Molecular pathways and targeted therapies in head and neck cancers pathogenesis.

The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors, combined with the prevalent late-stage diagnosis, poses significant challenges for clinical management. Genomic sequencing endeavors have revealed extensive alterations in key signaling pathways that regulate cellular proliferation and survival. Initiatives to engineer therapies targeting these dysregulated pathways are underway, with several candidate molecules progressing to clinical evaluation phases, including FDA approval for agents like the EGFR-targeting monoclonal antibody cetuximab for K-RAS wild-type, EGFR-mutant HNSCC treatment. Non-coding RNAs (ncRNAs), owing to their enhanced stability in biological fluids and their important roles in intracellular and intercellular signaling within HNC contexts, are now recognized as potent biomarkers for disease management, catalyzing further refined diagnostic and therapeutic strategies, edging closer to the personalized medicine desideratum. Enhanced comprehension of the genomic and immunological landscapes characteristic of HNC is anticipated to facilitate a more rigorous assessment of targeted therapies benefits and limitations, optimize their clinical deployment, and foster innovative advancements in treatment approaches. This review presents an update on the molecular mechanisms and mutational spectrum of HNC driving the oncogenesis of head and neck malignancies and explores their implications for advancing diagnostic methodologies and precision therapeutics.

A Review and Comparative Analysis of Transoral Surgical Treatment versus Conservative Management in Early-Stage Oropharyngeal Cancer.

INTRODUCTION: Oropharyngeal cancer requires a comprehensive evaluation of treatment options, including surgery, radiation therapy, and chemotherapy. It is crucial to customize these treatments based on the stage of the tumor and the overall health of the patient, enabling personalized or combined approaches. Transoral surgical techniques have regained popularity due to the advancements and limitations of non-surgical strategies. The potential influence of surgical procedures on patients' quality of life highlights the need for careful intervention selection; among them, the transoral approach has proven to be especially beneficial for early-stage oropharyngeal neoplasms. METHODS: To explore potential treatments for early-stage oropharyngeal malignancies, this study carefully reviews the literature, using information from papers, current research, and global databases. The review protocol commenced on November 2023. A comprehensive search of the PUBMED database was undertaken, employing pertinent terms associated with oropharyngeal, transoral surgery or radiotherapy, robotic surgery, and chemotherapy. RESULTS: Treating early-stage oropharyngeal neoplasms is particularly intriguing due to the multitude of variables influencing treatment decisions, leading to ongoing debates in specialized literature. Regardless of the chosen approach, maintaining a high quality of life is crucial. To assess this, standardized questionnaires from the European Organization for Research and Treatment of Cancer were employed, revealing superior outcomes for patients solely undergoing surgical intervention. Additionally, in the realm of specialized literature, cases of HPV-positive oropharyngeal neoplasms are recognized for their heightened radiosensitivity and more favorable long-term prognosis. CONCLUSIONS: Surgical intervention and radiotherapy are the main treatment options for oropharyngeal cancer, and they can be used separately or together for maximum effectiveness. Amid ongoing discussions, determining the superior effectiveness between the two options continues to be a matter of debate. This study provides a comprehensive analysis, offering valuable perspectives for future discussions. Neoplasm in the oropharynx can be effectively treated using transoral microsurgery.

Investigation of Th1/Th2 cytokine profiles in patients with laryngo-pharyngeal, HPV-positive cancers.

The aim of this study was to reveal the relationships between the features of the primary tumour, the degree of tumour stage, the presence of human papillomaviruses (HPV) in blood and the severity of Th1/Th2 serum cytokine imbalance in patients with laryngo-pharyngeal cancer. The study was performed on 50 patients (47 men and 3 women), with age ranging from 40 to 83 years (the mean of the patients' ages was 58.4 ± 9.43 years, with a median of 60 years). A control group was represented by age-matched healthy patients (with no clinical diseases). The viral DNA was detected by PCR; the cytokine levels were determined by ELISA. A clear switch from cytokine Th1 to cytokine Th2 in cancer patients, low levels of IL-2 and IFNγ in advanced stages, as well as a positive correlation of increased levels of both IL-2 and IL-12 with the early stages of laryngo-pharyngeal cancer was observed. Loco-regional metastases were correlated with increased levels of IL-8 and IL-10 and drastic decrease of IFNγ. In advanced cancer stages, we found that the most affected were IL-2 and IFNγ correlated with increased levels of Th2 cytokines. Patients with HPV present in both primary tumours and blood showed increased values of IL-4:IL-2 ratio as compared with patients with HPV-positive primary tumours only, demonstrating the aggravation of the immunosuppressive state. The most important finding of our study is that for a correct evaluation of the Th1 to Th2 switch in cancer patients, it is necessary to establish not only the negative/positive correlations between different Th1 and Th2 type cytokines, but also the ratio between them. These parameters allowed us to state that the presence of HPV DNA in blood was associated with the most severe immunological imbalance that could potentially lead to a poor prognosis of these patients. Our findings encourage us to consider that the ratio between different Th1 and Th2 cytokines could represent a useful marker for clinical and pathological evaluation of cancer patients.

Role of interferons in the antiviral battle: from virus-host crosstalk to prophylactic and therapeutic potential in SARS-CoV-2 infection.

Mammalians sense antigenic messages from infectious agents that penetrate the respiratory and digestive epithelium, as well as signals from damaged host cells through membrane and cytosolic receptors. The transduction of these signals triggers a personalized response, depending on the nature of the stimulus and the host's genetics, physiological condition, and comorbidities. Interferons (IFNs) are the primary effectors of the innate immune response, and their synthesis is activated in most cells within a few hours after pathogen invasion. IFNs are primarily synthesized in infected cells, but their anti-infective effect is extended to the neighboring cells by autocrine and paracrine action. The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 2019 was a stark reminder of the potential threat posed by newly emerging viruses. This pandemic has also triggered an overwhelming influx of research studies aiming to unveil the mechanisms of protective versus pathogenic host immune responses induced by SARS-CoV-2. The purpose of this review is to describe the role of IFNs as vital players in the battle against SARS-CoV-2 infection. We will briefly characterize and classify IFNs, present the inductors of IFN synthesis, their sensors, and signaling pathways, and then discuss the role of IFNs in controlling the evolution of SARS-CoV-2 infection and its clinical outcome. Finally, we will present the perspectives and controversies regarding the prophylactic and therapeutic potential of IFNs in SARS-CoV-2 infection.

Implications of oral dysbiosis and HPV infection in head and neck cancer: from molecular and cellular mechanisms to early diagnosis and therapy.

Head and neck cancer (HNC) is the sixth most common type of cancer, with more than half a million new cases annually. This review focuses on the role of oral dysbiosis and HPV infection in HNCs, presenting the involved taxons, molecular effectors and pathways, as well as the HPV-associated particularities of genetic and epigenetic changes and of the tumor microenvironment occurred in different stages of tumor development. Oral dysbiosis is associated with the evolution of HNCs, through multiple mechanisms such as inflammation, genotoxins release, modulation of the innate and acquired immune response, carcinogens and anticarcinogens production, generation of oxidative stress, induction of mutations. Thus, novel microbiome-derived biomarkers and interventions could significantly contribute to achieving the desideratum of personalized management of oncologic patients, regarding both early diagnosis and treatment. The results reported by different studies are not always congruent regarding the variations in the abundance of different taxons in HNCs. However, there is a consistent reporting of a higher abundance of Gram-negative species such as Fusobacterium, Leptotrichia, Treponema, Porphyromonas gingivalis, Prevotella, Bacteroidetes, Haemophilus, Veillonella, Pseudomonas, Enterobacterales, which are probably responsible of chronic inflammation and modulation of tumor microenvironment. Candida albicans is the dominant fungi found in oral carcinoma being also associated with shorter survival rate. Specific microbial signatures (e.g., F. nucleatum, Bacteroidetes and Peptostreptococcus) have been associated with later stages and larger tumor, suggesting their potential to be used as biomarkers for tumor stratification and prognosis. On the other hand, increased abundance of Corynebacterium, Kingella, Abiotrophia is associated with a reduced risk of HNC. Microbiome could also provide biomarkers for differentiating between oropharyngeal and hypopharyngeal cancers as well as between HPV-positive and HPV-negative tumors. Ongoing clinical trials aim to validate non-invasive tests for microbiome-derived biomarkers detection in oral and throat cancers, especially within high-risk populations. Oro-pharyngeal dysbiosis could also impact the HNCs therapy and associated side-effects of radiotherapy, chemotherapy, and immunotherapy. HPV-positive tumors harbor fewer mutations, as well as different DNA methylation pattern and tumor microenvironment. Therefore, elucidation of the molecular mechanisms by which oral microbiota and HPV infection influence the HNC initiation and progression, screening for HPV infection and vaccination against HPV, adopting a good oral hygiene, and preventing oral dysbiosis are important tools for advancing in the battle with this public health global challenge.

Management of Locally Advanced Laryngeal Cancer-From Risk Factors to Treatment, the Experience of a Tertiary Hospital from Eastern Europe.

Laryngeal cancer is an important oncological entity in which prognosis depends on the establishment of appropriate preventive and diagnostic measures, especially in high-risk populations. We present a retrospective two-year study (January 2021 to December 2022) with 152 patients diagnosed with laryngeal cancer from a tertiary hospital in Romania. The average age of the patients was 62 years old for both sexes, with a range from 44 to 83 years. The most frequent symptom was dysphonia with or without dyspnea in 142 cases (93.42%), followed by dyspnea alone in nine patients (5.92%) and dysphagia in one case (0.66%). Surgical treatment in this study consisted of partial laryngectomy (CO2 laser transoral tumor ablation, supraglottic horizontal laryngectomy or hemilaryngectomy), or total laryngectomy. The main treatment was total laryngectomy (63%). For the eight patients with initial organ preservation treatment, the average time of recurrence was about two-and-a-half years. For the four patients who underwent a total circular pharyngo-laryngectomy, the upper digestive tract needed to be rebuilt with a salivary bypass tube or with a tubed myocutaneous flap from the major pectoralis muscle. One strong point is characteristic of the study group in gathering patients with advanced stages of laryngeal carcinoma candidates for salvage surgery and extended reconstruction methods. The development of new prevention protocols is mandatory in Eastern European countries.

Quality-of-Life Assessment after Head and Neck Oncological Surgery for Advanced-Stage Tumours.

Squamous cell carcinoma of the head and neck (HNSCC) is a common malignancy often diagnosed in the advanced stage with a complex negative influence on the patient's quality of life (QoL). Given its multi-modal treatment, the first step is to adequately balance the needs of the patient, and the second step includes the consultations, interventions, and care provided by the medical team, with the purpose of improving the overall management of the HNSCC. Current attempts to develop and validate quality-of-life instruments specific to cancers of the head and neck have been reported, and certain questionnaires are now available. We performed a retrospective study in a tertiary centre, involving 89 patients who survived 3 years after HNSCC surgery. A patient-related outcome measurement was made using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-H&N35 instruments to assess QoL at admission and 3 years after treatment. The 3-year survivors reported an overall improvement in QoL compared with those in the pre-treatment period. The unique details of head and neck cancer treatments outline the importance of considering the characteristics of the patient population in quality-of-life research and also identify how quality-of-life data can contribute to the care provided by the multi-disciplinary team involved in a patient's follow-up.

The association between lncRNA H19 and EZH2 expression in patients with EBV-positive laryngeal carcinoma.

OBJECTIVE: Laryngeal cancer is the second most common malignancy in the head and neck, with Epstein-Barr virus infection as a risk factor. Our aim is to evaluate correlations between the expression of lncRNA H19 and EBV infection in laryngeal cancer and H19 involvement in neoplastic progression through EZH2 association. MATERIALS AND METHODS: 30 paired laryngeal tissue specimens (neoplastic and non-neoplastic) were included in the study. Nucleic acid isolation and cDNA synthesis was performed according to the manufacturer's protocol. EBV DNA and expression of lytic (BZLF1) and latent (LMP1) forms of infection were assessed in PCR assays; expression levels of H19 and EZH2 were quantified in qRT-PCR. Data was analysed using GraphPad Prism 5.0. RESULTS: Higher H19 relative expression in neoplastic vs paired non-neoplastic samples was found (p < 0.0001) with a significant increase in EBV DNA positive neoplasms (p = 0.0434). An inverse correlation between H19 and EZH2 expression levels was noticed in EBV positive cases. Additionally, increased levels of H19 in LMP1 positive samples compared with those positive for BZLF1 was found (p = 0.0593). CONCLUSIONS: lncRNA H19 and EZH2 significantly contribute to the development of laryngeal carcinoma, being correlated with EBV infection markers.

The Role of Biomaterials in Upper Digestive Tract Transoral Reconstruction.

This study aims to establish whether the use of biomaterials, particularly polydimethylsiloxane (PDMS), for surgical reconstruction of the esophagus with templates, Montgomery salivary tube, after radical oncology surgery for malignant neoplasia is an optimal choice for patients' safety and for optimal function preservation and organ rehabilitation. Structural analysis by Raman spectrometry and biomechanical properties with dynamic mechanical analysis are performed for fatigue strength and toughness, essential factors in durability of a prosthesis in the reconstruction practice of the esophagus. Nanocomposites with silicone elastomers and nanoparticles used in implantable devices and in reconstruction surgery present risks of infection and fatigue strength when required to perform a mechanical effort for long periods of time. This report takes into account the effect of silver (Ag) nanoparticles on the fatigue strength using polydimethylsiloxane (PDMS) matrix, representative for silicon elastomers used in implantable devices. PDMS with 5% (wt) Ag nanoparticles of 100-150 nm during mechanical fatigue testing at shear strength loses elasticity properties after 400 loading-unloading cycles and up to 15% shear strain. The fatigue strength, toughness, maximum shear strength, as well as clinical properties are key issues in designing Montgomery salivary tube and derivates with appropriate biomechanical behavior for each patient. Prosthesis design needs to indulge both clinical outcomes as well as design methods and research in the field of biomaterials.

Tracking down of laryngo-pharyngeal metastasis.

BACKGROUND: In Romania, the most optimistic statistics give a 5 years survival rate in approximately 33% of laryngo-pharyngeal cancer patients. Considering that a cell carrying the viral DNA is originating from primary tumor, we have tested whether HPV DNA could be detected in the blood cell of patients with laryngeal cancer as a marker of disease progression and metastases. METHODS: The study was performed on 85 patients (59 +/- 8.7 age) with laryngo-pharyngeal cancer. HPV DNA was detected in tumor using nested PCR with consensus primers, and also in local lymph nodes and/or blood cells from patients HPV positive in primary tumor. RESULTS: HPV DNA was detected in 75.29% of analyzed tumours, and all HPV16 positive samples were confirmed by mRNA E6 expression. 56.3% of patients presented HPV DNA in peripheral circulation as confirmed by PCR with E6 HPV16 specific primers followed by Southern Blot. CONCLUSION: Our results sustain that the detection of HPV DNA in blood is a "surrogate marker" of metastasis when extension of metastasis cannot be estimated, this observation is very important for management of cancer patients with laryngopharyngeal localization.

SARS-CoV-2: From Structure to Pathology, Host Immune Response and Therapeutic Management.

Coronaviruses are large, enveloped viruses with a single-stranded RNA genome, infecting both humans and a wide range of wild and domestic animals. SARS-CoV-2, the agent of the COVID-19 pandemic, has 80% sequence homology with SARS-CoV-1 and 96-98% homology with coronaviruses isolated from bats. The spread of infection is favored by prolonged exposure to high densities of aerosols indoors. Current studies have shown that SARS-CoV-2 is much more stable than other coronaviruses and viral respiratory pathogens. The severe forms of infection are associated with several risk factors, including advanced age, metabolic syndrome, diabetes, obesity, chronic inflammatory or autoimmune disease, and other preexisting infectious diseases, all having in common the pre-existence of a pro-inflammatory condition. Consequently, it is essential to understand the relationship between the inflammatory process and the specific immune response in SARS-CoV-2 infection. In this review, we present a general characterization of the SARS-CoV-2 virus (origin, sensitivity to chemical and physical factors, multiplication cycle, genetic variability), the molecular mechanisms of COVID-19 pathology, the host immune response and discuss how the inflammatory conditions associated with different diseases could increase the risk of COVID-19. Last, but not least, we briefly review the SARS-CoV-2 diagnostics, pharmacology, and future approaches toward vaccine development.

Insights on Metal Based Dental Implants and their Interaction with the Surrounding Tissues.

At present, the use of dental implants is a very common practice as tooth loss is a frequent problem and can occur as a result of disease or trauma. An implant is usually made of biocompatible materials that do not cause rejection reactions and allow the implant union with the respective bone. To achieve this goal, the implant surface may have different structures and coatings, generally used to increase the adherence of the implant to the bone and to decrease the risk of the periimplantar inflammatory reactions. This review gives some insights of the metal based materials used for dental implants, their limits, improvement strategies as well as the pathophysiology, diagnosis, treatment and prevention of periimplantary diseases.

Metallic-based micro and nanostructures with antimicrobial activity.

The spectacular progress of research in the nanotechnology field led to the achievement of important knowledge of materials at the atomic and molecular scale and the extent of the use of nanoparticles in the design of medical products, ecological processes, cosmetics and other biotechnological applications. One of the current focuses of the medical applications of nanotechnology is the development of new strategies to inhibit the activity of different microorganisms. The purpose of this review was to present the antimicrobial activity of metal cations in micro- and nanoparticulate forms and the dependence of this biological activity on shape, size and physico-chemical conditions.

Influence of Staphylococcus aureus attachment to the herpes simplex virus infected cells.

The purpose of this study was to investigate the response of HeLa cells to the interaction with inactivated Staphylococcus aureus cells and live challenge with herpes simplex virus (HSV).The results of this study are indicating that the interaction between the HeLa cells and S. aureus inactivated whole cells could modulate the host cell apoptosis and cytokine production, and therefore, influence the progression of HSV infection. The pre-treatment of HeLa cells with heat inactivated bacterial whole cells protects them from the occurrence of HSV mediated cytopathic effect, while the post viral infection treatment with bacterial cells prevents the high activation of bax/bcl-2 apoptotic pathway, a process that could change the fate of the infectious process triggered by the virus, and eventually reduce its multiplication rate. The pre-treatment of HeLa monolayer with inactivated bacterial cells 24 hours before the viral infection is increasing the expression level of TNF-a, IL-6 and IL-8 pro-inflammatory cytokines genes, also suggesting that bacterial antigens could contribute to the decrease of viral multiplication rate.

Polymicrobial wound infections: pathophysiology and current therapeutic approaches.

Acute and chronic wounds represent a very common health problem in the entire world. The dermal wounds are colonized by aerobic and anaerobic bacterial and fungal strains, most of them belonging to the resident microbiota of the surrounding skin, oral cavity and gut, or from the external environment, forming polymicrobial communities called biofilms, which are prevalent especially in chronic wounds. A better understanding of the precise mechanisms by which microbial biofilms delay repair processes together with optimizing methods for biofilm detection and prevention may enhance opportunities for chronic wounds healing. The purpose of this minireview is to assess the role of polymicrobial biofilms in the occurrence and evolution of wound infections, as well as the current and future preventive and therapeutic strategies used for the management of polymicrobial wound infections.

Biomedical applications of synthetic, biodegradable polymers for the development of anti-infective strategies.

The emergence of antibiotic resistance in microbial strains is representing one of the major threats to public health worldwide, due to the decreased or total cancelling of the available antibiotics effectiveness, correlated with the slow development of novel antibiotics. Due to their excellent biodegradability and biocompatibility, the synthetic polymers could find a lot of biomedical applications, such as the development of biomaterials with optimized properties and of drug delivery systems. This review is focusing on the applications of synthetic, biodegradable polymers for the improvement of antiinfective therapeutic and prophylactic agents (i.e., antimicrobial and anti-inflammatory agents and vaccines) activity, as well as for the design of biomaterials with increased biocompatibility and resistance to microbial colonization.

Fluorescence analysis of apoptosis induced by Pseudomonas aeruginosa in endothelial cells.

Intracellular invasion of professional phagocytic cells like monocytes and macrophages by a pathogen usually triggers the apoptosis of the host cells. The aim of this study was to evaluate if Pseudomonas aeruginosa, although not considered a classic intracellular pathogen, could adhere to endothelial cell surface, invade the intracellular compartment and subsequently induce apoptosis of the cells. The adherence and invasion capacity of P. aeruginosa to endothelial cells was monitored using Cravioto's adapted method. The apoptotic cells were evidenced by staining with Acridine orange/Ethidium bromide. The qualitative assay of bacterial adherence to the cellular substrate revealed that all tested strains adhered to endothelial cells surface, exhibiting a diffuse, aggregative or mixed (diffuse-aggregative or localized-aggregative) pattern and 20-70% adherence rates. The adherence of P. aeruginosa induced the reorganization of cytoskeleton filaments and formation of endocytic membrane expansions. Cell free P. aeruginosa culture supernatants did not induce any cell death response, as noticed in case of whole bacterial culture, showing the capacity to induce apoptosis of endothelial cells. The fluorescence microscopy examination revealed chromatin condensation, fragmented nuclei, and membrane blebbing and apoptotic bodies in pathogen invaded cells.

Significance of serum antibodies against HSP 60 and HSP 70 for the diagnostic of infectious diseases.

Heat shock proteins (HSP) represent important antigenic targets for the immune response, playing an important role in the pathology and infectious diseases control. The purpose of this work was to investigate the levels of HSP60 and HSP70 specific antibodies in the bloodstream of patients with different bacterial infections and cancer, in order to evaluate their potential role as diagnosis markers of different infectious diseases. Detection of specific anti-HSP 60 and HSP 70 serum levels was performed by ELISA. Statistical analysis of data by multivariate logistic regression was performed using GraphPadPrism software and statistical tests based on chi-square and Student t-test. High levels of anti-HSP60 were found in patients with localized infections, while the levels of anti- HSP70 were higher in the group with generalized infections. The serum levels of both anti-HSP 60 and anti-HSP70 were significantly increased in patients with Gram-negative bacterial infections, as compared with patients harbouring infections produced by Gram-positive and fungal strains, demonstrating their potential use as additional diagnosis and prognosis markers in infections with this etiology.

Orbital complications of fungal pan-sinusitis in uncontrolled diabetes.

ABSTRACT: The purpose of our clinical case presentation is to emphasize the role of ear, nose and throat specialist in early recognition and urgent treatment of mucormycosis, which is a rare infection caused by fungus belonging to the order Mucorales. They are known opportunistic organisms, which potentially invade and infect a host with depressed immunity. In our paper we present a case of an uncontrolled diabetic male with orbital complications caused by a fungal pan-sinusitis. The typical presentation of rhino-orbital fungal infection is that of anterior orbital inflammation, severe visual loss, external ophthalmoplegia and fever. Our diagnostic was based on an otolaryngological, ophthalmological, imagistic but especially biopsy exam, which is the only one that can make the certain diagnostic in this case. We followed the standard treatment for these situations. Early recognition and treatment with urgent surgical debridement and systemic antifungal therapy is the key to the management of rhino-orbital mucormycosis and is necessary to limit the spread of infection, which can lead to high morbidity and mortality. Therefore, health practitioners should be familiar with the signs and symptoms of the disease.The authors certify that they do not have any financial or personal relationships that might bias the content of this work.

Immunologic and cytogenetic markers expressed in non-Hodgkin lymphoma of head and neck.

Very often, the first doctor who examines a patient with malignant lymphoma is an ENT specialist, because non-Hodgkin lymphoma is five times more frequent than Hodgkin disease in the head and neck region. Approximately 25% of extranodal lymphoma occurs in the head and neck and extranodal presentation is twice as frequent as nodal presentation. This paper present a study of the patients from ENT, Head & Neck Surgery Clinic of Coltea Clinical Hospital, Bucharest, Romania, diagnosed with malignant lymphoma. We developed a specific scheme for collecting data about patients, together with pathology details, immunology and cytogenetic markers. We tried to establish a relation between immunologic and cytogenetic markers and the clinical evolution of non-Hodgkin lymphoma. For this study, we analyzed data regarding CD10, CD5, CD20, Bcl-2, Bcl-6, Ki67 expression obtained from 58 patients with follicular lymphoma. An attempt was made to correlate the presence of certain immunohistochemical and cytogenetic markers with the evolution and aggressiveness of the disease, and we can say that Bcl-2 is positive in all tumor subtypes, being associated relatively frequently with CD5 expression, and is a marker of poor prognosis, while Bcl-6 is positive especially in the tumor forms associated with the predominance of small cells and is a marker of favorable prognosis.