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Background: The novel nanomaterials PNA-TN (PN) and PNA-TN-Dox (PND) have been shown to have strong inhibitory effects on breast cancer; however, it is unclear whether PN and PND have anti-head and neck squamous cell carcinoma (HNSCC) activity, and their potential mechanisms of activity are unknown. So, our study aims to explore the therapeutic effects of PN and PND on HNSCC and their possible mechanisms., Methods: We used a series of phenotypic research to evaluate the effects of PN + Laser (L) and PND + L on the biological function of HNSCC cells in vitro and in vivo. We subsequently used mechanism research to examine changes in mRNA and protein expression related to apoptosis, epithelial‒mesenchymal transition (EMT), and the JNK signalling pathway., Results: Our study revealed that PN and PND have strong inhibitory effects on HNSCC cells both in vitro and in vivo. In vitro, PN and PND significantly inhibited the proliferation, migration, invasion and EMT ability of HNSCC cells and promoted apoptosis; the inhibitory effect in the PND + L group was significantly greater than that in the PN + L group. In vivo, both treatments led to significant reductions in tumour volume and weight. Notably, the tumour volume and weight in the PND + L group were significantly lower than those in the PN + L group. Mechanism research confirmed that PN + L activated the expression of apoptosis-related proteins and inhibited the expression of EMT-related proteins via the JNK pathway. Furthermore, the anti-HNSCC effect of PN + L was blocked after the use of a JNK pathway inhibitor., Conclusion: Treatment with PN + L or PND + L significantly inhibited the malignant progress of HNSCC cells, and the therapeutic effect of PND + L was significantly stronger than that of PN + L. The JNK signalling pathway is a key mechanism by which PN exerts its anti-HNSCC activity., Competing Interests: Declarations Ethics approval and consent to participate The Laboratory Animal Welfare and Ethics Committee of Renmin Hospital of Wuhan University reviewed and approved the animal procedures (Approval No: WDRM20240704B). All animal experiments were conducted following the NIH Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80 − 23; revised 1978). Consent for publication All authors have confirmed that all data from this study is publishable and have seen the final version of the article for publication. Written informed consent for publication was obtained from all participants. Competing interests The authors report no conflicts of interest in this work., (© 2024. The Author(s).)

Pembrolizumab-containing regimens are the standard first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC). The neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein-to-albumin ratio (CAR) have been reported to be important prognostic factors in a variety of carcinomas, but none have been investigated in combination with pembrolizumab and chemotherapy or in first-line treatment. Seventy-four patients with R/M HNSCC received pembrolizumab-containing regimens at Tohoku University Hospital, Sendai, Japan, from April 2020 to March 2023. Patient characteristics, tumor response, overall survival (OS), progression-free survival (PFS), and laboratory findings were reviewed. Associations between NLR, CAR, and survival outcomes were analyzed. The 1-year OS and 1-year PFS rates were 60.4% and 18.1%, respectively. The disease control rate was 66.2%. In multivariate analysis, low NLR (< 5) was significantly associated with better OS and PFS. NLR may be a predictive factor for OS and PFS in patients with R/M HNSCC treated with a pembrolizumab-containing regimen., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval This study was approved by the Ethics Committee of the Faculty of Medicine of the Tohoku University School of Medicine (Approval No.2021-1-351) and performed in line with the ethical standards described in the Declaration of Helsinki. Patient consent statement Patient consent for this study was obtained with the opt-out method., (© 2024. The Author(s).)

Purpose: With the coming era of digital medicine and healthcare technology, mathematical modeling of tumors has become a key step to optimize and realize precision radiation therapy. The purpose of this study was to develop a mathematical model for simulating the change of head and neck (HN) tumor volume during radiation therapy., Methods and Materials: A formula was developed to describe the dynamic change of oxygenated compartment within a tumor, which was combined with the lethal lesions model to describe various cell processes during radiation therapy, including potentially lethal lesion repair and misrepair, cell proliferation/loss, and tumor reoxygenation. Parameter sensitivity analysis was performed to evaluate the impacts of lesion- and repair-related biological factors on radiation therapy outcomes., Results: We tested our model on 14 available patients with HN cancer and compared the performance with 3 other models. The mean error of our model for the 12 good fit cases was 12.2%, which is considerably smaller than that of the linear quadratic model (19.7%), the generalized linear quadratic model (19.1%), and a 4-level cell population model (16.6%). Correlation analysis results revealed that for small tumors, there was a positive correlation (correlation coefficient r=0.9416) between hypoxic fraction (hf) and tumor volume, whereas the correlation became negative and not significant (r=-0.4365) for large tumors. It is demonstrated from sensitivity analysis that the production rate of lethal lesions (η l ) has a far greater impact on tumor volume than other parameters. The hf had an insignificant impact on tumor volume but had a notable influence on the volume of surviving cells. The final volume of surviving cells athf=0.5 was almost 8 ×10 2 times that of hf=0.01. The potentially lethal lesion-related parameters (the production rate of potentially lethal lessions per unit dose η pl , the rate of correct repair per unit time ε pl , and the rate of binary misrepair per unit time ε 2pl ) had rather small impacts (<1%) on both tumor volume and the volume of surviving cells, which indicates that the repaired and misrepaired sublethal cells only take up a small portion of the total cancer cell population., Conclusions: A population-based tumor-volume model for HN cancer during radiation therapy with a dynamic oxygenated compartment was developed in this study. Comprehensively considering the damage process of tumor cells caused by radiation therapy, the accurate prediction of the volume change of HN tumors during treatment was revealed. Meanwhile, various cell activities and their principles in the process of antitumor treatment were reflected, which has positive clinical reference significance for radiobiology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) is notorious for poor prognoses, and effective biomarkers are urgently needed for early diagnosis of HNSCC patients. We investigate the role of alkaline ceramidase 1 (ACER1) and its relationship with immune infiltration in HNSCC. The differential expression and clinical prognostic significance of ACER1 in HNSCC patients are explored using bioinformatics methods and verified in human HNSCC samples. Genetic mutation, DNA methylation and drug sensitivity linked with ACER1 are examined. The potential biological function of ACER1 co-expression genes is assessed, and a series of functional assays are performed on ACER1in vitro. The results comprehensively reveal a relationship between ACER1 and immune infiltration in HNSCC patients. ACER1 expression is significantly downregulated in HNSCC tissues and closely correlated with better prognoses for HNSCC patients, and this prognostic significance is determined by distinct clinical characteristics. Genetic alteration and promoter hypomethylation of ACER1 are involved in progression of HNSCC, and ACER1 expression is significantly related to several drug sensitivities. Functional analysis shows that ACER1 co-expression genes are mainly enriched in the sphingolipid signaling pathway associated with inhibition of tumorigenesis, leading to better prognoses for HNSCC patients. In vitro, ACER1 overexpression inhibits proliferation and migration, induces apoptosis, and promotes adhesion of Fadu and SCC9 cells. In addition, high ACER1 expression is closely linked with infiltration levels of immune cells, and strongly associated with biomarkers of immune cells in HNSCC, suggesting the important role of ACER1 in regulating tumor immunity in HNSCC patients. In summary, ACER1 may be a useful indicator for diagnosis and prognosis, and may regulate immune infiltration in HNSCC patients, thus promising targeted immunotherapy for HNSCC., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate This project was approved by the Institutional Ethics Committee at Qilu Hospital of Shandong University (Ethics approval number: KYLL-2019-2-095). The employment and processing of materials were permitted and obtained informed consent from each patient. All methods involved in human subjects were performed in accordance with the Declaration of Helsinki., (© 2024. The Author(s).)

Purpose: Adenoid cystic carcinoma (AdCC) of the head and neck harbors MYB/MYBL1::NFIB fusions in around 60% of cases, with unfavorable long-term survival due to frequent recurrences and metastases, currently lacking effective targeted therapy. The study aims to identify actionable alterations and to elucidate the molecular underpinnings of MYB/MYBL1::NFIB-negative AdCC using a large targeted RNA sequencing panel., Methods and Results: We retrospectively searched our MSK-Solid Fusion clinical sequencing database for head and neck AdCC sequenced between 2016 and 2023. Of a total of 55 cases, 28 showed MYB::NFIB, 7 showed MYBL1::NFIB, and one case each harbored MYB::MPDZ (case 1) and FUS::MYB (case 2). One base of tongue tumor expressed both MYB::NFIB fusion and MET exon 14 skipping transcripts due to concurrent MET splice site mutation, D1010N (case 3). One parotid tumor lacked MYB/MYBL1 rearrangement but instead showed an in-frame SEC16A::NOTCH1 fusion that preserved the secretase cleavage site (case 4). Clinical records on 4 cases with non-canonical sequencing findings were reviewed. Distant metastases were present at the initial diagnosis (case 2) or at recurrence (cases 1, 3, and 4). Disease-related mortality occurred in cases 2 and 4 despite radiotherapy and immunotherapy., Conclusions: The study improved the understanding of AdCC providing the first documentation of tumor clinical behavior associated with MYB::MPDZ and FUS::MYB fusions and reporting potentially actionable SEC16A::NOTCH1 fusion and MET exon 14 skipping mutation. Further research is needed to explore the therapeutic utility of MET inhibition and the efficacy of γ-secretase inhibitors against rare NOTCH1 fusions in AdCC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: For patients with locally advanced head and neck squamous cell carcinoma (HNSCC), combined programmed death receptor-1 inhibitor and chemotherapy improved response rate to neoadjuvant therapy. However, treatment response varies among patients. There is no tool to predict pathologic complete response (pCR) with high accuracy for now. To develop a tool based on radiomics features of MRI to predict pCR to neoadjuvant chemoimmunotherapy (NACI) may provide valuable assistance in treatment regimen determination for HNSCC., Methods: From January 2021 to April 2024, a total of 172 patients with HNSCC from three medical center, who received NACI followed by surgery, were included and allocated into a training set (n=84), an internal validation set (n=37) and an external validation set (n=51). Radiomics features were extracted from intratumoral and different peritumoral areas, and radiomics signature (Rad-score) for each area was constructed. A radiomics-clinical nomogram was developed based on Rad-scores and clinicopathological characteristics, tested in the validation sets, and compared with clinical nomogram and combined positive score (CPS) in predicting pCR., Results: The radiomics-clinical nomogram, incorporating peritumoral Rad-score, intratumoral Rad-score and CPS, achieved the highest accuracy with areas under the receiver operating characteristic curve of 0.904 (95% CI, 0.835 to 0.972) in the training cohort, 0.860 (95% CI, 0.722 to 0.998) in the internal validation cohort, and 0.849 (95% CI, 0.739 to 0.959) in the external validation cohort, respectively, which outperformed the clinical nomogram and CPS in predict pCR to NACI for HNSCC., Conclusion: A nomogram developed based on intratumoral and peritumoral MRI radiomics features outperformed CPS, a widely employed biomarker, in predict pCR to NACI for HNSCC, which would provide incremental value in treatment regimen determination., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors., Methods: Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high., Results: The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control., Conclusions: Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors., Trial Registration Number: NCT04510129., Competing Interests: Competing interests: KCF, JE, JH, RLW, MMP, DNM, JIG, and EJD are employed, have stock interests, and/or a financial relationship with Cofactor Genomics, maker of the OncoPrism-HNSCC test., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to develop and validate a nomogram using clinical variables to guide personalized treatment strategies for adenoid cystic carcinoma of the head and neck (ACCHN). Data from 1069 patients with ACCHN diagnosed between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were used to construct the nomogram. External validation was performed using an independent cohort of 70 patients from Fujian Cancer Hospital. Multivariate Cox regression analysis was conducted using IBM SPSS version 26.0 and R Software version 4.2.3. The concordance index (C-index) and receiver operating characteristic (ROC) curves were used to assess the predictive accuracy of the nomogram. Age, tumor site, surgery, N stage, M stage, and TNM stage were identified as independent prognostic factors through univariate and multivariate Cox analyses. The nomogram demonstrated superior predictive performance compared to the TNM staging system, effectively stratifying patients into high-risk and low-risk groups. This nomogram offers a valuable tool for predicting overall survival in patients with ACCHN and tailoring individualized treatment approaches., (© 2024. The Author(s).)

Background: An uncommon cancer, lymphoepithelioma-like carcinoma (LELC) resembles undifferentiated nasopharyngeal carcinoma (NPC) histologically. The aim is mainly to introduce the diagnosis and treatment of LELC and compare it with NPC in our descriptive study., Methods: A total of 278 patients with NPC and 157 patients with head and neck LELC had their medical records examined in this study. The propensity score matching (PSM) approach was employed to attain a 1:1 match between the LELC and NPC groups. Kaplan-Meier analysis was performed for overall survival (OS) of LELC and NPC. To determine their predictive values for OS, univariate and multivariate Cox regression analyses with significant survival differences (p < 0.05) were carried out., Results: Similar to NPC, 107 (68.2%) LELC cases had Epstein-Barr virus (EBV) infection. LELC of the parotid glands was present in nearly 46.5% of patients with head and neck LELC. Most patients were treated with surgery with neck dissection. After PSM, LELC had similar 5-year OS rates to NPC (81.6% vs. 79.0%). LELC was less prone to distant metastasis compared to NPC. Age, T stage, N stage, and distant metastases were found to be substantially correlated with the outcome of LELC, according to the multivariate Cox regression analysis (p < 0.05)., Conclusions: EBV infection in the head and neck has been associated with LELC and NPC. When compared to NPC, LELC is more likely to arise in the salivary glands and has a lower incidence of distant metastasis. Surgery with neck dissection is the primary treatment for LELC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: xCT, also known as SLC7A11 (solute carrier Family 7 Member 11), is a cystine/glutamate antiporter protein that mediates regulated cell death and antioxidant defense. The aim of this study was to investigate the effect of xCT on the outcome of patients diagnosed with new head and neck squamous cell carcinoma (HNSCC)., Methods: This retrospective cohort study utilized a population-based dataset, comprising all patients (n = 1033) diagnosed with new HNSCC during 2005-2015 in a population of 697,000 people. All patients (n = 585) with a tumor tissue sample available for immunohistochemical (IHC) staining were included. The follow-up rates were 97% and 81% at 3 and 5 years, respectively. Also, the specificity of the anti-xCT antibody was validated., Results: The expression level and prognostic significance of xCT were strongly dependent on tumor location. In oropharyngeal squamous cell carcinoma (OPSCC) patients, xCT expression was a significant prognostic factor for 5-year overall survival (OAS) (HR: 2.71; 95% CI 1.67-4.39; p < 0.001), disease-specific survival (DSS) (HR: 2.58; 95% CI 1.47-4.54; p = 0.001), and disease-free survival (DFS) (HR: 2.69; 95% CI 1.55-4.64; p < 0.001). Five-year survival rates for OPSCC patients with high and low levels of xCT were OAS 34% versus 62%; DSS 51% versus 73%; DFS 43% versus 73%, respectively. According to a multivariate model adjusted for age, T-class, nodal positivity, and tobacco consumption, xCT was an independent prognostic factor for 3-year survival, in which it outperformed p16 IHC. Similar associations were not observed in squamous cell carcinomas of oral cavity or larynx. Regarding treatment modalities, xCT was most predictive in HNSCC patients who received radiotherapy., Conclusions: High xCT expression was associated with poor prognosis in OPSCC. Our findings suggest that joint analysis of xCT and p16 may add significant value in OPSCC treatment stratification., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The purpose of this meta-analysis was to compare the surgical outcomes of head and neck reconstruction via free flap surgery, with neck vessels versus superficial temporal vessels as recipient vessels., Methods: The PubMed, Embase, and Scopus databases were systematically searched via the following keywords: ("superficial temporal" OR "temporal") AND ("free flap" OR "free tissue transfer") AND ("head and neck" OR "face"). The following data were extracted: first author, publication year, flap type, reconstruction region, concordant vein graft, recipient vessel, and postoperative complications, including thrombosis, partial necrosis, and flap failure. The recipient vessels were divided into two groups: the superficial temporal artery (STA)/V group and the neck group., Results: Six hundred and thirty-five studies that met the inclusion criteria were included and reviewed systematically for a meta-analysis. Compared with the neck vessel group, the STA/V vessel group had a significantly greater risk of flap failure (odds ratio: 2.18; 95% CI: 1.32-3.60; p = 0.002), with low heterogeneity (p = 0.84; I 2  = 0%). However, there were no significant differences in the rates of thrombosis or partial necrosis., Conclusions: Compared with the use of neck vessels, the use of STA/V vessels as recipient vessels for head and neck reconstruction could increase the risk of total flap necrosis. Considering these findings, surgeons should exercise caution when selecting the STV as the recipient site, and as some authors have suggested, proximal dissection may be necessary during surgery., (© 2024 The Author(s). Microsurgery published by Wiley Periodicals LLC.)

Background/aim: Xerostomia following (chemo-) radiotherapy (CRT) is common in head and neck (HNC) patients. This prospective study focused on investigating the link between salivary gland function and the onset of malnutrition in HNC patients., Patients and Methods: Between 2018 and 2020, 61 HNC patients scheduled for curative CRT were prospectively recruited. Nutritional status was assessed by bioelectrical impedance analysis (BIA) and xerostomia was evaluated based on the Common Terminology Criteria for Adverse Events, (CTCAE). Patient-reported outcomes for xerostomia-related symptoms, such as "dry mouth" and "sticky saliva", were also collected. Data were assessed at the beginning of therapy, during treatment, at the end of treatment, and during follow-up. Organs at risk were contoured including the submandibular and parotid glands. Dose-volume parameters were extracted for the mean Dose (D mean ), V15 Gy, V30Gy and V45Gy., Results: No correlation was found between the dosimetric parameters [D mean , V15Gy (%), V30Gy (%) and V45Gy (%)] and the occurrence of malnutrition [defined by a fat-free mass index (FFMI) <15 kg/m 2 (♀) and <17 kg/m 2 (♂) kg/m 2 and/or body-mass index (BMI) <18.5 kg/m 2 ] at any of the three time points tested. However, the volume of the parotid glands prior to therapy appeared to be related to the development of malnutrition. This effect was not observed with the submandibular glands. A cumulative parotid gland volume of 55.3 cm 3 was identified as the threshold for malnutrition at the second follow-up examination., Conclusion: Although none of the dosimetric factors were associated with the development of malnutrition, the baseline parotid gland volume emerged as an independent predictor of malnutrition in head and neck cancer patients with xerostomia., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Locally advanced squamous cell carcinoma of the head and neck (L/A SCCHN) is typically treated with surgery or chemoradiation therapy (CRT), whereas salvage surgery is considered for residual disease post-CRT. However, salvage surgery after radiation therapy presents challenges due to tissue fibrosis. Planned neck dissection (ND) combined with CRT, as well as positron emission tomography after CRT, have been proposed strategies, but no definitive consensus has been reached. Therefore, this study aimed to investigate the utility of "upfront ND" performed prior to CRT to enhance local control and reduce complications., Patients and Methods: We retrospectively reviewed 121 patients who underwent primary CRT for oropharyngeal, hypopharyngeal, or laryngeal cancer at Tokyo Medical University Hospital from January 2015 to September 2021. Patients without cervical lymph node metastasis or with unresectable nodes were excluded. All patients underwent pre-treatment imaging and staging. CRT consisted of intensity-modulated radiation therapy (IMRT) and cisplatin-based chemotherapy. Selective ND or modified radical neck dissection was performed based on lymph node involvement., Results: Overall, 35 patients underwent upfront ND, whereas 54 did not. The upfront ND group exhibited significantly better 2-year locoregional recurrence-free survival than the group without upfront ND (93.7% vs. 71.0%). No significant differences were noted in adverse events between groups., Conclusion: The findings highlight upfront ND before CRT as a viable option for locally advanced head and neck cancer, particularly beneficial in cases with extranodal extension. This approach enhances local control and may reduce the need for salvage surgery, thus improving patient outcomes., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The current study aimed to evaluate a treatment planning method that is robust against tumor growth and to assess its effectiveness in particle therapy for head and neck cancer., Patients and Methods: The proposed method optimizes dose distribution by replacing the relative stopping power ratio (rSPR) of the clinical target volume (CTV) cavity region with a tumor-equivalent rSPR (Condition 1). The optimized initial treatment plan template was then recalculated using in-room CT images acquired in the same treatment position, and the doses to the tumor and organs at risk were compared with those in the initial treatment plan. We evaluated this method in 10 patients with head and neck cancer treated with carbon ion radiotherapy. To evaluate the effectiveness of the proposed method, we compared it to the initial treatment plan without the replacement (Condition 2)., Results: CTV V95% reduction relative to that of the initial treatment plan at the end of treatment was 1.3%±2.9% and 2.6%±3.7% for Condition 1 and Condition 2, respectively, with Condition 1 (Replacement condition) providing better CTV coverage. Subgroup analysis showed a higher change in target coverage in the mucosal melanoma than in the adenoid cystic carcinoma, suggesting that this was influenced by the rate of tumor growth., Conclusion: The proposed treatment planning method, which adjusts for tumor growth by modifying the rSPR in the cavity region, improved robustness in carbon ion radiotherapy for head and neck cancer. Condition 1 (with replacement) achieved better CTV coverage than Condition 2 (without replacement), particularly in fast-growing tumors like mucosal melanoma. This method ensures consistent dose delivery to tumors while maintaining safe doses to organs at risk, offering potential for improved treatment outcomes., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study aimed to assess the impact of hypoxia on epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinoma (HNSCC), focusing on the involvement of transcription factors hypoxia inducible factor 1 (HIF-1α) and Jumonji Domain-Containing Protein 1A (JMJD1A)., Materials and Methods: FaDu and Cal33 cell lines were subjected to hypoxic and normoxic conditions. Cell proliferation was quantified electronically, while PCR and western blot analyses were used to measure mRNA and protein levels of HIF-1α, JMJD1A, and EMT markers. EMT was further characterized through immunofluorescence, migration, and invasion assays., Results: Hypoxic conditions significantly reduced cell proliferation after 48 hours in both cell lines. HIF-1α mRNA levels increased initially during short-term hypoxia but declined thereafter, while JMJD1A mRNA levels showed a sustained increase with prolonged hypoxia. Western blot analysis revealed contrasting trends in protein levels. EMT marker expression varied markedly over time at both the mRNA and protein levels, suggesting EMT induction in hypoxia within 24 hours. Immunofluorescence, migration, and invasion assays supported these findings., Conclusion: The study provides evidence of hypoxia-induced EMT in HNSCC, although conflicting results suggest a complex interplay among molecular regulators involved in this process., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) is experiencing a rising incidence and mortality worldwide, emphasizing the need for reliable prognostic markers. Tumor-infiltrating lymphocytes (TILs) have emerged as a promising biomarker for predicting HNSCC prognosis, yet no systematic reviews have exclusively focused on hematoxylin and eosin (H&E)-stained formalin-fixed paraffin-embedded (FFPE) samples, which are routinely used in clinical practice. This systematic review and meta-analysis followed the PRISMA guidelines to examine the prognostic value of TILs in HNSCC using H&E-stained FFPE samples. Data were pooled from 43 studies, including 26 studies in a meta-analysis, analyzing 5037 HNSCC samples. We found that a high TIL count associated with a significantly improved overall survival (OS) (HR 0.47, 95 % CI 0.41-0.55, p < 0.0001), disease-free survival (DFS) (HR 0.55, 95 % CI 0.41-0.55, p < 0.0001), and disease-specific survival (DSS) (HR 0.58, 95 % CI 0.46-0.73, p < 0.0001). The heterogeneity was moderate for the pooled analysis (OS: I² = 40 %; DFS: I² = 39 %; DSS: I² = 51 %), but low for the subgroup analysis based on tumor site in oral, oropharyngeal, laryngeal, and nasopharyngeal cancer (OS and DFS: I² = 0-14 %). This review is the first to systematically evaluate TILs in HNSCC using H&E-stained samples, confirming their prognostic value. A high TIL count is associated with improved survival outcomes, suggesting their potential as prognostic biomarkers in clinical settings., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ahmed Al-Samadi reports financial support was provided by Research Council of Finland. Ahmed Al-Samadi reports financial support was provided by Sigrid Jusélius Foundation. Meri Torri and Ahmed Al-Samadi reports financial support was provided by Minerva Foundation. Meri Torri and Ahmed Al-Samadi reports financial support was provided by Finnish Dental Society Apollonia. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Areas Covered: Here we describe novel agents, their mechanism(s) of action, preclinical results, and ongoing clinical trials in HNSCC., Expert Opinion: Established therapeutic targets in HNSCC include EGFR (cetuximab) and PD-1 (pembrolizumab and nivolumab). Despite the detection of many other possible targets in HNSCC cell lines and patient tumors, no other therapies have successfully advanced to date. Identification of predictive biomarkers may guide the use of targeted agents and combination therapies. Clinical trials supported by strong preclinical data in relevant models are more likely to advance treatment options.

Significance: Here, RNAi library screening reveals that multiple G2/M and kinetochore components, including TTK/monopolar spindle 1, modulate TNFα-induced NF-κB activation, cell survival, and genotoxicity, underscoring their potential importance as therapeutic targets in HNSCC., (©2024 The Authors; Published by the American Association for Cancer Research.)

The gut microbiome, a complex community of microorganisms residing in the gastrointestinal tract, plays a crucial role in maintaining human health and influencing disease outcomes. Recent advancements in sequencing technologies have revealed the intricate relationship between gut microbiota and various health conditions. This review explores the impact of gut microbiome dysbiosis on immune function, chronic inflammation, and cancer progression. Dysbiosis, characterized by an imbalance in microbial populations, can lead to immune dysfunction, creating a pro-inflammatory environment conducive to tumorigenesis. Gut microbiome metabolites, such as short-chain fatty acids and bile acids, also play a significant role in modulating these processes. The interplay between these factors contributes to the development and progression of HNC. Furthermore, this review highlights the potential of therapeutic interventions targeting the gut microbiome, including probiotics, prebiotics, and dietary modifications, to restore microbial balance and mitigate cancer risk. Understanding the mechanisms by which the gut microbiome influences HNC can provide valuable insights into novel preventive and therapeutic strategies. Future research should focus on elucidating the specific microbial taxa and metabolites involved in HNC, as well as the impact of lifestyle factors such as diet, alcohol consumption, and oral hygiene on the gut microbiome. By leveraging the growing knowledge of the gut microbiome, it may be possible to develop personalized approaches to cancer prevention and treatment, ultimately improving patient outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Head and neck squamous cell carcinomas (HNSCCs) are among the six most common cancers, with a constantly poor prognosis. Vitamin D has been found to have antineoplastic and immunomodulatory properties in various cancers. This study investigated the impact of Vitamin D on the initiation and progression as well as antitumor immune response in HNSCCs, both in vitro and in vivo., Methods: An immunocompetent, orthotopic oral carcinogenesis mouse model was used to examine the influence of Vitamin D 3 substitution on HNSCC initiation and progression in vivo. Tumor immune infiltration was analyzed by immunohistochemistry targeting CD3, CD8, NKR-P1C, FOXP3, and CD163. Two HPV- and two HPV+ HNSCC cell lines were treated with 1,25-dihydroxyvitamin D 3 to analyze effects on tumor cell proliferation, migration and transcriptomic changes using RNA-sequencing, differential gene expression and gene set enrichment analysis., Results: Vitamin D 3 treatment led to a significant suppression of HNSCC initiation and progression, while also stimulating tumor immune infiltration with CD3+, CD8+ and NKR-P1C+ cells and lowering levels of M2 macrophages and T reg cells in vivo. In vitro experiments showed an inhibition of HNSCC cell proliferation and migration in HPV+ and HPV- cell lines. RNA-sequencing showed significant regulations in IL6 JAK STAT3, hypoxia signaling and immunomodulatory pathways upon Vitamin D 3 treatment., Conclusion: The findings of our study highlight the promising potential of Vitamin D in the therapeutic repertoire for HNSCC patients given its immune modulating, anti-proliferative and anti-migratory properties. Clinical transferability of those in vitro and in vivo effects should be further validated in clinical trials., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maximilian Linxweiler reports financial support was provided by Else Kroner-Fresenius Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Importance: The eighth edition tumor, node, metastasis (TNM) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) is a poor predictor of survival in patients with lymph node metastases, possibly due to the inclusion of extranodal extension (ENE)., Objective: To identify the key determinants of prognosis in patients with nodal metastatic HNcSCC and analyze the association of ENE with TNM stage and investigate for prognostic heterogeneity in ENE-positive disease., Design, Setting, and Participants: This retrospective, multicenter cohort study was conducted at 4 Australian tertiary referral centers using prospectively collected data in patients treated between 1980 and 2017 with a median (IQR) follow-up of 3.2 (3.9) years. The study population included 1309 consecutive patients with HNcSCC that was metastatic to parotid and/or cervical nodes. After excluding cases with perioperative mortality, missing data, or follow-up, the final study population included 1151 patients., Exposure: Curative intent surgery ± adjuvant radiotherapy., Main Outcomes and Measures: Differences in locoregional control (LRC), disease-specific survival (DSS), and overall survival were determined using Cox regression analysis., Results: Among 1151 patients, 976 (84.8%) were male and 175 (15.2%) female, with a median age of 73.3 years (range, 18-100 years). On multivariable analysis, immunosuppression (hazard ratio [HR], 2.48; 95% CI, 1.64-3.74), perineural invasion (HR, 1.69; 95% CI, 1.25-2.30), ENE (HR, 1.53; 95% CI, 0.95-2.44), size (>3-6 cm vs ≤3 cm [HR, 1.41; 95% CI, 1.03-1.93]; >6 cm vs ≤3 cm [HR, 5.01; 95% CI, 2.98-8.42]), and number of nodal metastases (3-4 vs 1-2 [HR, 1.54; 95% CI, 1.01-2.34]; ≥5 vs 1-2 [HR, 2.86; 95% CI, 1.99-4.11]) were associated with DSS. Similar results were found for LRC and overall survival. More than 90% of the population was categorized as TNM stage IV, with 32% attributable to ENE. In the ENE-positive subset (n = 860), DSS ranged from 8% to 88% based on stratification using other clinicopathological factors., Conclusions and Relevance: The study results suggest that immunosuppression, perineural invasion, ENE, and size and number of nodal metastases are associated with reduced survival and LRC in HNcSCC with nodal metastases. The inclusion of ENE in HNcSCC staging needs to be reassessed, as it ascribes excessive importance to ENE and upstages most patients to TNM stage IV, despite many having a high chance of cure.

Head and neck squamous cell carcinoma ranks seventh globally in malignancy prevalence, with persistent high mortality rates despite treatment advancements. Glucose, pivotal in cancer metabolism via the Warburg effect, enters cells via glucose transporters, notably GLUT proteins. Glycolysis, aerobic oxidation, and the pentose phosphate pathway in glucose metabolism significantly impact HNSCC progression. HNSCC exhibits elevated expression of glucose metabolism enzymes and GLUT proteins, correlating with prognosis. Heterogeneity in HNSCC yields varied metabolic profiles, influenced by factors like HPV status and disease stage. This review highlights glucose metabolism's role and potential as therapeutic targets and cancer imaging tracers in HNSCC.

Bromodomain-containing protein 4 (BRD4) belongs to the bromodomain and extra-terminal domain (BET) protein family, which plays a crucial role in recognizing acetylated lysine residues in chromatin. The abnormal expression of BRD4 contributes to the development of various human malignant tumors, including head and neck squamous cell carcinoma (HNSCC). Recent studies have shown that BRD4 inhibition can effectively prevent the proliferation and growth of HNSCC. However, the specific role and mechanism of BRD4 in HNSCC are not yet fully clarified. This article will briefly summarize the critical role of BRD4 in the pathogenesis of HNSCC and discuss the potential clinical applications of targeting BRD4 in HNSCC therapy. We further inquiry the challenges and opportunities for HNSCC therapies based on BRD4 inhibition, including BRD4 inhibitor combination with conventional chemotherapy, radiotherapy, and immunotherapy, as well as new strategies of BRD4-targeting drugs and BRD4 proteolysis-targeting chimeras (PROTACs). Moreover, we will also offer outlook on the associated challenges and future directions of targeting BRD4 for the treatment of patients with HNSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The majority of neoplasms of the head and neck are of epithelial origin primarily including mucosal squamous cell neoplasms (papillomas; squamous cell carcinoma) as well as salivary gland neoplasms. However, the full spectrum of mesenchymal neoplasms (benign and malignant) typically arising in soft tissue sites may also develop in superficial layers of the upper aerodigestive tract. The diversity of mesenchymal neoplasms arising in the head and neck is beyond the scope of this article, and our focus will be on some of the more common and/or diagnostic problematic mesenchymal tumors occurring in the sinonasal tract, oral cavity/odontogenic, pharynx, larynx, and neck., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Oral and laryngeal squamous cell carcinoma (OSCC and LSCC) and papillary thyroid carcinoma (PTC) are common head and neck cancers (HNCs) typically treated surgically. Challenges in tumour delineation often lead to inadequate resection margins in OSCC and LSCC, and missed multifocality in PTC. Fluorescence imaging (FLI) using near-infrared tumour-targeting tracers may improve intraoperative identification of malignancy, facilitating precise excision. This study evaluates six potential FLI targets in OSCC, LSCC and PTC., Materials and Methods: Immunohistochemical staining was performed on OSCC (n = 20), LSCC (n = 10) and PTC (n = 10), assessing CEA, c-Met, EpCAM, EGFR, integrin αvβ6 and VEGF-α. Expression was scored (0-12) using the total immunostaining score (TIS) system, and categorized into absent (TIS 0), low (TIS 1-5), moderate (TIS 6-8) or high (TIS 9-12)., Results: Integrin αvβ6 showed significant overexpression in OSCC (TIS: 12; p < 0.001) and LSCC (TIS: 8; p = 0.002), with 80% of OSCC and 90% of LSCC exhibiting moderate-high expression. Similarly, EGFR expression was moderate-high in most OSCC (87.5%; TIS: 8) and universally high in LSCC (100%; TIS: 12). In PTC, EGFR and VEGF-α expressions were low-moderate, but significantly higher than in healthy tissue (TIS: 6; p < 0.006)., Conclusion: This study highlights integrin αvβ6 and EGFR as viable FLI targets in OSCC and LSCC, especially integrin αvβ6 for tumour margin delineation. In PTC, despite lower expressions, the significant overexpression of VEGF-α, c-MET, and EGFR suggests their potential as FLI targets. Our findings support the development of tumour-targeted FLI tracers to improve surgical precision in HNC., (© 2024. The Author(s).)

The aim of this study was to compare treatment modalities, pathological and clinical characteristics, and outcomes in patients with metastasis in a parotid gland. The medical records of 34 patients who received treatment for metastasis in the parotid gland over a twenty-year period were evaluated. Patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) metastasis were retrospectively reclassified using the P/N and N1S3 staging system. Patients with neck metastasis showed a significantly poorer prognosis (P = 0.025). Univariate analysis also revealed that extent of parotidectomy and type of neck dissection did not influence recurrence free survival (RFS) and overall survival (OS). When comparing the usefulness of the P/N and S1N3 staging systems, a positive correlation was observed between the P stage and the N1S3 stage in both RFS and OS. The extent of parotidectomy and concomitant neck dissection is still under discussion. Total parotidectomy and modified radical neck dissection did not improve RFS and OS. N1S3 is a less complex classification and possesses a higher predictive value when compared to the P/N staging system., Competing Interests: Declaration of competing interest There are no conflicts of interests in regard to this study., (Copyright © 2024 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Liquid biopsy profiling is gaining increasing promise towards biomarker-led identification and disease stratification of tumours, particularly for tumours displaying significant intra-tumoural heterogeneity (ITH). For head and neck squamous cell carcinoma (HNSCC), which display high levels of genetic ITH, identification of epigenetic modifications and methylation signatures has shown multiple uses in stratification of HNSCC for prognosis, treatment, and HPV status. In this study, we investigated the potential of liquid biopsy methylomics and genomic copy number to profile HNSCC. We conducted multi-region sampling of tumour core, tumour margin and normal adjacent mucosa, as well as plasma cell-free DNA (cfDNA) across 9 HNSCC patients. Collectively, our work highlights the prevalence of methylomic ITH in HNSCC, and demonstrates the potential of cfDNA methylation as a tool for ITH assessment and serial sampling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Immune-related gene expression levels in the tumor microenvironment (TM) of head and neck squamous cell carcinoma (HNSCC) patients was compared., Materials and Methods: The CD163, CD274, CD86, FUT4, FOXP3, and ITGAX levels of HNSCC patients in their tumor tissues (n =76) and surrounding tissues adjacent to the tumor (n =76) were determined using quantitative real-time PCR (qRT-PCR). Changes in these genes were also evaluated by associating with demographical data of the patients., Results: CD163, CD274, FUT4, and FOXP3 gene expression levels were significantly higher in tumor tissue than in surrounding tissue. FUT4 fold change was statistically higher in patients with lymph node involvement. CD86 expression was statistically lower in smokers of 50 boxes per year or more. CD163, CD274, and FUT4 expressions were increased in response to the presence of extranodal extension (ENE)., Conclusions: These preliminary results demonstrate the alterations in expression levels of immunologic markers are associated with the clinical presentations of HNSCC., Availability of Data and Materials: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background and Purpose: Radiotherapy (RT) is an integral treatment part for patients with head and neck squamous cell carcinoma (HNSCC), but radioresistance remains a major issue. Here, we use MitoTam, a mitochondrially targeted analogue of tamoxifen, which we aim to stimulate ferroptotic cell death with, and sensitize radioresistant cells to RT., Materials and Methods: We assessed viability, reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential, and lipid peroxidation in radiosensitive (UT-SCC-40) and radioresistant (UT-SCC-5) HNSCC cells following MitoTam treatment. To assess ferroptosis specificity, we used the ferroptosis inhibitor ferrostatin-1 (fer-1). Also, total antioxidant capacity and sensitivity to tert-butyl hydroperoxide were evaluated to assess ROS-responses. 53BP1 staining was used to assess radiosensitivity after MitoTam treatment., Results: Our data revealed increased ROS, cell death, disruption of mitochondrial membrane potential, and lipid peroxidation following MitoTam treatment in both cell lines. Adverse effects of MitoTam on cell death, membrane potential and lipid peroxidation were prevented by fer-1, indicating induction of ferroptosis. Radioresistant HNSCC cells were less sensitive to the effects of MitoTam due to intrinsic higher antioxidant capacity. MitoTam treatment prior to RT led to superadditive residual DNA damage expressed by 53BP1 foci compared to RT or MitoTam alone., Conclusion: MitoTam induced ferroptosis in HNSCC cells, which could be used to overcome the elevated antioxidant capacity of radioresistant cells and sensitize such cells to RT. Treatment with MitoTam followed by RT could therefore present a promising effective therapy of radioresistant cancers., Statement of Significance: Radiotherapy is applied in the treatment of a majority of cancer patients. Radioresistance due to elevated antioxidant levels can be overcome by promoting ferroptotic cell death combining ROS-inducing drug MitoTam with radiotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [J.N., J.S. and L.W. own part of MitoTam intellectual property]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: This meta-analysis aims to evaluate the efficacy and safety of antiprogressive disease (PD)-(L)1-based neoadjuvant therapy in head and neck squamous cell carcinoma (HNSCC) patients and identify potential prognostic biomarkers., Data Sources: Databases were systematically searched for prospective clinical trials evaluating the efficacy and safety of anti-PD-(L)1-based neoadjuvant therapy for HNSCC before January 12, 2024., Review Methods: We estimated the efficacy and safety of neoadjuvant immune checkpoint inhibitors. Subgroup and sensitivity analyses were further performed., Results: A total of 570 patients from 20 studies were included. The pooled major pathological response (MPR), pathological complete response (pCR), and partial pathological response (PPR) rates were 30.7%, 15.3%, and 68.2%, respectively. Surgical complications, surgical delayed rate, all grade treatment-related adverse effects (TRAEs) and ≥Grade 3 TRAEs were 0.6%, 0.3%, 82.6%, and 9.7%, respectively. Best MPR or pCR rate was detected in patients receiving neoadjuvant anti-PD-(L)1 therapy + radiotherapy (with MPR rate of 75.5% and pCR rate of 51.1%) and neoadjuvant anti-PD-(L)1 therapy + chemotherapy groups (with MPR rate of 57.5% and pCR rate of 26.7%). No differences were detected in subgroups stratified by neoadjuvant treatment cycles, human papillomavirus (HPV) status, and tumor location. Patients with baseline Combined Positive Score (CPS) ≥ 20 have higher MPR and pCR rates compared to patients with CPS < 20. High Tumor Cell Proportion Score was also associated with MPR and pCR. Objective response rate is a strong predictor of MPR (odds ratio [OR] = 7.78, 95% confidence interval [CI] = 3.20%-18.91%) and pCR (OR = 3.24, 95% CI = 1.40%-7.48%)., Conclusion: Anti-PD-(L)1-based neoadjuvant therapy was effective and safe for HNSCC patients., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

The incidence of head and neck cancers, particularly those associated with Human Papillomavirus (HPV) infections, has been steadily increasing. Conventional therapies exhibit limitations and drawbacks, prompting the exploration of new strategies over the years, with nanomedicine approaches, especially liposomes gaining relevance. Additionally, the functionalization of liposomes with aptamers enables selective delivery to target cells. For instance, AT11 can serve as a targeting moiety for cancer cells due to its high affinity for nucleolin, a protein overexpressed on the cancer cell's surface. In this study, liposomes functionalized with AT11 are proposed as drug delivery systems for imiquimod (IQ), aiming to maximize its potential as an anticancer agent for HPV-related cancers. To this end, firstly liposomes were produced through the ethanol injection method, functionalized with AT11-TEG-Cholesteryl, and characterized using dynamic light scattering. The obtained liposomes presented suitable properties for cancer therapy (with sizes from 120 to 140 nm and low polydispersity PDI < 0.16) and were further evaluated in terms of potential anticancer effects. AT11 IQ-associated liposomes allowed a selective delivery of IQ towards a tongue cancer cell line (UPCI-SCC-154) relative to the non-malignant cell line (Het1A). Specifically, they induced a selective reduction of the cell viability (∼52 % versus ∼113 %; p < 0.0001), proliferation (∼68 % versus ∼102 %; p<0.0001) and increased cell death (∼7-fold increase; p < 0.0001)). Additionally, they decreased the migration (from ∼24 % to ∼8 %; p < 0.0001) and invasion (to 11 %; p = 0.0047) capacities of the cancer cells. In summary, the produced liposomes represent a promising approach to enhance the anticancer potential of IQ in head and neck cancer, particularly in tongue cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate the diagnostic performance (DP) of the high-resolution contrast computed tomography (HR-contrast-CT) based Neck-Persistency-Net in distinguishing vital from non-vital persistent cervical lymph nodes (pcLNs) in patients with advanced head and neck squamous cell carcinoma (HNSCC) following primary concurrent chemoradiotherapy (CRT) with [18F]-fluorodeoxyglucose positron emission tomography and high-resolution contrast-enhanced computed tomography ([18F]FDG-PET-CT). Furthermore, the Neck-Persistency-Net's potential to justify omitting post-CRT neck dissection (ND) without risking treatment delays or preventing unnecessary surgery was explored., Methods: All HNSCC patients undergoing primary CRT followed by post-CRT-ND for pcLNs recorded in the institutional HNSCC registry were analyzed. The Neck-Persistency-Net DP was explored for three scenarios: balanced performance (BalPerf), optimized sensitivity (OptSens), and optimized specificity (OptSpec). Histopathology of post-CRT-ND served as a reference., Results: Among 68 included patients, 11 were female and 32 had vital pcLNs. The Neck-Persistency-Net demonstrated good DP with an area under the curve of 0.82. For BalPerf, both sensitivity and specificity were 78%; for OptSens (90%), specificity was 62%; for OptSpec (95%), sensitivity was 54%. Limiting post-CRT-ND to negative results would have delayed treatment in 27%, 40%, and 7% for BalPerf, OptSens and OptSpec, respectively, versus 23% for [18F]FDG-PET-CT. Conversely, restricting post-CRT-ND to positive results would have prevented unnecessary post-CRT-ND in 78%, 60%, and 95% for BalPerf, OptSens and OptSpec, respectively, versus 55% for [18F]FDG-PET-CT., Conclusion: The DP of the Neck-Persistency-Net was comparable to [18F]-FDG-PET-CT. Depending on the chosen decision boundary, the potential to justify the omission of post-CRT-ND without risking treatment delays in false negative findings or reliably prevent unnecessary surgery in false positive findings outperforms the [18F]-FDG-PET-CT., (© 2024. The Author(s).)

Objectives: This study aimed to compare the efficacy of chemoradiotherapy (CRT) with radiotherapy (RT) alone for elderly patients (≥ 65 years) with stage IV inoperable head and neck cancer (IV-HNC)., Methods: Elderly patients diagnosed with inoperable IV-HNC from 2010 to 2015 were identified using the SEER database. Then, we performed a 1:1 propensity-score matched (PSM) analysis to reduce treatment selection bias, and the prognostic role of CRT was investigated using Kaplan-Meier analysis, log-rank test, and Cox proportional hazard models. The main outcome was overall survival (OS), and the secondary outcome was cancer-specific survival (CSS)., Results: A total of 3318 patients were enrolled, of whom 601 received RT alone and 2717 received CRT. Through PSM, 526 patients were successfully matched, and balances between the two treatment groups were reached. In the matched dataset, multivariable Cox analysis revealed that CRT was associated with better OS (HR = 0.580, P < 0.001) and CSS (HR = 0.586, P < 0.001). Meanwhile, subgroups of patients with IV-HNC (younger age, male sex, being married, black race, grade I-II, oral cavity site, T3-T4 stage, N0-N1 stage, M1 stage) were inclined to benefit more from CRT treatment. Furthermore, the survival benefit of CRT was more pronounced in patients aged 65 to 80 years, but was absent in patients aged 80 years or older., Conclusions: This study indicated that CRT resulted in better survival than RT alone in elderly patients with inoperable IV-HNC, especially for those subpopulations that benefit more from CRT treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: This study aimed to explore the clinical, histopathologic, and immunohistochemical characteristics of myofibromas (MFs) affecting the head and neck region., Material and Methods: Formalin-fixed paraffin-embedded tissue blocks of patients diagnosed with MFs in the head and neck were retrieved from the archives of three oral and maxillofacial pathology laboratories. Data including clinical, radiographic, microscopic and immunohistochemical findings, treatment employed, and follow-up status were retrieved from the patient's medical records or pathology reports., Results: Sixteen cases were included in the study. Females were slightly more affected than males. The first and second decades of life were more prevalent. The most common locations were the alveolar ridge and cheek. Although rare, some of the patients were presented with intraosseous lesions. Microscopically, tumors consisted of plump, spindle-shaped myofibroblasts arranged in whorls or fascicles with varying degrees of differentiation. Immunohistochemically, diffuse positivity for vimentin and α-SMA was observed, while Ki-67 mostly showed low immunoreactivity (<5%). Treatment primarily involved complete excision., Conclusions: MFs in the head and neck region are rare and predominantly affect female patients during the second decade of life. Despite their rarity, central MFs should be considered in the differential diagnosis of intraosseous lesions in infants.

Background: Cancer cachexia is prevalent in head and neck cancer patients. The L3 skeletal muscle index (SMI) is often used to assess sarcopenia and cachexia but is infrequently able to be measured in this population. Masseter muscle thickness (MT) may serve as an alternative predictor of cachexia., Methods: SMI and MT were calculated from 20 trauma (CTRL) and 40 cachectic (CA-CX) and non-cachectic (CA-NCX) head and neck cancer patients. Area Under the Curve of the Receiver Operating Characteristics (AUC-ROC) analysis was performed for SMI and MT., Results: Both SMI and MT were significantly decreased in CA-CX patients (vs. CA-NCX mean difference -19.5 cm 2 /m 2 and -2.06 mm, respectively) and significant predictors of CA-CX (AUC = 0.985 and 0.805, respectively). When analyzed by sex, the same findings were observed for MT in males and trended toward significance in females., Conclusions: Compared with SMI, MT is a good alternative prognostic biomarker to determine CA-CX status in HNC patients., (© 2024 Wiley Periodicals LLC.)

Background: Positive surgical margin rates remain high in head and neck cancer surgery. Relocation is challenging given the complex, three-dimensional (3D) anatomy., Methods: Prospective, multi-institutional study to determine accuracy of head and neck surgeons and pathologists relocating margins on virtual 3D specimen models using written descriptions from pathology reports. Using 3D models of 10 head and neck surgical specimens, each participant relocated 20 mucosal margins (10 perpendicular, 10 shave)., Results: A total of 32 participants, 23 surgeons and 9 pathologists, marked 640 margins. Of the 320 marked perpendicular margins, 49.7% were greater than 1 centimeter from the true margin with a mean relocation error of 10.2 mm. Marked shave margins overlapped with the true margin a mean 54% of the time, with no overlap in 44 of 320 (13.8%) shave margins., Conclusions: Surgical margin relocation is imprecise and challenging even for experienced surgeons and pathologists. New communication technologies are needed., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Purpose: Recurrent head and neck cancer presents a therapeutic challenge because of cumulative toxicity from initial radiation therapy, limiting reirradiation options. Boron neutron capture therapy (BNCT) offers a promising alternative, selectively delivering a radical dose to tumors while sparing adjacent normal tissue. This study investigates the initial clinical outcomes and prognostic factors associated with BNCT for recurrent squamous cell carcinoma of the head and neck., Methods and Materials: This retrospective analysis investigated the initial 47 patients treated with BNCT between May 2020 and February 2021 in Japan. All patients had received radiation therapy with a median dose of 70 Gy (range, 44-176) before BNCT. Median tumor size was 11 cm 3 (range, 1-117 cm 3 ), with 23% of tumors larger than 30 cm 3 , and 87% of patients had prior systemic therapy. The most common prescribed dose to the pharyngeal mucosa was 15 Gy-Eq (36%), followed by 18 Gy-Eq (34%). The minimum dose given to tumor was 27.4 Gy-Eq (range, 13.3-45.2). In 23 patients, 18 F-fluoro-borono-phenylalanine positron emission tomography was performed within 1 week before BNCT, and the tumor-to-blood 10 B ratio was 3.5 (range, 2.0-8.7)., Results: Efficacy analysis revealed a 51% complete response rate and a 74% overall response rate. Disease-free survival rates at 1 and 2 years were 34.6% and 26.6%, respectively. Overall survival rates at 1 and 2 years were 86.1% and 66.5%, respectively. Multivariate analysis revealed that, among the patient characteristics, whether the lesion was mucosal had a significant effect on achieving complete response., Conclusions: This study provided valuable insights into the early integration of BNCT into routine clinical practice, highlighting its efficacy and safety. Technical improvements are needed to ensure precise dose administration. Ongoing prospective studies, such as the phase II REBIVAL study, will further elucidate the role of BNCT in recurrent head and neck cancer., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The study aimed to investigate the effect of the SUMOylation status of Drp1 on mitochondrial fission in CDDP-treated HNSCC cells cultured under hypoxic conditions., Materials and Methods: The effect of hypoxia on the chemosensitivity of HNCC cells was evaluated by flow cytometry and CCK-8 assays. The biological function of SUMO-specific peptidase 3 (SENP3) was evaluated by loss-of-function assays both in vitro and in vivo. SENP3-regulated deSUMOylation of Drp1 were performed with co-IP assays., Results: SENP3 expression correlated with chemosensitivity in clinical HNSCC samples subjected to hypoxic conditions. Hypoxia-induced ROS increased HIF-1α/SENP3 expression and mitochondrial fission in CDDP-treated HNSCC cells, and these effects were reversed by NAC treatment. SENP3 knockdown reversed hypoxia-induced mitochondrial fission and inhibited HNSCC cell apoptosis, which decreased CDDP sensitivity. Furthermore, hypoxia-induced SENP3 deconjugated SUMO2 from Drp1., Conclusion: Our findings revealed that hypoxia-induced SENP3 facilitates CDDP sensitivity and mitochondrial fission via deSUMOylation of Drp1., (© 2024 Wiley Periodicals LLC.)

Soft tissue type perineuriomas (STP), or Extraneural perineuriomas, are typically found in the superficial extremities or trunk of adult patients. Their incidence in the head and neck is exceptionally rare, particularly amongst the pediatric population. Since 1978, only 19 cases of pediatric STP have been reported, with only one in the neck. This case report describes the second case of STP in the neck of a child as well as reviews the current literature on pediatric STP. The pattern of patient genetic anomalies associated with the few pediatric STP cases encountered suggests an association between genetic aberrations and STP. Clinicians should be aware of STP when formulating a differential diagnosis of pediatric soft tissue masses in the head and neck despite the rarity of this tumor., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Limited information exists regarding the epidemiology, metastasis, and survival of dermatofibrosarcoma protuberans (DFSP)., Objective: To measure DFSP incidence and assess metastasis and survival outcomes., Methods: Incidence rate, overall and DFSP-specific survival outcomes for primary DFSP tumors contained in the Surveillance, Epidemiology, and End Results (SEER) registry were analyzed via quasi-Poisson regression, Cox, and competing risk analyses., Results: DFSP incidence rate was 6.25 (95% CI, 5.93-6.57) cases per million person-years with significantly higher incidence observed among Black individuals than White individuals (8.74 vs 4.53). DFSP with larger tumor size (≥3 cm, odds ratio [OR]: 2.24; 95% CI, 1.62-3.12; P < .001) and tumors located on the head and neck (OR: 4.88; 95% CI, 3.31-7.18; P < .001), and genitalia (OR: 3.16; 95% CI, 1.17-8.52; P = .023) were associated with significantly increased risk of metastasis whereas higher socioeconomic status was associated with significantly decreased risk of metastasis. Larger tumor size (≥3 cm), regardless of location, and age (≥60 years) were associated with significantly worse overall and cancer-specific survival., Limitations: Retrospective design of SEER., Conclusion: DFSP incidence is 2-fold higher among Black than White individuals. The risk of DFSP metastasis is significantly increased with tumor size ≥3 cm and tumors located on head and neck, and genitalia. Larger tumor size (≥ 3 cm), regardless of location, and age (≥60 years) are the most important prognostic indicators of survival., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2024. Published by Elsevier Inc.)

Oral cancer is the most prevalent head and neck cancer. Although tumor markers have been investigated for detecting the progression and prognosis of oral cancer, no reliable marker has been identified. We investigated the expression of ATP binding cassette subfamily B member 5 (ABCB5) positive stem cells in oral squamous cell carcinoma (OSCC) and in inflammatory gingival hyperplasia. We used tissue samples from normal subjects, patients with inflammatory gingival hyperplasia, and patients with OSCC. Samples were investigated using anti-ABCB5 monoclonal antibody immunohistochemistry to detect epithelial stem cells. Staining density, intensity, and immunoreactive scores of ABCB5 were analyzed for the three study groups. We found ABCB5 immunostaining in all three study groups, but different distributions of ABCB5 expression in different layers of the epithelium. We found no significant difference in staining intensity between inflammatory hyperplasia and normal mucosa, but we found significantly stronger expression in OSCC compared to normal and inflammatory hyperplasia individually. Elevated expression of ABCB5 in OSCC suggests an increased subpopulation of tumor cells with an undifferentiated stem cell phenotype, which facilitates cancer initiation and progression.

Purpose: The schedule of cisplatin concurrent with definitive radiation for squamous carcinoma of the head and neck remains controversial. Most institutions deliver either a high-dose "bolus" schedule once every 3 weeks or a low-dose weekly schedule. We compared these 2 schedules via a simplified network meta-analysis with a common comparator., Methods and Materials: We performed a PRISMA-concordant systematic review to identify randomized controlled trials comparing cisplatin with cetuximab for nonmetastatic, locoregionally advanced squamous carcinoma of the head and neck treated with definitive radiation. Trials incorporating primary surgery or induction therapy were excluded. Patient survival times were extracted on a per-event basis from the published curves using a digitizer and validated against published point estimates and hazard ratios (HRs). Survival was compared using random effects Cox regression under a frequentist framework. Toxicity and secondary endpoints were analyzed qualitatively. The Cochrane method assessed the risk of bias. The analysis plan was preregistered with the Open Science Foundation., Results: Five randomized trials were identified, including 1678 patients. There was no statistical difference in overall survival between weekly and bolus regimens (HR, 0.90; 95% CI, 0.53-1.52, P = .345). This Cox model suggested that for the average patient in the cohort, the absolute difference in 5-year overall survival between weekly and bolus regimens was +1.2% (95% CI, -6.1%-+5.9%, P = .345). Secondary endpoints and toxicity were not obviously different by regimen, qualitatively., Conclusions: The cetuximab trials provide indirect data suggesting that the differences between cisplatin schedules are subtle., Competing Interests: Disclosures Matthew C. Ward reports receiving grant support from Varian Medical Systems, Naveris, Inc, consulting honoraria from Exact Sciences, and participating in an ad board for Bayer Pharmaceuticals with publishing royalties from Demos Medical Publishing. All was paid to his institution and none was related to the subject of this manuscript. The remaining authors declare no conflicts of interest., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Investigation of various plant extracts using in-vitro/in-vivo assays has emerged as a promising avenue for identifying potential pharmacophores that can be developed into therapeutic drugs. This study aims to assess the bioactive compounds and antioxidant capacity of the Bolanthus turcicus (B. turcicus) and to investigate the effects on head and neck cancer (HNC) cell lines., Methods: Methanol (MeOH), ethyl acetate (EA) and aqueous (Aq) extracts were prepared from B. turcicus, and the amount of total phenolic content (TPC) and total flavonoid content (TFC) in the extracts were analyzed by the Folin-Ciocalteu and Aluminum chloride method, respectively. In addition, the total antioxidant capacity and iron reducing potential of B. turcicus extracts were determined by the Phosphomolybdenum and Ferric ion reducing antioxidant power (FRAP) method. The effect of B. turcicus on HEp-2, SCC-90, SCC-9, FaDu HNC cell viability, motility, and cell-nuclear morphology was evaluated by MTT, scratch-wound healing assay, and Pllalloidin-DAPI staining, respectively. The effect of B. turcicus on the expression of CASP-3, BAX, and BCL-2 genes at the mRNA, protein, and intracellular level was evaluated by quantitative PCR (qPCR), western blot, and immunofluorescence staining. Moreover, Annexin V-FITC/PI, was used in flow cytometry to investigate the effect of B. turcicus on apoptosis., Results: The MeOH extract exhibited the highest phenolic content, flavonoid content and antioxidant activity (p < 0.05 for all). HNC cells treated with extracts indicated delayed wound healing and decreased motility (p < 0.05 for all). Analysis of annexin V-PI staining indicated that the B. turcicus extracts induced apoptosis but not viability and necrosis in the HNC cell (p < 0.05 for all). Moreover, qPCR data regarding the apoptotic mechanism showed that the extracts could induce apoptosis by upregulation of pro-apoptotic CASP-3 and BAX genes and downregulation of anti-apoptotic BCL-2 gene (p < 0.05 for all). The expression of protein and intracellular levels of CASP-3 and BAX were increased, while the BCL-2 was decreased in cells treated with the extracts (p < 0.05 for all). In addition, diffuse pycnosis and DNA condensation in HNC cell nuclei, confirming apoptotic cell death (p < 0.05 for all)., Conclusion: This study data indicated that B. turcicus extracts have antioxidant, cytotoxic, anti-migratory and pro-apoptotic activity. In conclusion, it has been shown that B. turcicus can be used as a potential therapeutic agent against HNC., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Head and neck squamous cell carcinoma (HNSCC) negative for Human Papillomavirus (HPV) has remained a difficult to treat entity, whereas tumors positive for HPV are characterized by radiosensitivity and favorable patient outcome. On the cellular level, radiosensitivity is largely governed by the tumor cells` ability to repair radiation-induced DNA double-strand breaks (DSBs), but no biomarker is established that could guide clinical decision making. Therefore, we tested the impact of the expression levels of ATM, the central kinase of the DNA damage response as well as DNA-PKcs and Ku80, two major factors in the main DSB repair pathway non-homologous end joining (NHEJ)., Methods: A tissue microarray of a single center HNSCC cohort was stained for ATM, DNA-PKcs and Ku80 and the expression scored based on staining intensity and the percentages of tumor cells stained. Scores were correlated with clinicopathological parameters and survival., Results: Samples from 427 HNSCC patients yielded interpretable stainings and were scored following an established algorithm. The majority of tumors showed strong expression of both NHEJ factors, whereas the expression of ATM varied more. The expression scores of ATM and DNA-PKcs were not associated with patient survival. For HPV-negative HNSCC, the minority of tumors without strong Ku80 expression trended towards superior survival when treatment included radiotherapy. Focusing stronger on staining intensity to define the subgroup with lowest and therefore potentially insufficient expression levels in the HPV-negative subgroup, we observed significantly better overall survival for patients treated with radiotherapy but not with surgery alone., Conclusions: Our data suggest that HPV-negative HNSCC with particularly low Ku80 expression represent a highly radiosensitive subpopulation. Confirmation in independent cohorts is required., (© 2024. The Author(s).)

The mucosal epithelium of the head and neck region (including the oral cavity, nasal cavity, pharynx, nasopharynx, and larynx) is the primary site exposed to tobacco smoke, and its presence of nicotinic acetylcholine receptors (nAChRs) has been observed in the mucosal epithelial cells of this area. It remains unclear whether HNSC cells can migrate and invade through nAChR signaling. A model of HNSC cells exposed to nicotine is established. Cell proliferation following nicotine exposure is assessed using the CCK-8 assay, while migration and invasion are evaluated through wound healing and Transwell assays. The effects of CHRNA5 knockdown and overexpression are also investigated. Immunofluorescence staining is used to analyze CHRNA5 expression and localization, and clonogenic assays are performed to measure colony proliferation after CHRNA5 knockdown and overexpression. The interaction between CHRNA5 and CES1 is examined using molecular docking, co-immunoprecipitation, and immunofluorescence. Differentially expressed genes are subjected to pathway enrichment analysis, and MEK/ERK protein expression and phosphorylation are validated via western blot. Tumor formation assays are performed in nude mice using sh-CHRNA5 Cal27 cells, followed by western blot and immunohistochemical staining. Additionally, laryngeal and hypopharyngeal cancer tissues are analyzed through immunohistochemistry. Nicotine significantly enhanced the proliferation, migration, and invasion capabilities of head and neck tumor cells, including Cal27, Fadu, HN6, and Tu686 cells, through the expression of CHRNA5. Knockdown of CHRNA5 can reduce cell migration, invasion, and proliferation, whereas nicotine exposure can reverse this trend. Additionally, the mRNA and protein expression of CES1 decreases with the knockdown of CHRNA5, indicating a regulatory relationship between the two. Transcriptomics revealed that the knockdown of CHRNA5 is associated with the MEK/ERK signaling pathway. Further cellular- and tissue-level evidence confirmed that the levels of p-MEK/MEK, p-ERK/ERK, and CES1 decreased following knockdown of CHRNA5, a trend that nicotine can reverse. Nicotine promotes the proliferation, migration, and invasion of HNSC by upregulating CHRNA5 expression. Knockdown of CHRNA5 reduces these effects, which can be reversed by nicotine. Nicotine exposure activates CHRNA5, regulating CES1 expression via the MEK/ERK pathway, contributing to the recurrence and metastasis of head and neck squamous carcinoma., (© 2024. The Author(s).)