Comparative analyses of short- and long-term outcomes between endoscopic submucosal dissection and endoscopic laryngo-pharyngeal surgery for superficial pharyngeal carcinomas.

Objectives: Endoscopic treatment of superficial pharyngeal carcinomas includes endoscopic submucosal dissection (ESD; usually performed by endoscopists), and endoscopic laryngo-pharyngeal surgery (ELPS; primarily performed by otolaryngologists). Few studies have compared the efficacy of the two techniques in treating superficial pharyngeal carcinomas. In this study, we compared the outcomes of these two techniques to determine the advantages. Methods: We retrospectively examined the short- and long-term outcomes of 93 consecutive patients with superficial pharyngeal carcinoma who either underwent an ESD or ELPS between August 2008 and December 2021. Results: There were 35 lesions among 29 patients and 93 lesions among 71 patients in the ESD and ELPS groups, respectively. The ELPS group had a significantly shorter procedure time (121.2 ± 97.4 min vs. 54.7 ± 40.2 min, p<0.01), greater procedure speed (0.10 ± 0.06 min/min vs. 0.30 ± 0.23 min/min, p<0.01), and less laryngeal edema than that of the ESD group. There were no significant differences in the 3-year overall, relapse-free, or disease-specific survival rates between the two groups. Intervention with ESD during ELPS was most commonly required when it was difficult to secure the visual field. Conclusions: There were no differences in batch resection rates or long-term prognoses between the two groups; nevertheless, the ELPS group had a shorter treatment time and less laryngeal edema than the ESD group. However, the treatment of narrow areas, such as the esophageal inlet patch, is a technical limitation of ELPS; thus, ELPS should be combined with ESD techniques.

Head and Neck Paragangliomas: 16-year Single-center Experience and Mini Review on Diagnosis, Treatment, and Follow-up.

Objective: To investigate head and neck paraganglioma cases treated at a tertiary center from 2007 to 2023. The research includes a thorough examination of published studies that have focused on long-term outcomes. The additional goal is to contribute to the existing knowledge on head and neck paraganglioma, with a particular emphasis on refining diagnostic algorithms, treatment selection, and follow-up procedures. Methods: A total of 44 patients were retrospectively analyzed, and 39 were included. Demographic information, symptoms, radiological examination results, types, stages, and postoperative complications were recorded. A review was conducted to select articles that reported single-center experiences with large cohorts, long follow-ups, and different treatment modalities since 2010. Results: The mean age of the patients was 54 years, and the female/male ratio was 3.55:1. Among the 39 cases examined, 18 and 19 were identified as cervical paraganglioma and 19 as temporal bone paraganglioma. All patients initially underwent surgical resection. The mean follow-up duration was 5.42 years. Four residual cases and two recurrences were identified postoperatively, and a Gamma Knife was used as additional treatment. Subsequently, 17 articles were selected and summarized, and then a flowchart was prepared showing the possible options for diagnosis, treatment, and follow-up. Conclusions: Preoperative staging is essential for surgical planning and predicting potential intraoperative complications. Based on our findings and review of the articles, we have prepared a flowchart that includes all possibilities depending on the tumor stage to help in the diagnosis, treatment, and follow-up of head and neck paragangliomas.

Enhanced computed tomography radiomics predicts solute carrier family 7, member 11 in head and neck squamous cell carcinoma.

Introduction: Traditional prognostic indicators for head and neck squamous cell carcinoma (HNSCC), such as clinicopathological features, human papillomavirus status, and imaging examinations, often lack precision in guiding medical therapy. Therefore, discovering novel tumor biomarkers that can accurately assess prognosis and aid in personalized medical treatment for HNSCC is critical. Solute carrier family 7, member 11 (SLC7A11), is implicated in ferroptosis, and various malignant tumor therapies regulate its expression. However, the mechanisms regulating SLC7A11 expression, the transporter activity, and its specific role in controlling ferroptosis in cancer cells remain unknown. Thus, in this study, we aimed to develop an improved computed tomography (CT) radiomics model that could predict SLC7A11 expression in patients with HNSCC. Methods: We used patient genomic data and corresponding augmented CT images for prognostic analysis and building models. Further, we investigated the potential molecular mechanisms underlying SLC7A11 expression in the immune microenvironment. Our radiomics model successfully predicted SLC7A11 mRNA expression in HNSCC tissues and elucidated its association with relevant genes and prognostic outcomes. Results: SLC7A11 expression level was high within tumor tissues and was connected to the infiltration of eosinophil, CD8+ T-cell, and macrophages, which was associated with poor overall survival. Our models demonstrated robust predictive power. The distribution of radiomics scores (RAD scores) within the training and validation sets was markedly different between the high- and low-expression groups of SLC7A11. Conclusion: SLC7A11 is likely an important factor in the prognosis of HNSCC. SLC7A11 expression can be predicted effectively and reliably by radiomics models based on enhanced CT.

A bioengineered tumor matrix-based scaffold for the evaluation of melatonin efficacy on head and neck squamous cancer stem cells.

Head and neck squamous cell carcinoma (HNSCC) presents a significant challenge worldwide due to its aggressiveness and high recurrence rates post-treatment, often linked to cancer stem cells (CSCs). Melatonin shows promise as a potent tumor suppressor; however, the effects of melatonin on CSCs remain unclear, and the development of models that closely resemble tumor heterogeneity could help to better understand the effects of this molecule. This study developed a tumor scaffold based on patient fibroblast-derived decellularized extracellular matrix that mimics the HNSCC microenvironment. Our study investigates the antitumoral effects of melatonin within this context. We validated its strong antiproliferative effect on HNSCC CSCs and the reduction of tumor invasion and migration markers, even in a strongly chemoprotective environment, as it is required to increase the minimum doses necessary to impact tumor viability compared to the non-scaffolded tumorspheres culture. Moreover, melatonin exhibited no cytotoxic effects on healthy cells co-cultured in the tumor hydrogel. This scaffold-based platform allows an in vitro study closer to HNSCC tumor reality, including CSCs, stromal component, and a biomimetic matrix, providing a new valuable research tool in precision oncology.

Assessing Long-Term Quality of Life Concerns Through Survivorship Clinic in Head and Neck Cancer Patients.

OBJECTIVE: To characterize the concerns of head and neck cancer (HNC) patients and discern changes in quality-of-life (QoL) during long-term follow-up. STUDY DESIGN: Retrospective review. SETTING: Survivorship clinic at a tertiary academic center. METHODS: A retrospective review was conducted on HNC patients seen in our survivorship clinic between 1/2020 and 1/2024 using the University of Washington Quality of Life (UW-QOL) Questionnaire. RESULTS: Three hundred and forty-two patients were seen for 914 encounters. Patients were divided into 4 groups: pretreatment (n = 326), 0 to 12 months posttreatment (n = 247), 1 to 3 years posttreatment (n = 248), and more than 3 years posttreatment (n = 64). The average follow-up after treatment was 459 days (range: 0-5.2 years). Multivariable analysis revealed significant improvements in overall QoL, health-related QoL, social-emotional composite scores, activity, anxiety, appearance, chewing, mood, pain, speech, and recreation at more than 1-year posttreatment compared to less than 1-year posttreatment. However, declines were noted in saliva and taste scores. No differences in scores were observed between patients 1 to 3 years posttreatment and those >3 years posttreatment. At all timepoints before and after treatment, top concerns were pain, activity, and swallowing. Patients with oral cancer followed for more than 1-year posttreatment had worse scores in appearance, chewing, pain, and speech compared to those with oropharyngeal cancer. CONCLUSIONS: Understanding the evolving concerns of HNC patients is imperative for enhancing care. Most QoL domains improve at 1-year posttreatment except for saliva, taste, swallowing, and shoulder function. QoL scores stabilize after 1-year post-treatment. Pain, activity, and swallowing remain the top concerns at all time points.

A multicentre observational study of paediatric head and neck abscesses.

INTRODUCTION: In winter of 2022/3 paediatric ENT surgeons across the UK observed that the incidence of severe abscesses in the head and neck and associated complications was higher than seen in previous years. We aimed to collate and evaluate data from across the UK to establish if this was a true rise in cases, and to describe the factors associated. METHODS: A multicentre retrospective data collection was undertaken from 13 units across the UK. Patients admitted between September 2022-February 2023 with a head and neck abscess including sinogenic, otogenic, deep and superficial neck abscesses were included. Demographic, disease specific, management and outcome data were collected. Hospital episode statistic data were also requested and analysed to allow for comparison with previous 10 years of head and neck abscesses. RESULTS: 262 patients with abscesses of the head and neck were admitted during the study period, 100 between September and November and 163 between December and February. Mastoid abscesses were the most common abscess across both groups. The rate of group A streptococcus + culture results rose significantly from 12 % in autumn group to 30 % in winter (p = 0.02). The rate of intracranial complications rose from 10 % to 18 % (p = 0.11) and the rate of venous thrombosis rose over the same timeframe from 3 % to 14 % (p = 0.01). DISCUSSION: This study demonstrated a statistically significant rise in the rate of group A streptococcus associated abscesses when comparing Autumn and Winter 2022/2023. Over the same timeframe a statistically significant rise in the proportion of patients with venous thromboses associated with H&N abscesses was noted. Interestingly, despite perceived national consensus regarding a spike in abscess incidence, the number of abscesses seen in winter 2022/2023 was in keeping with expected rates of paediatric H&N abscesses, based on pre covid year-on-year rise in incidence.

Mild hyperthermia upregulates PD-L1 in the tumor microenvironment and enhances antitumor efficacy of PD-L1 blockade in murine squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) has a low five-year survival rate because of its high rate of recurrence and metastasis. After surgical resection or radiation, the main treatments for HNSCC, patients sometimes experience functional or aesthetic disorders. Therefore, there is a great demand for the development of non-surgical treatment strategies to improve clinical outcomes and patients' quality of life. One such non-surgical treatment is mild hyperthermia (mHT). Many studies have investigated combination treatments with mHT and immune checkpoint inhibitors in preclinical settings. However, there have been no detailed reports on the effects of mHT on immune checkpoint molecules. Here, we investigated the effects of mHT on the tumor microenvironment (TME), particularly on programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1), in SCCVII cells and a squamous cell carcinoma mouse model. First, we found that PD-L1 mRNA levels and surface PD-L1 expression significantly increased after mHT. Second, a single tumor model was used to determine the effect of HT on the TME. mHT enhanced the accumulation of CD4+ and CD8+ T cells, elevated PD-L1 expression in the TME, and decreased the PD-1 positive rate of CD4+ T cells. Finally, using a bilateral tumor model, we found that anti-PD-L1 monotherapy and combination therapy resulted in longer survival than the isotype control or mHT monotherapy. Moreover, the combination therapy resulted in a significantly higher survival rate than anti-PD-L1 monotherapy. In conclusion, our findings elucidate changes in PD-L1 expression in the TME and strengthen the rationale for mHT and PD-L1 blockade combination therapy.

Loss of MACROD2 drives radioresistance but not cisplatin resistance in HPV-positive head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide. In recent years, there has been an increase in the rate of HNSCC cases attributed to the infection of the oropharynx by the human papillomavirus (HPV). Given the significant treatment-related toxicities of the current standard of care for HPV-positive HNSCC, there is an urgent need for the development of precision patient stratification and treatment strategies to improve patients' quality of life while maintaining excellent survival rates. We have previously carried out whole genome sequencing of HPV+ HNSCC tumors that failed concurrent cisplatin and radiation treatment and discovered that MACROD2 deletion is enriched among these tumors. In the current study, we sought to investigate the mechanistic role of MACROD2 in HPV+ HNSCC treatment resistance. Our results indicate that MACROD2 depletion in HNSCC cell lines leads to increased cell viability and colony formation capacity. Interestingly, MACROD2 depletion did not alter cisplatin sensitivity but led to an increase in radiation resistance of HPV+ HNSCC cell lines. RNA sequencing and immunofluorescence microscopy demonstrated that MACROD2-depleted HPV+ HNSCC cells displayed elevated levels of hypoxia and an altered DNA damage response. Taken together, this study establishes and characterizes the role of MACROD2 in HPV+ HNSCC radioresistance. Further work is needed to validate MACROD2 as a biomarker of treatment failure and to understand how to overcome the identified molecular mechanisms of resistance.

Unveiling therapeutic avenues targeting xCT in head and neck cancer.

Head and neck cancer (HNC) remains a major global health burden, prompting the need for innovative therapeutic strategies. This review examines the role of the cystine/glutamate antiporter (xCT) in HNC, specifically focusing on how xCT contributes to cancer progression through mechanisms such as redox imbalance, ferroptosis, and treatment resistance. The central questions addressed include how xCT dysregulation affects tumor biology and the potential for targeting xCT to enhance treatment outcomes. We explore recent developments in xCT-targeted current and emerging therapies, including xCT inhibitors and novel treatment modalities, and their role in addressing therapeutic challenges. This review aims to provide a comprehensive analysis of xCT as a therapeutic target and to outline future directions for research and clinical application.

Squamous cell carcinoma involving the midline of the dorsum of the tongue: a case report.

Introduction: Most cases of squamous cell carcinoma (SCC) of the tongue occur on the lateral surface; however, SCC of the dorsum is extremely rare. Case presentation: The authors describe the case of a 79-year-old man with SCC involving the midline of the dorsum of the tongue. The lesion was surgically resected. The patient was followed up for 1 year and 6 months, and no recurrence was noted. Discussion: SCC of the dorsal midline is even rarer and accounts for less than 1% of tongue carcinomas. SCC involving the dorsum may have a worse prognosis than SCC of the lateral or ventral surface. This report is the first to use submental flap reconstruction to treat cancer of the midline dorsum of the tongue. Conclusion: The authors encountered a case of SCC involving the midline of the dorsum of the tongue, which has rarely been reported in the literature. The authors attained a favorable outcome through surgical intervention.

Probiotics in the management of radiation-induced oral mucositis.

Oral mucositis is a common and debilitating oral complication in head and neck cancer patients undergoing radiotherapy, resulting in diminished quality of life and potential treatment disruptions. Oral microbiota has long been recognized as a contributing factor in the initiation and progression of radiation-induced oral mucositis (RIOM). Numerous studies have indicated that the radiation-induced oral microbial dysbiosis promotes the occurrence and severity of oral mucositis. Therefore, approaches that modulate oral microbial ecology are promising for the management of RIOM. Probiotics as a relatively predicable and safe measure that modulates microecology have garnered significant interest. In this review, we discussed the correlation between RIOM and oral microbiota, with a particular focus on the efficacy of probiotics in the control of RIOM, in order to provide novel paradigm for the management of this disease.

Supervised deep learning-based synthetic computed tomography from kilovoltage cone-beam computed tomography images for adaptive radiation therapy in head and neck cancer.

PURPOSE: To generate and investigate a supervised deep learning algorithm for creating synthetic computed tomography (sCT) images from kilovoltage cone-beam computed tomography (kV-CBCT) images for adaptive radiation therapy (ART) in head and neck cancer (HNC). MATERIALS AND METHODS: This study generated the supervised U-Net deep learning model using 3,491 image pairs from planning computed tomography (pCT) and kV-CBCT datasets obtained from 40 HNC patients. The dataset was split into 80% for training and 20% for testing. The evaluation of the sCT images compared to pCT images focused on three aspects: Hounsfield units accuracy, assessed using mean absolute error (MAE) and root mean square error (RMSE); image quality, evaluated using the peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM) between sCT and pCT images; and dosimetric accuracy, encompassing 3D gamma passing rates for dose distribution and percentage dose difference. RESULTS: MAE, RMSE, PSNR, and SSIM showed improvements from their initial values of 53.15 ± 40.09, 153.99 ± 79.78, 47.91 ± 4.98 dB, and 0.97 ± 0.02 to 41.47 ± 30.59, 130.39 ± 78.06, 49.93 ± 6.00 dB, and 0.98 ± 0.02, respectively. Regarding dose evaluation, 3D gamma passing rates for dose distribution within sCT images under 2%/2 mm, 3%/2 mm, and 3%/3 mm criteria, yielded passing rates of 92.1% ± 3.8%, 93.8% ± 3.0%, and 96.9% ± 2.0%, respectively. The sCT images exhibited minor variations in the percentage dose distribution of the investigated target and structure volumes. However, it is worth noting that the sCT images exhibited anatomical variations when compared to the pCT images. CONCLUSION: These findings highlight the potential of the supervised U-Net deep learningmodel in generating kV-CBCT-based sCT images for ART in patients with HNC.

Keratin-based topical cream for radiation dermatitis during head and neck radiotherapy: a randomised, open-label pilot study.

Introduction: Radiation dermatitis (RD) is a frequent toxicity during radiotherapy (RT) for head and neck cancer (HNC). We report the first use of KeraStat® Cream (KC), a topical, keratin-based wound dressing, in patients with HNC receiving RT. Methods: This pilot study randomized HNC patients treated with definitive or postoperative RT (≥60 Gy) to KC or standard of care (SOC), applied at least twice daily during and for 1-month after RT. Outcomes of interest included adherence to the assigned regimen (at least 10 applications per week of treatment), clinician- and patient-reported RD, and skin-related quality of life. Results: 24 patients were randomized and completed the study. Most patients had stage III-IV disease and oropharynx cancer. Median RT dose was 68 Gy; the bilateral neck was treated in 19 patients, and 18 patients received concurrent chemotherapy. Complete adherence was observed in 7/12 (SOC) vs. 10/12 (KC, p = 0.65). Adherence by patient-week was 61/68 versus 64/67, respectively (p = 0.20). No differences in RD were observed between groups. Conclusion: A randomized trial of KC versus SOC in HNC patients treated with RT is feasible with good adherence to study agent. An adequately powered randomized study is warranted to test the efficacy of KC in reducing RD.

Cancer cell-specific PD-L1 expression is a predictor of poor outcome in patients with locally advanced oral cavity squamous cell carcinoma.

BACKGROUND: Locally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand 1 (PD-L1) expression in these tumors, focusing on its association with treatment outcomes and the immune microenvironment. METHODS: We assessed tumor-infiltrating lymphocytes (TILs) in 132 patients with OCSCC to evaluate their impact on survival. Multiplex immunohistochemistry staining for CD3, CD68, CD11c, PD-L1, and P40 was used to explore correlations with clinical outcomes in patients with early-stage (n=22) and locally advanced (n=36) OCSCC. These initial findings were validated through differential gene expression analysis, gene set enrichment, and immune cell deconvolution in a The Cancer Genome Atlas cohort of 163 locally advanced OCSCC tumors. Additionally, single-cell RNA sequencing (scRNA-seq) on a smaller cohort (n=10) further characterized the PD-L1hi or PD-L1lo cancer cells in these tumors. RESULTS: Elevated PD-L1 expression was associated with poor outcomes in patients with locally advanced OCSCC undergoing standard adjuvant therapy, irrespective of "hot" or "cold" classification based on TILs assessment. PD-L1hi tumors exhibited an active immune response phenotype, enriched with M1 macrophages, CD8+ T cells and T regulatory cells in the tumor microenvironment. Notably, the negative impact of PD-L1 expression on outcomes was primarily attributed to its expression by cancer cells, rather than immune cells. Furthermore, scRNA-seq revealed that immune interactions were not essential for PD-L1 upregulation in cancer cells, instead, complex regulatory networks were involved. Additionally, PD-L1lo locally advanced tumors exhibited more complex pathway enrichment and diverse T-cell populations compared with those in the early-stage. CONCLUSION: Our findings underscore the prognostic significance of PD-L1 expression in locally advanced OCSCC, and unveil the complex interplay between PD-L1 expression, immune responses, and molecular pathways in the tumor microenvironment. This study provides insights that may inform future therapeutic strategies, including the possibility of tailored immunotherapeutic approaches for patients with PD-L1hi locally advanced OCSCC.

Novel bispecific antibody-drug conjugate targeting PD-L1 and B7-H3 enhances antitumor efficacy and promotes immune-mediated antitumor responses.

BACKGROUND: Antibody-drug conjugates (ADCs) offer a promising approach, combining monoclonal antibodies with chemotherapeutic drugs to target cancer cells effectively while minimizing toxicity. METHODS: This study examined the therapeutic efficacy and potential mechanisms of a bispecific ADC (BsADC) in laryngeal squamous cell carcinoma. This BsADC selectively targets the immune checkpoints programmed cell death ligand-1 (PD-L1) and B7-H3, and the precise delivery of the small-molecule toxin monomethyl auristatin E. RESULTS: Our findings demonstrated that the BsADC outperformed its bispecific antibody and PD-L1 or B7-H3 ADC counterparts, particularly in terms of in vitro/in vivo tumor cytotoxicity, demonstrating remarkable immune cytotoxicity. Additionally, we observed potent activation of tumor-specific immunity and significant induction of markers of immunogenic cell death (ICD) and potential endoplasmic reticulum stress. CONCLUSION: In conclusion, this novel BsADC, through immune checkpoint inhibition and promotion of ICD, amplified durable tumor immune cytotoxicity, providing novel insights and potential avenues for future cancer treatments and overcoming resistance.

Comprehensive Review of Post-treatment Imaging in Head and Neck Cancers: From expected to unexpected and beyond.

Head and neck cancer management requires multidisciplinary approach in which radical surgery with or without flap reconstructions and neck dissection, along with radiotherapy (RT)/chemoradiotherapy (CRT) serve as the key components. Neoadjuvant chemotherapy (NACT) and immunotherapy are used in selected cases based on the institutional preference. Knowledge of expected posttreatment changes on imaging is essential to differentiate it from recurrence. In addition, awareness of various posttreatment complications is imperative for their early detection on imaging. Distorted anatomy after treatment poses diagnostic challenge, hence, proper choice of imaging modality and appropriate timing of scan is pertinent for accurate posttreatment evaluation. In this article, we have provided a comprehensive review on expected imaging appearances post RT/CRT and after major types of head and neck squamous cell carcinoma (HNSCC) surgeries. In addition, we have extensively reviewed the imaging appearances of various posttreatment complications, and recurrences at the primary and lymph nodal sites. We have also delved into the patterns of recurrence in human papillomavirus (HPV) positive HNSCC in this article. Furthermore, we have provided flowcharts and discussed recommendations on the site-specific and treatment related imaging modalities to be used along with their appropriate timing, for adequate evaluation of HNSCC after treatment. We have also reviewed posttreatment reporting of imaging findings using Neck Imaging Reporting and Data Systems (NIRADS) and Hopkins criteria. In addition, we have also touched upon the role of advanced imaging techniques for posttreatment HNSCC evaluation.

Overexpression of TPD52L2 in HNSCC: prognostic significance and correlation with immune infiltrates.

BACKGROUND: Evidence has been presented that the tumor protein D52 (TPD52) family plays a critical role in tumor development and progression. As a member of the TPD52 family, the changes in TPD52L2 gene status are instrumental in kinds of cancer development. However, its effects on patient prognosis and immune infiltration in Head and Neck Squamous Carcinoma (HNSCC) are still poorly understood. METHODS: The Tumor Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and c-BioPortal database was used to explore the expression pattern, prognostic value, and variation of gene status in HNSCC. The LinkedOmics database was used to obtain the co-expression genes of TPD52L2 and identify the diagnostic value of TPD52L2 in HNSCC. The correlations between TPD52L2 expression and six main types of immune cell infiltrations and immune signatures were explored using Tumor Immune Estimation Resource (TIMER). The correlation between TPD52L2 expression and immune checkpoint genes (ICGs) was analyzed by TCGA database. Immunohistochemistry (IHC) was performed to validate the expression of three ICGs (PDL1, PDL2, EGFR) and TPD52L2 using 5 paired HNSCC and normal head and neck tissues. Polymerase Chain Reaction (PCR) and Western Blot (WB) of HNSCC and normal head and neck cell lines were performed to verify the high level of TPD52L2 mRNA and protein expression. protein expression of TPD52L2 in pan-cancer was also validated using UALCAN. RESULTS: TPD52L2 was overexpressed in tumor tissues, and it predicted worse survival status in HNSCC. ROC analysis suggested that TPD52L2 had a diagnostic value. Multivariate Cox analysis identified TPD52L2 as an independent negative prognostic marker of overall survival. Functional network analysis suggested that TPD52L2 was associated with immune-related signaling pathways, cell migration pathways, and cancer-related pathways. High expression of TPD52L2 was associated with a more mutant frequency of TP53. Notably, we found that the expression of TPD52L2 was closely negatively correlated with the infiltration levels of 15 types of immune cells and positively correlated with several immune markers. PCR, WB experiments, and UALCAN database verified the high level of TPD52L2 mRNA and protein expression. CONCLUSION: TPD52L2 is upregulated in HNSCC, which is an independent factor for adverse prognosis prediction. It probably plays a role in the negative regulation of immune cell infiltration. TPD52L2 might be a promising prognostic biomarker and therapeutic target in HNSCC.

Phenotype remodelling of HNSCC cells in the muscle invasion environment.

BACKGROUND: Tumour invading muscle in head and neck squamous cell carcinoma (HNSCC) is often associated with destructive growth and poor prognosis. However, the phenotypic functions and pathological mechanisms of muscle-invasive cancer cells in tumour progress remains unknown. In this study, we aimed to investigate the phenotypic functions of muscle-invasive cancer cells of HNSCC and their potential crosstalk with tumour microenvironment. METHODS: We obtained scRNA-seq data (SC) from GSE103322 (N = 18) and GSE181919 (N = 37), spatial RNA-seq data (ST) from GSE208253 and GSE181300 (N = 4), transcriptomics of human HNSCC samples from GSE42743 (N = 12) and GSE41613 (N = 97). Utilizing the TCGA-HNSC dataset, we conducted univariate and multivariate Cox analyses to investigate the prognostic impact of muscle-invasion in HNSCC, with validation in an additional cohort. Through Stutility and AUCell approaches, we identified and characterized muscle-invasive cancer cell clusters, including their functional phenotypes and gene-specific profiles. Integration of SC and ST data was achieved using Seurat analysis, multimodal intersection analysis, and spatial deconvolution. The results were further validated via in vitro and in vivo experiments. RESULTS: Our analyses of the TCGA-HNSC cohort revealed the presence of muscle-invasion was associated with a poor prognosis. By combining ST and SC, we identified muscle-invasive cancer cells exhibiting epithelial-to-mesenchymal transition (EMT) and myoepithelial-like transcriptional programs, which were correlated with a poor prognosis. Furthermore, we identified G0S2 as a novel marker of muscle-invasive malignant cells that potentially promotes EMT and the acquisition of myoepithelium-like phenotypes. These findings were validated through in vitro assays and chorioallantoic membranes experiments. Additionally, we demonstrated that G0S2-overexpressing cancer cells might attract human ECs via VEGF signalling. Subsequent in vitro and in vivo experiments revealed G0S2 plays key roles in promoting the proliferation and invasion of cancer cells. CONCLUSIONS: In this study, we profiled the transcriptional programs of muscle-invasive HNSCC cell populations and characterized their EMT and myoepithelial-like phenotypes. Furthermore, our findings highlight the presence of muscle-invasion as a predictive marker for HNSCC patients. G0S2 as one of the markers of muscle-invasive cancer cells is involved in HNSCC intravasation, probably via VEGF signalling.

Alpelisib and Immunotherapy: A Promising Combination for Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck.

BACKGROUND: Recurrent squamous cell carcinoma (SCC) of the head and neck (SCCHN) remains a formidable clinical challenge despite available treatments. The phosphatidylinositol 3-kinase (PI3K) pathway has been identified as a potential therapeutic target, and alpelisib, a selective PI3Kα inhibitor, has demonstrated efficacy in certain malignancies. Combining this targeted therapy with immunotherapy has been suggested in previous studies as a promising strategy to bolster the immune response against cancer. CASES: A 69-year-old woman with locoregional recurrence of PIK3CA-mutated SCC of the left maxilla and cervical nodal metastases. Several chemotherapeutic regimens, including cisplatin, docetaxel, 5FU, chemoradiotherapy, and mono-immunotherapy, resulted in disease progression. Alpelisib combined with pembrolizumab led to a sustained response for 9 months. A 58-year-old man with recurrent metastatic PIK3CA-mutated SCC of the oropharynx, involving the left lung, hilar, and mediastinal lymph nodes. Despite prior palliative radiation and platinum-based chemotherapy with pembrolizumab and cetuximab, treatment with alpelisib and nivolumab resulted in a partial response. Severe hyperglycemia and rash led to treatment discontinuation. CONCLUSION: Our findings highlight the potential of this innovative therapeutic combination, suggesting a need for further investigations in this setting.

Surgical and functional outcomes after salvage oropharyngectomy.

OBJECTIVES: Salvage oropharyngeal surgery with free-flap reconstruction after failed radiation therapy (RT) presents unique challenges and complications. The aim of this retrospective review is to examine surgical complications and functional outcomes in patients who received salvage surgery for recurrent or persistent oropharyngeal cancer following RT. PATIENTS AND METHODS: Patients diagnosed with oropharyngeal cancer and underwent salvage oropharyngectomy at the University of Florida between 2016-2021 were identified from inpatient and outpatient records of the Head and Neck Oncology Team. Outcomes measured were tracheostomy dependence, tube-feed dependence, and intact oral intake status. Survival outcomes using Kaplan-Meier product limit method were calculated. RESULTS AND CONCLUSION: Twenty-six patients were included in the analysis. Average age was 63.7 years. Fourteen (53.8 %) oropharyngectomies used a transmandibular approach, ten (38.5 %) through a combined transoral and transcervical approach, and two (7.7 %) through a transcervical approach. Average time to tracheostomy decannulation was 25.1 days. At 6 months, twenty (83.3 %) patients were gastric tube independent with twelve (54.2 %) patients tolerating any oral intake. At 12 months, gastric tube independent feeds decreased to nine (60 %) patients with thirteen (92.9 %) patients tolerating oral intake. The median overall survival was 27 months with local cancer recurrence being the most common cause of death. Patients undergoing salvage oropharyngectomy for recurrent disease continue to face prolonged tracheostomy and tube dependent feedings. Despite intact swallowing function, patients preferred to use gastric tube feedings, likely for speed, ease, and convenience. Further studies are needed to analyze factors influencing these conflicting functional outcomes and predictive factors impacting survival.