Alternative Splicing Landscape of Head and Neck Squamous Cell Carcinoma.

Head and neck malignancies are a significant global health concern, with head and neck squamous cell carcinoma (HNSCC) being the sixth most common cancer worldwide accounting for > 90% of cases. In recent years, there has been growing recognition of the potential role of alternative splicing (AS) in the etiology of cancer. Increasing evidence suggests that AS is associated with various aspects of cancer progression, including tumor occurrence, invasion, metastasis, and drug resistance. Additionally, AS is involved in shaping the tumor microenvironment, which plays a crucial role in tumor development and response to therapy. AS can influence the expression of factors involved in angiogenesis, immune response, and extracellular matrix remodeling, all of which contribute to the formation of a supportive microenvironment for tumor growth. Exploring the mechanism of AS events in HNSCC could provide insights into the development and progression of this cancer, as well as its interaction with the tumor microenvironment. Understanding how AS contributes to the molecular changes in HNSCC cells and influences the tumor microenvironment could lead to the identification of new therapeutic targets. Targeted chemotherapy and immunotherapy strategies tailored to the specific AS patterns in HNSCC could potentially improve treatment outcomes and reduce side effects. This review explores the concept, types, processes, and technological advancements of AS, focusing on its role in the initiation, progression, treatment, and prognosis of HNSCC.

ITGB6 modulates resistance to anti-CD276 therapy in head and neck cancer by promoting PF4+ macrophage infiltration.

Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers. Preclinical studies and mouse models suggest that therapies targeting CD276 may outperform PD1/PD-L1 blockade. However, data from mouse models indicate a significant non-responsive population to anti-CD276 treatment, with the mechanisms of resistance still unclear. In this study, we evaluate the activity of anti-CD276 antibodies in a chemically-induced murine model of head and neck squamous cell carcinoma. Using models of induced and orthotopic carcinogenesis, we identify ITGB6 as a key gene mediating differential responses to anti-CD276 treatment. Through single-cell RNA sequencing and gene-knockout mouse models, we find that ITGB6 regulates the expression of the tumor-associated chemokine CX3CL1, which recruits and activates PF4+ macrophages that express high levels of CX3CR1. Inhibition of the CX3CL1-CX3CR1 axis suppresses the infiltration and secretion of CXCL16 by PF4+ macrophages, thereby reinvigorating cytotoxic CXCR6+ CD8+ T cells and enhancing sensitivity to anti-CD276 treatment. Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment.

Robot-assisted versus conventional neck dissection: a propensity score matched case-control study on perioperative and oncologic outcomes.

The widespread acceptance of robotic surgery is extending to oral procedures. The demand for minimally invasive techniques is driving research into the cosmetic and oncologic benefits of robotic neck surgery. This study used propensity score matching to analyze the clinical course and postoperative outcomes of robot-assisted neck dissections for oncologic efficacy and surgical safety. Between May 2020 and April 2024, 200 OSCC patients underwent surgery and 42 were excluded. The cohort included 158 patients, 128 of whom underwent unilateral neck dissection and 30 of whom underwent bilateral neck dissection. Robotic-assisted neck dissection (RAND) was performed in 36 patients while conventional transcervical neck dissection (CTND) was performed in 122 patients. Data analysis included several factors, including lymph node retrieval and perioperative outcomes, with 1:1 propensity score matching to ensure fairness. Each of the 39 neck specimens with 36 patients was selected. The CTND group was 8 years older overall than the RAND group, but otherwise similar in terms of primary site and clinical stage. The RAND group had a 55-min longer operative time and 140 cc more hemovac drainage than the CTND group, but the hospital stay and intensive care unit duration were the same, and the number of lymph nodes retrieved was the same. Survival rates also showed no difference across all stages. This shows that RAND is in no way inferior to CTND in terms of perioperative or oncologic outcomes, and demonstrates the safety of robot-assisted surgery, even in patients who require flaps or in patients with advanced stages.

Current Landscape of Antibody-Drug Conjugate Development in Head and Neck Cancer.

Antibody-drug conjugates (ADCs) are fusions of therapeutic drugs and antibodies conjugated by a linker, designed to deliver a therapeutic payload to cells expressing the target antigen. By delivering the highly cytotoxic agent directly to cancer cells, ADCs are designed to enhance safety and broaden the therapeutic window. Recently, ADCs have demonstrated promising efficacy in various solid tumors and are rapidly expanding their indications. The prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor, with no new therapeutics since the advent of anti-PD-1 antibodies in 2016, highlighting a critical need for innovative therapies. Recent preliminary results suggest that ADCs could be promising treatment options for HNSCC as they explore a variety of target antigens, payloads, and linkers. However, for successful adaptation of ADCs in the treatment of HNSCC, addressing key challenges such as payload toxicities, antigen heterogeneity, and adaptive resistance will be essential. Current research focused on new ADC structures, including multispecific antibodies and noncytotoxic payloads, and diverse combination approaches, show promise for future advancements.

Validity of a single-item indicator of treatment side effect bother in patients with head and neck cancer.

PURPOSE: Patients with head/neck squamous cell carcinomas (HNSCC) experience significant tumor- and treatment-related side effects. No efficient summary measure capturing the totality of side effect burden currently exists. We examined associations between a single patient-reported outcome (PRO) item evaluating side effect bother (FACT GP5, "I am bothered by side effects of treatment") with overall side effects in HNSCC. METHODS: We performed a retrospective secondary analysis of development of the Functional Assessment of Cancer Therapy (FACT) Head/Neck Symptom Index (FHNSI-10), which included completing FACT-HN (including Head/Neck Cancer Subscale (HNCS) and Trial Outcome Index (TOI)) and the pain intensity numeric rating scale (NRS). We calculated Spearman's correlations between GP5 and these measures of patient-reported global health, head/neck side effects, and pain intensity NRS. A correlation of > 0.4 was considered sufficient evidence of association. RESULTS: Ninety-seven patients completed baseline and 85 completed 3-month follow-up surveys. GP5 was highly correlated with FACT-HN total score (baseline r = 0.66, 3 months r = 0.67) and FHNSI-10 (baseline r = 0.63, 3 months r = 0.65). GP5 correlated with multiple FACT-HN subscales including FACT-G, physical well-being, functional well-being, HNCS, and TOI (range baseline r = 0.53-0.77, range 3 months r = 0.49-0.77). Worsening GP5 score was associated with worsening overall HNCS (p = 0.002), worsening FHNSI-10 score (p < 0.001), and worsening mean pain intensity (p < 0.001). CONCLUSION: GP5 exhibited validity within HNSCC, exhibiting substantial correlations with a number of HNSCC-related PRO measures including FACT-HN and FHNSI-10. Worsening GP5 was associated with worsening HNCS, FHNSI summary score, and pain intensity. GP5 has promise as a summary indicator of symptom and side effect bother in HNSCC.

Development and validation of the head and neck cancer psychosocial distress scale (HNCPDS) to identify patients at high risk for psychological problems : a multicenter study.

To develop the Head and Neck Cancer Psychosocial Distress Scale (HNCPDS) with the aim of identifying high-risk individuals for psychosocial distress among patients, and to assess its reliability, validity and applicability. Using the classical test theory, a total of 435 head and neck cancer patients from six tertiary hospitals in China were recruited for developing the HNCPDS. Delphi expert consultation and item analysis were used to improve the content validity of the preliminary HNCPDS. Factor analysis (FA) and Structural equation modeling (SEM) were used to test the structural validity of HNCPDS. Cronbach's alpha coefficient, Spearman-Brown coefficient and Intra-class correlation coefficient (ICC) were used to test the internal consistency and retest reliability of HNCPDS. Multiple stepped-linear regression was used to analyze the risk factors of psychological disorder, and Pearson correlation coefficient was used to analyze the correlation between psychosocial distress and quality of life (QOL). The HNCPDS consisted of 14 items, which were divided into 3 subscales: 3 items for cancer discrimination, 5 items for anxiety and depression, and 6 items for social phobia. The HNCPDS had good validity [KMO coefficient was 0.947, Bartlett's test was 5027.496 (P < 0.001), Cumulative variance contribution rate was 75.416%, and all factor loadings were greater than 0.55], reliability (Cronbach's alpha coefficient was 0.954, Spearman-Brown coefficient was 0.955, test-retest reliability was 0.845) and acceptability [average completion time (14.31 ± 2.354 min) and effective completion rate of 90.63%]. Financial burden, sex, age and personality were found to be independent risk factors for HNCPDS (P < 0.05), and patients with higher HNCPDS scores reported a lower QOL (P < 0.01). The HNCPDS is effective and reliable in early identification and assessment of the level of psychosocial distress in patients with head and neck cancer, which can provide an effective basis for health education, psychological counseling, and social support in the future.

A study of risk factors associated with the presence of oral potentially malignant disorders: a community-based study from Northeastern Thailand.

BACKGROUND: The principal objective of this study is to ascertain the connections between well-known risk factors of oral cancer, including smoking (cigarette and tobacco), alcohol consumption, betel quid chewing, irritations in the oral cavity, history of head and neck cancer, and history of working outdoor more than 4 days/week, and the presence of OPMDs within the Thai population. METHOD: 349,318 subjects were recruited for initial screening, then 1,483 subjects who had at least 1 risk factor and a suspicious lesion underwent comprehensive oral examinations followed by a clinical diagnosis and then received initial treatment from either oral surgeons or oral medicine specialists. Among these subjects, individuals with at least 1 risk factor and with a clinical diagnosis of OPMDs were classified as cases, while those with at least 1 risk factor but without OPMDs were categorized as controls. The case group comprised a total of 487 subjects, whereas the control group consisted of 996 subjects. Exclusion criteria were known cases of currently having oral cancer or OPMDs. RESULTS: The outcomes of the multivariate analysis revealed that among the variables assessed, betel quid (adjusted OR 5.12 [3.93-6.68], p < 0.001) and smoking (adjusted OR 1.46 [1.08-1.97], p = 0.013), there were an association with the presence of OPMDs. Conversely, alcohol drinking, having irritations in the oral cavity, a history of head and neck cancer, and a history of working outdoors more than 4 days/week were not associated with the presence of OPMDs. Furthermore, we also study the synergistic effect of alcohol drinking, irritations in the oral cavity, history of head and neck cancer, and history of working outdoors more than 4 days/week using subgroup analysis. The analysis showed that alcohol consumption combined with smoking or betel quid chewing expressed a significantly increased risk of OPMDs, from 1.46 to 2.03 (OR 2.03 [1.16-3.56], p = 0.014) and from 5.12 to 7.20 (OR 7.20 [3.96-13.09], p < 0.001). CONCLUSION: Smoking and exposure to betel quid were a significant risk factors for the presence of OPMDs. The combination of alcohol with smoking or betel quid chewing was also found to increase the risk of OPMDs in this Thai northeastern population.

Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma.

Background: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

Letters to editor regarding the article "P4HA2 contributes to head and neck squamous cell carcinoma progression and EMT through PI3K/AKT signaling pathway".

We have read the original article titled "P4HA2 contributes to head and neck squamous carcinoma progression and EMT through PI3K/AKT signaling pathway" by Yan-Ling Wu et al., which was published in the Medical Oncology journal, with great interest. This study provides valuable insights into the involvement of P4HA2 in the progression of head and neck squamous cell carcinoma (HNSCC), highlighting its potential as an oncogenic factor that promotes epithelial-mesenchymal transition (EMT), motility, invasion, and proliferation of cancer cells through the PI3K/AKT signaling pathway. While this work enhances our understanding of the role of P4HA2 in HNSCC, there are certain aspects that remain unexplored. These areas could be further investigated in future research to obtain a more comprehensive understanding. Specifically, the study did not investigate other signaling pathways or molecular mechanisms through which P4HA2 may impact the development of HNSCC. By exploring these molecular pathways, it may be possible to identify specific targets for pharmaceutical intervention to inhibit the production of P4HA2. Examining these aspects in future research would significantly contribute to our understanding of the role of P4HA2 in HNSCC and its potential as a therapeutic target. We appreciate the authors for their significant contribution and eagerly await future studies that expand upon these findings.

Histone-methyltransferase KMT2D deficiency impairs the Fanconi anemia/BRCA pathway upon glycolytic inhibition in squamous cell carcinoma.

Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.

Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer-Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of Stromal Cell-Based Pharmacological Strategies.

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.

Feasibility of a Novel Surface-Guided Setup Technique to Reproduce Neck Curvature Using two Regions of Interest.

PURPOSE: To improve the setup reproducibility of neck curvature using real-time optical surface imaging (OSI) guidance on 2 regions of interest (ROIs) to infer cervical spine (c-spine) curvature for surface-guided radiotherapy (SGRT) of head-and-neck (HN) and c-spine cancer. METHODS: A novel SGRT setup approach was designed to reproduce neck curvature with 2 ROIs: upper-chest ROI and open-face ROI. It was hypothesized that the neck curvature could be reproduced if both ROIs were aligned within ±3 mm/2˚ tolerance. This was tested prospectively in 7 volunteers using real-time 3D-OSI guidance and lateral 2D-photography verification after the 3D and 2D references were captured from the initial conventional setup. Real-time SGRT was performed to align chest-ROI and face-ROI, and the longitudinal distance between them was adjustable using a head-support slider. Verification of neck curvature anteriorly and posteriorly was achieved by overlaying edge-extracted lateral pictures. Retrospectively, the relationship between anterior surface and spinal canal alignment was checked in 11 patients using their simulation CT (simCT) and setup cone-beam CT (CBCT). After the anterior surface was rigidly aligned, the spinal canal alignment was checked and quantified using the mean-distance-to-agreement (MDA) and DICE similarity index, and surface-to-spine correlation was calculated. RESULTS: The reproducibility of neck curvatures using the 2xROI SGRT setup is verified and the mean neck-outline-matching difference is within ±2 mm in lateral photographic overlays. The chest-ROI alignment takes 110 ± 58 s and the face-ROI takes 60 ± 35 s. When the anterior body surface is aligned (MDA = 1.1 ± 0.6 mm, DICE = 0.96 ± 0.02,) the internal spinal canal is also aligned (MDA = 1.0 ± 0.3 mm, DICE = 0.84 ± 0.04) in 11 patients. The surface-to-spine correlation is c = 0.90 (MDA) and c = 0.85 (DICE). CONCLUSION: This study demonstrates the feasibility of the novel 2-ROI SGRT setup technique to achieve reproducible neck and c-spine curvature regardless of neck visibility and availability as ROI. Staff training is needed to adopt this unconventional SGRT technique to improve patient setup.

Simultaneous p53 and p16 Immunostaining for Molecular Subclassification of Head and Neck Squamous Cell Carcinomas.

PURPOSE: Our aim was to assess the ability of simultaneous immunohistochemical staining (IHC) for p16 and p53 to accurately subclassify head and neck squamous cell carcinomas (HNSCC) as HPV-associated (HPV-A) versus HPV-independent (HPV-I) and compare p53 IHC staining patterns to TP53 mutation status, p16 IHC positivity and HPV status. METHODS: We stained 31 HNSCCs for p53 and p16, and performed next-generation sequencing (FoundationOne©CDx) on all cases and HPV in-situ hybridization (ISH) when sufficient tissue was available (n = 23). p53 IHC staining patterns were assessed as wildtype (wt) or abnormal (abn) patterns i.e. overexpression, null or cytoplasmic staining. RESULTS: In a majority of cases (28/31) interpretation of p16 and p53 IHC was straightforward; 10 were considered HPV-A (p16+/p53wt) and 18 cases were HPV-I (p16-/p53abn). In the remaining three tumours the unusual immunophenotype was resolved by molecular testing, specifically (i) subclonal p16 staining and wild type p53 staining in a tumour positive for HPV and with no TP53 mutation (HPV-A), (ii) negative p16 and wild type p53 staining with a TP53 mutation and negative for HPV (HPV-I), and (iii) equivocally increased p16 staining with mutant pattern p53 expression, negative HPV ISH and with a TP53 mutation (HPV-I). CONCLUSION: Performing p16 and p53 IHC staining simultaneously allows classification of most HNSCC as HPV-A (p16 +, p53 wild type (especially basal sparing or null-like HPV associated staining patterns, which were completely specific for HPV-A SCC) or HPV-I (p16 -, p53 mutant pattern expression), with the potential for limiting additional molecular HPV or mutational testing to selected cases only.

Do Posterior Neck Lumps Need Ultrasound Evaluation: A Case Series of 623 Neck Ultrasound Studies at a Single Institution.

INTRODUCTION/OBJECTIVES: Neck lumps are a common presentation to primary care services. The aetiology of posterior neck lumps is poorly explored in the literature, and therefore remain a concern to patients and clinicians. This often results in an urgent referral for ultrasound assessment. The authors of this study sought to evaluate the aetiology of posterior neck lumps from a radiological perspective, to assess whether ultrasound can be used as a useful adjunct, rather than a first-line urgent investigation. METHODS: A retrospective case series was carried out, examining all primary care referred ultrasound studies for assessment of posterior neck lumps, performed at a single institution in Essex, United Kingdom, over a period of over 10 years dating between 2nd February 2012 to 8th November 2022. Data was collected on: patient age at the time of study, patient sex, whether the lump was single or multiple as palpated and documented by the primary care physician, size of the lump to the nearest 0.5 cm as documented on ultrasound using the longest dimension, sonographic diagnosis and any follow up imaging (not limited to ultrasound). RESULTS: A total of 623 neck ultrasounds were performed on 615 adults. Of the overall radiological diagnoses made from the 623 scans, 555 (89.09%) scans were benign, 63 (10.11%) scans had no lump found on sonography, and 3 (0.48%) scans showed malignancy. In the remaining 2 (0.32%) scans, the lump was deemed indeterminate. The most common aetiologies for benign lumps were due to: normal lymph nodes (n = 263; 42.21%), lipomas (n = 152; 24.39%), and benign dermal cysts (n = 105; 16.85%). All 3 malignant cases had co-existing anterior and posterior neck lumps. CONCLUSIONS: Given that the overwhelming majority of posterior neck lumps in our study had benign findings, we propose that patients with solitary or even multiple posterior neck lumps alone, regardless of size can either be investigated routinely or can be reassured depending on other clinical examination characteristics. Patients who have the presence of co-existing anterior and posterior neck palpable neck lumps justifies urgent or 2-week wait radiological investigation.

Anlotinib reversed resistance to PD-1 inhibitors in recurrent and metastatic head and neck cancers: a real-world retrospective study.

Patients with recurrent or metastatic head and neck cancers (R/M HNCs) are prone to developing resistance after immunotherapy. This retrospective real-world study aims to investigate whether the addition of anlotinib can reverse resistance to PD-1 inhibitors (PD-1i) and evaluate the efficacy and safety of this combination in R/M HNCs. Main outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Potential biomarkers included PD-L1 expression, lipid index, and genomic profiling. Twenty-one patients with R/M HNCs were included, including 11 nasopharyngeal carcinoma (NPC), five head and neck squamous cell carcinoma (HNSCC), three salivary gland cancers (SGC), and two nasal cavity or paranasal sinus cancers (NC/PNC). Among all patients, ORR was 47.6% (95% CI: 28.6-66.7), with 2 (9.5%) complete response; DCR was 100%. At the median follow-up of 17.1 months, the median PFS and OS were 14.3 months (95% CI: 5.9-NR) and 16.7 months (95% CI:8.4-NR), respectively. The median DOR was 11.2 months (95% CI: 10.1-NR). As per different diseases, the ORR was 45.5% for NPC, 60.0% for HNSCC, 66.7% for SGC, and 50.0% for NC/PNC. Most treatment-related adverse events (TRAEs) were grade 1 or 2 (88.9%). The most common grades 3-4 TRAE was hypertension (28.6%), and two treatment-related deaths occurred due to bleeding. Therefore, adding anlotinib to the original PD-1i could reverse PD-1 blockade resistance, with a favorable response rate, prolonged survival, and acceptable toxicity, indicating the potential as a second-line and subsequent therapy choice in R/M HNCs.

The role of herpes simplex virus infection in the etiology of head and neck cancer-a Mendelian randomization study.

Introduction: Head and neck cancer (HNC) is a complex disease, and multiple risk factors can lead to its progression. Observational studies indicated that herpes simplex virus (HSV) may be correlated with the risk of HNC. However, the causal effects and direction between them were still unclear. Methods: This study utilized a Mendelian randomization (MR) approach for causality assessment between HSV infection and Head and neck cancer based on the latest public health data and Genome-Wide Association Study (GWAS) data. The causal effects were estimated using IVW, weighted median, and MR-Egger. A reverse MR analysis was subsequently performed. Cochrans Q test, MR-Egger intercept test, leave one out analysis, and the funnel plot were all used in sensitivity analyses. Results: Genetically predicted higher level of HSV-1 IgG was causally related to HNC (OR=1.0019, 95%CI=1.0003-1.0036, p=0.0186, IVW) and oral and oropharyngeal cancer (OR=1.0018, 95%CI=1.0004-1.0033, p=0.0105, IVW). The reverse MR analysis did not demonstrate a reverse causal relationship between HSV and HNC. However, HSV-2 infection was not causally related to HNC data and oropharyngeal cancer data. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy. Conclusion: Collectively, a significant association was noted between HSV infection and increased risk of HNC, providing valuable insights into the etiology of this malignancy. Further in-depth study is needed to validate these findings and elucidate the underpinning mechanisms.

Therapeutic application of extracellular vesicular EGFR isoform D as a co-drug to target squamous cell cancers with tyrosine kinase inhibitors.

Targeting wild-type epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) never achieved its purported success in cancers such as head and neck squamous cell carcinoma, which are largely EGFR-dependent. We had previously shown that exceptional responders to TKIs have a genetic aberration that results in overexpression of an EGFR splice variant, isoform D (IsoD). IsoD lacks an integral transmembrane and kinase domain and is secreted in extracellular vesicles (EVs) in TKI-sensitive patient-derived cultures. Remarkably, the exquisite sensitivity to TKIs could be transferred to TKI-resistant tumor cells, and IsoD protein in the EV is necessary and sufficient to transfer the phenotype in vitro and in vivo across multiple models and drugs. This drug response requires an intact endocytic mechanism, binding to full-length EGFR, and signaling through Src-phosphorylation within the endosomal compartment. We propose a therapeutic strategy using EVs containing EGFR IsoD as a co-drug to expand the use of TKI therapy to EGFR-driven cancers.

Overall Survival, Treatment Duration, and Rechallenge Outcomes With ICI Therapy for Recurrent or Metastatic HNSCC.

Importance: Immune checkpoint inhibition (ICI) is a frontline treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but questions remain surrounding optimal duration of therapy, benefits and risks of ICI rechallenge, and efficacy in first vs subsequent lines of therapy. Objectives: To estimate survival in US patients receiving ICI-based treatment for R/M HNSCC, compare outcomes associated with treatment discontinuation vs continuation at 1 or 2 years, and assess outcomes after immunotherapy rechallenge. Design, Setting, and Participants: This retrospective, population-based cohort study included adult patients in the Flatiron Health nationwide oncology database treated with immunotherapy for R/M HNSCC from 2015 to 2023. Data cutoff was August 31, 2023; data analysis was conducted from December 2023 to February 2024. Exposures: Treatment continuation vs discontinuation at 1 and 2 years; rechallenge with ICI after at least a 60-day period off ICI therapy without intervening systemic treatment (immediate rechallenge), or with intervening systemic treatment (delayed rechallenge). Main Outcomes and Measures: Overall survival (OS) from ICI initiation was analyzed using the Kaplan-Meier method. Cox multivariable regression was used to examine associations of key variables (line of therapy, human papillomavirus [HPV] status, Eastern Cooperative Oncology Group [ECOG] performance status) with survival. Results: The cohort included 4549 patients with R/M HNSCC who received ICI-containing therapy (median [IQR] age, 66 [59-72] years; 3551 [78.1%] male; 56 [1.2%] Asian, 260 [5.7%] Black or African American, 3020 [66.4%] White, 1213 [26.7%] other or unknown race; 3226 [70.9%] ECOG performance status 0 or 1). There were 3000 patients (65.9%) who received ICI in frontline and 1207 (26.5%) in second line; 3478 patients (76.5%) received ICI monotherapy. Median (IQR) OS was 10.9 (4.1-29.1) months and was longer in patients who received ICI in frontline therapy (12.2 [4.8-32.0] vs 8.7 [3.2-22.4] months), had HPV-positive cancer (16.6 [6.5-43.9] vs 8.8 [3.5-24.0] months), and had ECOG performance status 0 or 1 (13.5 [5.2-33.9] vs 5.5 [2.0-13.7] months). There were no survival differences on adjusted analysis between patients who stopped vs those who continued ICI at 1 or 2 years. Median (IQR) OS after ICI rechallenge was 15.7 (13.7-21.9) months in the immediate rechallenge group and 9.9 (3.7-18.1) months in the delayed rechallenge group. Conclusions and Relevance: In this large cohort study of patients with R/M HNSCC receiving ICI-based therapy, survival estimates closely mirrored clinical trial results, both in frontline and later-line settings. Discontinuation of ICI in long-term responders at 1 or 2 years may be a reasonable strategy that does not appear to compromise survival. ICI rechallenge was associated with clinical benefit in a subset of patients.

The role of genetic variants in the prediction of hearing loss due to cisplatin chemoradiotherapy.

BACKGROUND: Concomitant high-dose cisplatin with radiotherapy is commonly used for treating head and neck squamous cell carcinoma (HNSCC). Cisplatin, often used with radiotherapy, is known for causing irreversible sensorineural hearing loss, with individual variability suggesting a genetic component. This study aims to enhance the predictive ability of the clinical prediction model for cisplatin-induced hearing loss (CIHL) in HNSCC patients, as outlined in Theunissen et al., by incorporating significant genetic variants. METHODS: Conducted at the Netherlands Cancer Institute, this retrospective study included 74 patients treated between 1997 and 2011. Thirty-one SNPs that were previously associated with CIHL or other cisplatin-induced toxicities were identified and incorporated into the model. The primary outcome measured was the change in decibels at posttreatment 1-2-4 kHz hearing levels per additional minor allele of these SNPs, evaluated using linear mixed-effects regression models. The model's predictive accuracy was determined by the area under the curve (AUC) using 10-fold cross-validation. RESULTS: The rs2289669 SNP in the SLC47A1/MATE1 gene was linked to a significant 2.67 dB increase in hearing loss per allele (95% CI 0.49-4.86, p = 0.017). Incorporating rs2289669 improved the model's AUC from 0.78 to 0.83, a borderline significant improvement (p = 0.073). CONCLUSIONS: This study underscores the importance of the rs2289669 SNP in CIHL and demonstrates the potential of combining genetic and clinical data for enhanced predictive models in personalized treatment strategies.