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.

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.

Exploring the HIV-1 Rev Recognition Element (RRE)-Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs.

Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to exhibit strong anti-HIV activity likely based on inhibitory actions on virus transcription and Rev-mediated viral RNA export. After obtaining six analogs designed to modify the benzo[c]fluorenone system of the parent molecule, we examined their antiretroviral and toxicity properties together with their capacity to recognize the Rev Recognition Element (RRE) of the virus RNA and inhibit the RRE-Rev interaction. The results indicated that both the benzo[c] and cyclopentanone components of benfluron are required for strong RRE-Rev target engagement and antiretroviral activity and revealed the relative impact of these moieties on RRE affinity, RRE-Rev inhibition, antiviral action and cellular toxicity. These data provide insights into the biological properties of the benzo[c]fluorenone scaffold and contribute to facilitating the design of new anti-HIV agents based on the inhibition of Rev function.

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.

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.

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.

The low-resolution structural models of hepatitis C virus RNA subdomain 5BSL3.2 and its distal complex with domain 3'X point to conserved regulatory mechanisms within the Flaviviridae family.

Subdomain 5BSL3.2 of hepatitis C virus RNA lies at the core of a network of distal RNA-RNA contacts that connect the 5' and 3' regions of the viral genome and regulate the translation and replication stages of the viral cycle. Using small-angle X-ray scattering and NMR spectroscopy experiments, we have determined at low resolution the structural models of this subdomain and its distal complex with domain 3'X, located at the 3'-terminus of the viral RNA chain. 5BSL3.2 adopts a characteristic 'L' shape in solution, whereas the 5BSL3.2-3'X distal complex forms a highly unusual 'Y'-shaped kissing junction that blocks the dimer linkage sequence of domain 3'X and promotes translation. The structure of this complex may impede an effective association of the viral polymerase with 5BSL3.2 and 3'X to start negative-strand RNA synthesis, contributing to explain the likely mechanism used by these sequences to regulate viral replication and translation. In addition, sequence and shape features of 5BSL3.2 are present in functional RNA motifs of flaviviruses, suggesting conserved regulatory processes within the Flaviviridae family.

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.

De-escalation studies in HPV-positive oropharyngeal cancer: How should we proceed?

Human papilloma virus (HPV) is a well-established causative factor in a subset of squamous cell carcinomas of the head and neck (HNSCC). Although HPV can be detected in various anatomical subsites, HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is the most common HPV-related malignancy of the head and neck, and its worldwide incidence is constantly rising. Patients with OPSCC are generally younger, have less co-morbidities and generally have better prognosis due to different biological mechanisms of carcinogenesis. These facts have generated hypotheses on potential treatment modifications, aiming to minimize treatment-related toxicities without compromising therapy efficacy. Numerous randomized clinical trials have been designed to verify this strategy and increasingly real-world evidence data from retrospective, observational studies is becoming available. Until now, the data do not support any modification in contemporary treatment protocols. In this narrative review, we outline recent data provided by both randomized controlled trials and real-world evidence of HPV-positive OPSCC in terms of clinical value. We critically analyze the potential value and drawbacks of the available data and highlight future research directions. This article was written by members and invitees of the International Head and Neck Scientific Group.(www.IHNSG.com).

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 impact of the COVID-19 pandemic on the management of head and neck cancer patients at a tertiary care institution in Poland.

AIM OF THE STUDY: To assess the impact of the COVID-19 pandemic on the diagnosis and treatment of patients at a tertiary hospital in Poland. MATERIAL AND METHODS: This was a retrospective review of head and neck cancer patients who presented to the multidisciplinary tumour board (MTB) during the 12-month period from March 2020 to February 2021 and compared to patients who presented to the MTB during the prior, pre-pandemic 12-month period from February 2019 to March 2020: Patient demographic and clinical variables were compared: sex, age at diagnosis, distance from hospital, date of first visit, radiological diagnosis, pathology specimen, MTB meeting, and initiation of primary and adjuvant treatment. RESULTS: The number of patients who presented to the MTB increased by 22% (278 to 340) from the pre-pandemic to the pandemic period. The mean time from MTB presentation to treatment initiation increased significantly from 17.1 to 21.7 days. The mean time from first visit to treatment start increased from 44.7 to 54.4 days. The proportion of patients with early-stage oropharyngeal cancer who underwent primary surgery rose from 47.3% to 86.6%. The percentage of patients who received palliative radiotherapy increased from 20.5% to 32.9%. The proportion of patients who received best supportive care rose from 1.8% to 6.2%. CONCLUSIONS: One of the most notable findings of this study was the increased time from first visit to treatment initiation, which could negatively impact patient outcomes. The differences in the treatment received in these two periods should be further evaluated to determine their influence on survival.

Management of clinically negative neck in salivary gland cancers - elective neck dissection, irradiation, or surveillance?

AIM OF THE STUDY: To retrospectively assess treatment outcomes among patients treated for salivary gland cancers at our institution to determine which of the three most common treatment approaches - elective neck dissection (END), elective neck irradiation (ENI), or observation - provide the best results. MATERIAL AND METHODS: A total of 122 patients were identified who had undergone primary surgery for SGC followed by END, ENI, or observation. The patients were classified into three groups according to the treatment approach used to manage the neck: END, ENI, or observation. The main outcome measures were disease-free survival (DFS) and overall survival (OS). We also sought to identify the risk factors potentially associated with neck metastasis and treatment failure. RESULTS: 106 patients met all inclusion criteria. Of these 106 patients, 27 (25.7%) underwent END, 17 (16.0%) underwent ENI, and 62 (58.5%) observation. There were no statistically significant differences between the three groups in any of the following variables: advanced age (> 70); presence of locally advanced disease (T3 or T4); perineural invasion; lymphovascular invasion; and primary tumour location. Treatment failure was higher (non-significantly) in the END group (25.9%) vs. the observation (21.0%) and ENI (11.8%) groups. No differences (Kaplan-Meir curves) were observed among the three groups in terms of DFS or OS. CONCLUSIONS: Our results show that elective neck dissection does not appear to provide any benefit to patients treated for malignant salivary gland cancer. Importantly, these findings contradict most of the currently available research. However, due to methodological differences among the available studies, our findings cannot be compared directly to other studies.

Organ Preservation and Late Functional Outcome in Oropharyngeal Carcinoma: Rationale of EORTC 1420, the "Best of" Trial.

Dysphagia represents one of the most serious adverse events after curative-intent treatments with a tremendous impact on quality of life in patients with head and neck cancers. Novel surgical and radiation therapy techniques have been developed to better preserve swallowing function, while not negatively influencing local control and/or overall survival. This review focuses on the current literature of swallowing outcomes after curative treatment strategies. Available results from recent studies relevant to this topic are presented, demonstrating the potential role of new treatment modalities for early- and intermediate-stage oropharyngeal cancers. Based on this, we present the rationale and design of the currently active EORTC 1420 "Best of" trial, and highlight the potential of this study to help prioritizing either surgery- or radiation-based treatment modalities for the treatment of oropharyngeal cancer in the future.

Skin barrier function in patients under radiation therapy due to the head and neck cancers - Preliminary study.

AIM: To present the possibility of non-invasive monitoring of the skin after radiotherapy in regards of epidermal barrier function. BACKGROUND: Radiodermatitis constitutes 95% of all side effects in patients after radiotherapy. The proper assessment of the severity of radiodermatitis can be determined using semi-quantitative clinical scores [Common Terminology Criteria for Adverse Events v 4.0 (CTCAE)].The most accepted way to analyze the epidermal barrier function is to determine Transepidermal Water Loss (TEWL). MATERIAL AND METHODS: In prospective study, we included 16 patients diagnosed with head and neck cancer treated with radiotherapy or concomitant chemoradiation in whom we performed non-invasive assessments of the skin barrier function, including TEWL measurement. The final analysis included 6 patients (4 treated with adjuvant radiotherapy, 2 with radical chemoradiation). Clinical assessment of irradiated skin was based on target lesion score (TLS) and CTCAE v 4.0. RESULTS: The mean TLS score in the middle of irradiation was 1.6 points, after last irradiation it was 2.3 points; 3 months later the mean TLS score was: 0. CTCAE v 4.0 criteria: 2 patients had grade 0, 3 patients - grade 1; 1 patient - grade 2. There were statistically significant differences in TEWL related to irradiated skin in the following time intervals: before vs. in the middle; before vs. day after; in the middle vs. day after; in the middle vs. 3 months after; day after vs. 3 months after. CONCLUSIONS: The study showed that radiotherapy causes skin barrier dysfunction in all patients independently of clinical radiodermatitis. The biophysical features of this dysfunction can precede clinical symptoms and they can be assessed by non-invasive and objective methods.

An ultrasonographic monitoring of skin condition in patients receiving radiotherapy for head and neck cancers.

Radiodermatitis is one of the commonest side effects of radiotherapy. They are usually assessed by semi-quantitative clinical scores, which are not validated and may be subject to inter-observer variability. A few previous studies suggested that high-frequency ultrasonography (HF-USG) is useful in the assessment of the acute phase of radiation dermatitis in breast cancer patients. (a) To monitor skin changes by HF-USG during the course of radiotherapy due to head and neck cancers, and (b) to determine whether there is any connection between skin sonograms and the skin scoring criteria. This prospective, observational study includes patients diagnosed with head and neck cancers, treated with radiotherapy or concomitant chemoradiation. The final analysis includes six patients. In every patient, the HF-USG as well as dermatological assessment (target lesion score-TLS and CACE v. 4.0) were performed 4×: before, in the middle, day after, and 3 months after radiotherapy. There were significant differences between non-irradiated skin thickness and thickness of skin with clinically obvious radiodermatitis (TLS grade 1-4; P < .0001), as well as between irradiated, unchanged skin thickness (TLS grade 0) and thickness of skin with clinically obvious radiodermatitis (TLS grade 1-4; P = .0002). There was no significant difference between non-irradiated and irradiated, unchanged skin thickness (TLS grade 0; P = .9318). In four patients, we demonstrated subepidermal low echogenic band (SLEB). HF-USG can be useful tool to noninvasive and objective assessment of skin changes during radiotherapy.

Prognostic markers in salivary gland cancer and their impact on survival.

BACKGROUND: The role of molecular markers in salivary gland carcinoma (SGC) is not well understood. We evaluated molecular marker expression and their prognostic value. METHODS: Immunohistochemical analysis of 124 tumor specimens was performed to determine expression of androgen (AR), estrogen (ER), and progesterone (PR) receptors and epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 receptor (PD-L1), and PD-L1 in tumor-infiltrating mononuclear cell (TIMC). Survival outcomes (disease-free survival [DFS] and overall survival [OS]), pT and N classification, margin status, and treatment failure were assessed. RESULTS: Most patients (78; 62.9%) had early-stage SGC. AR positivity and EGFR positivity were detected in 21.0% and 78.6%, respectively, of tumors. AR positivity and PD-L1 negativity were associated with locally advanced disease. PD-L1-negativity was associated with higher recurrence (38.5% vs 0%; P < .001) and worse DFS. OS and DFS were worse in patients with AR+ or HER2+ disease. CONCLUSIONS: Several molecular markers-AR and HER2 positivity and PD-L1 negativity-were associated with worse clinical outcomes. Prospective, multi-institutional trials are needed to determine the prognostic value of these markers.