SRS group it was 100% and for hFSRT group 87.5% (p=0.29). Progression free survival (PFS) for the whole group was 89.3%; for SRS group it was 87.5% and for hFSRT 89.5% at 5 years (p=0.93).SRS and hFSRT were effective with excellent local control rates and they can be an alternative treatment option for patients with inoperable meningiomas.

p16 (gene locus: 9p21) tumor suppressor gene is considered an important biomarker for the progression and prognosis in a variety of malignancies and pre-cancerous lesions, including high-risk (HR-) human papilloma virus (HPV)-mediated squamous intraepithelial lesions (SILs), based on cytological and the corresponding cervical intraepithelial neoplasia (CIN) histopathological categorization. p16 acts as a cyclin-dependent kinase-4 inhibitor negatively regulating the cell cycle. In persistent HPV infection, E7 oncogenic protein binds retinoblastoma protein leading to its proteolytic transformation, also triggering E2F dissociation, which increases DNA transcription and progression to S phase. This mechanism promotes aberrant p16 over-expression. Our aim was to comparatively analyze p16 protein expression patterns in laryngeal squamous cell carcinomas (LSCC) and also in SILs.Fifty (n=50) primary LSCCs tissues all non-HPV-dependent, and a set of 50 liquid-based SILs, were analyzed by immunohistochemistry and immunocytochemistry, respectively. Concerning the screening process in cytological slides, a novel real-time reference and calibration grid platform was implemented and employed.Decreased protein expression was observed in 34/50 (68%) tissues regarding LSCCs. Overall p16 expression was associated to smoking status of the patients (p=0.001), and also with the p-stage of the examined malignancies (p=0.033). A strong statistical significance was assessed correlating LSIL/HSIL cases with a progressive p16 over expression (p=0.001), also reflecting a higher CIN diagnosis (p=0.001).p16 down-regulation is a frequent genetic event in LSCCs, which is associated with advanced disease. In contrast to this, p16 over-expression triggered by a specific molecular mechanism shows a strong relationship with a progressively aggressive phenotype due to upgraded SIL/CIN cervical categorization. The first described application of the grid platform demonstrated a considerable improvement in the immunocytochemistry slide screening process enhancing the diagnostic reliability.

Human papillomavirus (HPV) is implicated in carcinogenesis of a variety of epithelia, including oropharyngeal and laryngeal. High risk (HR) HPV persistent infection in head and neck squamous cell carcinomas (HNSCC) is a significant event, but its influence regarding the prognosis and survival in these patients remains under consideration. Our aim was to analyze a series of oropharyngeal (OP) SCCs at the HPV DNA level, correlating them to the survival status of the corresponding patients.Using HPV DNA polymerase chain reaction (PCR) microarray technology, 28 formalin-fixed, paraffinembedded primary OPSCCs were cored and analyzed.Positive DNA amplicons for HPV infection were detected in 3 SCC cases (sub types: HPV 31/35/70). Interestingly, HPV persistent infection was associated with larger tumors (p=0.029) which also affected survival status (p=0.007) in the corresponding patients. Overall survival was also significantly dependent on the stage of the malignancies (p=0.022). Furthermore, tumor size was significantly and negatively correlated with age (p=0.015), meaning that younger patients will probably develop larger tumors.HPV-depended OPSCCs - although not so common as the laryngeal ones, but still not so rare in the rural population in Greece - are characterized by a combination of specific features. Our results showed that survival was adversely effected by the stage of the disease and tumor size and indirectly by the presence of HPV - especially in young adults - while the combined surgery/radiotherapy/ chemotherapy therapy seems to prolong survival. Additionally, HPV co-existence seems to be associated with larger tumors and poor survival.

BACKGROUND Oral squamous cell carcinoma (OSCC) is an aggressive neoplasm. Many chromosomal and gene alterations have been identified in OSCC, including structural and numerical changes. In this study, we implemented a molecular assay of chromosome 7 (Chr7) in order to investigate the level of its numerical instability in OSCC. MATERIALS AND METHODS Using tissue microarray technology, 30 primary OSCCs were cored and re-embedded into one recipient block. Chromogenic in situ hybridization assay was performed based on Chr7 centromeric probedetection. RESULTS Chr 7 numerical analysis detected polysomy (trisomy/ tetrasomy) in 4/30 (13.3%) of the examined tissue OSCC cores. Statistical significance was assessed correlating Chr7 numerical aberrations with stage (p=0.015), especially detected in cases not related to human papillomavirus (HPV) (p=0.01). CONCLUSION Although Chr7 polysomy is a relatively rare gross genetic event in OSSC, it affects their biological behavior leading toa progressively aggressive phenotype (advanced stage). Furthermore, Chr7 polysomy is observed more frequently in non-viral (HPV) cases.

Human papillomavirus (HPV)-mediated cervical carcinogenesis represents a well analyzed model of viral implication in epithelial malignant transformation. Mechanisms of high risk (HR) HPV-related infection seem to demonstrate a similar action regarding its implication in head and neck (HN) carcinomas, predominantly in squamous cell carcinoma (SCC) histological type. The prevalence of HR HPV subtypes - mainly HPV16 - is characterized by a broad geographic heterogeneity. Furthermore, HPV-associated HNSCCs demonstrate differences regarding sexual, molecular, epidemiological, and prognostic features compared to alcohol and tobacco dependent ones. Based on these differences, HPV-derived HNSCC appear to be a specific well-defined entity mostly affecting young to middle-aged - male mainly - non-smokers. This is a strong reason of detecting an increased HR-HPV DNA levels -due to viral transmission - in oropharyngeal and laryngeal anatomic regions. Additionally, different response rates to chemoradiation and targeted therapeutic regimens are another significant field for handling these SCC malignancies in the corresponding patients. In the current special article we explored the role of HPV-related carcinogenesis in oropharyngeal and laryngeal SCC focused on the latest molecular aspects.