Matrix-based molecular mechanisms, targeting and diagnostics in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a head and neck cancer (HNC) with a high mortality rate. OSCC is developed in the oral cavity and it is triggered by many etiologic factors and can metastasize both regionally and distantly. Recent research advances in OSCC improved our understanding on the molecular mechanisms involved in and the initiation of OSCC metastasis. The key roles of the extracellular matrix (ECM) in OSCC are an emerging area of intensive research as the ECM macromolecular network is actively involved in events that regulate cellular morphological and functional properties, transcription and cell signaling mechanisms in invasion and metastasis. The provisional matrix that is formed by cancer cells is profoundly different in composition and functions as compared with the matrix of normal tissue. Fibroblasts are mainly responsible for matrix production and remodeling, but in cancer, the tumor matrix in the tumor microenvironment (TME) also originates from cancer cells. Even though extensive research has been conducted on the role of ECM in regulating cancer pathogenesis, its role in modulating OSCC is less elucidated since there are several issues yet to be fully understood. This critical review is focused on recent research as to present and discuss on the involvement of ECM macromolecular effectors (i.e., proteoglycans, integrins, matrix metalloproteinases) in OSCC development and progression.

Insights into metastatic roadmap of head and neck cancer squamous cell carcinoma based on clinical, histopathological and molecular profiles.

The incidence of head and neck cancer (HNC), constituting approximately one in ten cancer cases worldwide, affects approximately 644,000 individuals annually. Managing this complex disease involves various treatment modalities such as systemic therapy, radiation, and surgery, particularly for patients with locally advanced disease. HNC treatment necessitates a multidisciplinary approach due to alterations in patients' genomes affecting their functionality. Predominantly, squamous cell carcinomas (SCCs), the majority of HNCs, arise from the upper aerodigestive tract epithelium. The epidemiology, staging, diagnosis, and management techniques of head and neck squamous cell carcinoma (HNSCC), encompassing clinical, image-based, histopathological and molecular profiling, have been extensively reviewed. Lymph node metastasis (LNM) is a well-known predictive factor for HNSCC that initiates metastasis and significantly impacts HNSCC prognosis. Distant metastasis (DM) in HNSCC has been correlated to aberrant expression of cancer cell-derived cytokines and growth factors triggering abnormal activation of several signaling pathways that boost cancer cell aggressiveness. Recent advances in genetic profiling, understanding tumor microenvironment, oligometastatic disease, and immunotherapy have revolutionized treatment strategies and disease control. Future research may leverage genomics and proteomics to identify biomarkers aiding individualized HNSCC treatment. Understanding the molecular basis, genetic landscape, atypical signaling pathways, and tumor microenvironment have enhanced the comprehension of HNSCC molecular etiology. This critical review sheds light on regional and distant metastases in HNSCC, presenting major clinical and laboratory features, predictive biomarkers, and available therapeutic approaches.

The interplay between tumor and nodal microenvironments for the formation of nodal premetastatic niche in head and neck cancer.

Head and neck cancer (HNC) encompasses a number of malignancies originating in the head and neck area. In patients with HNC, cervical lymph nodes constitute metastatic sites for cancer cells that escape primary tumors. The premetastatic niche (PMN) is a crucial concept in understanding metastatic disease. PMN refers to the microenvironment resulting mainly from primary tumor cells to foster metastatic tumor cell growth at a distant organ. Tumor microenvironment (TME) plays an important part in the pathogenesis of PMN. A significant prognostic factor is the close association between metastases of lymph nodes and organ dissemination in many different malignancies. The nodal premetastatic niche (NPMN) is a particular type of PMN located within the lymph nodes. NPMN formation is specifically important in HNC as regional lymph node metastasis commonly occurs. The formation happens when tumor cells create a supportive microenvironment within lymph nodes, facilitating their survival, growth, spread, and invasion. This complex mechanism involves multiple steps and cellular interactions between the primary tumor and tumor microenvironment. Several extracellular matrix (ECM) macromolecules, cytokines, and growth factors are implicated in this process. The aim of this article is to present the most recent data on the regulation of the lymph node PMN at molecular and cellular levels in HNC, as well as insights with respect to the relationship between primary tumor cells and the microenvironment of lymph nodes, and the formation of NPMN. We also critically discuss on potential targets for preventing or disrupting nodal metastases and identify potential biomarkers for predicting HNC outcomes.

mTOR deregulation in oral cavity squamous cell carcinoma.

Signal transduction pathways consist of a variety of inter- and intra-cellular molecules. They act as supporting mechanisms for cell survival and homeostasis. Among them, the phosphatidylinositol 3-kinase (PI3K)/tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role in regulating normal cell growth based on growth factor receptors (GFRs) interaction, including epidermal GFR (type II-HER2) and insulin GFR (IGF). mTOR protein acts as a serine-threonine kinase that belongs to the PI3K-related kinase family. It mediates protein and lipid synthesis, mitochondrial metabolism, biogenesis, proliferation and also negatively regulates autophagy. Two distinct multiprotein complexes have been mainly identified and cloned: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTOR is deregulated predominantly due to mutations, deletions, loss of heterozygosity (LOH) or abnormal phosphorylation of the upstream molecules inside the current pathway. Pure mTOR mutations are very rare. Development of specific inhibitors at the basis of targeted therapeutic strategies such as rapamycin (rapalogs) is an evolution in handling patients with mTOR abnormal overactivity. In the current special article we explored the role of the gene deregulation leading to abnormal protein expression in oral cavity squamous cell carcinoma (SCC).

Topoisomerase I deregulation in laryngeal squamous cell carcinomas based on tissue microarray analysis.

PURPOSE: Topoisomerases (types: I/IIa-b/IIIa-b) represent a super-family of nucleic enzymes involved in the DNA replication, transcription, recombination, and also chromosome topological formation. Topoisomerase's I (Topo I- gene location: 20q12) aberrant expression is a frequent genetic event in a variety of solid malignancies. Topo I inhibition promotes cell death due to DNA damage and for this reason it is a target for specific targeted chemotherapy (camptothecin, topotecan, irinotecan). Our aim was to investigate the role of abnormal Topo I protein expression in laryngeal squamous cell carcinomas (LSCC) in which there are very limited data regarding the influence of the marker. METHODS: Using tissue microarray (TMA) technology, 50 formalin-fixed, paraffin-embedded primary laryngeal SCCs were cored and re-pembedded into one recipient block. Immunohistochemistry was performed using anti- Topo I antibody. Digital image analysis was also implemented for evaluating objectively the protein expression levels on the corresponding stained nuclei. RESULTS: Topo I protein overexpression (moderate to high staining intensity values) was observed in 32/50 (64%) tissue cores, whereas low expression rates were detected in 18/50 (36%) cases. Topo I overall expression was strongly associated with the differentiation grade of the examined tumors (p=0.021). No other statistical correlations were identified. CONCLUSIONS: Topo I overexpression is observed in a significant subset of LSCCs affecting the level of differentiation in them. Additional molecular studies focused on the mechanism of Topo I gene/protein deregulation (i.e. amplification, abnormal epigenetic promoter methylation, mRNA aberrant expression) are necessary discriminating the eligible patients for applying specific chemotherapeutic strategies based on anti-Topo I agents.

Chronic rhinocerebral mucormycosis: a rare case report and review of the literature.

Rhinocerebral mucormycosis is an invasive infection caused by filamentous fungi of the Mucoraceae family. The rhinocerebral form of the disease represents the most common form and has two distinct clinical entities. The common presentation consists of a rapidly progressive infection with high mortality rate, while the other presentation is that of a chronic infection with lower mortality. In the present paper we report a rare case of chronic rhinocerebral mucormycosis. An 85-year-old male with a 6-month history of purulent and odorous nasal discharge, and sporadic episodes of epistaxis and anosmia, presented to the outpatient department of our clinic. Initial cultures were positive only for Pseudomonas aeruginosa. The patient was unresponsive to ciprofloxacin treatment, developing necrotic areas of the nasal septum suspicious for rhinocerebral mucormycosis. Admission to the ENT clinic followed, with histopathologic evaluation of the vomer bone confirming the diagnosis. The patient was treated with amphotericin B and was discharged 3 weeks later on oral posaconazole therapy. Chronic rhinocerebral mucormycosis may present with atypical symptoms or coinfection with another agent. A high degree of clinical suspicion is required for correct diagnosis and prompt initiation of appropriate treatment.

Extracellular matrix biomechanical roles and adaptation in health and disease.

Extracellular matrices (ECMs) are dynamic 3D macromolecular networks that exhibit structural characteristics and composition specific to different tissues, serving various biomechanical and regulatory functions. The interactions between ECM macromolecules such as collagen, elastin, glycosaminoglycans (GAGs), proteoglycans (PGs), fibronectin, and laminin, along with matrix effectors and water, contribute to the unique cellular and tissue functional properties during organ development, tissue homoeostasis, remodeling, disease development, and progression. Cells adapt to environmental changes by adjusting the composition and array of ECM components. ECMs, forming the 3D bioscaffolds of our body, provide mechanical support for tissues and organs and respond to the environmental variables influencing growth and final adult body shape in mammals. Different cell types display distinct adaptations to the respective ECM environments. ECMs regulate biological processes by controlling the diffusion of infections and inflammations, sensing and adapting to external stimuli and gravity from the surrounding habitat, and, in the context of cancer, interplaying with and regulating cancer cell invasion and drug resistance. Alterations in the ECM composition in pathological conditions drive adaptive responses of cells and could therefore result in abnormal cell behavior and tissue dysfunction. Understanding the biomechanical functionality, adaptation, and roles of distinct ECMs is essential for research on various pathologies, including cancer progression and multidrug resistance, which is of crucial importance for developing targeted therapies. In this Viewpoint article, we critically present and discuss specific biomechanical functions of ECMs and regulatory adaptation mechanisms in both health and disease, with a particular focus on cancer progression.

Survival Analysis of Elderly Patients With Laryngeal Cancer After Total Laryngectomy: A Retrospective Cohort Study.

Objective This study investigates the overall survival (OS) of elderly patients who underwent total laryngectomy for laryngeal cancer (LC) and examines the impact of tumor-node-metastasis (TNM) staging on survival rates. Methods A retrospective cohort study utilized data from the Otorhinolaryngology Clinic at the University Hospital of Patras, including 75 elderly patients (>65 years) who underwent total laryngectomy for LC between 2000 and 2015. Survival analysis was performed using the Kaplan-Meier estimator, with comparisons made using the Log-rank test. Statistical significance was defined as the p-value being less than or equal to 0.05. Results Over the 16-year period, new LC cases were predominantly male (97.3%) with a mean age of 73.88 years (range: 65-89 years). Most patients were smokers (96%) and alcohol users (54.7%). Histologically, 18.7% of tumors were classified as poorly differentiated, 65.3% as moderately differentiated and 16% as well differentiated. Post-surgical TNM staging indicated 10.7% stage II, 37.3% stage III and 52% stage IV, primarily located in the glottis (62.7%) and followed by supraglottis (34.7%). All patients underwent total laryngectomy, with 69.3% and 37.3% receiving neck dissection and adjuvant therapy (chemotherapy or radiotherapy), respectively. During follow-up, 39 patients died, with 74.3% due to disease-related causes. Five-year OS rates were 44.6%, with variations by stage (stage II: 62.5%, stage III: 55.8%, stage IV: 32.4%; p=0.039) and age (65-75 years: 51.7%, >75 years: 34.7%; p=0.039). Conclusions TNM staging of the laryngeal cancer significantly influences the overall survival of elderly patients undergoing total laryngectomy for LC. Early diagnosis of the disease is crucial for patient survival.

Non­Hodgkin's lymphomas of the lacrimal sac: Current insights and future directions (Review).

Non-Hodgkin's lymphoma (NHL) of the lacrimal sac is a rare, yet clinically significant entity within the spectrum of ocular malignancies. While primary lacrimal sac lymphoma is uncommon, it poses unique diagnostic and therapeutic challenges due to its anatomical location and potential for aggressive behavior. Despite advancements being made in the current understanding and treatment of NHL, research that specifically addresses the involvement of the lacrimal sac is currently lacking. Thus, the present review aimed to provide insight into the epidemiology, clinical presentation, diagnostic modalities, histopathological features, treatment strategies and prognosis of lacrimal sac NHL. Through a methodical analysis of previous literature, the present review highlights the diverse spectrum of NHL subtypes that affect the lacrimal sac, including diffuse large B-cell lymphoma, extranodal marginal zone lymphoma, mantle cell lymphoma and follicular lymphoma. Moreover, the present review discusses the role of advanced imaging techniques in accurate staging and treatment planning, including computed tomography (CT), magnetic resonance imaging and positron emission tomography-CT. The present review also discusses evolving treatment approaches, such as surgical intervention, chemotherapy, radiotherapy, immunotherapy, combinations of the aforementioned treatments and targeted therapy. In addition, the present review highlights the significance of multidisciplinary collaboration in attaining optimal outcomes for individuals with lacrimal sac NHL. The present review aimed to provide a basis for 'further investigations into novel treatment modalities and prognostic markers that may aid in guiding personalized management strategies, ultimately improving outcomes for patients with NHL.

Medialization thyroplasty for voice restoration after transoral cordectomy.

Fourteen dysphonic patients who had previously undergone total or extended cordectomy underwent medialization thyroplasty. A minimum delay of 6 months was respected to allow the spontaneous "neocord" formation, to evaluate the voice recovery achieved by speech therapy alone and to avoid an undiagnosed early recurrence. Surgery was performed under general anaesthesia, using a laryngeal mask, because undermining the fibrous tissue at the inner side of the thyroid ala is a prolonged and difficult procedure. This step was essential to ensure an easy placement of the implant and to avoid tearing the fibrous tissue, with subsequent risk of implant extrusion. Visual control of the implant implementation was obtained by flexible videoendoscopy. The Montgomery(®) implant system (Boston, Westborough, MA) was used for the majority of the cases. Hand-made modified Montgomery implants or Gore-tex(®) were used in case of extended scarring or peculiar anatomic defect. The voice assessment showed a decrease of the VHI score from 50.5 to 39.4; a decrease of G from 2.4 to 2; an increase of maximum phonation time (MPT) from 6.2 to 7.3 s; a decrease of the maximum fundamental frequency (Fo-high) from 338.7 to 242.4 Hz and a decrease of the phonation quotient from 1,144.9 to 544.9 ml/s. The lower intensity (I-low) remained unchanged, from 60 to 58 dB. Statistically significant improvement was noted only for VHI and G grading. A decrease of the voice efforts and fatigue were noticed by all the patients.

The Role of Exosomes in Epithelial-to-Mesenchymal Transition and Cell Functional Properties in Head and Neck Cancer.

Exosomes are nanosized vesicles that are produced in normal and cancer cells, promoting intracellular communication. In head and neck cancer (HNC), exosomes are involved in many undesirable events of cancer development and progression, including angiogenesis, tumor microenvironment (TME) remodeling, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, extracellular matrix (ECM) degradation, and drug resistance. Exosomes are involved in altering the signaling pathways in recipient cells by the cargoes they carry. Proteins, lipids, and nucleic acids such as DNA fragments and RNAs (i.e., mRNAs, miRNAs, and long non-coding RNAs) are carried in the exosomes to promote cell communication. EMT is a critical cellular process in which epithelial cells are forced to become mesenchymal cells by the actions of SNAIL/SLUG, TWIST, and ZEB family transcription factors carried in exosomes that facilitate metastasis. In this critical review, we focused on exosome biogenesis, their cargoes, and their involvement in EMT induction and metastasis during HNC. Insights into exosome isolation and characterization, as well as their key role in ECM remodeling and degradation, are also presented and critically discussed. More importantly, this article addresses the role of exosomes in HNC and drug resistance induced in drug-sensitive cancer cells. In addition, exosomes have a great potential to be used as diagnostic and therapeutic tools. A better understanding on exosome biogenesis, composition, and functions in HNC will aid in developing novel therapeutic strategies to treat HNC, overcome therapy resistance, and avoid metastasis, which is a significant cause of cancer death.

Deep Learning Techniques and Imaging in Otorhinolaryngology-A State-of-the-Art Review.

Over the last decades, the field of medicine has witnessed significant progress in artificial intelligence (AI), the Internet of Medical Things (IoMT), and deep learning (DL) systems. Otorhinolaryngology, and imaging in its various subspecialties, has not remained untouched by this transformative trend. As the medical landscape evolves, the integration of these technologies becomes imperative in augmenting patient care, fostering innovation, and actively participating in the ever-evolving synergy between computer vision techniques in otorhinolaryngology and AI. To that end, we conducted a thorough search on MEDLINE for papers published until June 2023, utilizing the keywords 'otorhinolaryngology', 'imaging', 'computer vision', 'artificial intelligence', and 'deep learning', and at the same time conducted manual searching in the references section of the articles included in our manuscript. Our search culminated in the retrieval of 121 related articles, which were subsequently subdivided into the following categories: imaging in head and neck, otology, and rhinology. Our objective is to provide a comprehensive introduction to this burgeoning field, tailored for both experienced specialists and aspiring residents in the domain of deep learning algorithms in imaging techniques in otorhinolaryngology.

MMP-2 expression in 102 patients with glottic laryngeal cancer.

In order to evaluate the potential of matrix metalloproteinase 2 (MMP-2) as a prognostic factor for glottic laryngeal cancer. One hundred and two surgical specimens from patients with glottic laryngeal cancer who underwent laryngectomy for their disease in the University Hospital of Patras, Greece from 1998 to 2005 were reviewed retrospectively regarding MMP-2 expression via immunohistochemistry. Immunostaining was performed using a streptavidin-biotin peroxidase complex technique (LSAB). Results revealed that 54 of 102 patients (52.9%) had positive cytoplasmic staining for MMP-2. Kaplan-Meier analysis demonstrated statistically significant difference (p = 0.037) for the 5-year overall survival rate between the groups with positive and negative MMP-2 expression, and marginal statistical significance for the disease free survival rate (p = 0.048). The capsule rupture of metastatic lymph nodes and MMP-2 expression in primary tumor site also seems to be related (p = 0.047). Statistical significance could not be established between MMP-2 expression and the clinicopathological features of the disease (T stage, N stage, clinical stage, differentiation). In conclusion, MMP-2 expression was related with worse overall and disease-free survival and could be considered as a potential marker of poor prognosis.

Laryngeal cancer and passive smoking: the neglected factor?

In the present paper we investigate the relationship of environmental tobacco smoke (ETS) exposure to laryngeal cancer. 209 patients who were diagnosed with laryngeal cancer from 2000 to 2009 at the University Hospital of Patras, Western Greece, were reviewed with regard to patient age, disease stage at presentation, tumor differentiation, tobacco product use, alcohol consumption, occupation, and ETS exposure in the working environment. Pearson Chi-square method was used to determine the effect of ETS exposure on cancer stage, TNM classification and tumor differentiation in the dichotomized population (exposed vs. not exposed) and in groups of low, medium and high ETS exposure. ETS exposure in the working environment was found to significantly affect overall disease stage and T stage (p < 0.01) both in the dichotomic analysis and the group analysis. Minor significance was also noted for N stage (p = 0.047) in the exposure group analysis. Our data suggest that occupational ETS exposure presents a contributing risk factor for laryngeal cancer that requires further research to determine its significance.

Pharyngocutaneous fistula complicating laryngectomy: can metronidazole help?

AIM: To evaluate the use of metronidazole as a prophylactic agent against pharyngocutaneous fistula (PCF) formation. PATIENTS AND METHODS: Seventy patients who underwent total laryngectomy between 2000 and 2008 in our department were divided into two groups. The first group (M+ group) was placed on a 10-day metronidazole regimen (2 days prior to surgery and 7 days following). The second group (M- group) received only regular preoperative chemoprophylaxis. RESULTS: In total, 17 (24.3%) incidents of PCF were reported, 3 of which were in the M+ group, with the remainder in the M- group. A statistically significant reduction in the PCF rate was noted in favor of metronidazole in the overall population (p = 0.005), as well as in the patient group that had received radiotherapy prior to surgery (p = 0.03). CONCLUSION: Metronidazole administered for a total of 10 days pre- and postoperatively seems to lower the incidence rate of PCF formation.

Ruptured infectious ICA pseudoaneurysm into the sphenoid sinus after maxillofacial infection, successfully treated by selective embolization.

BACKGROUND: Intracranial infectious aneurysms are cerebral aneurysms caused by pathogen-induced inflammation undermining the arterial wall. We present a rare case of inflammatory pseudoaneurysm of cavernous internal carotid artery (ICA). CASE DESCRIPTION: A 51-year-old female with a recent diagnosis of acute lymphoblastic leukemia developed maxillofacial infection with Pseudomonas and Acinetobacter after chemotherapy onset. Initial plain computed tomography (CT) revealed bony dehiscence of the left ICA canal, as well as bilateral protrusion of the vessel within the sphenoid sinus. Following infection spread into the left sphenoid sinus, she presented with episodes of intermittent epistaxis, without any profound vascular abnormalities on postcontrast CT. CT angiography that was performed 15 days later, due to refractory epistaxis, illustrated a large narrow necked irregular shape pseudoaneurysm of the left paraophthalmic ICA, extending into the ipsilateral sphenoid sinus. The aneurysm was completely occluded by selective embolization without parent or adjacent vessel sacrifice, documented on both intraoperative and follow-up angiogram, with no recurrence of epistaxis. CONCLUSION: Conclusively, ruptured internal carotid infectious aneurysms are rare but potentially fatal causes of epistaxis when extended into the sphenoid sinus. Selective coiling is feasible and can provide definitive treatment of these lesions.