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.

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.

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.

Does experience of the surgeon affect surgical margins in head and neck basal cell carcinoma?

<b>Aim:</b> The aim of our study was to evaluate the impact of surgical experience in a high volume head and neck surgery department on basal cell carcinoma margin status. </br></br> <b>Material and methods:</b> A retrospective analysis of 546 patients surgically treated for primary basal cell carcinoma of the head and neck region was carried out. Resections were performed by 4 specialists with equal experience in head and neck surgery and 4 ENT residents at the same level of surgical training. A margin of 3-5 mm was chosen, according to guidelines. </br></br> <b>Results:</b> The study consisted of 304 males and 242 females, mean age of 69 (range 26-100). Most of the tumors were loca-ted on the nose (165 pts; 30.2%) and auricle (119; 21.7%). The most common histological subtype was nodular (119; 21.7%). Tumor size was up to 20 mm in 394 cases (72%). Positive surgical margins were found in 112 cases (20.5%). There was no difference in terms of positive surgical margins between residents (19/119 cases; 15.9%) and specialists (93/426; 21.8%; p = 0.161). </br></br> <b>Conclusions:</b> The results of our study have shown that adequate surgical training in a dedicated head and neck surgery de-partment is an efficient factor in obtaining free surgical margins in head and neck basal cell carcinoma.

Influence of Semiquantitative [18F]FDG PET and Hematological Parameters on Survival in HNSCC Patients Using Neural Network Analysis.

The aim of this study is to assess the influence of semiquantitative PET-derived parameters as well as hematological parameters in overall survival in HNSCC patients using neural network analysis. Retrospective analysis was performed on 106 previously untreated HNSCC patients. Several PET-derived parameters (SUVmax, SUVmean, TotalSUV, MTV, TLG, TLRmax, TLRmean, TLRTLG, and HI) for primary tumor and lymph node with highest activity were assessed. Additionally, hematological parameters (LEU, LEU%, NEU, NEU%, MON, MON%, PLT, PLT%, NRL, and LMR) were also assessed. Patients were divided according to the diagnosis into the good and bad group. The data were evaluated using an artificial neural network (Neural Analyzer version 2.9.5) and conventional statistic. Statistically significant differences in PET-derived parameters in 5-year survival rate between group of patients with worse prognosis and good prognosis were shown in primary tumor SUVmax (10.0 vs. 7.7; p = 0.040), SUVmean (5.4 vs. 4.4; p = 0.047), MTV (23.2 vs. 14.5; p = 0.010), and TLG (155.0 vs. 87.5; p = 0.05), and mean liver TLG (27.8 vs. 30.4; p = 0.031), TLRmax (3.8 vs. 2.6; p = 0.019), TLRmean (2.8 vs. 1.9; p = 0.018), and in TLRTLG (5.6 vs. 2.3; p = 0.042). From hematological parameters, only LMR showed significant differences (2.5 vs. 3.2; p = 0.009). Final neural network showed that for ages above 60, primary tumors SUVmax, TotalSUV, MTV, TLG, TLRmax, and TLRmean over (9.7, 2255, 20.6, 145, 3.6, 2.6, respectively) are associated with worse survival. Our study shows that the neural network could serve as a supplement to PET-derived parameters and is helpful in finding prognostic parameters for overall survival in HNSCC.

Profiling of microRNAs in actinic keratosis and cutaneous squamous cell carcinoma patients.

Actinic keratosis (AK) is a common skin lesion often defined as premalignant with more evidence indicating it as early stage of cutaneous squamous cell carcinoma (cSCC). The AK may remain stable, transform towards incisive cSCC or in some cases revert spontaneously. Several different underlying conditions can increase risk of cSCC, however, advanced age represents major risk of AK and its progression towards cSCC indicating increased risk during chronological aging. Importantly, AK and cSCC are characterized by similar genetic profile, which lead researchers to search for novel biomarkers allowing early detection. As skin sampling is often invasive and causes scaring, in the current study, we investigated a novel approach to establish potential blood circulating genetic markers in patients diagnosed with AK and cSCC. Based on clinical diagnosis and dermoscopy, we recruited 13 patients with AK (divided into two groups: the first included patients with no more than three lesions, the second group included patients with at least ten lesions) and two additional individuals diagnosed with cSCC. Deep sequencing analysis of serum circulating miRNAs detected a total of 68 expressed miRNAs. Further analysis indicated 2 regulated miRNAs for AK cohort and 12 miRNAs for cSCC patients, while there were 26 miRNAs differentially regulated between cSCC and AK patients. There was also one commonly regulated miRNA between AK and cSCC patients and ten miRNAs that were regulated in cSCC when compared with both control and AK patients. We did not observe any differences between the AK groups. In conclusion, our analysis detected in circulation some miRNA that were previously recognized as important in AK, cSCC, and other type of skin cancer supporting this approach as potential non-invasive diagnosis of AK and cSCC.

A European survey on the practice of nutritional interventions in head-neck cancer patients undergoing curative treatment with radio(chemo)therapy.

PURPOSE: As the practice of nutritional support in patients with head and neck cancer (HNC) during curative radio(chemo)therapy is quite heterogeneous, we carried out a survey among European specialists. METHODS: A 19-item questionnaire was drawn up and disseminated via the web by European scientific societies involved in HNC and nutrition. RESULTS: Among 220 responses, the first choice was always for the enteral route; naso-enteral tube feeding was preferred to gastrostomy in the short term, while the opposite for period longer than 1 month. Indications were not solely related to the patient's nutritional status, but also to the potential burden of the therapy. CONCLUSION: European HNC specialists contextualize the use of the nutritional support in a comprehensive plan of therapy. There is still uncertainty relating to the role of naso-enteral feeding versus gastrostomy feeding in patients requiring < 1 month nutritional support, an issue that should be further investigated.

Pectoralis major myocutaneous flaps vs. revascularised free tissue flaps following salvage surgery for recurrent head and neck cancer.

PURPOSE: To assess the efficacy of two reconstructive methods: pectoralis major myocutaneous flap and revascularised free flap in salvage surgery for recurrent head and neck cancer. PATIENTS AND METHODS: We retrospectively analysed 100 cases of patients who had recurrent head and neck cancer and were treated in the Department of Head and Neck Surgery between 2011 and 2021. The study participants were divided into two groups depending on the method of reconstruction: 62 patients who underwent revascularised free flap reconstruction and 38 patients with pectoralis major myocutaneous flap. RESULTS: In total, flap necrosis was observed in 20 cases, 18 of which were in the group who received revascularised free flaps (29.03%) and 2 in the pectoralis major myocutaneous flap group (5.26%). The OR of flap failure in the free flap group vs. pectoralis major flap group was 7.36 (95% CI 0.85-63.75; p=0.067) In the group who underwent revascularised free flap reconstruction the total surgery time was significantly longer than in the other group (p < 0.0001). CONCLUSION: We suggest the advantages of using pectoralis major myocutaneous flaps for recurrent head and cancers, which is of the utmost importance for malnourished patients in poor general health and whose primary treatment comprised of a combination therapy.

miRNAs as Biomarkers for Diagnosing and Predicting Survival of Head and Neck Squamous Cell Carcinoma Patients.

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. These tumors originate from epithelial cells of the upper aerodigestive tract. HNSCC tumors in different regions can have significantly different molecular characteristics. While many microRNAs (miRNAs) have been found to be involved in the regulation of the carcinogenesis and pathogenesis of HNSCC, new HNSCC related miRNAs are still being discovered. The aim of this study was to explore potential miRNA biomarkers that can be used to diagnose HNSCC and prognose survival of HNSCC patients. For this purpose, we chose a panel of 12 miRNAs: miR-146a-5p, miR-449a, miR-126-5p, miR-34a-5p, miR-34b-5p, miR-34c-5p, miR-217-5p, miR-378c, miR-6510-3p, miR-96-5p, miR-149-5p, and miR-133a-5p. Expression of these miRNAs was measured in tumor tissue and neighboring healthy tissue collected from patients diagnosed with HNSCC (n = 79) in either the oral cavity, oropharynx, or larynx. We observed a pattern of differentially expressed miRNAs at each of these cancer locations. Our study showed that some of these miRNAs, separately or in combination, could serve as biomarkers distinguishing between healthy and tumor tissue, and their expression correlated with patients' overall survival.

Prognostic Factors Associated with Successful Salvage Surgery in Recurrent Oral Cancer.

Most patients with recurrent oral cancer are not eligible for salvage surgery. Among those who are candidates for surgical salvage, failure rates are high. Given the potential negative impact of salvage surgery on quality of life (QoL)-particularly in unsuccessful interventions-the decision to operate must be weighed carefully. However, the variables associated with successful surgical salvage in oral cancer have not been clearly established. In the present retrospective study, we sought to determine the factors associated with disease recurrence and successful salvage surgery. We evaluated the following parameters in patients (n = 261) treated for primary oral cancer at our institution from 2010 to 2017: age; T/N status; perineurial invasion; lymphovascular invasion; extranodal extension; and margin status. In total, 36 patients (33%) were considered eligible for salvage surgery. Four variables were significantly associated with suitability for salvage surgery: early primary T stage, no primary neck disease (N0), no positive margins in the primary resection, and no adjuvant radiotherapy following primary resection. The only variable significantly associated with improved salvage outcomes was negative margin status after the primary tumor resection, underscoring the importance of margin status on treatment outcomes. Additional studies are needed to identify other factors associated with successful salvage surgery in order to better stratify patients according to the likelihood of success, thus potentially avoiding the negative impact on QoL in patients who undergo unsuccessful surgery.

The m6A RNA Modification Quantity and mRNA Expression Level of RNA Methylation-Related Genes in Head and Neck Squamous Cell Carcinoma Cell Lines and Patients.

RNA methylation at the nitrogen sixth of adenosine (m6A, N6-methyladenosine) is the most abundant RNA modification which plays a crucial role in all RNA metabolic aspects. Recently, m6A modification has been assigned to mediate the biological processes of cancer cells, but their significance in HNSCC development is still poorly described. Thus, the main aim of this study was to globally quantify m6A modification by the mass spectrometry approach and determine the mRNA expression level of selected m6A RNA methyltransferase (METTL3), demethylase (FTO), and m6A readers (YTHDF2, YTHDC2) in 45 HNSCC patients and 4 cell lines (FaDu, Detroit 562, A-253 and SCC-15) using qPCR. In the results, we have not observed differences in the global amount of m6A modification and the mRNA level of the selected genes between the cancerous and paired-matched histopathologically unchanged tissues from 45 HNSCC patients. However, we have found a positive correlation between selected RNA methylation machinery genes expression and m6A abundance on total RNA and characterized the transcript level of those genes in the HNSCC cell lines. Moreover, the lack of global m6A differences between cancerous and histopathologically unchanged tissues suggests that m6A alterations in specific RNA sites may specifically influence HNSCC tumorigenesis.