The impact of XPC gene single nucleotide polymorphism rs2228001 on head and neck cancer patients' response to radiotherapy treatment.

Background: Head and neck squamous carcinoma (HNSC) is the sixth most common neoplasm, with a 40-50% overall survival rate. HNSC standard treatment depends on tumor size, metastasis or human papillomavirus (HPV) status including surgery, chemotherapy, and radiotherapy. The last two may lead to defects in the tumor microenvironment and cancer cell biology as disorders in DNA damage repair systems. Here, we evaluate the correlation between single nucleotide polymorphism (SNP) rs2228001 in the XPC gene with the early and late adverse effects of radiotherapy, determine the distribution of the SNP and post-treatment follow-up in HNSC patients. Materials and methods: Head and neck cancer tissues and clinical data were obtained from 79 patients. The SNP of the XPC gene (rs2228001) was evaluated with polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). The chi-square test was used to determine the correlation between mutation and adverse effects occurrence. Results/Conclusion: Single nucleotide polymorphism rs2228001 in the XPC gene is correlated with the early adverse effect of skin reaction and the late adverse effect of elevated C-reactive protein (CRP) levels in the HNSC patients.

Risk factors for local and nodal recurrence in patients with head and neck cutaneous squamous cell carcinoma in a high-reference oncological center in Poland.

Background: The behavior of cutaneous squamous cell carcinoma (cSCC) of the head and neck remains poorly understood. There is much controversy regarding the risk of local and nodal recurrences, as well as individual/environmental factors that increase the risk, such as tumor size, perineural invasion, and the state of the immune system. The objective was to analyze factors influencing local and/or regional lymph node recurrence in patients with cSCC in the head and neck region. Material and methods: This retrospective single-centre study included 521 patients with cSCC of the head and neck region, with local recurrence observed in 11% and nodal recurrence in 5%. Various potential risk factors were analyzed. Results: Statistically significant risk factors for both local and nodal recurrence include: tumor recurrence (p < 0.0001, p < 0.0001 respectively), tissue inflammation confirmed histopathologically (p < 0.0001, p = 0.0019, respectively), tumor size ≥ 10 mm (p = 0.018, p = 0.0056, respectively), invasion depth > 2 mm (p = 0.0238, p = 0.0031, respectively). Risk factors significant only for local recurrence include: surgical margins (p = 0.0056), tumor differentiation grade (p = 0.0149). No risk factors were found to be significant solely for nodal recurrence. Conclusion: The authors argue that, in addition to classically recognized risk factors for local and nodal recurrence, attention should be paid to the presence of tissue inflammation confirmed histopathologically. It is also suggested to consider a tumor size of 10 mm as a threshold, increasing the risk of recurrence, instead of the frequently proposed 20 mm.

Chloride intracellular channels in oncology as potential novel biomarkers and personalized therapy targets: a systematic review.

Background: The chloride intracellular channels (CLICs) family includes six ion channels (CLIC1-CLIC6) expressed on the cellular level and secreted into interstitial fluid and blood. They are involved in the physiological functioning of multiple systems as well as the pathogenetic processes of cancer. CLICs play essential roles in the tumor microenvironment. The current systematic review aimed at identifying and summarizing the research of CLICs in oncology on clinical material to assess CLICs' potential as novel biomarkers and personalized therapy targets. Materials and methods: The authors systematically searched the PubMed database for original articles concerning CLIC research on clinical material of all types of cancer - fluids and tissues. Results: Fifty-three articles investigating in summary 3944 clinical samples were qualified for the current review. Studied material included 3438 tumor samples (87%), 437 blood samples (11%), and 69 interstitial fluid samples (2%). Studies investigated 21 cancer types, mostly hepatocellular carcinoma, colorectal, ovarian, and gastric cancer. Importantly, CLIC1, CLIC2, CLIC3, CLIC4, and CLIC5 were differently expressed in cancerous tissues and patients' blood compared to healthy controls. Moreover, CLICs were found to be involved in several cancer-associated signaling pathways, such as PI3K/AKT, MAPK/ERK, and MAPK/p38. Conclusion: CLIC family members may be candidates for potential novel cancer biomarkers due to the contrast in their expression between cancerous and healthy tissues and secretion to the interstitial fluid and blood. CLICs are investigated as potential therapeutic targets because of their involvement in cancer pathogenesis and tumor microenvironment.

Radiation-induced skin injury in the head and neck region: pathogenesis, clinics, prevention, treatment considerations and proposal for management algorithm.

Worldwide increase of head and neck cancers ranks these malignancies among top causes of cancer in human population. Radiation induced skin injury (RISI) is one of the major side effects of radiotherapy (RT). Skin of the neck is exposed to radiation due to necessity of therapeutic or prophylactic (elective) irradiation of neck lymph nodes and target organs, including the larynx and hypopharynx. The location of the neck exposes these regions of the skin to various additional exposomes such as ultraviolet radiation (UVR), pollution and cigarette smoke. There are many controversies or inconsistencies regarding RISI, from molecular aspects and therapy to terminology. There is lack of high-quality and large-sample studies in both forms of RISI: acute (aRISI) and chronic (cRISI). Finally, no gold standards in the management of aRISI and cRISI have been established yet. In this article, the authors discuss the pathogenesis, clinical picture, prevention and clinical interventions and present a proposed treatment algorithm.

Improving therapeutic strategies for Head and Neck Cancer: Insights from 3D hypoxic cell culture models in treatment response evaluation.

Hypoxia in the tumor core negatively affects the outcome of patients with head and neck squamous cell carcinoma (HNSCC). Nevertheless, its role in predicting treatment response requires further exploration. Typically, reduced oxygen levels in the tumor core correlate with diminished efficacy of radiotherapy, chemotherapy, and immunotherapy, which are commonly used for HNSCC patients' treatment. Understanding the mechanistic underpinnings of these varied treatment responses in HNSCC is crucial for enhancing therapeutic outcomes and extending patients' overall survival (OS) rates. Standard monolayer cell culture conditions have major limitations in mimicking tumor physiological features and the complexity of the tumor microenvironment. Three-dimensional (3D) cell cultures enable the recreation of the in vivo tumor attributes, encompassing oxygen and nutrient gradients, cellular morphology, and intracellular connections. It is vital to use the 3D model in treatment response studies to mimic the tumor microenvironment, as evidenced by the decreased sensitivity of 3D structures to anticancer therapy. Accordingly, the aim of the study was to delineate the utility of the 3D models of hypoxic head and neck tumors in drug screening and treatment response studies.

The two-faced role of RNA methyltransferase METTL3 on cellular response to cisplatin in head and neck squamous cell carcinoma in vitro model.

Background: RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of N 6-methyladenosine (m6A) modification. This epigenetic feature contributes to the structural and functional regulation of RNA and consequently may promote tumorigenesis, tumor progression, and cellular response to anticancer treatment (chemo-, radio-, and immunotherapy). In head and neck squamous cell carcinoma (HNSCC), the commonly used chemotherapy is cisplatin. Unfortunately, cisplatin resistance is still a major cause of tumor relapse and patients' death. Thus, this study aimed to investigate the role of METTL3 on cellular response to cisplatin in HNSCC in vitro models. Materials and methods: HNSCC cell lines (H103, FaDu, and Detroit-562) with stable METTL3 knockdown (sgMETTL3) established with CRISPR-Cas9 system were treated with 0.5 tolerable plasma level (TPL) and 1 TPL of cisplatin. Further, cell cycle distribution, apoptosis, CD44/CD133 surface marker expression, and cell's ability to colony formation were analyzed in comparison to controls (cells transduced with control sgRNA). Results: The analyses of cell cycle distribution and apoptosis indicated a significantly higher percentage of cells with METTL3 knockdown 1) arrested in the G2/S phase and 2) characterized as a late apoptotic or death in comparison to control. The colony formation assay showed intensified inhibition of a single cell's ability to grow into a colony in FaDu and Detroit-562 METTL3-deficient cells, while a higher colony number was observed in H103 METTL3 knockdown cells after cisplatin treatment. Also, METTL3 deficiency significantly increased cancer stem cell markers' surface expression in all studied cell lines. Conclusion: Our findings highlight the significant influence of METTL3 on the cellular response to cisplatin, suggesting its potential as a promising therapeutic target for addressing cisplatin resistance in certain cases of HNSCC.

Understanding Hypoxia-Driven Tumorigenesis: The Interplay of HIF1A, DNA Methylation, and Prolyl Hydroxylases in Head and Neck Squamous Cell Carcinoma.

Hypoxia-inducible factor 1-alpha (HIF1A) is a key transcription factor aiding tumor cells' adaptation to hypoxia, regulated by the prolyl hydroxylase family (EGLN1-3) by directing toward degradation pathways. DNA methylation potentially influences EGLN and HIF1A levels, impacting cellular responses to hypoxia. We examined 96 HNSCC patients and three cell lines, analyzing gene expression of EGLN1-3, HIF1A, CA9, VEGF, and GLUT1 at the mRNA level and EGLN1 protein levels. Methylation levels of EGLNs and HIF1A were assessed through high-resolution melting analysis. Bioinformatics tools were employed to characterize associations between EGLN1-3 and HIF1A expression and methylation. We found significantly higher mRNA levels of EGLN3, HIF1A, GLUT1, VEGF, and CA9 (p = 0.021; p < 0.0001; p < 0.0001; p = 0.004, and p < 0.0001, respectively) genes in tumor tissues compared to normal ones and downregulation of the EGLN1 mRNA level in tumor tissues (p = 0.0013). In HNSCC patients with hypermethylation of HIF1A in normal tissue, we noted a reduction in HIF1A mRNA levels compared to tumor tissue (p = 0.04). In conclusion, the differential expression of EGLN and HIF1A genes in HNSCC tumors compared to normal tissues influences patients' overall survival, highlighting their role in tumor development. Moreover, DNA methylation could be responsible for HIF1A suppression in the normal tissues of HNSCC patients.

The Assessment of the Long-Term Impact of Radiotherapy on Biophysical Skin Properties in Patients after Head and Neck Cancer.

Background and Objectives: Chronic radiotherapy-induced skin injury (cRISI) is an irreversible and progressive condition that can significantly impact a patient's quality of life. Despite the limited literature available on the assessment of the epidermal barrier in cRISI, there is a consensus that appropriate skincare, including the use of emollients, is the primary therapeutic approach for this group of patients. The aim of this study was to evaluate the biophysical properties of the skin during the late period (at least 90 days) following radiation therapy (RT) for head and neck cancer. Materials and Methods: This was a single-center prospective non-randomized study. It involved the analysis of 16 adult patients with head and neck cancer who underwent RT at the Greater Poland Cancer Center, along with 15 healthy volunteers. The study and control groups were matched for gender and age (p = 0.51). Clinical assessment, based on the LENT-SOMA scale, was conducted for all patients. Evaluation of the skin's biophysical properties included: an analysis of transepidermal water loss (TEWL), stratum corneum hydration (SCH), and skin visualization using high-frequency ultrasonography (HF-USG). Results: A significantly higher TEWL was observed in the irradiated area compared to the control area in the study group (p = 0.004). However, there was no statistically significant difference in SCH (p = 0.073). Additionally, no significant difference was observed in the values of TEWL and SCH in the irradiated area between the group of patients with and without clinically obvious RISI (p = 0.192 and p = 0.415, respectively). The skin thickness of the irradiated area, assessed by HF-USG, did not differ significantly from the skin thickness of the control area (p = 0.638). Furthermore, no difference in skin thickness was observed in patients with clinical features of cRISI in the irradiated and control areas (p = 0.345). The mean time after RT was 6.1 years. Conclusions: This study marks the first demonstration of epidermal barrier damage in patients in the long term following RT for head and neck cancer. The impairment of the epidermal barrier was observed independently of evident cRISI features. This observation underscores the necessity to recommend appropriate skin care, including the use of emollients, for all patients following RT. We also suggest that HF-USG examination is generally inconclusive in determining the degree of skin damage in the late period after RT.

Skull base surgery for malignant tumors: The 2nd international collaborative study (1995-2015).

BACKGROUND: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. PATIENTS AND METHODS: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. RESULTS: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. CONCLUSION: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

A Matter of Margins in Oral Cancer-How Close Is Enough?

In patients with oral cancer, the risk factors for local, regional, and distant recurrence according to margin status have not been well established. We aimed to determine the risk factors for recurrence by margin status and to identify a margin cut-off point for improved survival in patients with close margins. We retrospectively reviewed adult patients treated at our centre from 2009 to 2021 for primary oral cancer. Margins were classified as positive (<1 mm), close (1 to 4.9 mm), or clear (>5 mm). Univariate and multivariate analyses were performed. A total of 326 patients (210 men) were included. The mean age was 59.1 years. Margin status was close (n = 168, 51.5%), clear (n = 83, 25.4%), or positive (n = 75, 23.0%). In the univariate analysis, positive surgical margins (HR = 7.53) had the greatest impact on distant failure. Positive surgical margins-without nodal involvement-had the greatest impact on the risk of distant failure. In the close margin group, the optimal cut-off for disease-free survival (AUC = 0.58) and overall survival (AUC = 0.63) was a deep margin > 3 mm, with survival outcomes that were comparable to the clear margin group. These finding suggest that margins < 5 mm may be sufficient in certain well-defined cases. Prospective studies are warranted to confirm these findings.

Oral cancer in young adults: should we approach these patients differently?

Objective: The influence of age on treatment outcomes in oral cancer is unclear. We aimed to determine the prevalence of oral cancer in adults under age 45 and to compare treatment outcomes by age. Methods: Retrospective study of 284 patients treated for oral cancer from 2010 to 2021. The primary analysis involved the full cohort stratified by age (< vs. ≥ 45y). The second analysis included all patients under age 45 (n=44) matched 1:1 by sex and stage to older patients (age 55-70). Results: In the primary analysis, the only significant difference was more comorbidities in the older group (p<0.001). In the matched-pair analysis, older patients were more likely to be smokers (75% vs. 54%; p=0.045) and had more comorbidities (p=0.007). The mean PLR and NLR values were significantly higher in the younger group. Conclusions: No significant differences were observed between age groups in disease stage or outcomes, suggesting that other variables are more important.

Artificial intelligence in head and neck surgery: Potential applications and future perspectives.

Artificial intelligence (AI) has the potential to improve the surgical treatment of patients with head and neck cancer. AI algorithms can analyse a wide range of data, including images, voice, molecular expression and raw clinical data. In the field of oncology, there are numerous AI practical applications, including diagnostics and treatment. AI can also develop predictive models to assess prognosis, overall survival, the likelihood of occult metastases, risk of complications and hospital length of stay.

Senescence in head and neck squamous cell carcinoma: relationship between senescence-associated secretory phenotype (SASP) mRNA expression level and clinicopathological features.

BACKGROUND: Cellular senescence is a state characterized by cell-cycle arrest and apoptotic resistance. Senescence in cancer may be induced by oncogenes or therapy. While cellular senescence might play an important role in protection against cancer development, elevated and uncontrolled senescent cells accumulation may promote carcinogenesis by secreting a collection of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). MATERIAL AND METHODS: We determined the gene expression at mRNA level of selected cellular senescence markers (p16 and LMNB1) and SASP factors (IL-6, IL-1b, CXCL-1 and TNF-α) in 72 cancerous tissues and 64 normal tissues obtained from patients with head and neck squamous cell carcinoma (HNSCC) and correlated this data with patients' clinical follow-up. RESULTS: Our results indicate higher levels of selected SASP factors in cancerous compared to normal tissues. We presented the relationship between SASP factors expression at the transcript level and the progression of the disease. Moreover, we proposed CXCL1 as a candidate biomarker differentiating normal tissues from cancerous ones and IL1b expression as a molecular factor related to increased TNM stage. CONCLUSION: Our primary study indicates that SASP expression may be associated with some clinicopathological features. However, a more detailed study is needed to present specific role of senescence-related mechanism and SASPs especially in tumor therapy response and in relation to the patient's immune system condition.

The Analysis of Selected miRNAs and Target MDM2 Gene Expression in Oral Squamous Cell Carcinoma.

MiRNAs could play an important role in tumorigenesis and progression. The oncoprotein MDM2 (murine double minute 2) was identified as a negative regulator of the tumour suppressor p53. This study aims to analyse the expression of the MDM2 target miRNA candidates (miR-3613-3p, miR-371b-5p and miR-3658) and the MDM2 gene in oral squamous cell carcinoma tumour and margin samples and their association with the selected socio-demographic and clinicopathological characteristics. The study group consisted of 50 patients. The miRNAs and MDM2 gene expression levels were assessed by qPCR. The expression analysis of the miRNAs showed the expression of only one of them, i.e., miR-3613-3p. We found no statistically significant differences in the miR-3613-3p expression in tumour samples compared to the margin samples. When analysing the effect of smoking on miR-3613-3p expression, we demonstrated a statistically significant difference between smokers and non-smokers. In addition, we showed an association between the miR-3613-3p expression level and some clinical parameters in tumour samples (T, N and G). Our study demonstrates that miR-3613-3p overexpression is involved in the tumour progression of OSCC. This indicates that miR-3613-3p possesses potential prognostic values.

Polydopamine-Based Material and Their Potential in Head and Neck Cancer Therapy-Current State of Knowledge.

Head and neck cancers (HNC) are among the most common cancers in the world. In terms of frequency of occurrence in the world, HNC ranks sixth. However, the problem of modern oncology is the low specificity of the therapies used, which is why most of the currently used chemotherapeutic agents have a systemic effect. The use of nanomaterials could overcome the limitations of traditional therapies. Researchers are increasingly using polydopamine (PDA) in nanotherapeutic systems for HNC due to its unique properties. PDA has found applications in chemotherapy, photothermal therapy, targeted therapy, and combination therapies that facilitate better carrier control for the effective reduction of cancer cells than individual therapies. The purpose of this review was to present the current knowledge on the potential use of polydopamine in head and neck cancer research.

CLIC1 plasma concentration is associated with lymph node metastases in oral squamous cell carcinoma.

BACKGROUND: Previous studies have shown that the chloride intracellular channel 1 (CLIC1) protein is overexpressed in oral squamous cell carcinoma (OSCC) and nasopharyngeal carcinoma. Patients with these diseases had significantly higher CLIC1 plasma levels than healthy controls. OBJECTIVES: To determine the plasma concentration of CLIC1 in patients with OSCC and laryngeal squamous cell carcinoma (LSCC). MATERIAL AND METHODS: We collected blood samples from patients diagnosed with OSCC (n = 13) and LSCC (n = 7), as well as from healthy controls (n = 8). The blood samples were centrifuged to obtain plasma and stored at -80°C. The CLIC1 plasma concentration was determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean CLIC1 plasma concentration was higher in the OSCC group than in the LSCC and control groups. Patients with OSCC and nodal metastases had significantly higher CLIC1 plasma concentration levels than nonmetastatic patients (p < 0.0001; Tukey's multiple comparisons test) and controls (p = 0.0004). The CLIC1 concentration correlated significantly with the presence of nodal spread (p = 0.0003; Spearman's r = 0.8613) and overall TNM staging (p = 0.0167; Spearman's r = 0.6620). No differences in CLIC1 plasma levels were observed between the LSCC and control groups. The CLIC1 plasma concentration was not associated with age, sex, tumor stage, or tumor grade. CONCLUSIONS: There were no differences in CLIC1 plasma concentration between healthy controls and patients with LSCC. However, our findings suggest that the presence of this protein in plasma may be associated with lymphatic metastasis in patients with OSCC. More research is needed to confirm this possible association.

Dietary intervention for tertiary prevention in head and neck squamous cell carcinoma survivors: clinical and translational results of a randomized phase II trial.

Background: There is a strong need for preventive approaches to reduce the incidence of recurrence, second cancers, and late toxicities in head and neck squamous cell carcinoma (HNSCC) survivors. We conducted a randomized controlled trial (RCT) to assess a dietary intervention as a non-expensive and non-toxic method of tertiary prevention in HNSCC survivors. Methods: Eligible participants were disease-free patients with HNSCC in follow-up after curative treatments. Subjects were randomized 1:1 to receive a highly monitored dietary intervention plus the Word Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention (intervention arm) or standard-of-care recommendations (control arm). The planned sample size for the event-free survival evaluation (primary endpoint) was not reached, and the protocol was amended in order to investigate the clinical (nutritional and quality-of-life questionnaires) and translational study [plasma-circulating food-related microRNAs (miRNAs)] as main endpoints, the results of which are reported herein. Results: One hundred patients were screened, 94 were randomized, and 89 were eligible for intention-to-treat analysis. Median event-free survival was not reached in both arms. After 18 months, nutritional questionnaires showed a significant increase in Recommended Food Score (p = 0.04) in the intervention arm vs. control arm. The frequency of patients with and without a clinically meaningful deterioration or improvement of the C30 global health status in the two study arms was similar. Food-derived circulating miRNAs were identified in plasma samples at baseline, with a significant difference among countries. Conclusion: This RCT represented the first proof-of-principle study, indicating the feasibility of a clinical study based on nutritional and lifestyle interventions in HNSCC survivors. Subjects receiving specific counseling increased the consumption of the recommended foods, but no relevant changes in quality of life were recorded between the two study arms. Food-derived plasma miRNA might be considered promising circulating dietary biomarkers.

Local recurrence risk in head and neck basal cell carcinoma.

PURPOSE: The aim of the study was to ascertain the risk factors of local recurrence in primary basal cell carcinoma of the head and neck Material and methods: A retrospective analysis of 545 patients with head and neck primary basal cell carcinoma treated in years 2008 - 2018 was done. The following data was recorded: age, sex, tumor site, histological subtype, greatest dimension, margin status, experience of operating surgeon and local recurrence Results: Most of the tumors were located nose (165; 30,2%) and auricle (119; 21,8%). The most common pathological subtype was nodular (119; 21,8%). Three hundred and ninety-four tumors (72,2%) were under 20mm in diameter. Positive surgical margins were noted in 107 (19,6%) cases. Local recurrence was observed in 52 (9,5%) cases, of which 29 (29/107; 27%) had positive surgical margins, in 23 (23/438; 5,2%) cases margins were free, which was the only statistically significant factor (p<0,001; OR 6,71; CI 3,69 - 12,2). CONCLUSIONS: The results of our study have shown that positive surgical margin remains the strongest risk factor for local recurrence. With surgical excision being the gold standard of treatment the greatest emphasis should be placed on avoiding such scenario in high risk patients.

European Head and Neck Society recommendations for head and neck cancer survivorship care.

Survivors of head and neck cancer can experience long-term consequences of the cancer and subsequent treatments even after the cancer has resolved. Increasingly clinicians are aware of the social, psychological, financial, and emotional impacts of these cancers, in addition to the support required for the physical symptoms. This review provides recommendations on the long-term management and support required for survivors of head and neck cancer in the European healthcare setting.

Current indications and patient selection for transoral robotic surgery in head and neck cancer - a brief review.

Transoral robotic surgery (TORS) continues to gain momentum in minimally invasive surgery. Not only is TORS potentially curative in many cases, but it also addresses the growing emphasis on functional outcomes and quality of life. The main anatomical areas in which TORS is used are the oropharynx and larynx; however, it is becoming increasingly common in thyroid surgery and neck dissections. With growing popularity, the number of indications for TORS in oropharyngeal and laryngeal cancer also increases. However, not all patients are good candidates for this technique, and thus patient selection is essential, with careful assessment of patient-related factors (e.g. comorbidities and endoscopic access) and disease-related variables, such as tumour location, disease staging, and the involvement of surrounding anatomical structures. The aim of the present article is to briefly review the current and emerging indications for TORS in head and neck cancer and the main factors related to patient selection.